THE INTERNAL SECRETORY ORGANS:
THEIR PHYSIOLOGY AND PATHOLOGY

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The Internal Secretory Organs:

THEIR PHYSIOLOGY AND PATHOLOGY

BY

PROFESSOR DR. ARTUR B1EDL

VIENNA

With an Introductory Preface

BY
LEONARD WILLIAMS, M.D., M.R.C.P.,

Physician to the French Hospital ;
Assistant Physician to the Metropolitan Hospital

Translated by LINDA FORSTER

NEW YORK

WILLIAM WOOD & COMPANY
MDCCCCXIII

PRINTED IN GREAT BRITAIN

10 3 5 0

FOREWORD.

THE subject of the Internal Secretions, or Glandular Physio-
logy as it is sometimes called, is one which is destined to occupy
the attention both of physiologists and clinicians for a long time
to come. The admirable manner in which the microbic theory
of disease has been developed and pressed into practical employ-
ment has served completely to revolutionize the surgery, and
profoundly to modify the medicine, of thirty years ago. But the
truth of the theory and the wonders which it has wrought leave
unexplained certain problems in pathology which cry aloud for
solution. Microbes do not explain gout, diabetes, Graves's
disease or Hodgkin's disease, to mention but a few which inhabit
tfie vast territory which remains to be conquered. Upon these
and allied diseases the study of the internal secretions promises
to throw some light. It has already illuminated myxoedema,
acromegaly, Addison's disease, and some others, and the promise
which it holds is as enticing and fascinating as its pursuit is
baffling.

The condition precedent of any real progress on the clinical
side is an exhaustive study of the physiological side. Professor
Biedl's book supplies this in a painstaking and methodical man-
ner. It comprises all the work of an experimental kind which
has been done in any country up to within a very recent dale.
It is for the most part content to leave that work to speak for
itself, and does not unduly burden the reader with explanations,
or mislead him with premature theories.

To unravel the tangled skein of the inter-relation of the
various internal secretory glands must be a task for many workers

vi. Foreword

over a long period. Professor Biedl has rendered this task very
much more simple than it could have been in the absence of some
co-ordinating and focussing text-books such as he has now given
to labourers in this field.

The English translation has been done in a manner deserving
of the highest praise. I have had many opportunities of com-
paring it with the original German text, and have in every case
had cause to admire the faithful, accurate, and even graceful
rendering of the meaning of obscure and highly technical

passages.

LEONARD WILLIAMS.

CONTENTS

PART I.— GENERAL.

PAGE

Historical and Introductory ... ... ... ... ... ... ... i

Definition and Limitation of the term li Internal Secretion "... ... 5

Classification ... ... ... ... ... ... ... ... ... 8

The Activity of the Hormones ... ... 12

The Origin of the Hormones ... ... 15

Sources of Information and Methods of Investigation 16

PART II. — SPECIAL.

THE THYROID APPARATUS 26

Anatomy ... ... ... ... ... ... ... ... 26

Histology ... ... ... ... ... ... ... ... 26

Chemistry ... ... ... ... ... ... ... ... 29

Anatomy of the Parathyroid Glands ... 31

Histology of the Parathyroid Glands ... ... ... 32

History of the Development of the Organs of the Neck ... 33

Comparative Anatomy of the Parathyroid Glands ... 34

Physiology of the Thyroid Apparatus ... ... 36

Historical 36

Tetania Parathyropriva ... 39

Tetany in Man 44

Other Pathological Conditions in Man arising from
Derangement of the Function of the Parathyroid

Glands ... ... ... ... ... ... ... 46

The Therapeutics of Tetania Parathyropriva ... ... ... 47

The Relationship between the Thyroid and Parathyroid Glands 51

The Function of the Parathyroid Glands ... ... ... ... 55

The Tetany Toxin ... ... ... ... ... ... 55

The Parathyroid Glands and the Metabolism of Calcium 57

The Point of Attack of the Hypothetical Tetany Toxin ... 59

Physiology of the Thyroid Gland ... 62

Experimental Extirpation ... ... ... ... ... 62

Athyrosis and Hyperthyrosis in Man 71

Operative Athyrosis ... ... ... ... ... ... 71

True Athyrosis and Hyperthyrosis ... 73

Substitution Therapy 83

The Metabolic Changes in Hypothyrosis and the manner
in which they are influenced by the Exhibition of

Thyroid Extract 88

The Physiological Effects of Thyroid Substances 89

Experimental Hyperthyroidism ... ... ... ... 92

Hyperthyroidism in Man ... ... ... ... ... ... 92

As Produced by the Exhibition of Thyroid Gland ... 92
Conditions which may be classed as those of true Hyper-
thyroidism ... ... ... ... ... ... ... 93

Theory of the Thyroid Function 104

THE THYMUS GLAND no

Involution of the Thymus ... 112

Physiology of the Thymus ... 113

Effects of Thymus Extract ... 121

Mors Thymica and the Status Thymicolymphaticus 122

viii. Contents

PAGE

THE SUPRARENAL SYSTEM 124

The Interrenal and Adrenal Systems, Historical ... 124

Comparative Morphology and Embryology 127

Physiology of the Suprarenals 134

Experimental Extirpation ... 134

The Results of the Extirpation of the Cortical and

Medullary Substances ... ... 146

Experimental Extirpation with Fish ... ... 150

Symptomatology of Suppression of the Suprarenal Function ... 153

Suppression of the Suprarenal Function in Man 158

The Symptomatology of Addison's Disease 163

Suprarenal Substitution ... 165

Organotherapy 165
Transplantation of the Suprarenals ... 168
The Activity of Suprarenal Extract ... 173
Chemistry of the Specific Active Substance present in the Supra-
renals ... ... ... ... ... ... ... ... ... 177

The Physiological Activity of Adrenalin ... ... 183

The Physiological Effects of Adrenalin upon the Sympathetic

System ... ... ... ... 10,6

The Site of Action of Adrenalin 227

The By-effects of Adrenalin 234

Toxic Action ... ... ... ... ... ... ... 236

Adrenalin as a Secretory Produce of the Adrenal System ... 246

Experimental Suprarenal Stimulation, Experimental

Hypersecretion ... ... ... ... ... ... 260

Pathological Adrenalinsemia as Seen in Man ... ... 262

The Function of the Adrenal System ... ... ... ... 264

The Interrenal System ... ... ... ... ... ... ... 267

Histology of the Suprarenal Cortex ... ... 270

Chemistry of the Suprarenal exclusive of Adrenalin ... ... 274

Theory of the Function of the Interrenal System 292

The Suprarenal considered as an Entity ... ... 295

Carotid Gland and Coccygeal Bodies ... 302

HYPOPHYSIS CEREBRI (Cerebral Appendage, Pituitary Gland) 305

Anatomy ... ... ... ... ... ... ... ... 306

Histology ... ... 308

History of Development ... ... ... ... ... 313

Physiology of the Hypophysis ... ... 315

Pituitary Extract ... 321

The Physiological Activity of Pituitary Extract ... ... 323

Experimental Stimulation of the Hypophysis 328

Diseases of the Hypophysis in Man ... 330

Theory of the Function of the Hypophysis 348

THE PINEAL BODY (Glandulse pinealis, Epiphysis, Conarium) 350

THE GENERATIVE GLANDS 355

The Results of Castration ... ... ... 376

The Sexually Undifferentiated Activity of the Hormone

in the Generative Glands ... ... ... ... ... 382

Extract of the Generative Glands ... ... ... ... 389

The Internal Secretory Tissue Elements of the Generative

Glands ... ... 391

Internal Secretion of other parts of the Genital Apparatus ... 410

THE INTERNAL SECRETION OF THE PANCREAS 412

Metabolism in Pancreatic Diabetes ... 415

Theory of Pancreatic Diabetes ... ... ... ... ... 420

The Internal Secretory Tissue Elements of the Pancreas ... 432

THE INTERNAL SECRETION OF THE GASTRIC AND INTESTINAL MUCOSA ... 438

THE INTERNAL SECRETION OF THE KIDNEY 440

LITERATURE 446

List of Contractions used in the Literature Reference? ... ... 446

The Internal Secretory Organs
their Physiology and Pathology.

PART I, -GENERAL

HISTORICAL AND INTRODUCTORY.

WE have long been aware of a reciprocity of activity between
different parts of the body, and this inter-relation of function is
called the consensus partium. But, until very recently, the
haziest ideas prevailed as to the manner in which the individual
organs react upon one another and the mechanism by which their
interbalance is maintained.

We are now, however, in a position to advance the logical
postulate, that the mediating agents can be those only which, while
having access to each organ, yet come together at a common
centre. The central nervous system supplies an excellent example
of such a mechanism, affecting and controlling as it does the
correlation of the various physiological activities. Messages are
carried by the centripetal nerves from the extreme periphery to
the centre, and this centre is enabled, by means of the centrifugal
nerves, to convey ever-changing impressions to different parts of
the body. When the so-called " reflexes " were discovered, partly
by Descartes in the lyth, and finally by Prochaska in the iQth
century, the prompt and purposeful intervention of the central
nervous system in the regulation of organic function became
firmly established.

An impression conveyed from the periphery to the nervous
centre will excite activity in an entirely different part of the body.
Though this is accomplished without the assistance either of the
consciousness or of the will, it is neither casual nor purposeless
in its happening. On the contrary, the degree of activity is
calculated to the needs of the organism and is in accordance with
changes in the conditions surrounding it. This reflex character
is in part congenital and is an integral factor in the organization
of the nervous system ; in part it is acquired, and is the result
of habits formed during life. By its means the co-ordinated
activities of the different parts of the body are regulated and
controlled and it was for this reason that scientists until recently

i

2 INTERNAL SECRETION

believed that the nervous system was the sole mediating agent
by which the consensus partium was maintained.

Such was, naturally enough, the view adopted by clinicians,
to explain disturbances of functional equilibrium. Derangement
of function in any direction was said to produce a change, both
qualitative and quantitative, in the nature of the stimuli and,
reacting through the nervous system upon other organs, was
believed to produce in them also a departure from the normal,
thus giving rise to the most varied pathological symptoms. From
this arose the doctrine of the reflex manifestation of diseases, a
doctrine which was until quite recently universally accepted and
is not, even now, entirely discredited. The changes, for example,
which for centuries have been known to take place in the organism
after suppression of the secretion of the sexual glands, whether
by castration or by the physiological phenomena of the climacteric,
were believed to result from a purely nervous reflex action.

But, logically faultless though this hypothesis be, and
founded as it certainly is upon a sound physiological and anatomi-
cal basis, it has not always maintained an undivided supremacy.
Looking back over the fields of biology and general pathology
we find that the neural theory of the correlation of organs was
companioned by a belief in their humoral relationship, and that
this latter theory is even the older of the two.

In the healing arts of primitive peoples, as wrell as in the
earlier periods of scientific .medicine, remedies were employed
and measures resorted to, which are the direct forerunners of the
organo-therapy of to-day. Hahnemann's homoeopathy threw out
a branch — isopathy — which in certain directions proved itself
stronger than the parent stem. In every organic disease it was
the practice of isopathy to administer the healthy animal
organ ; fox-lung was given in pulmonary disease, wolf's liver in
liver troubles, ox-eyes in ocular affections, and so on. In spite
of the haziness of the ideas which prompted these measures, they
were certainly carried out in the spirit which animates the humoral
pathology of to-day, for they recognized the fact that each organ
plays a part in maintaining the balance of secretion and has
thus an influence upon the organism as a whole.

The discovery of the circulation of the blood supplied a
second channel by means of which the different parts of the body
may be brought into relationship. And yet in the early days of
the new humoral pathology, at a time when changes in the con-
stitution of the blood-plasma were universally recognized as
causes of disease, the blood-stream was very rarely admitted as
a factor in the consensus partium. This was due to the fact that
at that time changes in the nature of the blood-plasma were
believed to result, partly from external conditions and partly from
retention in the blood of normal secretions. Thus, Bordeu (a
predecessor of Brown-Sequard, who lived in the second half of

HISTORICAL AND INTRODUCTORY 3

the 1 8th century and was discovered by Neuburger) ascribed the
changes which occur after removal of the sexual organs and in
certain other conditions, to a deficiency or superfluity of the
glandular secretions. The existence of normal and pathological
secretions was known, but no account was taken of substances
which are formed by all the organs, including those which are
not in the first instance secretary organs, and which contribute
something to the composition of the plasma.

An important step forward was marked by Johannes Miiller
in his text-book of physiology. He drew a sharp distinction
between secretion — the formation of a specific chemical substance
by the organ — and excretion — the change of place of the already
formed substance. He recognized secretory cells, secretory mem-
branes, and secretory glands. Among the latter he included
those organs which are known as the vascular ganglia or blood
glands, namely : the spleen, the thyroid, the suprarenals, the
thymus, and the placenta.

Miiller believed that these ductless glands " exert a plastic
influence upon the juices which are within them, which circulate
through them, and which are carried from them by the general
circulation. Unlike the other glands, however, they exercise no
external influence."

It was Professor A. A. Berthold, of Gottingen, who, in 1849,
first demonstrated by means of experiment the nature of the
activity of a true ductless gland ; that is to say, he showed the
influence which an organ through which the blood-stream circu-
lates, can exert upon the composition of the blood and thus upon
the entire organism. He removed the testicle from cocks and
grafted it upon another part of the body; and he found that " the
animals remained male in regard to voice, reproductive instinct,
fighting spirit, and growth of comb and wattles." He concluded
that " the consensus is maintained by the productive influence
of the testicle ; that is to say, by its effect upon the blood and,
through the blood, upon the organism." The honour of having
first proved the existence of an " internal secretion ' and of
having recognized its significance, belongs undoubtedly to
Berthold.

Berthold's discovery, howrever, received no recognition in
his own day. The physiologist, Rudolf Wagner, was unable to
confirm the experiments, and Berthold was probably unknown in
general circles. Claude Bernard, in 1855, is generally credited with
having been the first to give expression to the doctrine of an
internal secretion. He maintained that, not only the glands by
their secretory processes — secretion externe — by means of which
substances are withdrawn from the blood, but that every organ
of the body, by a process of secretion interne whereby it yields its
products up to the blood, determines the composition of the blood
and can, under certain conditions, modify and even change it.

4 INTERNAL SECRETION

Bernard showed that, in the case of the liver, in addition to
the external secretion of gall there is an internal secretion or
glycogenesis, that is to say, the aggregation of glycogen and the
formation of sugar, the latter being afterwards conveyed into the
blood-stream. He endeavoured to prove that the function of
internal secretion is under the control of the nervous system.

That the composition of the blood is susceptible to the
influence of the specific products of individual organs w?as, as we
see, known as long ago as the middle of the last century. Even
the designation " internal secretion " dates from that time. And
yet the introduction of the theory of the internal secretions is
universally ascribed to Brown-Sequard. This is because he was
the first to express the idea* that all glands, with or without ducts,
supply to the blood substances which are either useful or essential,
and the lack of which may produce pathological signs. It was
not until twenty years later that he was able to give experimental
proof of his views.

The actual date upon which the doctrine of the internal
secretions may be said to have been born is June i, 1889. It was
the occasion of that memorable meeting of the Societe de Biologic,
Paris, when Brown-Sequard, then 72 years of age, described the
experiments which, in order to prove his hypothesis, he had
carried out upon his own person, by the subcutaneous injection
of testicular extract. He found that after the injections, and
indisputably as a result of them, he experienced an access of
physical strength and an invigoration of cerebral function which
were quite extraordinary. Appetite improved, the bowels were
regulated, and there wras a marked increase in mental activity.
This lecture and the detailed publication which followed it, a few
weeks later, were not only the actual foundations of the theory
of internal secretion, but they furnished the first practical appli-
cation of a new method of treatment, namely, that now known
as organo-therapy, or the Brown-Sequard method.

It is not possible to estimate Brown-Sequard's work at its
proper value, unless it is kept distinct from the method \vhich he
inaugurated and more especially from the abuses which followed
it, with which Brown-Se"quard himself was unfortunately not
entirely unconnected. What he really did do was to prove
by experimental means the existence of a process of internal
secretion, which is in the nature of a chemical interchange between
the different organs and which is of the highest importance to
the economy. His theories were at once accepted in France and
to some extent in England. German physiologists and clinicians
were extremely sceptical. Nevertheless it should not be forgotten
that Hansemann, in Germany, soon afterwards adopted a similar
standpoint. Like Brown-Se"quard, he assumed a physiological

* In his address before the Medical Faculty of Paris in 1869.

DEFINITION OF THE TERM ' INTERNAL SECRETION ' 5

interchange between the cells of different organs, and this
functional interdependence he designated "cell-altruism." As
the founder of the doctrine of internal secretion, Brown-S^quard
has opened to physiology a new and fruitful field for experiment ;
he has paved the way for the right understanding of many
pathological derangements ; and he has pointed out a rational and,
in many cases, a remarkably successful method of treatment.

DEFINITION AND LIMITATION OF THE TERM
-INTERNAL SECRETION/'

Two agents are concerned in ordering and maintaining the
complex activity of the animal organism. In addition to the
nervous intercommunication, which is admittedly the agent in
effecting rapid adjustments, there is also a chemical correlation
of the different organs. In accordance with the latter, each
organ, each tissue, and even each cell, by means of its specific
secretory products, acting through the agency of the blood-stream,
is enabled to exert a definite influence upon other parts of the
body. In this manner the equilibrium of the various parts is
guaranteed.

It must not be imagined, however, that chemical communi-
cation is effected by the agency of the blood-stream only. We
know, for instance, that the acid secretion which is elaborated
upon the superficial membrane of the stomach, causes the pyloric
sphincter to relax at regular intervals, and that movements of the
intestinal canal are provoked by the bowel-contents. Granting
that in these instances there is also a nervous reflex wrhich is
set in motion by the secretions of the gastric and intestinal mucosa,
yet the formation of secretin is clearly an instance of chemical
interaction taking place upon an internal surface.

As soon as it enters the duodenum, the acid gastric secretion
(then called chyme) excites the cells of the intestinal mucosa
to form secretin, which, in its turn, acting through the blood-
stream, stimulates the liver to an increased production of bile,
excites the formation of pancreatic secretion, and promotes
secretion by the glands of the intestinal walls. Bayliss and
Starling, who have made a special study of these processes,
propose that the name " hormone ' should be given to those
physiological substances which act as chemical stimuli and serve
as intermediaries between different parts of the body.
" Hormone ' is derived from the Greek op/.idw, meaning to
awake or excite, and the term has been universally adopted.

All organs which supply substances which are capable of
exciting or in any way of affecting the functions of other organs,
may be described as " hormone-producing." Schiefferdecker
proposes that they should be called " Beeinflussungsorgane '

0 INTERNAL SECRETION

(organs of influence), which might be contracted into B-organs.
It is, however, more expedient to call them internal secretory
organs. It must be clearly understood, however, that not every
change in the blood-plasma due to organic intervention, and not
all metakerastic organic activity, is to be included under the
heading " internal secretory." The term can apply to the form-
ation of chemical substances only. Those organs, for instance,
which are known to be the formative agents of the morphological
elements of the blood (as the spleen, the lymphatics and the
bone marrow) — in so far as the changes they effect in the character
of the blood are due to the contribution of new form-elements—
are not to be regarded as internal secretory.

Very little is known about the specific form in which the
true internal secretions, or hormones, find their way into the blood.
It may be that they enter the circulation as morphological con-
stituents of the blood, or perhaps in combination with such.
But, in the present state of our knowledge, we must bear in mind
that, though the cellular elements of the bloocl may possess
internal secretions, they are not internal secretions in themselves.

The internal secretions include the chemical products of
organic metabolism only, though this limitation of the term is
not accepted without question by morphologists.

Assuming always that the elaboration of substances from
materials withdrawn from the blood and the returning of the
changed materials back to the blood again, is a property common
to all living tissue, yet, from the point of view of the morphologist,
certain tissues only possess a true secretory value. According
to this view, those tissues only are able to secrete which possess his-
tologically differentiated epithelial cells, whether occurring singly
or in groups. An excretory gland is no longer to be recognized
in virtue of its possession of an excretory duct, but by its consti-
tution in epithelial elements. Should the duct be absent but the
epithelial structure present, then, and then only, should the
term " internal secretory gland ' be employed. Following out
this idea, the internal secretory glands would include : The
thyroid, the parathyroids, the epithelial layer of the suprarenals,
the glandular portion of the hypophysis cerebri (pituitary gland),
and the inter-tubular cell-agglomerations of the pancreas. Other
tissues, as, for instance, the so-called carotid gland, the medullary
substance of the suprarenals, and the chromaffine tissue in
general, would be excluded from this group.

The last-named example clearly shows, however, that there
is not sufficient grounds for adopting a morphological and genetic
limitation of the term " internal secretion," and that to do so
would not in any way conduce to a solution of the question. We
have unequivocal proof of the internal secretory -activity of the
chromaffine tissue, for we are able to obtain its secreted substance
in a state of chemical purity. Yet the chromaffine tissue cannot be

DEFINITION OF THE TERM ' INTERNAL SECRETION ' 7

described, either genetically or morphologically, as epithelial or
glandular tissue. If, in considering the activity of the true glands
—whether ductless or otherwise — we are prepared to recognize
one secretion only, and to describe it as internal or external
according to the direction in which it is discharged, then we are
compelled to regard all glands as having more than one secretory
surface, and should need proof, moreover, that both internal and
external secretion are elaborated by the same morphological ele-
ments. But it will be obvious, from what has gone before, that
such a theory cannot be made to include all the facts. For
instance, it is very possible that, in the case of the male sexual
glands, the internal secretion is not elaborated from the
spermatozoa-producing elements, but from the interstitial tissues.

Looking at the matter from the physiological point of view,
we must assume that all organs, in addition to their special
function which is determined by their structure, possess a specific
productive activity, otherwise an internal secretion, which is
largely independent of structure. The description " internal secre-
tion " is hardly to be improved upon. It expresses the idea which
has animated the doctrine from its earliest inception, namely,
that the specific internal secretions are physiological hormones
affecting the activity of other parts of the body and affecting the
body as a whole, and that they are the means by which the
chemical correlations of the different organs are brought about.

There is a large group of chemical adjustments which cannot
be included among the internal secretions. It comprises all those
readjustments which take place when drugs or poisons are intro-
duced into the economy. During the last decades, investigation
has revealed a not inconsiderable group of chemical interactivities
which are aroused in the body for purposes of offence and defence,
not only by the causes of disease, but by poisons of all sorts.
There is no doubt whatever that the processes by which anti-
toxins and antibodies are formed, are the outcome of a modifica-
tion of the chemical activity of the tissues, and that the most
important part is played by the internal secretion of the cells. It
is, however, expedient to the present purpose to confine the dis-
cussion solely to those chemical correlationships which are
maintained between the different parts of the body without the
intervention of external agents.

Nevertheless, it is not possible, in the nature of things, to keep
entirely within these limits, seeing that no organism lives for itself
alone, but is in constant relationship with its surroundings.
Foreign materials are introduced into the economy by means of
foodstuffs; in the intestinal canal they become so changed by the
flora and the ferments that poisonous products of decomposition
are formed, and these find their way into the blood-stream. The
intermediary toxic substances formed from the splitting up of the
foodstuffs, especially of albumen, are rendered innocuous by the

8 INTERNAL SECRETION

agency of the internal secretions of various organs, more
particularly the liver. It is a question of expediency and one
which each physiologist will decide for himself, whether or not
these antitoxic processes — the measures, that is, which are adopted
on the part of the organism to guard against auto-intoxication—
should be included in the definition of the internal secretions,
while the antitoxic activity of the liver, where exogenic poisons
are concerned, is excluded from it.

CLASSIFICATION.

Having defined the field which the internal secretions cover,
the next step is to classify them. Berzelius divided the true
glandular secretions into recrementitial and excrementitial, and, up
to now, a similar distinction has been maintained in regard to
the internal secretions. As far as we can judge at present, the
process of internal secretion has a twofold aspect. In the first
place there is positive recrementitial secretion or production of
hormones. In the second, there is that activity of the organs
which is sometimes called negative secretion, which concerns
itself with the neutralization of materials circulating in the blood
which might otherwise impair the activity of other organs, or
even endanger the well-being of the entire organism. The latter
function is a parallel to the external secretion of the true excretory
organs, as the skin, the intestine, the lungs and the kidneys, by
whose agency the body is freed from useless and harmful
substances.

But it is very obvious that there is an essential difference
between the two processes. The excretory organs are able to
expel undesirable material from the body, but in the case of the
internal secretory organs this method is impossible. In the
absence of any channel communicating with the exterior, the
substances which have been withdrawn from the blood must,
sooner or later, be returned to the blood. The organism as a
whole, therefore, can be relieved in only one of two ways. Either
the effete substances must be retained in the organ, or they must
be rendered innocuous before they are again returned to the blood.

The former process comes into play chiefly in the management
of those waste materials which circulate in the blood as formed
elements. The adenoid or lymphatic tissue distributed over the
body, the bone-marrow, the spleen, and the liver are all organs
which, by a kind of filtering process, retain the broken-down
remains of old red and white corpuscles, remnants of tissue, traces
of pigment, &c., and in this way they free the blood of useless
morphological elements. The particles which have become fixed
then undergo secondary changes, after which they supply the
material for fresh organic activity; thus, iron goes to build up the
red blood corpuscles, pigment to the preparation of bile.

CLASSIFICATION 9

The second method of dealing with soluble toxic substances
is by a process of chemical neutralization. Here also, to a large
extent, the toxins are first fixed and then deposited in the indi-
vidual organs. The juices of the body and the component parts
of the cells and tissues play the part of chemical prophylactics.
Thus, exogenous and endogenous toxins combine with the alkali
and albumin of the blood, with the nuclein in the nuclei of the
white corpuscles, and with glycogen and the biliary acids in the
liver.

Neutralization in the narrower sense, that, namely, of the
conversion of poisons into harmless substances, is carried on by
chemical processes of various kinds ; such are : oxidation and
reduction, hydration and dehydration, building up and breaking
down, £c.

A special significance attaches to the chemical affinity which
certain toxins display for substances normally occurring in the
body. In 1824, Woehler discovered the affinity of benzoic acid
for glycocoll, a product of the decomposition of albumin.
Baumann, in 1879, was able to prove that the highly toxic bodies
of a phenol-like nature which occur in the body and are the
products of the decomposition of albumin, together with the sul-
phates derived from the same source, have an affinity for the
non-toxic hydrogen ethyl sulphates which are discharged in the
urine. Other chemical affinities \vere discovered later as, for
instance, that of glycuronic acid, which is derived from the
carbohydrates, for mercapturic acid, and carbamic acid for urea.
The parts of the body where these chemical pairings take place
are largely unknown. We only know that in the dog, and
probably also in man, hippuric acid is formed in the kidney,
while in the herbivora it is also formed in other organs, such as
the liver and spleen.

The best known example of the antitoxic function of an
organ is the formation of urea by the liver. Urea is the principal
end-product of the metabolism of albumin, but the simple
hydrolytic division of the albumin-molecule produces it in the
most minute quantities only. It comes into existence by means of
a synthetic process strictly in conformity with its constitution.
There are various hypotheses regarding this synthesis ; according
to one, the base of urea is ammonium carbamate, according to
another it is ammonium carbonate. It is certain, however, that
ammonia is formed in considerable quantities by the body, and
that the body is able to convert the ammoniacal salts which
reach it from the exterior into urea. The organ which is most
concerned in converting the toxic agents into the comparatively
non-toxic urea is undoubtedly the liver. Blood containing
ammonia is being constantly carried by the portal vein to the liver
(Drechsel proved the presence of ammonium carbamate in the
blood of dogs) and is there rendered innocuous. This can be shown

10 INTERNAL SECRETION

experimentally by establishing a communication by means of
Eck's fistula between the portal vein and the vena cava of dogs,
thus enabling the blood from the portal vein to pass directly into
the general circulation without traversing the liver. After a few
days such animals show symptoms of acute poisoning; there are
changes in the sensorium, intervals of excitement and depression,
clonic and tonic spasms, and coma. These are sometimes spon-
taneous, but they are more likely to appear if the animals are
fed on meat. A similar picture of intoxication can be produced
in healthy dogs by the subcutaneous injection of carbamates.
When given by the mouth, there is no reaction to these salts
in normal animals ; those with Eck's fistula present the same
symptoms as after feeding with meat. The amount of ammonia
in the urine is increased, while the amount of urea is proportionally
diminished.

These experiments show that, by the formation of urea, the
liver exercises a neutralizing activity, whereby the organism is
safeguarded from poisoning by ammonia.

Up to the present, however, this is the only case in which we
are in a position to point with certainty, not only to the exact
nature of the poison but also to the organ which neutralizes it,
and, though this is only partial, to the chemical process by which
the transformation takes place.

In most cases suspension of function, in man or animals,
gives rise to symptoms resembling those of auto-intoxication. It
must not be forgotten, however, that an assumption of auto-
intoxication founded upon the symptom-complex, has no real
explanatory value as long as we are without definite information
as to the nature of the toxic agent. Formerly, while the doctrine
of internal secretion was still in its infancy, the antitoxic action
of the organs was all too frequently invoked to explain the
symptoms which appear upon the suppression of any organic
function. But the fruitlessness of the search for the supposed
poison has led to a considerable modification of this hypothesis.
Indeed, the theory necessarily falls to the ground if we are able
to find another satisfactory explanation of the symptoms which
follow suppression.

As a matter of fact, we have ample foundation upon which
to formulate another hypothesis. In every organ there is a store
of potential energy, a reserve of labour laid by in a special manner,
enabling it, upon adequate provocation, to fulfil its specific
function. Under normal conditions the potential energy is kept
in check and prevented from manifesting itself. The sight of an
organism showing signs of extreme suffering, racked with pain,
and with all the organs in a state of excessive activity, would
suggest, even to the untutored intelligence, that the potential
energy is relieved from its normal check, and that the bonds
are burst which had hindered the individual parts from the full

CLASSIFICATION I I

display of their powers. It has long been known that the nervous
system has control not only of the stimuli which promote function,
but also of those inhibitory activities which are essential to the
regulation of the working economy.

That many chemical substances present in the body also
exercise this inhibitory influence is a discovery of very recent
date.

We know, from Loeb's interesting experiments, that certain
activities of muscles, nerves, and glands, especially the muscular
irritability which manifests itself as rhythmic contraction, depend
upon the presence under certain conditions of Na-, K-, Ca-,
and probably also Mg-ions ; and that every change in the
relations of these ions changes the properties of the tissues. A
sudden change in the relationship of the ions will, according
to the nature of the change, bring about either stimulation or
inhibition of function.

The Ca-ions, which are necessary to all life, act as inhibitors
of muscular activity, and Loeb draws attention to the fact that, if
it were not for the presence under normal conditions of Ca-ions in
the blood, the skeletal muscles of the body would be in a state
of constant rhythmic contraction.

If, then, certain organs produce substances which are
inhibitory to the activity of other organs, it is obvious that failure
on the part of an organ to provide its inhibitory material may
give rise to symptoms similar to those of poisoning.

Having obtained definite proof that in certain tissues sub-
stances are formed which, by acting as chemical stimuli, bring
about a decreased activity on the part of other organs — in other
words, they exercise an inhibitory influence upon functional activity
—we are in a position to abandon the hypothesis of auto-
intoxication and to adopt that of the presence of inhibitory
hormones. This theory attains its highest measure of probability
when we find it supported by the results of organo-therapy ;
when, in fact, the disturbances which regularly ensue upon the
cessation of any organic function, may be prevented or even cured
by the administration of the extract of that organ or of the
chemical material obtained from it.

In those cases where organo-therapy has failed, while the
symptoms of suppression have disappeared upon the direct trans-
plantation of the organ, the results have usually been ascribed
to an antitoxic activity. But this conclusion is by no means
incontestable. The transplantation of an organ is a method which
closely reproduces the natural conditions and, where successful,
restores the organ to the body in its natural structure and function.
All that has happened is that the organ in question has, to a
certain extent, changed its locality. The medical method
is, in reality, a substitute for the surgical and is a less perfect
and less certain imitation of natural measures. Where the extract

12 INTERNAL SECRETION

is employed, only that proportion of the active substance which is
for the time being in the tissues, and this is doubtless very small,
becomes absorbed; while under natural conditions or after trans-
plantation, the increase is almost incalculable because there is
constant production.

In face of the difficulties which beset the theory that the
neutralization of toxins takes place within the organ itself, we
are forced to assume that there is a relationship between the
process of neutralization and that of secretion. The neutralization
of the hypothetical toxin is assumed to take place, not within
the organ itself, but in the blood-stream and by the agency of a
specific antitoxic organic secretion. In that case the function
exercised by the organ would not be merely excrementitial (using
the word in its special sense), but truly secretory.

This hypothesis can only hold good where the presence of
the supposed toxin on the one hand, and the process of
neutralization on the other, can be demonstrated in vitro. As our
knowledge of the internal secretions increases, the idea of a
process of neutralization of toxins becomes narrowed in its appli-
cation and, though to-day it may still be essential to the doctrine
as a whole, in course of time it will probably disappear altogether.

THE ACTIVITY OF THE HORMONES.

We will now endeavour to classify the internal secretory
organs according to the manner in which their secretions act.
The secretory products fall readily into two groups. The first
of these comprises those secretions which, either from their organic
constitution or because they act as sources of energy, assist in
the building up or the activity of other organs. These may be
called the " nutritive secretions." /The second group includes
those substances whose sole influence is upon the manner in which
the materials and energies, already collected in the organs, are
employed. These are the true hormones.

In addition to the antitoxic and neutralizing substances
already described, the first group includes the nutrient or pro-
ductive internal secretions. These are the nutritive material of the
organs, and they are derived by the chemical agency of the
intestinal wall and glands of the appendix, from the foodstuffs.
As products of assimilation, they pass into the blood- and lymph-
streams and are carried to the different tissues. The albumin,
which is absorbed by and circulates in the blood, and the sugar,
formed from glycogen by the liver, are instances of such waste-
secretions, for they supply the direct material for the renovation
and activity of the organs.

A large number of these substances, however, act also as
hormones and exert a modifying influence upon the very
processes by which they are changed and consumed. We know,

THE ACTIVITY OF THE HORMONES 13

for instance, that an increased amount of albumin in the cir-
culation, by its direct influence upon the organs, gives rise to
an increased decomposition of albumin. Thus, albumin in the
form in which it is produced by the digestive apparatus, is both
a nutrient and a hormone. Another nutrient which acts likewise
as a hormone, is the oxygen inhaled by the lungs, though its
production is not the result of any organic activity.

In spite of this dual function it is, in many instances, not
only possible but expedient to draw a distinguishing line between
the nutrient secretions and the hormones. The factor of dif-
ferentiation is to be found in the quantitative conditions. Sub-
stances which supply either material or energy, or both, must
inevitably be present in considerable quantities. Hormones, on
the other hand, which give rise to energetic processes, or influence
them in a special direction, must be able to produce their effect
even in minimal quantities. The practical outcome is this; that,
where a nutrient secretion is lacking it is useless to attempt
artificial substitution, because of the large amount of material
which would be required ; whereas we are frequently able artifi-
cially to replace a missing hormone.

The true hormones have been variously classified according
to the manner in which they act. Thus we have formative and
protective, growth-promoting and growth-retarding, stimulant and
inhibitory.

If we adopt Hering's theories upon the chemical processes
in living matter as a basis for classification, the hormones will
fall into two groups ; according to the nature of their activity
they are either assimilatory or disassimilatory. Those in the first
group promote the anabolic phase of metabolism — those processes,
that is, which conduce to the building up of living matter. Those
in the second promote the katabolic phase, for they favour and
promote the decomposition of living matter. Each stimulus to
assimilation necessitates an inhibition of disassimilation, and
vice versa.

All the known hormones can be included in one of these two
classes. The promotion of growth supplies an example of an
assimilatory hormone which, at the same time, exerts an inhibitory
influence upon disassimilation. In the case of retardation of
growth the process is reversed. Every increase in normal activity,
whether this be an improved secretion, a stronger muscular action,
or any other augmented performance, is always associated with
an increased disassimilation, which is the work of a dis-
assimilatory hormone. But it must be remembered that, in the
organism, as elsewhere, no work can be performed without ex-
penditure. So long as the metabolic equilibrium is maintained,
every decomposition must be inevitably succeeded by a regenera-
tion. Even in the case of hyperactivity, so long as exhaustion
does not supervene, there will be a continual regeneration of the

14 INTERNAL SECRETION

living substance and therewith a restitution of provision for
labour. With the cessation of the disassimilatory stimulus assimi-
lation becomes excessive and, if the process is frequently repeated,
the well-known phenomena of organic hypertrophy will make
their appearance.

Some experiments by Kronecker and Cutter are interesting
in this connection. These authors found that, after the exercise of
the lower extremities by mountain climbing, the upper extremities,
which did not participate in the exercise, showed a perceptible
increase in the development of the biceps group. This increased
capacity for labour without previous direct exercise of function,
which, by repetition of the same process, would certainly lead
to a " labour-hypertrophy without labour," can only be accounted
for in one way. The assumption is that, by means of a chemical
agent, a secondary increased assimilatory growth takes place in
organs which are not affected by the disassimilatory decom-
position.

That inhibition of function of certain organs may be due to
the intervention of the nervous system is, of course, admitted,
but we now know that such inhibition may also be induced by
chemical substances. This is readily explained by a combination
of increased assimilation with one of decreased disassimilation ;
while, by reversing the process, we account for the existence of
organic activity. Some years ago the physiologist, W. Gaskell,
pointed out that, if we assume an assimilatory activity on the
part of the vagus nerve, its effects are no more mysterious and
inexplicable than are those of the motor-nerves in their character
of stimulants of disassimilation. As a matter of fact, there is
considerable ground for the belief that the chemical changes
brought about in the heart muscle by the agency of the vagus
are assimilatory in their nature. Thus, after vagal irritation,
there is increased muscular power and capacity for work and an
improved conduction of stimulus, especially of the positive current
oscillation. This positive current oscillation is the antithesis of
the negative current oscillation, which is due to intervention of
the motor-nerves and is to be regarded as a symptom of dis-
assimilation.

By inhibitory hormone, then, we understand a chemical agent
which excites an assimilatory process in another organ. The
increased activity (muscular contraction, secretion, &c.) which
follows the suppression of a hormone, is to be regarded as a sign
of the unchecked disassimilation consequent upon such suppres-
sion.

The method of classification, as defined above, does not
pretend to be more than the outline of a plan into which the
greater number of details have still to be fitted. The data which
we possess are very scanty and, in many directions, are in need
of revision.

THE ORIGIN OF THE HORMONES 15

THE ORIGIN OF THE HORMONES.

The internal secretions may also be classified according to
their origin. The distinction is between (a) products of the
chemistry of the organs which are simply the end-products of
decomposition, i.e., the waste or by-products of the process of meta-
bolism ; and (b) substances which are the outcome of a synthetic
process. It would be wrong, however, to imagine that the true
hormones are all included in the latter group. For, in many
instances, it is just the products of decomposition formed during
cell-activity which are the stimulating agents, by whose aid the
function, not of the cells only, but of other tissues, is promoted
and maintained.

That form of activity which is usually ascribed to automatic
irritation of the nervous centre, is not really automatic; it is in
reality brought about by the agency of the products of cell-
metabolism and by the vital processes of the protoplasm. Thus,
in suffocation, the changes in the respiratory and cardiac activity,
the spasms of the voluntary muscles, and the tonic contractions
of the muscular tissue of the vessels, are due solely to over-
irritation by the products of decomposition, an excessive quantity
of wrhich is circulating in the blood. The regulation of normal
respiration, moreover, is due to the agency of chemical stimuli.
Nervous irritation coining from the periphery is able to modify
respiration, but is unable to regulate it. It is more probable that
the so-called automatic irritation of the centre of respiration, is
brought about by the effete products, formed during and by the
activity of the tissues. According to Miescher, and there is good
grounds for his view7, the actual agent is carbonic acid (CO2),
one of the end-products of oxidation. The fluctuating quantity
of CO2 in the blood brings about changes in the respiration and
in the supply of oxygen, which are entirely suited to the momen-
tary needs of the organism. If the amount of CO2 in the blood
increases, the need of the tissues for oxygen is satisfied by means
of deeper and accelerated respiration. It is possible that, where
the activity of the tissues is excessive, especially in the case of
muscular exertion, the breathing apparatus is influenced by other
acid products of incomplete combustion, as lactic acid (Geppert
and Zuntz). But in normal respiration, the clisassimilatory hor-
mone is carbonic acid, the common product of protoplasm. It
must, however, be remembered that, in the opinion of many, the
essential factor in the regulation of normal respiration is not the
accumulation of carbonic acid, but the lack of oxygen. It may
be a combination of both.

This example — it is not the only one but it is the best known

—goes to show that the end-products of metabolism play an

important part in the accomplishment of chemical correlations.

1 6 INTERNAL SECRETION

Starling's idea, that many of the by-products of organic activity
have become hormones only because certain apparatuses have a
specific sensibility for them, seems very probable.

Our knowledge of the chemistry of hormone formation is very
slight. All that can be affirmed with certainty is that substances
of widely different origin and of the most varied chemical com-
position may operate as stimulating agents. Internal secretions
may result from complicated synthetic processes, as iodothyrin
in the suprarenals ; they may be of very complex chemical
structure, as adrenalin, which is a methylamino-alcohol of pyro-
catechin ; but they may just as easily be the simple products of
decomposition, as carbonic acid and lactic acid.

As far as we know at present, the sole characteristic which
all hormones possess in common is a negative one. They cer-
tainly do not belong to that group of substances which are known
as antigens, which, according to Ehrlich, possess a haptophoric
affinity with protoplasm and one or more by-affinities which are
determined by specific activities. The hormones resemble the
antigens in that, like the latter, they are active in minimal
quantities, but they differ in certain essential points. The
hormones do not require a period of incubation and, what is still
more important, they never provoke the formation of antibodies.
These negative properties of hormones are readily understood
when considered in the light of their physiological activity. The
accomplishment of rapid adjustments and the frequent repetition
of the same form of activity, are not functions which can be
performed by agents which are antigenic in character.

It is for the future to supply a minute characterization of
the individual hormones and to decide whether their activity
arises from their chemical constitution or is due to other chemico-
physical causes.

SOURCES OF INFORMATION AND METHODS

OF INVESTIGATION.

The oldest information about the internal secretions, and
undoubtedly the most valuable, is that derived from what may
be called clinical observation.

The castration of males, whether of man or of the lower
animals, is a proceeding which illustrates in the clearest manner
the results of the suppression of an organic function. It could
not fail to be remarked that castration is followed, not only by
the cessation of sexual activity, but also by other phenomena
pointing to a deep-seated change in the nature of the entire
organism. These changes have long been very well known, and
are brought about for definite ends. For instance, the knowledge
that castration is followed by an increased deposit of fat is used

SOURCES OF INFORMATION 17

in connection with the fattening of animals for slaughter. But
the older and more obvious belief, that the somatic and psychic
modifications resulting from castration were due to a change in
the balance of the bodily secretions, was, as we have already
seen, more and more undermined by advances in anatomy and
physiology. With the knowledge of the intimate relationship
to the nervous system in which the individual organs stand, the
theory of nervous correlation became firmly established, and the
results of castration were regarded simply as signs of the changed
activity of the nervous system.

A closer study of the structure of the individual organs led
to a better knowledge of their specific functions, but threw little
light upon internal secretory activity, even in the case of what
were known as the ductless glands.

The first fact in connection with these mysterious organs
to receive experimental proof, was the discovery that the supra-
renal capsules are indispensable to life, and this we owe to human
pathology. It is to the undying credit of Thomas Addison (1855)
that he connected a pathological condition observed by him in
man with a disturbance of function of the suprarenal capsules.

The results of human pathology, especially the comparison
of the clinical signs with the post-mortem findings, have in other
directions supplied the most valuable evidence in favour of the
doctrine of internal secretion. Instances are afforded by myx-
cedema on the one hand and by exophthalmic goitre and
acromegaly on the other. These pathological conditions have
supplied facts concerning the physiology of the thyroid and
pituitary glands, the value of which is incalculable. In Addison 's
disease and myxcedema, the normal processes become destructive
or generally pathologically hypoplastic, whereby a decrease is
brought about in the activity of certain organs, which manifests
itself in pathological signs. In Graves's disease, on the other
hand, and to a certain extent in acromegaly also, there is excess
of activity on the part of the thyroid and pituitary glands, and
these diseases may be taken as classic examples of hyperfunction
by an internal secretory organ.

It is certain that in clinical medicine we have an almost
inexhaustible source of knowledge, for we find that the careful
observation of clinical signs when taken in conjunction with the
anatomical findings, continually discloses fresh chemical relation-
ships between the different organs. Thus, the form of pituitary
disease described by A. Frohlich in 1901, under the name of
dystrophia adiposogenitalis, revealed facts regarding the rela-
tionship of the pituitary gland to metabolism which were entirely
new.

Operative surgery in man has not only contributed largely
to our knowledge (cachexia strumipriva and tetany following the
extirpation of the thyroid), but in doubtful cases it frequently

2

1 8 INTERNAL SECRETION

plays the part of determining factor. Instances are afforded by
the operative treatment of Graves's disease and the extirpation of
pituitary tumours in acromegaly.

Experimental pathology has reached a high stage in its
development and experiments upon animals have done much to
clear up the mystery which surrounds the internal secretory
processes.

Addison's discovery supplied the incentive to the first orderly
experiments on living animals. It was thought that the
extirpation or destruction of the suprarenals would not only throw
light upon the pathogenesis of Addison's disease, but would also
help to an understanding of the physiology of the organs them-
selves. The experimental extirpation of various organs has, in
the first place, decided their indispensability to the life of the
organism. In the second place, from symptoms arising after the
suppression of any organic function, the most certain knowledge
regarding the normal activity of that organ has been deduced.
The internal secretory function of the pancreas, which plays a
very important part in the economy, was discovered by means
of experimental extirpation by v. Mehring and Minkowski. Quite
recently, the removal of the pituitary body of animals has supple-
mented to a remarkable degree the observations of pathologists in
regard to its function.

Extirpation experiments with animals have certain advantages
over pathological destruction in man. In the first place it is
possible to choose a subject suitable for experiment; and in the
second, it is possible to localize exactly the destructive process,
even to a single portion of a single tissue. It is to this that
we owe the discoveries which have been made concerning the
function of the parathyroid glands. The value of the method,
when employed on different species of animals, will appear later
when we are dealing with the suprarenal system.

Another method, that of the destruction of certain tissue
elements by means of cytotoxic sera, has not fulfilled all that
was expected of it. The method is based upon the experiments
of Bordet, Landsteiner, Ehrlich and Morgenroth. These
observers found that, if an animal is treated with the red blood
corpuscles of another species, substances — the so-called ha?mo-
lysins — are formed in its serum which will dissolve, in vitro
and in vivo, the blood corpuscles of the species from which the
red blood corpuscles were taken. It was expected, therefore, that
treatment with either cells or organic extracts would induce the
formation of cytolysins (which correspond to the ha^molysins)
and of cytotoxins, and that these could be employed to bring
about by chemical means specific injury or complete destruction
of the organs.

Acting upon this hypothesis, substances which were cytotoxic
to different organic cells were prepared, and this method of

SOURCES OF INFORMATION 1(J

functional and anatomical destruction was tried upon the internal
secretory organs. But the results of a large number of experi-
ments did not contribute very materially to the solution of the
problems under discussion. In the most favourable instances,
the destruction of tissue elements by specific cytotoxic sera merely
confirmed the results which had been obtained in other ways.
A closer study of their action showed that, though they have
an affinity for the organic cells, this affinity is by no means
confined to specific organs. Moreover, the cytotoxic sera nearly
always contain ha^molysins and other components, which exert
a toxic influence upon other organs.

A more satisfactory method is the elective destruction of
certain tissue formations by means of the Rontgen rays. Very
interesting results have already been obtained and it is probable
that this method will contribute largely to our knowledge of the
internal secretory activity of certain tissue elements.

Extirpation is attended by certain by-effects by which the
results of experiment may be prejudiced. These are : The degree
of surgical shock; derangement of the circulation; and injury to
the nerves. In human pathology, when any organic function is
suddenly suppressed, an important factor is supplied by the
vicarious intervention of another organ possessing the same or
a similar function ; but it must be borne in mind that such inter-
vention is hardly to be expected in the case of the lower animals.

For this reason, partial destruction — especially the destruction
of one of a pair of organs— will be found to yield very suggestive
results. The compensatory hypertrophy of the other one of the
pair is a proof of their functional relationship.

Compensatory or correlative hypertrophy (which is the
anatomical expression of the functional over-activity of a tissue)
appears primarily in the accessory organs, in tissues of a similar
structure belonging to the same system, or, in the case of the paired
organs, in the sound half of the pair. But where there is under-
activity of any organ possessing chemical functions, tissues of
entirely different structure may vicariously intervene and may even,
as a result, become hypertrophied. An instance of this is the
hypertrophy of the pituitary gland which follows extirpation of the
thyroid. Finally, processes of growth may lead to hypertrophy
in individual organs, if the function of another chemically cor-
related organ becomes deranged, thus increasing or diminishing
the amount of hormone which it supplies. In such a case there
is no compensatory activity on the part of the hypertrophied
organ. The cardiac hypertrophy which accompanies hypertrophy
of the thymus, as in the status thymicolymphaticus and the
well-known "goitre heart," is an instance of such a condition.
The cardiac enlargement in these cases may be due to the con-
tinued over-production of substances which stimulate cardiac
activity.

20 INTERNAL SECRETION

In the larger number of cases, experimental extirpation does not
yield reliable results, unless these are supplemented by experimental
substitution. This method offers the best means of combating
the old argument, that the symptoms of suppression which follow
the extirpation of an organ are really due to unavoidable secondary
injuries. But if after transplantation — where the normal nerve
connections are severed and the local conditions changed — there are
no pathological symptoms, while these appear as soon as the
transplanted organ is extirpated, then it is obvious that the cor-
relative activity of the organ in question is not nervous in its
origin, nor dependent upon an external secretory function, but
is wholly chemical and internal secretory in its nature. Clinically
successful transplantation, whereby a threatening pathological
condition has been averted or a declared one cured, would com-
plete the chain of evidence. Nor is such confirmation lacking.
The testicle, ovary, thyroid, suprarenals, &c., have all been
transplanted with good result. It must be remembered, however,
that, even where transplantation is apparently successful, the
supply of blood and of nutrition may, under the new conditions,
prove insufficient and the organ may eventually cease to function.

The discovery that the implantation of an organ which does
not successfully heal in, may yet temporarily replace the sup-
pressed function, pointed the way to a simpler method of
substitution, namely, that known as organo-therapy, or the
Brown-Sequard method. This method is founded upon the
assumption that the internal secretion elaborated by an organ
is contained in the tissue of that organ and, more particularly, in
the juice expressed therefrom. It was thought that, even though
the actual amount of active substance present in the organ must
necessarily be small, yet, in view of the extreme activity of the
extract, it must be possible to obtain all the effects of substitution,
especially if the administration was continued over a long period
of time. The brilliant results of organo-therapy in the patho-
logical conditions due to suppression of the thyroid, amply prove
the justice of this theory. Similar results, though by no means
so striking, have been obtained in connection with other organs;
while in the case of yet others, the extract of the organ in question,
whether given by the mouth or by subcutaneous, intraperitoneal,
or intravenous injection, produced but unimportant and, in some
instances, barely perceptible, effects. The organic extract and
expressed juices depend for their effects, not only upon the
method of their preparation and employment, but also upon
certain other conditions, of undoubted importance, but of which
little is at present known. For reasons which have already been
discussed, the failure of organo-therapy in any given instance is
not to be regarded as evidence against the existence of an internal
secretory function of the organ in question.

Quite apart, however, from their substitutive effects, the

SOURCES OF INFORMATION 21

organic extracts have a distinct value in determining the nature
of organic function.

The study of the chemistry of the organic extracts has
brought many important facts to light and promises to yield still
further results. The lipoid substances, which are of the highest
biological importance but to which, as yet, little attention has
been paid, deserve a closer investigation.

There is one direction in which the extracts of the various
organs have been submitted to frequent tests. It has been found
that, when injected under the skin or into the veins of normal
animals, these substances exercise a more or less toxic action,
leading, in some instances, to death. Where, however, the
toxic action appears after intravenous injection only, the effect
cannot be regarded as in any sense specific. Most tissues contain
substances, in varying quantities, which promote the coagulation
of blood — thrombokinesic substances — and these, when injected
into the veins, may cause intravascular coagulation. It will
depend, therefore, upon the localization and the extent of the
thrombi whether there is more or less pronounced functional
derangement of the circulation and respiration, or whether the
condition becomes acute and terminates fatally. Tests of the
coagulability of the blood together with the post-mortem findings
may perhaps help the diagnosis. And it must be further borne
in mind that, however slowly and carefully the injections are
given, the introduction into the blood of substances having
thrombokinesic properties, whether in large or small quantities,
is very likely to provoke a negative action — that, namely, which
prevents the coagulation of blood.

The toxic effects of the subcutaneous or intraperitoneal
injection of organic extracts, on the other hand, may be regarded
as specific — always supposing that the extracts have been prepared
from fresh organs under sterile conditions. But though the
method proves their toxicity, it does not permit of any definite
conclusion as to their physiological activity, for we are dealing
with substances, in exceptionally large quantities, which have
been obtained from the tissues by the mechanical destruction,
the literal breaking-up, of the cells.

Far more reliable data are supplied by those activities of the
organic extracts which are purely physiological. Brown-Sequard's
discovery that the watery extract of the testicle — his liquide
testiculaire — possessed a marked tonic property, led to numerous
experiments, the object of which was to discover the physiological
activities of the extracts of various other organs. The most
important results were those obtained by Oliver and Schafer
(1894), who discovered the peculiar influence which certain tissue
extracts have upon the circulatory apparatus of normal animals.
The intravenous injection of certain organic extracts, as supra-
renal, pituitary, and renal, brings about a more or less charac-

22 INTERNAL SECRETION

teristic increase in blood-pressure, while in the case of others
the effect is to reduce blood-pressure. These changes of tension
form the basis for a classification of the internal secretory organs
into " hypertensive " and " hypotensive " (Livon).

But it must be remembered, and the warning will be repeated
when we are dealing with the organs separately, the effect of an
organic extract in changing blood-pressure is not a proof that
the internal secretion of the organ is active in the same way.
An organic extract is a mixture of substances, the chemical
properties of which are by no means clearly defined. Moreover,
the effects which we are able to observe are not necessarily due
to the activity of a single substance specific to a single organ ;
but may result from the activity of one or more substances, which
may be common to many organs. Thus, the depressing action
of many organic extracts may be due to the fact that they contain
choline, which, it is known, reduces blood-pressure. In addition
it may be remarked that changes in blood-pressure may also be
caused by intra-vascular coagulation.

It is obvious, from wrhat has been said, that conclusions as
to the physiological and hasmodynamic activities of any organic
extract, should be accepted only with the greatest caution. Well-
defined results must be obtained and an exact knowledge of the
chemical characterization of the active substance is essential. But
even where these requirements are fulfilled, there must be definite
proof that the active substance is formed intravitally, and that
it does pass into the blood-stream. Then, and then only, are
we in a position to state, that the substance in question is the
product of the internal activity of a certain organ. This con-
clusion will be confirmed by the morphological proof of secretory
cells in the organ in question, and by the histological evidence
of the different stages of secretory activity.

The physiological activity of the organic extracts is not
confined to the circulatory system, but may show itself in modifi-
cation of the function oif other organs. A closer investigation
of their effects shows that many organic extracts contain substances
which exercise a specific influence upon the nervous system, the
muscular structure, the glandular cells, &c., and which affect the
general metabolic processes in a special manner. In cases where
this influence is extended to functions which are modified inversely
by suppression of the organ, there are eminently rational grounds
for a substitution therapy.

Naturally, many of the physiological effects of the organic
extracts upon certain tissues are to be observed only after pro-
longed use. They sometimes take the form of structural
alteration.

The material which has been collected during the last two
decades has materially altered the point of view with regard to
the interrelation of the bodily parts. Twenty years ago, the

SOURCES OF INFORMATION 23

only known organic relationships were those effected by means
of the nervous system and, until very recently, these alone were
considered worthy of attention. It was only after a long time
and as the result of infinite labour, that the existence of the
chemical correlationships was recognized, and the part which
they play in the animal economy estimated at its proper value.

To-day, the doctrine of the internal secretions plays an
important part in almost every department of physiology and
pathology, and is employed in the solution of some of the greatest
problems that biology affords. Nothing is more characteristic
of this change of view than Schiefferdecker's hypothesis of the
part performed by specific internal secretion in the functions of
the nervous system. " Internal secretion," he says, " determines
the effect which the products of metabolism, excreted by the
nerve cells during the simple processes of nutrition, will exercise
upon other nerve cells or upon the cells of the end organ, such
activity being called ' trophic.' It also determines the effect
which the products of metabolism excreted in the course of
specific activity will produce, and this effect is known as ' irrita-
tion ' or ' stimulus.'

This view of the origin of nervous activity can hardly be
accepted as final, but the mere proposition of such a hypothesis
illustrates the magnitude of the difference between "then " and
" now." The older physiologists thought that each organic
interactivity was due to nervous intervention ; to-day we believe
that even the nervous correlationships themselves are effected by
means of chemical agents.

PART II.-SPECIAL

IN Part I, a brief account was given of the history of the
doctrine of internal secretion, of its physiological basis, and of
the general principles upon which the teaching is founded. In
Part II we propose to take the internal secretory organs separately
and to describe what is known of the nature and significance of
their activities. In the present state of our knowledge anything
in the nature of a systematic classification is impossible. The
only rational basis would be a morphological one, but this is
rendered impracticable by the insufficiency of the data at our
disposal. There is a general tendency to ascribe a specific activity
to every cell-form and to every kind of tissue, but though, in
a sense, we are justified in so doing, there is as yet no certain
proof of the internal secretory activity of the greater number
of cells and tissues. From the structure of a tissue we are, no
doubt, able to deduce its specific function, but we are a long
way from being able to infer the nature of its chemical correlative
function.

There are also drawbacks to a classification upon purely
physiological grounds. In any such attempt organs and tissues
of the most dissimilar type would, on account of the similarity
of their function, be classed together; while organs possessing
activities in more than one direction wrould be included in several
different groups.

Such being the state of matters it is better to avoid all
attempts at classification and simply to give a list of the internal
secretory organs, taking them, as far as possible, in the order
of their importance.

It is more in deference to custom than in support of any
personal conviction that the so-called " vascular " or " ductless '
glands are first dealt with, leaving the second place to the other
internal secretory organs. The first group includes :-

The organs of the thyroid apparatus, namely, the thyroid
gland and the parathyroid glands ;

The thymus gland ;

The two suprarenal systems, namely, the interrenal and the
adrenal, together with the carotid and coccygeal glands;

The hypophysis cerebri or pituitary gland, consisting of the
anterior and posterior portions, together with the pineal gland.

The spleen, which was formerly considered a vascular gland,
is now regarded as essentially haematopoietic in its activity, its
internal secretion having no great physiological significance.

The second group includes : —

26 INTERNAL SECRETION

The sexual glands and other tissues concerned in the processes
of reproduction ;

The pancreas ;

The intestinal and gastric mucosa ;

The kidneys.

It is not proposed to enter into the questions of glycogenesis
and the neutralizing activity of the liver. These secretory func-
tions are the oldest known to us and are fully described in the
current text-books of physiology.

The plan adopted in each instance is : First, to give the
necessary information concerning the morphology and the
development of the organ ; second, to describe in detail its
physiological and experimental aspects; and finally, to estimate
its pathological significance by means of material gained from
clinical observation.

THE THYROID APPARATUS.

The thyroid apparatus comprises two distinct organic systems
which differ both in structure and in function. They are the
thyroid gland, Glandula thyroidea, and the parathyroid glands,
Glandules parathyroidece.

ANATOMY.

The thyroid gland of man consists of two lateral lobes,
situated upon the lateral surface of the larynx, united by a
transverse portion, the isthmus. Accessory lobes (Glandules
thyroidecc aberrantes), distinct from the principal organ, may
occur within a triangular area, the apex of which is at the root of
the aorta, the base being formed by the edge of the lower jaw.
In animals these accessory glands may prejudice the results of
experiment, while in man they may give rise to retrosternal
goitres and so acquire a pathological significance.

The thyroid gland is remarkably vascular, being supplied
with blood by no less than three to five large arteries. According to
Tschuewsky, the whole of the blood in the body of the dog passes
through the thyroicl sixteen times a day.

The blood is carried away from the gland by a system of
large veins. The lymph passages, which are present in large
numbers, open into the deep cervical glands. The nerves, which
are comparatively scanty, proceed in part from the ganglia of
the cervical sympathetic nerve and in part from the superior
laryngeal nerve.

HISTOLOGY.

In an early stage of development the thyroid gland is a
compound tubular gland with a duct (ductus thyroglossus), which

THE THYROID APPARATUS 27

opens at the foramen caecum lingua?, but which becomes obliterated
during foetal life. The developed thyroid contains numerous
vesicles or follicles, formed by the subdivision of the embryonal
tubuli.

The parenchyma of the thyroid, which is exceedingly vascu-
lar, consists of a stroma formed of connective tissue, in the meshes
of which the follicles are situated. These follicles are surrounded
by a network of capillaries and are bound together by means of
connective tissue to form lobules. The follicles are hollow spaces
of different sizes and shapes, lined with cubical or cylindrical
epithelium. The epithelial cells, in both man and animals, contain
a varying number of small and large granules. These are situated
in the free end of cells, facing the lumen of the follicle. These
granules are highly refractive and, from the reactions which they
give, are believed to consist of fat in combination with oleic
acid. Except during the first month of foetal life, these granules
are always present ; they continuously increase in number until
old age is reached ; and it is probable that they play a part in
the formation of the secretion.

The follicle contents are composed of a peculiar substance,
known as thyroid colloid. Morphologically it is a colloidal sub-
stance, though chemically it is not. It varies in consistency and
is insoluble in water, alcohol, ether, and diluted acids. It swells
in acetic acid and strong alkalis, and is, in general, acidophile.
It stains with acid aniline dyes and most readily with eosin.
After staining by van Gieson's method it assumes an orange
tone, the connective tissue and hyaline substance becoming a
brilliant fuchsine red. As a general rule, it does not stain with
the basic aniline dyes, hasmatoxylin, or the specific stains for
mucus, though at times it appears to be readily basophile.
Nearly all authors are agreed that the colloid contents of the
follicles are a product of the secretion of the epithelial cells, though
it is probable that a very small proportion is also evolved in the
course of cell-decomposition. In sections of thyroid gland pre-
pared by the Ehrlich-Biondi method, Langendorff was able to
distinguish between principal cells and colloid cells, the former
remaining uncoloured, the latter staining red and their nuclei
green. The secretory processes of the thyroid have since been
closely studied by many authors (Andersson, Bozzi, Galleotto,
Hurthle, L. R. Miiller, E. Schmidt), and it is now generally
accepted as a fact that specific granules are formed in the proto-
plasm of the epithelial cells, which swell up and pass out of the
cell body in the form of drops, and that these drops constitute
the contents of the follicles. The various phases of secretory
activity are accompanied by characteristic changes in the structure
of the cells. The follicular contents, which at first are fluid,
become viscid and undergo secondary changes, until finally they
attain the characteristic colloid consistency.

28 INTERNAL SECRETION

Microscopic examination of the thyroid gland shows that, in
its finished state, it is what F. Kraus very aptly terms a " storage "
gland. In regard to the continuous formation of colloid, it is
assumed that a proportion of the secretion passes into the blood-
stream, though opinions differ as to the manner in which this
takes place.

According to Biondi, the passage of the secretion into the
lymph-vessels is effected by dehiscence of the epithelial cells and
the breaking through of the colloid mass into the lymph-spaces ;
Hiirthle believes that the secretion passes out by way of the
intercellular passages ; while Lewandowski is of the opinion that
the process is osmotic. One thing, however, is certain, namely,
that a substance is found in the lymphatics which appears to be
identical with the colloid substance of the thyroid.

Although a certain amount of information is forthcoming
concerning the effect which nervous excitement and other momenta
exercise upon the secretory process, the data are insufficient to
form the ground-work of a hypothesis. Hiirthle found that
electric stimulation of the thyroid nerves did not produce con-
comitant changes in the histological aspect of the secretion.
Katzenstein found that, after resection of the superior and inferior
laryngeal nerves of one side, there was histological degeneration
of the thyroid upon both sides. On the other hand, Martini was
unable to discover any departure from the normal tissue, and
A. Exner found that the amount of iodine in the gland remained
unchanged.

Wiener has recently discovered that pilocarpin is without
effect upon the thyroid, while adrenalin brings about an increase
in the amount of thyroglobulin. Marked effects were obtained
with iodide of sodium, which also induced a hypersecretion of
thyroglobulin. In cases where the gland had previously been
removed, iodide of sodium not only induced a suppression of
compensatory hypertrophy, but it is probable that it even gave
rise to atrophy. The action of thyroidin, though much less in-
tense, was identical with that of the inorganic iodine combinations.

According to Wyss and E. A. Schafer, the cells of the
thyroid gland react to pilocarpin in the same way as the cells of the
true secretory glands. Hiirthle described the histological signs of
increased glandular activity in dogs after ligature of the gall-duct,
and he believed that the bile, which thus passed into the blood,
stimulated the thyroid gland to increased secretory activity.
This, however, was not confirmed by Miiller's experiments with
cats, which were highly jaundiced as a result of the ligature
of the common bile duct. In dogs, however, this operation was
followed by enlargement of the thyroid follicles and formation
of tissue similar to that seen in colloid goitre. These changes are
attributed, by both Miiller and Lewandowski, to acute
degeneration of the gland.

THE THYROID APPARATUS 2Q

H. Wiener found that, after removal of the inferior cervical
ganglion, there was a decrease in the cell-mass, together with an
increase in the thyroglobin contents, of the thyroid gland upon
the same side. The resection of the fifth and sixth spinal nerves
caused a reduction in the weight of the gland, unaccompanied,
however, by a decrease in the amount of thyroglobin. Wiener
concludes that the rami communicantes of these spinal nerves
are the roots of the sympathetic nerves of the gland ; though they
convey only trophic impulses, the secretory fibres having another
origin.

CHEMISTRY.

The earlier investigators (Kiihne, Oicltmann, Bubnow,
Gurlay, Morkuton, Notion, Drechsel, Hutchison) showed that,
among the chemical constituents of the thyroid gland are the
albuminoids — both albumins and nucleoproteids containing
phosphorus — albumose, leucin, xanthin, hypoxanthin, paralactic
acid, and succinic acicl. Of the inorganic substances, it contains
sodium chloride and oxalate of calcium.

E. Baumann showed, in 1895, tnat the normal thyroid gland
contains large quantities of iodine in organic combination. It
was suggested by Kocher, even earlier, that the favourable effects
of the iodine preparations in goitre might be due to the fact
that iodine is a normal constituent of the thyroid gland.

The amount of iodine present in the normal gland of man
and animals is 0.3-0.9 mg. to i grm. of the dried substance.
The entire organ contains 2-9 mg., or, according to Aschbacher,
an average of 6.48 mg. The thyroid gland of the foetus and of
the new-born infant contains no iodine, and it appears from this
that iodine is introduced into the organism with the food and
is stored in the thyroid gland. In children the amount of iodine
in the gland is less than in adults; according to Jolin, from i-io
years, it is 0.145 mg. According to Aschbacher, the average
up to 25 years is 2.43 mg. ; from 25-30 years, it is 8.98 mg. ; and
over 50 years of age it is 4.6 mg. Among animals, the thyroid of
herbivore contains a high percentage of iodine; that of
omnivorag is low; while the lowest percentage of all is contained
in the thyroid of carnivore, from which iodine may even be
absent altogether.

The amount of iodine present in the thyroid may be taken
as a measure of the amount of iodine taken into the economy,
whether in food or as a medicament. According to Jolin, who
gives the average amount of iodine in the normal human thyroid
as 8.5 mg. the amount increases under iodine treatment to 15.6 mg.
Baumann states that the proportion of iodine is lowest in localities
where goitre is endemic — such as Freiburg — while the gland
weighs very heavily. In localities which are free from goitre
(Hamburg, Berlin) the opposite holds good, the weight of the

30 INTERNAL SECRETION

gland being low and its iodine content high. The absolute iodine
content of goitrous glands is, however, considerably higher, and
may reach 50, or even 100 mg. Oswald pointed out that the
amount of iodine in the thyroid gland is a parallel to its colloid
content. True parenchymatous goitres, the goitres of Graves's
disease — in so far as these are parenchymatous — the purely fibrous
goitres, portions of goitres which have undergone cell-
degeneration, and the hyperplastic goitre of calves, do not contain
iodine, or, at least, contain very little; while, on the other hand,
goitres containing much colloid substance are very rich in iodine.
Oswald is of the opinion that, wherever there is pronounced
colloid degeneration, the proportion of iodine decreases and may,
indeed, disappear altogether.

Iodine is present in very nearly all the human organs, though
this was not Baumann's original opinion. The thyroid gland is,
however, S-io times richer in iodine than the other organs
(hypophysis, liver, kidney, ovaries). According to Baldi, bromine
is also present in the thyroid ; and Gautier and Bertrand assert
that arsenic is present in both the thyroid and the ectodermal
organs. The presence of arsenic, however, is denied by
Hodelmoser. Fiirth and Schwarz, as previously stated, believe
that choline is present in the thyroid.

Iodine is undoubtedly the most characteristic, as it is the most
important, of the chemical constituents of the thyroid gland, and
it occurs, according to Baumann, in combination with an
albuminoid. Baumann gave the name of thyroidin to this sub-
stance, but the name was afterwards altered to iodothyrin.
lodothyrin is obtained by boiling the thyroid gland for several
hours in 10 per cent, sulphuric acid, and extracting the residuum
with 90 per cent, alcohol.

Oswrald believes that thyroid colloid is a mixture of two
albuminoids, the thyroglobulins. Of these, one contains iodine
and, after treatment with boiling mineral acids, yields iodothyrin
as the product of hydrolytic division. lodothyrin is a peculiar
atom-complex contained in the larger molecule of thyroglobulin.
Oswald has recently shown that, if it is treated with trypsin for
several weeks, iodine-thyroglobulin also breaks up into the final
products of hydrolytic division, for by this means the iodine
is set free and passes into the ionised state. The second
albuminoid is free from iodine, but contains phosphorus, and is a
nucleoproteid.

Iodine-thyroglobulin forms by far the largest proportion of
the weight of the dried thyroid gland, being one-third to one-half;
while it forms three-quarters and more of the weight of colloid
goitres. In hyperplastic goitre and the goitre of Graves's disease,
the amount of iodine-thyroglobulin is reduced, while the amount
of the albuminoids containing phosphorus is much increased.
The amount of iodine in thyroglobulin obtained from the thyroid

THE THYROID APPARATUS 3 I

gland is not constant ; this is ascribed to the fact that thyroglobulin
is present in two forms, one of which contains iodine and one not.
The relative quantity of iodine to the whole amount of thyro-
globulin becomes smaller in proportion as the degenerative pro-
cess is more advanced. There is no iodine in the thyroglobulin of
goitres which are free from colloid substance.

Oswald believes that thyroglobulin is formed in the interior
of the follicles, and that it is only after it emerges from them that
it becomes iodized ; or after iodization it may be excreted as a
colloid into the follicular space. He thinks that the production
of iodine-thyroglobulin is the physiological function of the thyroid
gland; that iodine thyroglobulin is the physiologically active
secretion ; and that the degree of activity depends upon the amount
of iodine present. Thyroglobulin obtained from goitres has a
physiological activity precisely similar to that obtained from
normal glands. Thyroglobulin which does not contain iodine does
not produce physiological results.

It is Oswald's opinion that goitres, including the goitre of
Graves's disease, are not to be regarded as a manifestation of
increased thyroid activity ; for, seeing how poor in iodine goitrous
glands are, the value of their function is diminished rather than
increased. They either do not form any secretion at all, or that
which they do form has a smaller physiological activity than that
of normal thyroid glands. F. Kraus, on the other hand, explains
the lack of iodine in the goitre of Graves's disease by a decrease
in the storage power of the gland, which thus parts with its
secretion too readily. Oswald is unable to deny that goitrous
glands are hyperactive, but he maintains that, though there is
increased secretory activity, the substance secreted has less
physiological value.

ANATOMY OF THE PARATHYROID GLANDS.

In development and function the parathyroid glands are
entirely independent of the thyroid, but anatomically they are
closely related to it. In man they are kidney-shaped bodies,
3-15 mm. long and 2-4 mm. broad and thick, and yellowish brown
to a brown-red in colour. As a general rule, they are four in
number and are situated in such a manner with regard to the
lobes of the thyroid, that it is customary to distinguish between a
posterior superior, and an inferior anterior parathyroid gland.
The upper body usually lies upon the dorsal surface, and at the
upper edge, of a nodulated process of the thyroid gland, known
as the pyramidal process, and it is found by following up the
inferior thyroid artery. The lower body is less constant in its
localization ; it may be situated at the lower edge of the pyramid,
or it may be found at the lower pole or on the medial surface of
the thyroid gland. Accessory parathyroids are sometimes present,
and these may extend downwards into the cavity of the thorax;

32 INTERNAL SECRETION

or they may be simulated by lobules thrown out from the thyroid
itself.

The parathyroids are extremely vascular and are supplied
with blood from the inferior thyroid artery. The veins open into
the lateral portion of the thyroid venous system. Up to now
there is no anatomical proof that nerves are present.

HISTOLOGY OF THE PARATHYROID GLANDS.

The parathyroid gland usually has the appearance of a closed
capsule composed of fibrous connective tissue. It is filled with
parenchyma, which is divided into more or less regular columns
of epithelial cells, by delicate septa which proceed from the
envelope. These septa convey the capillary vessels, and they
unite to form a kind of network, in the meshes of which the
parenchyma is enclosed. Occasionally, the parenchyma appears
to be a single coherent cell-mass traversed by a very close network
of capillaries. In other cases, owing to pronounced development
of the connective tissue, it is divided up into portions resembling
lobules or follicles. Sometimes all three structural forms appear
in one organ ; in other cases the structure is uniform throughout.

The greater proportion of the parenchyma consists of rather
large polygonal cells, called principal cells (Hauptzellen), the
protoplasm of which does not stain readily. The nuclei, which
stain well, are about the size of erythrocytes ; they are furnished
\vith a regular, net-like, chromatin framework and have several
nucleoli. A second group of cells is oxyphile. These have a
delicate granulated protoplasm, which colours strongly with eosin
and other acid dyes, and a small central nucleus. The oxyphile
cells are, as a rule, smaller than the principal cells, but there
are numerous transition forms. Of these, one is believed by some
authors to constitute a separate cell-form. It is intimately
associated with the connective tissue of the capsule and the septa,
and appears as a cubic or cylindrical cell with an elliptical nucleus.
These cells unite to form palisade-like rows, which are arranged
either radially or perpendicularly to the direction in which the
septa run.

The numerous capillary vessels unite to form a close net-
work ; their endothelial cells rest partly on the epithelial cells and
in part are covered with a delicate sheath of connective tissue.
Occasionally, and more particularly in old age, the arteries are
accompanied by large lymphatics. According to Sacerdotti and
Anderson, the vessels in the interstitial tissue are accompanied
by nerve-fibres by which they are enclosed as by a network, and
which may also penetrate between the epithelial cells.

That the parathyroids possess a secretory function is shown
by the presence of fat-granules in the epithelial cells of the
parathyroids of both man and animals. These fat-bodies are

THE THYROID APPARATUS 33

found during the first month of life, and they increase in number
with age, though they are not affected by the general nutritional
conditions. Petersen found glycogen in the parathyroid glands
of man at all ages ; its distribution was irregular, the principal
cells containing much, the oxyphile cells little. Glycogen is also
present in the connective tissue and the blood-vessels. Petersen's
view is endorsed by Guizetti, v. Verebely and Yanase.
H. Koenigstein considers that .upon histological grounds glycogen
may be regarded as a secretory product of the parathyroid glands.

The parathyroid glands sometimes contain colloid, which
occurs in agglomerations situated, as a general rule, near the
edge, and which is occasionally contained in follicles similar to
those of the thyroid. There is a follicle-like arrangement of the
oxyphile cells, and at a later stage, the centre of this follicle
contains a colloid deposit, generally circular in shape, the edge
of which stains readily with eosin. Later on, the follicle cells
group themselves round the colloid to form a gland-tubule.
Colloid masses are also found within the larger cell-agglomera-
tions (Petersen).

Chemical examination of the parathyroid glands is yet to
come. Gley proved the presence of iodine, though Chenu and
Morel found that both the external glands of the dog and the
rabbit contained something less than 0.025 mg., a proportion far
smaller than that in the same weight of thyroid tissue.

According to Berkeley and Beebe, the parathyroid glands
contain a nucleo-proteid of specific activity.

HISTORY OF THE DEVELOPMENT OF THE ORGANS

OF THE NECK.

To understand the anatomy of the parathyroid glands and
their relation to the thyroid, it is necessary to have some insight
into the history of the development of the organs of the neck.
This may be briefly stated as follows : —

At a very early stage of development, epithelial thickenings
form at the third and fourth branchial arches, one being situated
on the dorsal or cranial side, and one upon the ventral or sacral
side of the branchial clefts of both sides. The ventral thickening
of the third branchial cleft is the definitive primordial beginning
of the thymus gland, and is called thymus III. The thickening
upon the ventral side of the fourth branchial cleft was formerly
believed to be the primordial beginning of the thyroid gland,
but it is now very generally regarded as one of the beginnings of
the thymus, and is called thymus IV.

It \vas formerly believed that the thyroid gland was derived
from the t\vo ventral portions of the fourth branchial cleft, in
combination with material derived from the median portion of the
fauces. This view has become very much modified, and it is now

3

34 INTERNAL SECRETION

held that, not the thyroid, but the thymus, is derived from ihe
lateral branchial clefts and that, as a matter of fact, the lateral
lobes of the thyroid gland have not a separate area of origin.
This view is confirmed by discoveries made by Maresch and
Peucker. They each describe an instance in man in which the
thyroid was absent, while the parathyroids and the remains of the
thymus were present in their full number. It is highly probable,
therefore, that the lateral portions of the thyroid gland are derived
from a diverticulum of the primitive median thyroid process.

The parathyroid glands are developed from the dorso-cranial
thickenings of the branchial clefts, the parathyroid III from the
third branchial cleft, and the parathyroid IV from the fourth
branchial cleft. In the neighbourhood of the latter is a cyst-like
hollow lined with pavement epithelium, which is called the post-
branchial body. This is derived from a lateral portion of the
fourth branchial cleft.

In a further stage of development, the entire complex evolved
from the fourth branchial cleft becomes very intimately associated
with the thyroid and is, eventually, entirely covered by it. In
many species of animals, the parathyroid IV, together with the
thymus IV and, in some cases, the post-branchial body, are
found within the thyroid gland and, on account of their topo-
graphical position, are described as " internal."

It would be more accurate if we were to follow the example
of French authors and call these branchial organs by a name
expressing their origin, namely, glandular branchiales parathy-
mica^ and parathyroideas. And it would serve still further to
elucidate the matter if we were to add the numbers III and IV, in
accordance with the branchial process from which the organ
takes its origin.

The descriptions " internal ' and " external ' cannot be
applied to the parathyroid glands of man, because these are all
placed externally to the thyroid. The glandula branchialis
parathyroidea III is situated at the aboral pole of the thyroid, and
represents the inferior parathyroid body. The glandula
parathyroidea IV, which represents the internal parathyroid
gland of many animal species, lies, in man, on the dorsal surface
and near the upper edge of the thyroid and is called the superior
parathyroid gland.

COMPARATIVE ANATOMY OF THE PARATHYROID

GLANDS.

The organs of the neck, even in the embryo, do not ahvays
occur in the classic number. The most constant is the thymus
III, and the origins of the parathyroids are also of fairly regular
occurrence. The primordial beginning of the parathyroid III

THE THYROID APPARATUS 35

has never been known to be absent. A. Pepere's investigations
show that, in all mammals, including man, the development of
the thymus is invariably accompanied by a persistent accessory
parathyroid system, which is derived from the third branchial
cleft. It is seen most clearly in the thymus or in the region
of the thymus of live rabbits, where it appears in the form of
single groups of epithelial cells, or of relatively large islands
composed of parathyroideal tissue.

As a general rule, all the embryonic beginnings of para-
thyroid glands develop into definitive organs. Variations occur in
their topographical relationship to the thyroid, and for this reason
there is a wide diversity in the anatomical conditions of species
and individuals.

The position of the parathyroids is most constant in cats.
The glandula parathyroidea III, representing the external para-
thyroid gland, lies upon the dorsal surface of the thyroid gland
and generally at its upper pole, though sometimes at the middle.
The glandula parathyroidea IV, representing the internal para-
thyroid gland, is placed at about the middle of the thyroid,
more or less deeply embedded in the tissue.

A similar arrangement is found in the dog. The external
parathyroid body lies in a depression situated at the upper pole
of the thyroid, while the internal parathyroid body is found in
the upper third or in the middle of the thyroid, and is likewise
embedded in the tissue. Supernumerary parathyroid bodies are
by no means infrequent in the dog, though in the cat they are
scarcely ever met with.

In ruminants the topographical-anatomical conditions are
aberrant. The glandula parathyroidea III of the sheep and the
goat is much nearer to the cranium, and is found on the inner
surface of the submaxillary gland or at the fork of the carotid.
The glandula parathyroidea IV is embedded in the centre of
the thyroid.

In the rabbit, the glandula thyroidea IV also remains in
association with the thyroid, and is found in the interior of the
gland. The glandula parathyroidea III, representing the ex-
ternal parathyroid body, lies from J-iJ cm. below the thyroid
gland. Under typical conditions, it lies close to the carotid and
depends from a delicate arterial peduncle. It is about 4-6 mm.
long, ij mm. broad, and weighs 4-6 mg. Erdheim and Pepere
found numerous accessory parathyroids in the thymus of rabbits.
Cristiani's investigations show that, in the case of other rodents,
one parathyroid body is either embedded in the thyroid tissue or
projects from its surface. A glandula parathyroidea III is
generally absent, but in the field-mouse there is a free parathyroid
gland which lies at either the upper or the lower edge of the
thyroid. Erdheim found that, in the rat, in addition to the one
parathyroid body embedded in the thyroid tissue, there is fre-

36 INTERNAL SECRETION

quently a second larger body. In every case, however, there is
a larger or smaller number of small and minute accessory bodies,
and these are found distributed over the space between the
principal parathyroid body and the tip of the thymus gland, in
and on the thyroid, below the lower pole of the thyroid, and about
and within the tip of the thymus.

In apes, it frequently happens that both the parathyroid
glands are situated outside the capsule upon the lateral surfaces
of the thyroid gland. In Macacas rhesus an external parathyroid
gland is frequently found at or about the middle of the lateral
surface of the thyroid ; or it may occur, though more rarely, at
the upper or lower pole. The other gland is found embedded
in the substance of the thyroid, near the internal surface, and at
about the middle of the organ. This second gland is usually
the larger.

In birds, the entire thyroid apparatus lies in the cavity of
the thorax, on both sides of the trachea, and consists of the
thyroid and 1-2 parathyroids, which are placed at the upper or
lower poles of the thyroid.

In the tortoise, Doyon and Kareff found at the base of the
neck a parathyroid body of a yellow colour on each side of the
thvmus.

•/

In fish, the only portion of the thyroid apparatus which is
known is the thyroid gland, and this is situated at the fork of the
branchial artery.

PHYSIOLOGY OF THE THYROID APPARATUS.

HISTORICAL.

From very early times the thyroid gland has been regarded as
an organ possessing specific physiological functions. We gather
from the older physiologists, Horsley (1891), Hellin (1893), Langen-
dorff (1899), that before any definite information as to its structure
was forthcoming, the most extraordinary notions regarding the
nature of its activity prevailed. It was believed to enhance the
beauty of the form and contour of the neck; to be a kind of
cushion for the larynx ; to act as a sounding-board for the
voice, &c.

An early theory, based on the anatomical aspects of the
thyroid gland and, more particularly, upon its extreme
vascularity, held that the function of this organ was the regulation
of the cerebral circulation. As a matter of fact, the thyroid
glands, with their exceptionally numerous blood-vessels — which
are in direct communication with the great vessels of the brain—
and their enormously developed capillary system, do, to a certain
extent, influence the blood which circulates through the brain.
These conditions might seem to suggest that the thyroid apparatus

THE THYROID APPARATUS 37

serves as the blood reservoir for the brain, and that, when a
change takes place in the circulatory conditions, it may either
prevent a rush of blood to the arteries of the brain, or it may
receive large quantities of blood from the cerebral veins.

This theory has recently been revived by E. von Cyon. He
suggests that iodothyrin, the active substance formed by the
thyroid gland, stimulates the nerves of the heart which regulate
pressure, and that by this means the blood-pressure is lowered
and the circulation retarded. At the same time, the central vagal
irritation is conveyed by means of vasodilators to the vessels
of the thyroid gland, causing them to dilate and thus still further
reduce the flow of blood to the brain.

When we have discussed the activity of the thyroid extracts,
we shall be in a position to judge whether or not there is justifica-
tion for this hypothesis. Suffice it for the present that, though
experimental proof of changes in the cerebral circulation due to
chemical or nervous intervention of the thyroid, if they really
exist, ought to be readily obtainable, and wrould be very con-
vincing. Such proof is, up to the present, not forthcoming.

Another of the older theories has recently been advanced
by J. F. Meckel. It postulates an intimate physiological
association between the thyroid gland and the female organs of
generation. This theory owes its origin to the fact that the
thyroid gland of women is larger than that of men, and that it
increases in size during menstruation, deflorescence, and
pregnancy.

The swelling of the thyroid is a well-known phenomenon in
menstruation and pregnancy. This increase in size may be
partly clue to general vascular turgescence, but, as we shall see
later, there is an actual biological relationship between the thyroid
and the sexual glands.

Tiedemann was the first to suggest that the thyroid is con-
cerned in the formation of blood, and that it aids, or may even
replace, the function of the spleen. He bases his view upon the
histological construction of the thyroid and its structural analogy
with the lymphatic glands and the spleen. The latest experiments
show that there is some ground for the belief that the thyroid
exerts an influence, though indirectly, upon the formation of the
blood.

The functional significance of the thyroid gland and its
importance to the life of the organism, \vere first demonstrated by
the serious nature of the results which follow its extirpation.

Numerous instances in which goitre in man has been treated
by total extirpation of the gland, confirm the results obtained by
means of hundreds of experiments with animals, and there is no
doubt that the removal of the thyroid gland gives rise to severe
pathological conditions which often terminate fatally. The
results of extirpation may show themselves in two conditions,

38 INTERNAL SECRETION

which differ radically, both in their symptom-complex and in the
course which they run. Of these conditions, one appears
promptly and is attended by violent muscular spasms. It is
obviously a disease affecting the nervous system and has been
called "tetany," on account of its resemblance to a well-known
idiopathic disease of man. The second condition is more chronic
in its development and is characterized by nutritional disturbances
of the most varied description. In man there is a peculiar
cedematous swelling of the skin, a decrease in mental power, and,
in young -people, a remarkable arrest of development. This
condition was named myxcedeme postoperatoire by Reverdin, and
by Kocher, general cachexia strumipriva or thyropriva. These
two conditions were not regarded as separate pathological
entities, but as etiologically and pathogenetically the same. For
either might make its appearance in man after extirpation of the
thyroid gland, and transition forms between the two conditions
were known to exist.

It seemed a remarkable thing that the suppression of an
organic function should be expressed by means of two totally
different symptom-complexes. Experiments with animals were
undertaken to show that this was due to the operation of factors as
widely divergent as species, age, external conditions such as
temperature, and nutrition. The latter appeared to be the deciding
factor; for it was invariably found that removal of the thyroid in
the carnivoras caused death, while in the herbivoras it only pro-
duced nutritional derangements, these taking the form of chronic
cachexia, or, in young animals, disturbance of growth.

The discovery of the parathyroid glands by Sandstroem in
1880 first provided a means of interpreting this difference in its
relation to species. A long time, however, elapsed before any-
thing \vas done in this direction. It was not until 1890 that the
French physiologist, E. Gley, was able to show that herbivorous
animals, such as rabbits, develop tetany if, in ^addition to the
thyroid, the parathyroid glands, which lie at some distance away
at the side of the carotid artery, are also removed.

The anatomy of the thyroid glands was finally cleared up
by experiments undertaken by A. Kohn ; and, in 1896, Vassale
and Generali showed that in the dog, extirpation of all the
parathyroids wras followed by tetany, while extirpation of the
thyroid was unattended by pathological signs. These results
were confirmed in many directions (Rouxeau, 1896; Gley, 1897;
Moussu, 1897; Welsh, 1898; Capobianco, 1899), ^ut there was
considerable divergence of opinion as to their interpretation.
Surgeons were by no means unanimous in conceding to the
parathyroid glands a pathogenetic significance in tetania strumi-
priva.

My own experience has shown that, not only does tetany
follow extirpation of the parathyroid glands, but that extirpation

THE THYROID APPARATUS 39

of the thyroid, leaving the parathyroids intact, produces derange-
ment of the processes of growth in young carnivone. I became
convinced, from the results of my experiments, that cachexia and
tetany cannot have a common origin; and I urged (1901) that,
in the surgical treatment of goitre, the parathyroids should in
all cases be left intact, and that, wherever possible, a portion
of the thyroid should be spared.

My opinion was confirmed later by Jeandelize (1903), Wal-
baum (1903), Pineles (1904), Erdheim (1906), Pfeiffer and Meyer
(1907), Hagenbach (1907), Haberfeld and Schilder (1909). There
are observers who have adopted a different standpoint (Blum ;
Caro, 1903 ; Kishi, 1904), but they are very few.

We may, then, take it as established : that the acute nervous
symptoms which appear after extirpation of the thyroid apparatus,
are genetically independent of the thyroid gland and occur only
where the parathyroids have also been removed ; and that tetany
arises from the suppression of the function of the parathyroids
and should, rightly, be called tetania parathyropriva. Whether
this form of tetany is identical with that which follows the
extirpation of the entire thyroid apparatus is, as yet, undecided.
It is, however, barely possible to distinguish between the clinical
pictures presented by the two conditions in animals of similar
species and of the same age. The only apparent difference lies
in the intensity of the symptoms and the rapidity with which
they make their appearance.

TETANIA PARATHYROPRIVA.

The results produced by extirpation of the parathyroid
glands or of the entire thyroid apparatus of animals, vary some-
what with the species and age of the subject. In addition to
the typical acute tetany, which shows itself in characteristic
muscular convulsions, there are other acute forms which are
associated with symptoms of paralysis. Abortive forms are
occasionally seen, as well as a latent tetany, which is shown
only by a hypersensibility of the nerves and occurs most fre-
quently after partial parathyroidectomy. Finally, many animals
develop a chronic tetany which is associated with certain trophic
disturbances.

The typical picture of an acute tetany is most frequently seen
in the dog and the cat, and may be described as follows : There
is, first, a latent period lasting 24 to 72 hours, during which time
appetite falls off and the animal may refuse food ; thirst increases ;
the temperature may fall and the number of red blood corpuscles
be diminished; and later on there may be mechanical hyper-
sensibility of the peripheral nerves. This is followed by fibrillary
contractions in certain muscles of the head, face, back and tail.
In the course of the next day or two the temperature rises and

40 INTERNAL SECRETION

the muscular spasms become more frequent and more intense ;
the animal rubs its snout, walks stiffly, and steps on the dorsum
of the paws. Frequently, there is a peculiar position of the paws
caused by tonic contraction, accompanied by diffuse clonic con-
tractions in different groups of muscles and, more particularly,
by the tremor of an extremity, due to lightning contractions.

As the condition progresses, the clonic contractions spread
to nearly all the muscles of the body, when what is known as
a tetanic seizure comes on. It begins with a marked increase
in the respiratory and cardiac activity, and the temperature rises
to 41-42.5° C. (about 106-108° F.). The animal suddenly lies over
on its side and the breathing becomes extremely rapid, interrupted
by occasional deep convulsive inspirations ; or there is opis-
thotonus and tetanic convulsion of the diaphragm and the animal
dies from suffocation. Very frequently, however, there is spon-
taneous recovery even after severe attacks ; the cardiac and
respiratory activity become gradually slower ; the temperature
sinks and may become even subnormal ; and a condition of
extreme weakness supervenes. After an interval varying from
one to forty-eight hours, the fibrillary contractions again become
stronger and a fresh attack comes on. After several attacks the
animals become very emaciated and, ten to fourteen days after
operation, they die. Apart from pneumonia, which is frequent,
the post-mortem finding is negative.

Gozzi has recently described severe and extensive lesions of
the liver, which he found regularly in dogs after extirpation of
the parathyroids, and which affected the vessels as well as the
cells.

A slightly aberrant form of tetany is observed in young dogs.
There may be clonic contraction of the muscles in certain regions,
but the seizures are more frequently characterized by tonic con-
tractions of the muscles of the glottis, respiratory apparatus and
extremities. The body, especially in the hinder extremities, is
stiffly extended and this seal-like attitude persists when the
animal is held away from the ground. After frequent repetition
of these seizures, a spastic paralysis develops in the hinder
extremities and these are dragged along the ground when the
animal tries to walk. The paralysis spreads and the animal dies.

Complete thyroidectomy produces an extremely acute tetany
in rabbits (to remove all parathyroids it is necessary to extirpate
the whole or the major portion of the thyroid). For one to three
days the condition of the animal remains unchanged; then there
is quivering of the masseters, accompanied by single clonic
contractions in various muscles; there is a sudden and violent
tetanic seizure and death from suffocation results. Sometimes
the extirpation of the external parathyroids only is sufficient to
bring about a fatal tetany though it more frequently provokes
the chronic form. Frequently, however, and especially in the

THE THYROID APPARATUS 41

case of old animals, the extirpation of all four parathyroids is
not followed by tetany. Haberfeld and Schilder found that if,
in such cases, the thymus and the accessory parathyroids em-
bedded in it were also extirpated, fatal tetany followed. It is
worthy of notice, however, that a proportion of animals continue
to live, even after removal of all the parathyroid glands.

Christiani (1893) produced tetany in the rat by extirpation
of the entire thyroid apparatus. The results of destroying the
parathyroids by cauterization are minutely described by Erdheim,
who distinguishes between four degrees of tetany in rats. The
lightest form is shown by a rapid tremor of the extremities,
accompanied by single coarser spasms when the animal is lifted
from the ground. A more severe form consists in spontaneous
clonic contractions, trembling of the extremities, twitching in
the region supplied by the facial nerve, and quivering in nearly
all the muscles of the body. The third degree manifests itself
in tonic convulsions, which may be artificially provoked by
ligaturing the extremities, but which also occur spontaneously ;
the animals walk with the feet doubled up and there are tetanic
spasm in the muscles of the back and the extremities. The
severest form is characterized by epileptiform seizures, or by an
epileptic state lasting several hours. As a general rule the tetany
of rats is chronic in character and is accompanied by trophic
disturbances, to which we shall have occasion to refer later.

The parathyroid tetany of mice, as described by Pfeiffer and
Meyer, is characterized by two stages. After a latent period of
twelve to twTenty-four hours, there are attacks of clonic convulsion
alternating with tonic rigidity. The second stage is characterized
by an extreme motor restlessness, ataxia, and tonic rigidity;
somnolence follows, in which the animal slowly passes away.

Parathyroidectomy of goats, according to Christens, is fol-
lowed by violent tetany. He finds, and his experiments are
confirmed by my own, that similar effects are produced by
extirpation of the thyroid and the superior parathyroids.

Horsley observed that extirpation of the thyroid apparatus
of apes was in some cases followed by acute tetany. He believes
that the acute nervous after-symptoms appear only in young
animals when kept in a cold place. Horsley and others (Munk,
Langhans, Murray, W. Edmunds, Kocher, v. Eiselsberg, Capo-
bianco, Mazzioti) are of the opinion that a fatal termination is
less frequent than in the case of the carnivore, and that the
condition frequently passes into a stage of chronic cachexia with
extreme apathy. After extirpation of the four parathyroids, I
found that there was increased nervous irritability, fibrillary
twitchings, and finally, there were tetanic seizures and a fatal
termination. Pineles describes a case in which the symptoms
were similar, but the condition ran a more chronic course.

Doyon and Jouty produced a typical tetany in birds by cauteri-

42 INTERNAL SECRETION

zation of the parathyroid glands. The same method produced
paralysis in tortoises, ending in death.

It would appear from the foregoing that the extirpation or
destruction of the parathyroid glands in all those species of
animals which have come under observation, gives rise to a
pathological condition, characterized by peculiar symptoms of
nervous derangement, and which, sooner or later, ends in death.

My attempts to destroy the parathyroid glands of cats by
means of X-rays or radium emanations were, in all cases, un-
successful.

According to Gontscharnkow, Mankowsky, Demoor, and van
Lint, the injection of thyrotoxic sera is followed by nervous
symptoms and by tetanic muscular convulsions. MacCallum tried
to obtain a cytolytic serum by immunizing geese with parathyroid
gland obtained from dogs. His careful experiments with dogs
show that the repeated injection of this serum was not followed
by clinical appearances, suppression of function, or by any
pathologico-histological change whatsoever in the activity of the
parathyroid glands.

Partial parathyroidectomy, two of the glands being left intact,
is constantly performed in removing the thyroid from rabbits,
goats and sheep ; it is not usually followed by nervous symptoms.
In these cases, the remaining glands are uninjured, but with the
carnivore it is different. Here the partial removal of the para-
thyroids is attended either by unavoidable lesion of the remaining
glands, or by a disturbance of their blood supply. These cases
nearly always show more or less severe symptoms of tetany,
which, however, disappear spontaneously. 1 observed this
transient condition in dogs, in a fox, and in an ape where, in
removing the thyroid, the enucleation of the parathyroids was
attended with difficulty and these organs became unavoidably
crushed. The animals recovered after a short time.

Tetany almost invariably follows the extirpation of more than
two parathyroids, but here also, if one parathyroid is left, the
effect is frequently only transitory. Should death, however,
result, it will be found that the remaining gland is atrophied or,
what is more frequent, that it is destroyed by secondary processes.

If, after partial parathyroidectomy (removal of two to three
glands) no symptoms appear, the animal is then in the condition
known as "latent" tetany. Vassale observed this condition for
the first time in a bitch from which three parathyroid glands
had been removed. She developed a passing tetany, but com-
pletely recovered and had two puppies, which were, however, not
carried to term. She littered a second time, eighteen months
after operation ; she had four puppies and there was a profuse
secretion of milk. She was attacked quite suddenly by violent
tetany, but recovered after treatment with thyroid extract.

The occurrence of tetany after partial parathyroidectomy in

THE THYROID APPARATUS 43

pregnant animals has been frequently described. It has been
proved, moreover (Adler and Thaler) that when animals, which
appear perfectly sound after the removal of two or three para-
thyroids become pregnant, pregnancy is heralded by an outbreak
of tetany. Fromme provoked tetany in such animals by injecting
them with placental extract. Rudinger sho\ved that a passing
tetany may be produced in cats from which the external para-
thyroids have been removed, by the introduction of certain toxins
(atropin, calomel, morphine, ergQtin, tuberculin), and by pro-
found ether anaesthesia. The assumption is that, in these cases,
a relative parathyroid insufficiency is latent and that any metabolic
derangement causes the symptoms of tetany to appear.

In addition to the nervous symptoms, every acute tetany is
accompanied by secondary signs, such as shaggy appearance of
the coat; falling of the hair; eczema; and extreme emaciation.
These manifestations become more pronounced the longer the
animal lives after operation. Similar conditions are seen in
rabbits. If tetany does not develop after partial parathyroidec-
tomy, and if the animals continue to live, the nutritional con-
dition of all such animals is more or less seriously disturbed.

Tetany in rats is strikingly chronic in character. The animals
in Erdheim's experiments survived from fifty-four to 162 days,
and invariably showed changes in the teeth. Between the sixth
and tenth w-eeks, opaque white spots appear upon the enamel of
the anterior surfaces of the upper and under incisors and these
move upwards from the base to the apex. These spots are cir-
cumscribed defects in the enamel, which may scale off and cause
the tooth to break. The upper incisors grow again quickly after
fracture, but fracture of the lower ones is frequently followed by
necrosing ulcers. As the changes in the teeth prevent the animal
taking a sufficiency of nourishment, extreme inanition and
cachexia follow. Histological examination of the teeth shows
that the trophic disturbances appear very soon after removal of
the parathyroids, and that they result from imperfect calcification
of the dentine together with hypoplasia of the enamel.

Erdheim's observations are confirmed by Pfeiffer and Meyer
and by Iselin. Iselin also describes disturbances of the processes
of growrth in the bones of speckled mice after removal of the
parathyroids. He found that in young animals there was com-
plete arrest of growth, unaccompanied, however, by secondary
bony deformity.

Erdheim saw cataract in a rat with chronic tetany and he
regards this as a symptom of trophic disturbance. Albuminuria,
which was first observed in the tetany of animals by Pfeiffer and
Meyer, is an almost constant finding. Massaglia considers the
nephritis and albuminuria to be symptoms of an auto-intoxication
consequent upon parathyroidectomy.

Iselin's account of the effects of the parathyroidectomy of

44 INTERNAL SECRETION

the mother upon the offspring are very interesting. The young
of rats from which the parathyroids had been removed were found
to be highly sensitive to electric stimuli, and were so susceptible
to parathyroidectomy that four to ten hours after operation they
succumbed to tetany in its most violent form.

TETANY IN MAN.

Experiments with animals, such as those described above,
paved the way for a closer investigation of the part played by
the parathyroid glands in the tetany of man.

There is no doubt that the tetania strumipriva of man, like
the tetania thyropriva of animals, is due to injury or removal of
the parathyroids when extirpating a goitre. This view was
originally propounded by Vassale and Generali and it has been
confirmed by many other observers (Biedl, Jeandelize, Pineles).
Benjamins showed that one to three parathyroids may be found
attached to an extirpated goitre and this sufficiently explains the
occurrence of post-operative tetany. Erdheim found that in three
cases of tetany following partial excision of a goitre, all four
parathyroids had been removed. In a fourth case, one para-
thyrofd had been left, but it had become necrosed, as the artery
below it had been ligatured.

Whether or not the extirpation of a goitre will be followed
by tetany, depends entirely upon the amount of parathyroid tissue
left intact and the functional capacity of the tissue thus remaining.
The first care of the surgeon who extirpates a goitre should be
to spare, wherever possible, all parathyroid glands. It is also
essential, as we shall see later, that a sufficient amount of thyroid
parenchyma should be left intact. For this reason, methods of
intracapsular resection or enucleation are by far the best. Of
such are Mikulicz's wedge-resection, and Kocher's resection-
enucleation methods.

In man, as in animals, a post-operative transient tetany, due
to mechanical lesions of the parathyroid glands or injury of their
blood supply, is sometimes observed. Cases have been described
where thyroidectomy has not been followed by any apparent
symptom and yet a condition of latent tetany must have existed,
for under the influence of certain momenta, such as pregnancy,
tetany has appeared.

A second form of tetany, which we know from the results
of both animal and human pathology to owe its origin to the
parathyroid glands, is that known as the tetany of maternity, or
puerperal tetany. That there is an intimate connection between
tetany and the functions of the female organs of generation
(menstruation, pregnancy, lactation) has been frequently pointed
out by clinicians.

It has been shown that the partial parathyroidectomy of

THE THYROID APPARATUS 45

animals is not invariably followed by symptoms of tetany, but
that these may be provoked by pregnancy or lactation. It appears
highly probable that in man also, parathyroid insufficiency may
be the originating cause of tetanic outbreaks, the determining
causes of which are metabolic changes arising from alteration
of function of the organs of generation. In the absence of any
definite anatomical information regarding this condition in man
it is impossible to be sure whether the assumed insufficiency of
these organs was pre-existent, or whether it occurs as the result
of changes in the female organism.

Another form of tetany is that seen in infants, and here we
have definite anatomical grounds for associating it with the para-
thyroid glands. Erdheim found haemorrhages, or traces of
haemorrhages, together with blood pigment, in the parathyroid
tissues of children who had had tetany during life. Yanase,
working in Escherich's clinic, was able to demonstrate the pre-
sense of haemorrhages in the parathyroid glands of all children
under one year wrho, during life, showed hypersensibility to
electric stimulus. After one year, he found traces of old haemor-
rhages or the finding was normal. Fleischmann found that the
teeth of all the persons he examined who had a history of infantile
tetany, showed hypoplasia of the enamel. Escherich concluded
from these results that all forms of infantile tetany are due to
parathyroid insufficiency.

There are certain authors, however, who adopt a different
standpoint (Thiemich, 1906; Forsyth, 1908). They point to the
fact that the most diverse changes may be seen after death in
the parathyroid glands of persons who, during life, never showed
any symptom of tetany. But in these cases, it may very well
be that there was sufficient healthy parathyroid tissue to carry
on the function of the glands. Also, as Rudinger points out,
the cardinal symptoms of tetany are those which are latent ; they
may be supplemented by secondary convulsive symptoms, but
these are not an essential feature of the condition. And it is
just the latent signs which most easily escape observation. The
second point, namely, that cases occur where the clinical signs
are unmistakably those of tetany, while the post-mortem findings
are negative, loses its significance in face of the fact that a
transient tetany may be provoked in man, as in animals, by a
passing lesion of the parathyroid glands.

The lack of anatomical material makes it difficult to discuss
the genesis of the other forms of tetany, namely, those of gastro-
intestinal origin, that which follows certain forms of poisoning,
and the tetany which is associated with some nervous diseases ;
but from what we know of analogous conditions in animals, it
seems highly probable that here also we have to do with in-
sufficiency of the parathyroid glands.

Rudinger remarks the frequency with which the parathyroids

46

INTERNAL SECRETION

become tuberculous and the striking frequency of the Chvostek
phenomenon in tuberculosis, as noted by many observers. He
mentions a very instructive case described by Carnot and Delion,
that of a tuberculous woman who on the day before her death
was seized by tetanic convulsions of the most violent description.
The post-mortem examination showed that the internal para-
thyroids were atrophied, while the external parathyroids were
entirely destroyed.

The generally accepted view to-day (Pineles, v. Frankl-
Hochwart, Chvostek) is that all forms of clinical tetany are of
parathyroid origin.

OTHER PATHOLOGICAL CONDITIONS IN MAN
ARISING FROM DERANGEMENT OF THE FUNC-
TION OF THE PARATHYROID GLANDS.

H. Lundborg (1904) was the first to associate not tetany only,
but a number of pathological conditions included in the term
" motor-neuroses," with the function of the parathyroid glands.
He based his conclusions upon the results obtained by Vassale
and Generali, Biedl, Jeandelize in the tetania parathyropriva of
animals. According to his hypothesis, Myotonia congenita

Cretinism
endemic & sporadic

Myxoedema

«:
,o

Benign chronic

hypothyroid is m

(Hertoghe)

Goiire

Normal

thyroid

gland

Paralysis
agitans

Tetany

Normal

Parathyroid

glands

Myoc/onia

{Myoclonic

epilepsy)

Myotonia

Condition of
psychic exaltation

Graves' Myasthenia Myaton/a

disease pseudo-paralytics period/ca

t:

(Thomsen's disease), Parcilvsis agitans (Parkinsen's disease), and
myoclonia are to be regarded as chronic progressive conditions
due to hypoparathyroidism.

On the other 'hand, Myotonia periodica and Myasthenia
grams pseudoparalytica (Jolly), or Paralysis myasthenica (Oppen-
heim) are diseases which, Tike Graves's disease, arise from an
increased or disturbed function of the parathyroid glands (hyper-
parathyroidism or dysparathyroidism). Lundborg regards these

THE THYROID APPARATUS 47

glands as regulatory organs whose task it is to maintain the
balance of neuro-muscular activity. This view is illustrated by
the accompanying diagram, in which parallel conditions originat-
ing with the thyroid gland are also included.

Chvostek (1908) made a minute analysis of the clinical sym-
ptoms of Myasthenia gravis. He rejected the hypothesis that
this condition is primarily of nervous or muscular origin, and is
of the opinion that, in all essential points, myasthenia and tetany
are diametrically opposed. " They have the same relationship to
one another that the negative has to the photograph," and yet
they have certain points in common which make it impossible to
deny them a common origin. Chvostek believes that tetany is
produced by hypo-function of the parathyroids, while hyper- or
dysfunction gives rise to myasthenia. The originating cause of
this disturbance of function may lie in changes which take place
either within the gland itself, or in the centres or channels by
which its function is regulated. Thymus persistency, which so
frequently accompanies myasthenia, has no pathogenic signifi-
cance : it merely points' to the existence of a constitutional
anomaly, favourable to the manifestation of symptoms of func-
tional parathyroid derangement.

THE THERAPEUTICS OF TETAXIA PARA-

THYROPRIVA.

Once we are assured that tetany results from the suspension
of function of the parathyroid glands, the therapeutics of the
condition become much simplified. The object of any therapy
must be to restore to the organism the function of the gland which
has become incapacitated. The simplest method is by trans-
plantation, and before the parathyroid origin of tetany was
recognized, the condition was frequently treated by thyroid
transplantation. But the subjects of experiment were invariably
animals in wrhich, as we now know, the implantation of the
thyroid necessarily included the implantation of the parathyroids.

In 1884 Schiff succeeded in keeping a thyroidless dog alive for
some time by implanting fresh thyroid glands in the abdominal
cavity. V. Eiselsberg (1892) showed more positively that the
thyroid gland, when implanted in the abdominal fascia or in the
peritoneum of cats, healed in and prevented the occurrence of
tetany. When the healed-in tissue was removed, tetany followed
and the animal died.

Enderlen (1898) recognized the significance of the para-
thyroids and in the experiments which he carried out with clogs
and cats he found that these glands preserved their structure
after implantation better than the thyroid.

Following E. Payr's method with the thyroid, I have grafted

48 INTERNAL SECRETION

the parathyroids of dogs and cats in their spleen. I found that
the subsequent removal of the thyroids and inner parathyroids
was not attended by untoward results. Violent tetanic symptoms
sometimes appeared, but these were usually transient. These
animals may remain for months (a dog lived for eighteen months)
without symptoms, but they eventually die of tetany. This
applies also to animals in the spleen of which two to four para-
thyroids from other animals of the same species have been trans-
planted, their own thyroid being afterwards removed. Post-
mortem examination shows that only cicatricial tissue remains at
the implantation site, the grafted parathyroids being completely
absorbed.

In two experiments out of three carried out on young dogs
by Pfeiffer and Meyer, the parathyroids were successfully im-
planted in the rectus muscle, and tetany did not follow the
extirpation of the remaining portion of the thyroid apparatus.

Halstead, and later Hermann and Harvey, also described the
successful transplantation in dogs of both their own parathyroid
glands and those of other dogs. The latter authors are of
opinion that the visceral peritoneum is a more suitable site for
implantation than either the muscular structure or the spleen.

Walbaum (1903) found that after implantation of the external
parathyroids in the serous membrane of the stomach of rabbits,
the internal parathyroids being removed at the same time or later,
the animals lived from five to nine months. There was no tetany,
but there were trophic derangements, such as dermatitis, emacia-
tion, and arrest of growth, which in the end caused death. The
grafted organs generally retained their normal histological
character for a certain length of time, showing few and in-
considerable changes. Christiani, who since the beginning of
the nineties has carried out many hundreds of greffcs
thyroidiennes and parathyroidiennes with rats, finds that the
structure of the implanted glands remains unchanged, though
they at first show a slight central necrosis which is, however,
soon replaced by normal tissue. After two years in rats, and
after even five years in cats, the glands will be found to be-
practically unchanged.

Camus found that the parathyroid glands, when transplanted
into the ear of rabbits, invariably atrophied if a sufficiency of active
parathyroid tissue was allowed to remain in situ.

Leischner implanted the parathyroids of rats, with a portion
of the thyroid tissue attached, in the abdominal wall. The
simultaneous transplantation of both parathyroids provoked a
passing tetany. The grafted organs healed in and, one to two
months later, the removal of the abdominal rectus muscle in
which they were implanted, produced tetany.

These experiments show that transplanted glands, whether
of the subject of the experiment or of another animal of the same

THE THYROID APPARATUS 49-

species, will not only heal into place, but will prevent the appear-
ance of symptoms of suppression of the glands. The grafted
organs undoubtedly retain their normal structure for some time,
but after a few months retrogressive changes usually set in which
lead, in time, to the disappearance of the organ.

The transplantation of a parathyroid gland has been success-
fully performed in man by v. Eiselsberg. The patient was a
woman aged 42 who, twenty-seven years previously, had had
the whole of her thyroid removed and was suffering from tetany.
A parathyroid gland was implanted in the abdominal rectus
muscle. This gland was taken from a woman who had had a
cyst enucleated from one lobe of the thyroid gland, and in whom
the other parathyroids were intact. The transplanted gland
healed in, the tetany became reduced to isolated spasms of the
glottis, and the sensibility to electric stimulus became normal.

The results of this experiment naturally suggested a sub-
stitution therapy by means of organic extracts.

Experiments by parathyroid extract with man as the subject
have been repeatedly carried out. Some authors, especially those
who employed Vassale's so-called parathyroidin, obtained good
results; others (v. Frankl-Hochwart, Escherich, Reinsberg and
Rey) were unsuccessful. Pineles treated three cases of tetany
with 0.15 to 0.45 grm. (about 2\ to 7 gr.) of dried para-
thyroid substance daily, and continued the treatment for months,
but he was unable to report any change in either the frequency
or the intensity of the seizures.

Quite recently Halstead (1907) and Putman (1909) described
favourable results obtained in post-operative tetany with the
parathyroid extract prepared by Berkeley of New York. When
given by the mouth, or, better still, by subcutaneous injection,
these nucleo-proteids are said immediately to subdue all symptoms
of tetany.

J. Ott (1909) describes the physiological activity of this
substance as well as that of the watery extracts of parathyroid
gland. These substances increase intestinal peristalsis and the
muscular contractions of the uterus. When injected in small
doses into the veins of cats and rabbits, they produce a fall, which
is followed by a rise, in the blood-pressure. In large doses they
bring about a fall in blood-pressure unaccompanied by any change
in the frequency of the pulse; there is a slight reduction in
temperature, with slightly accelerated respiration. But the most
marked symptom is the extraordinary increase in diuresis, which
may rise to ten times the normal, and is due to stimulation of
the epithelial cells of the kidneys.

It will be evident from what has gone before that the thyroid
preparations play an important part in the management of post-
operative tetany, whether therapeutically in man or experimentally
in animals. At a first glance, it seems reasonable to suppose

4

50 INTERNAL SECRETION

that the beneficial results of thyroid administration are due to
the fact that parathyroid tissue is given at the same time ; experi-
ments by Pineles have, however, shown this view to be untenable.
He found that the amount of parathyroid substance contained
in the thyroid glands of sheep and calves is by weight i in 309
and 379 respectively; while 200 times that amount of parathyroid
substance, when added to thyroid tabloids, had no therapeutic
effect whatsoever.

There are numerous accounts by reliable observers of the
favourable effects of thyroid gland and thyroid extracts in the
tetania parathyropriva of animals.

Kocher, the greatest authority upon the parallel condition in
man, wrote in 1906, at a time, therefore, when the significance
of the parathyroids in post-operative tetany was well known to
him, as follows :-

" We found that by energetically pushing the thyroid extract
and iodothyrin in large doses, we were able to procure a rapid
abatement of the symptoms of tetany and, by continuing the
treatment over long periods, we obtained a cessation of the
attacks."

The favourable influence of the thyroid extracts in post-
operative tetany will not be questioned by those who have wit-
nessed the remarkable improvement which takes place, almost
immediately, after the subcutaneous injection of soluble thyroid
preparation, in the condition of animals with severe tetanic
symptoms ; or that which, after one to two hours, follows the
administration by the mouth of fresh or dried thyroid gland.
Nor will the efficacy of these substances be held in doubt by
anyone who has, by this means, kept animals alive for two to
three weeks after parathyroidectomy, while the animals not so
treated died of tetany in a very much shorter time.

But these results must not be accepted without criticism. It
must always be taken into consideration that the clinical picture
produced by experimental tetany is in the highest degree variable ;
that spontaneous remissions and far-reaching improvements are
of as frequent occurrence as sudden relapses, and that in certain
cases this renders the prognosis extremely difficult. The sudden
termination of a tetanic seizure, the cessation of the muscular
tremors, and even the temporary disappearance of the nervous
hypersensibility, cannot always be taken as evidence in favour
of the treatment, for all this may, in rare cases, occur spon-
taneously.

It is an important point in favour of thyroid extract that
improvement follows rapidly upon treatment, and that the life
of tetanic animals is very much prolonged by its use. Vassale
tries to explain the results of thyroid treatment in tetany by the
presence of supernumerary parathyroid glands, which are sup-
posed to exercise the same effect as the implanted glands or those

THE THYROID APPARATUS 5!

purposely left in situ. It seems, however, highly improbable
that accessory glands should be present in just those cases which
have been treated by thyroid extract, especially as such super-
numerary bodies are extremly rare in certain species, such as
the cat. But even allowing that there is some foundation for
Vassale's assumption, a certain measure of efficacy must be
granted to the thyroid extract, for it is undoubtedly the agent
by which the animals are carried through a phase of disease in
which they would otherwise certainly perish.

With so little knowledge at our disposal we are not in a
position to give any definite explanation of the effects of the
thyroid preparations in tetany, but I do not think this should
prevent us from drawing from the analogy of experimental
pathology a conclusion which is of the utmost importance to man.
It is, that treatment with thyroid gland should always be tried
where the extirpation of goitre is followed by symptoms of
tetany. By this means time is gained, during which the para-
thyroids and any accessory parathyroids are enabled to attain
the full measure of their functional activity; or a substitute for
such activity may be provided by means of transplantation.

»

THE RELATIONSHIP BETWEEN THE THYROID AND
PARATHYROID GLANDS.

Gley's view that the parathyroids are embryonal organs
which, after the removal of the thyroid gland, assume the function
of the principal organ, and thereupon acquire the structural
characteristics of thyroid tissue, has not been endorsed by later
authors. His discovery that, after the removal of the thyroid
and inner parathyroids, the external parathyroids became
hypertrophied, is confirmed by many, but no proof is forthcoming
of a histological structural transformation of parathyroid tissue
into thyroid tissue. Gley himself, in combination with Nicolas,
has recently repeated his experiments, and has been compelled to
abandon his former view. Vincent and Jolly describe such
structural transformation of the parathyroids in cats, but they
are alone in their experience.

Quite recently Vincent, Halpenny and Thompson found that
the external parathyroids of a dog from which the thyroid and
internal parathyroids had been removed eighty-three days
previously, wrere hypertrophied and changed in such a manner
that it was difficult to distinguish them from thyroid tissue. In
addition to parathyroid tissue composed of compact rows of cells,
the drawings of these organs show numerous irregular vesicles,
lined with a single layer of epithelial cells, in part empty and
in part filled with colloid. The histological picture of these
glands has a strong resemblance to that of a thyroid which the

52 INTERNAL SECRETION

authors found in a dog thirty days after total parathyroidectomy.
This gland also contained irregular vesicles, together with an
increase in the quantity of intravesicular tissue. The clinical
course of this experiment is interesting. After removal of the
last hypertrophied parathyroid gland, the animal lived for forty-
four days ; it did not show any symptoms of tetany, but there
were trophic disturbances, such as falling of the hair, eczema
and idiocy. It is probable that this animal possessed accessory
parathyroid glands.

The occasional occurrence of gland-like hollow spaces in the
parathyroids has been frequently described. These hollows are
lined with epithelium ; they are sometimes empty and sometimes
filled with a homogeneous mass believed to be colloid.

I have found in numerous cases that removal of the thyroid,
together with the internal parathyroids, is nearly always followed
by hypertrophy of the external parathyroids. The hypertrophy is
more or less clearly marked according to the length of time
after operation. Many authors (Walbaum, Erdheim, Pepere) have
failed to observe an appreciable increase in the volume of the
parathyroids embedded in the thyroid, after extirpation of the
two external glands. But Haberfeld and Schilder have recently
shown that the internal parathyroid glands of rabbits show a
very high degree of vicarious hypertrophy if, in addition to the
external parathyroids, the accessory glands situated in the thymus
are also removed.

I found that the parathyroids of a growing dog, from which
the thyroid had been removed, were at the end of a year twice as
large as those of control animals taken from the same litter.
Hypertrophy of the parathyroids is by no means always
associated with important structural changes, although gland-like
hollows filled with colloid are of decidedly more frequent
occurrence in hypertrophied than in normal parathyroid glands.
Whether or not this colloid formation is a compensatory secretory
process which is set up in the gland after the suppression of the
thyroid, is at present unknown. It suggests, however, that there
may be a functional relationship between the two organs.

That there is a relationship between the thyroid and the
parathyroid glands is suggested by the fact that hypertrophy of
the thyroid gland has been frequently (W. Edmunds, Lusena,
Vassale and Generali, Halpenny, and Thompson) observed after
removal of the parathyroids. The tissue changes in these
hypertrophied organs consist in a new formation of intravesicular
tissue, which either forms solid cell rows or causes irregularity irr
the shape of the follicles. There is also a wasting away of the
colloid, together with vacuolization of the contents of the follicles^

These changes are difficult of interpretation, but the examina-
tion of a large number of thyroids shows that many apparently
normal glands present a similar picture. Vassale thinks that

THE THYROID APPARATUS 53

the new formation of tissue points to a hyper-function of the
gland, the wasting of the colloid to a hypo-function. If this
view is correct the same operation, namely, the removal of the
parathyroids, is able to produce conditions in the thyroid which
are opposed to one another.

There are three directions, then, in which the evidence of
a functional relationship between the thyroid and the parathyroid
glands may be regarded as conclusive. In the first place, there
is the favourable "influence of thyroid treatment in the tetania
parathyropriva of animals. In the second place we have certain
proof of hypertrophy of the external parathyroids after extirpa-
tion of the thyroid gland. And in the third place, there is the
hypertrophy of the thyroid gland, described by many authors,
which follows the removal of the parathyroids. These facts do
not, however, supply any definitive information concerning the
manner in \vhich this interrelationship is effected.

Vassale and Generali advanced the theory that toxic products
of metabolism are formed by the thyroid, and that these become
neutralized by the activity of the parathyroids. They based their
theory upon the fact that after parathyroidectomy the symptoms
are much more acute, the condition runs a more violent course,
and that death follows far more rapidly than after extirpation
of the entire thyroid apparatus. In the latter case, according to
this theory, both the toxin-forming and toxin-neutralizing agents
are removed. The explanation, however, can hardly be con-
sidered satisfactory. In the first place, it offers no solution of
the problem as to why animals from which the whole of the
thyroid apparatus has been removed, should yet develop fatal
tetany, seeing that the toxic agent is supposed no longer to be
present. In the second place, I was unable, in spite of repeated
experiments, to obtain any confirmation of the results described
by Vassale and Generali. I could not find any difference in the
intensity of the tetanic seizures, nor could I discover that animals
from which the thyroid apparatus had been removed in toto,
lived longer than those from which the parathyroids only had
been removed. Everyone who has had experience of post-
operative tetany knows how the clinical picture varies in regard
to intensity and duration, and will be careful how he allows these
factors to influence his conclusions in regard to the functional
relationship between the thyroid and parathyroid glands.

What then is the inference which we may safely draw from
the results of these experiments ? First, that the hypertrophy of
the one group of organs after removal of the other is to be
regarded, upon general pathological grounds, as compensatory ;
and second, that a vicarious activity of the thyroid and para-
thyroids is to be assumed.

It is remarkable that Rudinger employs these facts to support
a theory of antagonism between the thyroid and parathyroid

54 INTERNAL SECRETION

glands. He thinks that the hypertrophy of the parathyroids
which follows thyroidectomy is due to the fact that an antagonistic
organ has been removed. He remarks : " We have to suppose
that, under normal conditions, the function of the one gland is
controlled by the other, and that when this balance is disturbed
by the extirpation of one, the remaining organ becomes func-
tionally, and later organically, hypertrophied." Rudinger brings
the following as evidence in support of this theory : Moussu and
Charrin found that the exhibition of the parathyroid gland of
horses was followed by unfavourable symptoms in myxoedema, but
that in Graves's disease it had a very beneficial effect. Rudinger
believes that the hyper-function of the thyroid in Graves's disease
is restrained by the exhibition of parathyroid gland, while in
myxcedema the hypo-function is intensified. He is also inclined,
with Walbaum, to attribute the favourable action of Moebius's
serum and of rhodagen — a preparation obtained from the milk
of thyroidless goats — to the presence of a large proportion of
parathyroid secretion. " The removal of the thyroid permits of
an increased activity on the part of the parathyroids ; thus the
serum and the milk contain substances which, being stronger
than those in normal serum and milk, are better able to counteract
the activity of the thyroid gland." Rudinger also brings forward
the results obtained by Eppinger, Falta and Rudinger in their
investigation of the interrelationships which subsist between the
different glands possessing internal secretory functions. These
authors found that the effects of adrenalin upon dogs from which
the entire thyroid apparatus had been removed, differed markedly
from those which it exercised upon dogs in which the thyroid
gland only was lacking. After thyroidectomy, the subcutaneous
or intraperitoneal injection of adrenalin did not, as it invariably
does in normal animals, produce glycosuria, and the intravenous
injection of adrenalin was not followed by a rise of blood-pressure.
But in animals with tetany after thyroparathyroidectomy, the
same experiments provoked both the glycosuria and the rise in
blood-pressure. From these results the observers infer that the
thyroid secretion stimulates the sympathetic nerve, while that of
the parathyroids has an inhibitory effect upon it. Stimulation and
inhibition are so balanced by the activity of the two glands that,
under normal conditions, oscillation is possible within a very small
margin only. The suppression of the thyroid reduces the irrit-
ability of the sympathetic nerve, not only by robbing it of its
stimulating agent, but by releasing the inhibitory activity of the
parathyroid glands. With the extirpation of the parathyroids, the
inhibitory agent is removed and this brings in its train a con-
dition of hypersensibility of the sympathetic nerve.

The evidence which Rudinger advances cannot be regarded
as a sufficient basis for his theory. The interrelationships between
the thyroid and parathyroid glands, and between the pancreas

THE THYROID APPARATUS 55

and the chromaffine tissue will be discussed in a later chapter.
The most important point in favour of the theory of antagonism,
is that provided by the hypertrophy of the thyroid and para-
thyroid glands, which is provoked in each by the suppression of
the other. But it must be borne in mind that anatomical hyper-
trophy is the result of functional hypertrophy; and that the hyper-
trophy of an organ can be ascribed to the suppression of its
antagonist, only where evidence is forthcoming of the manner in
which the one organ is excited to functional hyperactivity by
the suppression of another, the normal function of which is
antagonistic to it. A correlative hypertrophy of antagonistic
organs is, so far, unknown to us, and such a state of matters
does not seem very probable.

Rudinger himself points out that the well-known variation
in intensity of the symptoms in Graves's disease makes it very
difficult to estimate exactly the beneficial effects of any therapy.
This does not enhance the value of Mossu and Charrin's experi-
ments and of the experiments with Moebius's serum, as evidence
in support of Rudinger's theory. And it has been shown, more-
over, that there is no proof of the difference, described by Vassale
and Generali, between the clinical picture presented by tetany in
animals in which the thyroid is intact, and that presented by the
condition in animals which have undergone thyroidectomy.

The inevitable conclusion is, then, that a hypothesis of func-
tional antagonism between the thyroid and parathyroid glands, is
not supported by the evidence at our disposal.

THE FUNCTION OF THE PARATHYROID GLANDS.

THE TETANY TOXIN.

The first attempt to account for the tetany which follows
parathyroidectomy was the neutralization theory advanced by
Vassale and Generali. We have seen that these authors regarded
the thyroid as the organ in which the toxin was elaborated and
that, in its original form, their doctrine was untenable. Later
authors (Pineles, Pfeiffer and Meyer), however, are agreed that
a poisonous substance, the tetany toxin, is elaborated within the
organism, but that its exact source is unknown.

Pfeiffer and Meyer endeavoured to demonstrate the presence
of this toxin in the blood of animals suffering from tetany. They
found that blood taken from dogs dying of tetany had a more
marked hasmolytic effect upon the blood corpuscles of guinea-pigs
than the blood of normal dogs. The observers do not attach any
particular significance to this result. On the other hand, they
emphasize the fact that the serum of tetanic dogs (in six out of
seventeen examined) was toxic to mice which had undergone
partial parathyroidectomy, causing tetany which, in some cases,

56 INTERNAL SECRETION

terminated fatally. They conclude from this that tetany causes
a specific toxin of uniform activity to accumulate in the serum, and
that this toxin does not pass into the urine. Seeing that latent
tetany is produced by partial parathyroidectomy and that tetanic
symptoms are occasioned by many poisons, this assumption
cannot be regarded as having any very great value.

I have repeatedly found in the course of my own experiments
that violent tetanic attacks are arrested by copious blood-letting
and that the improvement may be maintained for as long as
twenty-four hours by the transfusion of fresh blood into the veins.
This seems to point — and far more conclusively than do the results
obtained by Pfeiffer and Meyer — to the presence of a toxin, cir-
culating in the blood, from which the organism may be tem-
porarily freed by bleeding.

Ceni and Besta assumed that the toxin of tetany was of the
nature of an antigen, and they endeavoured to obtain specific
antibodies with which to treat the acute symptoms which follow
thyroparathyroidectomy. They immunized rabbits and goats with
serum obtained, at the height of an acute tetanic seizure, from
dogs deprived of the entire thyroid apparatus. The immune
serum they injected in doses of 9 to 15 c.cm. into dogs which had
undergone thyroparathyroidectomy and which showed severe
tetanic symptoms. They found that, although the course of the
condition was as a whole very little affected, there was a rapid,
and sometimes a complete, cessation of the acute phenomena in
nearly all their cases. The authors lay stress upon the fact that
the effects which they obtained with the immune serum are much
more energetic, prompt and complete than those obtained by
Gley with antipyrin, by Ughetti with chloral-hydrate, or by
Canizzaro with bromide of potassium. But they were not able
by means of the serum to produce a modification of the disease
and a prolongation of life, such as that which follows the
exhibition of thyroid gland.

The suggestion that parathyroid tetany is due to the agency
of a toxic product of metabolism, was recently put forward by
Berkeley and Beebe. They believe that the toxin is formed by
the decomposition of albumin, for they found that with an ex-
clusively flesh diet, the symptoms were more violent and there
was a marked increase in the excretion of ammonia. They also
found that the symptoms provoked by the injection of ammonia
or xanthin, like those of tetania parathyropriva, are arrested by
the exhibition of calcium or strontium salts.

Frouin found that the urine of animals from which the
thyroid and parathyroids had been removed, contained an excess
of ammonia and carbamic acid. He regards tetany as the result
of carbamic-acid poisoning. He produced a typical tetany in from
twenty-four to forty-eight hours after removal of the entire thyroid
apparatus, by the exhibition of 3-4 grammes of carbamate of

THE THYROID APPARATUS 57

soda. When the same subjects were treated with this salt in
combination with a soluble calcium salt, symptoms of tetany did
not follow.

THE PARATHYROID GLANDS AND THE
METABOLISM OF CALCIUM.

In the first part of this book reference \vas made to J. Loeb's
discoveries in connection with the physiological significance of
the kathions, especially of the effect which calcium salts have in
reducing neuro-muscular irritability. These discoveries have
some bearing upon the pathogenic aspects of tetany and they
have led the way to other experiments, undertaken with the object
of determining the connection between the parathyroid glands and
the metabolism of calcium. Quest (1905) induced a condition of
electric hypersensibility of the peripheral nerves in young dogs,
by means of a diet from which lime was excluded. He attributed
a genetic significance in infantile tetany to the scarcity of calcium
in the organism, and his view is confirmed by the fact that the
brains of children who die of tetany contain a smaller proportion
of calcium than those of normal children. Oddo and Sarles found
that the urine of tetanous children contained an increased amount
of calcium salts. Quest's results, however, were not confirmed by
those of either M. Cohn, or Leopold and v. Reuss.

Netter found that the convulsions of infantile tetany were
favourably influenced by the exhibition of calcium chloride, but
Stoeltzner obtained only an increased sensibility to electric
stimulus by this means. Unlike Quest, Stoeltzner explains the
spasmophilia as the result of calcium poisoning. He assumes
that the galvanic irritability of the peripheral nerves depends on
the calcium concentration in the tissues, and believes that an
excess of calcium inhibits convulsions.

The relationship which the quantity of calcium in the urine
and faeces bears to the general metabolism of calcium, has also
formed the subject of investigation. Experiments conducted with
dogs suffering from tetany, and similar clinical experiments, have
not, however, yielded conclusive results. Czybulski found that,
in a child of 7 months with tetanic symptoms, there was a far
smaller retention of calcium at the time of the seizures than in
the intervals between the attacks. In dogs from which the para-
thyroids had been removed and which were either starved or
kept on a uniform diet, MacCallum and Vogtlin found a con-
spicuous increase in the amount of calcium in the urine and faeces
as compared with the control animal. V. Reuss and Welde found
that, after partial parathyroidectomy, a dog showed increased
retention of calcium.

The contradictory nature of these results induced v. Reuss
and Leopold to try other methods to obtain more definite data

58 INTERNAL SECRETION

concerning the metabolism of lime. They investigated the entire
amount of lime, in both normal rats and those which had been
deprived of the parathyroid glands. The latter showed no change
which could be described as abnormal and there was certainly no
reduction in the quantity of excreted lime. They found, however,
that in young growing rats afflicted with tetany, the entire amount
of lime was less than in normal rats; moreover, the proportion
of lime in the bones to that in the soft parts, was invariably lowrer
than in the control animal. The soft parts contained more lime,
the bones less, and this finding is in accordance with the histo-
logical changes in the bones and the teeth.

As a matter of fact, a knowledge of the total amount of
calcium does little to furnish a solution of the problem, for it
supplies no information as to the amount of physiologically active
free kathions. Leopold and v. Reuss think that the results of
their experiments justify them in the belief that the amount of
active calcium in the organism is reduced in tetany. This might
occur as the result of the activity of the tetany toxin in pre-
cipitating calcium ; while at the same time the passive calcium
of the soft parts, which is ultimately excreted, is not only not
reduced but, by means of food rich in lime, may even be in-
creased.

The relationship between tetany and the metabolism of cal-
cium, though not as yet fully understood, forms the basis of
the therapeutic treatment of tetany by means of calcium salts.
MacCallum and Vogtlin found that the administration of a 5
per cent, solution of calcium acetate and calcium lactate, whether
by the mouth or by intravenous or subcutaneous injection, to
dogs from which the parathyroids had been removed, was followed
by disappearance of the tetanic symptoms. The improvement
lasted twenty-four hours ; the convulsions then recurred, but these
were again subdued by a repetition of the treatment. Similar
results were obtained with magnesium salts, but in this case the
therapeutic effects were obscured by the anaesthetic toxic by-
effects. Calcium salts increased the tetanic symptoms, but these
were reduced by the exhibition of larger doses. MacCallum and
Vogtlin are of the opinion that, taken in conjunction with their
discoveries regarding the excretion of calcium, these therapeutic
results point to an activity on the part of the parathyroid glands
in controlling the metabolism of calcium. They believe that, after
removal of the parathyroids, active calcium is withdrawn from
the tissues and that there is, in all probability, an imperfect
absorption and assimilation of calcium. Suppression of the
calcium-ions causes muscular convulsion similar to that produced
in normal animals bv Loeb and MacCallum bv the administration

»• •P'

of oxalates which, in combination with calcium, form insoluble
precipitates. In these cases also, the tetanic symptoms disappear
after the administration of fresh soluble calcium salts.

THE THYROID APPARATUS 59

The results obtained by Parhon and Urechie, Berkeley and
Beebe, and Bell and Martin, Ott, and by my own researches,
furnish unquestionable proof of the susceptibility of tetany to the
therapeutic influence of calcium salts. Slight, and even more
severe, attacks are very much ameliorated by the exhibition of
these salts, the symptoms sometimes disappearing altogether.
After eighteen to twenty-four hours, the symptoms return in
their former intensity. I did not find that the daily administra-
tion of calcium salts had any effect in prolonging the life of cats
from which the thyroid and parathyroids had been removed. It
must, however, be borne in mind that our knowledge of the
therapeutic effects of calcium salts in tetania parathyropriva does
not justify us in forming a definite conclusion with regard to the
pathogenetic significance of these salts. It appears very probable
that the calcium salts exercise an inhibitory effect upon the patho-
logical muscular convulsions, similar to that which they exercise
upon all forms of muscular contraction. This applies to the other
kathions (magnesium, barium, strontium), which also exercise a
favourable influence upon tetanic convulsions.

THE POINT OF ATTACK OF THE HYPOTHETICAL

TETANY TOXIN.

The first experiments with the object of localizing the seat
of tetany were carried out by O. Lanz in Horsley's laboratory.
Similar investigations have recently been undertaken by Mac-
Callum, by Falta and Rudinger, and by Biedl. The results are
as follows : —

If, after parathyroidectomy, the nerve of one of the extremi-
ties is severed, no convulsion will take place in that limb. If
the nerve is resected at a moment when the whole body is con-
vulsed with tetany, the muscular contractions of that limb will
cease, and the hypersensibility of the nerve will rapidly disappear.
Pressure upon a nerve which has been severed some hours pre-
viously, will not produce a muscular contraction ; also, the nerve
is insensitive to galvanic stimulus. I have confirmed these
results by repeated experiment, but the findings do not agree with
those obtained by Falta and Rudinger. These observers severed
the sciatic nerve after the appearance of tetany; they found that
the electric hypersensibility persisted for several days and that the
normal irritability of the nerve persisted until the death of the
animal, which occurred nine days later. This discrepancy in
the findings is probably explained by the fact that in each case
I severed the whole of the nerve plexus of the front extremity,
while Falta and Rudinger severed the sciatic nerve only. The
resection of the sciatic nerve alone is not sufficient to arrest the
muscular contractions in the limb, and MacCailum for this reason

6O INTERNAL SECRETION

severed also the anterior crural nerve and the obturator nerve.
Moreover, if the sciatic nerve is not divided high up, at the place
where the plexus emerges from the pelvis, communication with
the centre is not entirely cut oft", and hence the persistence of
the nervous irritability. In view of this fact, the explanation
given by the authors appears superfluous. This explanation is
that the increased excitement in tetany is due to the continued
abnormal loading of the entire neuron from the trophic centre
(the ganglion cell of the anterior cornu) with a substance, at
present unknown and not definable ; and that this substance re-
mains for a time in the peripheral portion of the severed nerve.

The relationship of tetany to the spinal cord is best studied
in animals in which the cord is severed at the sixth or eighth
dorsal vertebra. The parathyroids may be removed at the same
time, or subjects with tetany may be employed; the results in
either case will be identical. After resection of the cord, there
will be complete flaccid paralysis of the hinder part of the body
with, at first, normal or exaggerated reflexes. If tetanic move-
ments either remain or reappear, the whole of the paralysed
portion of the body will show, in addition to slight fibrillary
contraction, rapid, lightning-like spasms of large muscular areas,
which resemble voluntary movements. It as an extraordinary
thing to see the paralysed hinder extremities contract so rapidly
and so violently that they appear to make running movements.
But there is a marked difference between the behaviour of the
fore and hinder parts of the body and this becomes particularly
suggestive as the muscular spasms work up to the height of a
tetanic seizure. The fore part of the body is affected with violent
clonic muscular contractions which are interrupted by tonic con-
tractions, the muscles being rigid in the intervals. The hinder
part of the body is much less affected. The muscles are relaxed,
there are fibrillary tremors, and single coarser lightning con-
tractions; movements resembling running movements occur, but
there is no trace of tonic rigidity. From these results it appears
highly improbable that the seat of the tetanic changes is in the
ganglion cells of the anterior cornua. MacCallum thinks that the
site of hyper-irritation is in the higher motor neuron, probably
just below the cortex.

Not enough attention has been given to the part played in
tetany by the higher portions of the brain, the cerebrum and
cerebellum. Horsley and Lanz are frequently cited as having
proved that extirpation of the motor areas of the cortex of one
side does not affect tetany of the other. But if the subjects are
closely watched, it will be seen that the half of the body which
has lost its motor centre is affected much more intensely than
the other, and that during the tetanic seizures the tonic muscular
rigidity of this side is very pronounced. During remission, on
the other hand, whether spontaneous or, as in my experiments,

THE THYROID APPARATUS 6 1

effected by means of thyroid extract, the hemiparesis, both in
dogs and cats, is far more pronounced than that usually seen after
extirpation of the cortical areas, where this is unaccompanied by
thyroidectomy. In one case extirpation of the cortical layer of
one side of the cerebellum of a cat, was followed by a distinct
increase in the tetanic symptoms of the same side of the body.
Some years ago, Lanz described a similar but " not entirely
conclusive result." He points out that the remarkable disturb-
ance of equilibrium and the staggering walk of many thyroidless
dogs, suggest that a portion of the cerebellum is concerned in
the causation of tetany. Lanz believes that his experiments point
to the medulla oblongata as the chief seat of tetany, but that
the higher centres also exercise an influence upon the contractions.

All attempts to localize the site of tetany have not, as yet,
led to any satisfactory solution of the problem. Rudinger's con-
tention that the condition of hyperirritability arises in the ganglion
cells of the anterior cornua, if not in the entire peripheral neuron,
did not survive the test of experiment. In a later publication by
Falta and Rudinger, the theory is modified to this extent, that
the condition of hypersensibility is attributed to the sensory and
motor ganglion cells, more particularly those of the peripheral
nerves. The authors suggest that the hyperirritability after para-
thyroidectomy arises from the suppression of the inhibition which,
under normal conditions, is conveyed from the parathyroids to
the spinal cord. Hence, " the continued storing of fresh energy
in the motor ganglion cells leads eventually to an overflow of
irritability, and this constitutes a tetanic attack."

This complicated hypothesis derives its sole support from
the fact that adrenalin glycosuria reappears in dogs from which
both the thyroid and the parathyroids have been removed; the
inference being that the parathyroids exercise an inhibitory effect
upon the sympathetic nerve. The theory cannot be said to have
stood the test of experiment, and it does not in any way add
to our understanding of the symptoms which follow cerebral
lesions and the resection of the spinal cord. These symptoms
point to the involvement of other and higher nerve centres in
the genesis of tetany, though they do not explain the manner
in which the intervention of the higher portions of the brain
takes place. The pathologico-histological findings, described by
MacCallum, in the central nervous system of tetanous animals,
which consisted in acute degenerative changes such as swelling
of the nuclei of the cells of the anterior cornua and chromatolysis
in the cortical cells, also point to the involvement of the central
nervous system.

In the present imperfect state of our knowledge of tetany,
all that we can do is to point to the increased irritability of the
nervous centres and of the peripheral nerves connected with them,
together with the spasmophilia to which this irritability gives

62 INTERNAL SECRETION

rise as the characteristic features of the condition ; but we are
not in a position to define either the exact anatomical seat of
tetany, nor indeed the nature of the tetanic changes. One thing
only can be affirmed with certainty, and that is, that the affection
of the muscles is not myopathic in origin.

PHYSIOLOGY OF THE THYROID GLAND.

EXPERIMENTAL EXTIRPATION.

A certain amount of light is thrown upon the functional
significance of the thyroid gland by the results which follow its
extirpation. It will be clear from what has gone before that,
before the function of the parathyroid glands was understood,
experimental extirpation of the thyroid could be of value in the
case of those animals only in which removal of the thyroid did
not necessarily include removal of the parathyroids. Hence, the
only results of any value were those obtained exclusively with
the herbivoras. As a matter of fact, it is only the more recent
experiments, those in which the parathyroids have been purposely
spared, which can be regarded as a rational basis for the investi-
gation of the phenomena associated with the thyroid gland. This
applies more particularly to the investigation of the pathogenesis
of those symptoms which characterize the suppression of the
parathyroid, as well as of the thyroid, glands.

The results of thyrotoxic serum in the thyroid disturbance
have been investigated by various authors (Gontscharnkoff,
Mankowsky, Yates, MacCallum, Portis, Demoor and van Lint,
Liithke, Slatineano), but with very partial success. Several of
these describe a condition resembling cachexia thyropriva, but
in the greater number of instances the symptoms are those of
acute tetania parathyropriva. Slatineano found that, in addition
to its haemolytic action, thyrotoxic serum exercises a specific and
very decided influence upon the thyroid. In small doses, it acts
as a stimulant and promotes the secretion of colloid; after larger
doses, the colloid diminishes and there is hypertrophy of the
epithelial cells of the follicles, followed by acute degeneration
of these cells and their rapid destruction. Portis found that
the exhibition of thyrotoxic serum was followed by degeneration,
not of the thyroid only, but of the liver, spleen and kidneys.
Marchetti's finding, that the blood of patients with thyroid
affections gives a precipitation with thyrotoxic serum from
rabbits, was not confirmed by Schutze.

.Both the recognition of the symptoms of suppression and the
estimation of their pathological significance are influenced by
one very important factor. It must always be remembered that
accessory glands, distinct from the principal organ and situated

THE THYROID APPARATUS 63

at a greater or less distance from it, are of by no means rare
occurrence. Many animals, especially dogs, are not necessarily
thyroidless because the thyroid gland has been removed from
the neck. After thyroidectomy, cases such as these frequently
show only passing symptoms of suppression, or the signs may
be absent altogether.

There is a certain amount of difference between the signs of
thyroid suppression in young growing animals and in adults.
This difference does not affect the essential character of the
changes, the so-called athyrosis, which always involves the
metabolic processes of the entire organism. In the case of young
individuals, however, the derangement of metabolism is mani-
fested with peculiar distinctness in the changes which take place
in the processes of growth.

Hofmeister (1892) found that the extirpation of the thyroid of
young rabbits, the external parathyroids being left in situ, was
followed by a retardation of growth and the development of a
condition of chronic cachexia.

Further experiment showed that the arrest of growth was
due to a remarkable retardation of the process of ossification,
both of the epiphyses and of the synchondroses. The long
bones, the pelvis and the vertebral column, showed the greatest
departure from the normal, the skull the least. The growth of
the long bones was retarded to the extent of at least a third of
their proper length, and microscopic examination of the epiphysial
line showed specific degeneration, consisting in a reduction of
normal cell proliferation, combined with vesicular swelling of
the cartilage lacunas and shrinkage, or even partial destruction,
of the cells.

In the internal organs, Hofmeister found a condition similar
to that described by Rogowitsch in the case of adult rabbits,
namely, enlargement of the glandular portion of the hypophysis
cerebri, and the appearance of large vacuoles in the protoplasm
of the enlarged principal cells. Moreover, he observed a similar
formation of vacuoles, together with degenerative changes, in
the epithelial cells of the looped uriniferous tubules. The con-
dition of the organs of generation was particularly striking. In
addition to degenerative changes, the ovaries invariably showed
premature maturity of many of the follicles. Jeandelize dis-
covered later that, in male animals, there is imperfect development
of the testicles.

v. Eiselsberg found that in sheep whose thyroids had been
removed at the age of ten days, there was conspicuous retardation
of growth and a change in the mental condition, which forcibly
suggested the idiocy of cretinism. Post-mortem examination
showed that, in addition to a high degree of derangement of the
processes of skeletal growth, there was widespread atheromatous
degeneration in the aorta. The intima was covered with very

64 INTERNAL SECRETION

I

hard, smooth, white plates which, under the microscope, showed
either calcification or fatty degeneration. The testicles were very
small.

In goats, operated on three weeks after birth, the same author
was able to observe a difference in growth in comparison with
the control animal as early as one month after operation. At the
end of four months, the thyroidectomized goat was half the weight
of the control animal. In addition to shortening of the bones
of the extremities, there was marked shortening of the frontal
part of the head, the occipital part appearing exaggerated by
comparison. There were also remarkable changes in the growth
of the hair. The thyroidectomized sheep had poor fleece and
the fur of the young rabbits was scanty, but in the young goats
there was a conspicuous increase in the growth of the hair, and the
long hairs could be pulled out in handfuls. The horns, however,
of both sheep and goats, were equally stunted in growth. There
was also meteoristic swelling of the abdomen, reduction of
temperature, and arrested development of the sexual glands.
Both the general apathy and the atheromatous degeneration of
the aorta were very marked in goats. Pick and Pineles found
pronounced sclerotic changes in the aorta and enlargement of the
suprarenals of two goats, from which the thyroid had been
removed at the age of 6-10 weeks, one of which had been treated
with iodothyrin. In a pig which had been thyroidectomized at the
age of 4 weeks, v. Eiselsberg found that there was marked
arrestation of growth unaccompanied, however, by apathetic
idiocy, the animal being as lively as normal animals.

In pigs, which had been thyroidectomized at the age of a
few weeks, Moussu saw a condition several weeks later, which
closely resembled myxcedema. There was swelling of the
abdomen and formation of infiltrated cutaneous folds; the skin
became bald in places and, in others, was covered wTith remarkably
long and thick bristles; there was also arrestation of growth.

The infantilism, the imperfect activity of the sexual glands
and the general torpor, are very apparent after thyroidectomy in
hens. Lanz found that such birds lay very few eggs and that
these are abnormally small and covered with a very thin shell.
The laying capacity may be increased by feeding with thyroid
gland.

In those species where the parathyroids are in close
anatomical relationship with the thyroid, and where extirpation
of the latter necessarily included the removal of the former, the
operation was invariably followed by acute symptoms of sup-
pression. The violent and fatal tetany in carnivora was believed
to result from suppression of the thyroid function. After the
discovery of the parathyroid origin of tetany, I set myself to \vork
to produce the same clinical picture in dogs as that presented by
the herbivora after removal of the thyroid. I was especially
anxious to reproduce the arrestation of growth in young animals.

THE THYROID APPARATUS 65

After the thyroid has been removed from dogs 3-5 weeks old,
the parathyroid bodies being left intact, the animals may be kept
alive for months or even years, provided that post-operative tetany
does not supervene. After about two months, the animals show a
considerable difference in size, as compared with control animals
of the same litter. After six months, this difference becomes so
marked that the control animals will weigh two or three times
as much as the thyroidectomized animals.

I found that the constitutional changes were also very
noticeable.* The thyroidectomized animals are much smaller, the
legs are short and fragile, and the skull is rounded, with a
projecting infantile forehead. As a result, apparently, of
disproportion between the size of the viscera and that of the
skeleton, the abdomen appears to be very much distended.
Occasionally there is a peculiar deformity of the breast-bone.
It is remarkable that the mental apathy and impaired intelligence
which, according to v. Eiselsberg, is invariably displayed by
thyroidectomized sheep and goats, is absent in the case of young
dogs. This is the more remarkable in view of the fact that
spontaneous cretinism is known to occur in young dogs (v.
Wagner). Examination of the skeleton shows that all the bones,
and especially the hollow long bones, are remarkably fragile in
thyroidectomized dogs, while in the herbivora, on the other hand,
the bones are short, thick and heavy. The post-mortem
examination of my thyroidless dwarfed dogs revealed the per-
sistence of an exceptionally large thymus, where normally only
slight traces of this organ are found ; up to the second or third
year there was distinct hypertrophy of the hypophysis cerebri
with increase of colloid; a slight hypertrophy of the cortical part
of the suprarenals ; and a very noticeable hypoplasia of the sexual
glands. In one instance I found a very much hypertrophied
accessory thyroid gland embedded in the adipose tissue of the
aorta. The skin showed neither the clinical nor the histological
changes characteristic of myxcedema. Similar results have since
been obtained with dogs by Massaglia, and by Parhon and Gold-
stein with cats. The arrest in the growth of the skeleton and in
the development of the sexual organs is the typical and invariable
result of the absence of the thyroid function in both carnivora and
herbivora.

The changes seen in older animals after thyroidectomy are,
as a general rule, much less clearly marked. They are principally
confined to changes in the metabolic processes, the clinical mani-
festations of which are : Loss of appetite, sluggish digestion,
increased emaciation, and, finally, cachexia thyropriva.

Loss of intelligence is rarely seen. The disinclination for

* Illustrations will be found in A. Biecll, " Innere Sekretion," Vorlesungen, 1902,
Vienna, 1903. Wiener Klinik, xxix, 1903.

5

66 INTERNAL SECRETION

active movement and the indolence of the movements are
symptoms of apathy. Trophic disturbances of the cuticle are
very frequent, and consist in falling of the hair, dryness of the
skin, and more or less extensive eczema. A myxcedematous
swelling of the subcutaneous cellular tissue, together with idiocy,
has been described by Horsley in apes, by Moussu in pigs, goats
and sheep, and by v. Wagner in cats. Personally I have never
seen, in any animal species, changes in the skin resembling those
of myxcedema.

The changes in the blood are also remarkable. There is a
marked and continued decrease both in the number of red blood
corpuscles and in the amount of haemoglobin, accompanied by an
increasing leucocytosis, in which, more particularly, the number
of the mononuclear and eosinophile cells is augmented (Falta
and Berterelli).

The typical and, in my experience, the invariable result of
suppression of the thyroid function in adult animals, is a pro-
gressive emaciation, which increases to pronounced cachexia and
culminates in death. These results are absent only in those, not
very rare, cases where accessory thyroids are present, the hyper-
function of which more or less completely replaces the suppressed
activity of the principal organ. Such accessory glands are of
somewhat frequent occurrence in dogs, and may be reckoned
upon in one case out of five; in cats they are rarer.

In cats, the emaciation begins after two or three days, before
there is any appreciable diminution of appetite. Later, the
appetite disappears entirely, the animals refusing all food but
milk, and after a few weeks become extremely emaciated in
consequence. In dogs, the loss of weight begins a good deal
later and progresses so slowly that the animals may live for
months, even one to two years, after removal of the thyroid. They
then present, however, a wretched picture of emaciation and trophic
cuticular derangement. Death in such cases most frequently
occurs from infective diseases accidentally acquired.

Of the post-mortem findings, the most characteristic is the
enlargement of the hypophysis cerebri," which varies in degree
according to the length of life after operation. In animals which
have lived for some time after thyroidectomy, the hypophysis is
frequently two or three times as large as in control animals.

The changes which take place in the pituitary after
thyroidectomy were first described by Rogowitsch in 1888. He
found an increase in the size of this organ in rabbits and dogs
as early as eight to fourteen days after operation. The histological
changes consisted in an increase in the amount of cell protoplasm
and an enlargement of the space between the nuclei ; the number of
vacuoles in the cell-body and the amount of colloid were both
increased. In addition, there was a marked dilatation of the
blood-vessels, and the organ contained a very large amount of

THE THYROID APPARATUS 67

blood. These findings were confirmed by those of later authors
(Stieda, Tizzoni and Centanni, Hofmeister, Gley, Leonhardt,
Pisenti and Viola, Alquier, Lusena, Thaon, Torri, Lucien and
Parisot). Katzenstein and Traina were unable to find hyper-
trophy of the hypophysis after thyroidectomy, and this is
obviously due to the fact that their subjects were examined too
soon after the removal of the gland. Cimoroni showed that the
hypertrophy of the pituitary gland is due to the removal, not of
the parathyroids, but of the thyroid. According to this author,
the hypertrophy of the hypophysis, consequent upon thyroidec-
tomy, acquires a specific character from the presence of certain
cells, which distinguish it, more particularly by their size, from
the hypertrophy which follows castration.

Herring describes noticeable changes affecting the glia cells in
the nervous parts of the hypophysis after thyroidectomy.

The enlargement of the spleen, which is sometimes seen
after removal of the thyroid, cannot be regarded as typical of
the condition.

The changes in the processes of metabolism which follow
thyroidectomy are constant and, to a certain extent, characteristic.
The older experiments, those in which thyroparathyroidectomy was
carried out with dogs and cats, can scarcely be employed as evid-
ence in this connection. The muscular contractions characteristic
of the acute tetany which follows this operation bring about an
augmented metabolism ; moreover, as animals in this condition
are either unable to take food or take it very spasmodically, it is
obvious that accurate observation of metabolic changes is
impossible. For this reason, a large number of experiments
undertaken with the object of determining the metabolism of gases
and of albumin (E. Maier, Smith, Michaelsen, Dutto and Monaco,
E. Roos, Ver Ecke, Verstraeten, Gluzinski and Lemberger,
Formanek, Ducceschi, &c.) are highly contradictory in their
results.

Extirpation of the thyroid alone brings about a diminution
of metabolism, a fall in the physiological interchange of gases
and a reduction in the amount of albumin required by the
organism. Eppinger, Falta and Rudinger found that, in
thyroidectomized dogs in which the parathyroids were left intact,
the metabolism of albumin in the fasting state is lower than in
normal dogs of the same weight. In larger animals, provided
that hypertrophied accessory glands are not present, the reduction
in the amount of albumin metabolized in the fasting state amounts
to one-third. The exhibition of carbohydrates or fats either
does not lower the metabolism of albumin, or does so in a
lesser degree than under normal conditions.

The metabolism of the carbohydrates in thyroidless animals
has been dealt with by various authors. According to Falkenberg
and R. Hirsch, the removal of the thyroid produces glycosuria and

68 INTERNAL SECRETION

a diminished capacity for ' the assimilation of grape sugar.
Eppinger, Falta and Rudinger found, on the contrary, that
thyroidectomy never produced glycosuria, and that feeding with
large quantities of sugar was not followed by sugar in the urine.
They pointed to the remarkable fact that an adrenalin injection
which, in normal animals, provokes extreme glycosuria together
with an increased metabolism of albumin in the fasting state,
does not produce glycosuria in thyroidectomized animals, even
where sugar is given at the same time. Moreover, the
decomposition of albumin in the fasting state is decreased in such
animals after the injection of adrenalin. These authors account for
the glycosuria and the diminution of the normal assimilation of
sugar in Falkenberg and R. Hirsch's animals, by the fact that
in all their experiments the entire thyroid apparatus was removed.
After thyroparathyroidectomy, there is a disturbance of the
metabolism of the carbohydrates; this, according to Underhill
and Tadasu Saiki, is illustrated by the fact that, after the sub-
cutaneous injection of 5-7 grm. sugar in 20 per cent, solution for
every kilogramme of weight, there is a marked excretion of sugar,
which is continued over a considerable period. Eppinger, Falta
and Rudinger showed, further, that adrenalin produces in dogs
from which the entire thyroid apparatus has been removed, a
more marked glycosuria than in normal animals, and that, at
the same time, the metabolism of albumin in the fasting state
may be augmented. After the extirpation of several parathyroids,
there was a more or less marked reduction in the assimilation of
sugar, and this applies also to those cases where there were no
apparent symptoms of tetany. The effect upon metabolism of the
suppression of the parathyroid function is the reverse of that
produced by suppression of the thyroid ; for in true athyrosis the
assimilation of sugar is increased and the exhibition of adrenalin is
not followed by glycosuria. R. Hirsch, however, regards the
reduced capacity for the metabolism of sugar and starch after
parathyroidectomy as a typical symptom of tetany. The
glycosuria makes its appearance in tetany after the nervous
symptoms have become manifest, and this led Hirsch to believe
that it is due to intervention of the nervous system.

The experiences of Eppinger, Falta and Rudinger in regard
to the absence of glycosuria after the exhibition of adrenalin in
thyroidectomized animals, was confirmed by Grey and de Santelle
with dogs, and by Pick and Pineles with young goats but not
with rabbits ; while Underhill and Hilditch found that there was
distinct glycosuria after the exhibition of adrenalin in dogs.
Ritzmann found that, in the first two days after thyropara-
thyroidectomy, the intravenous infusion of diluted adrenalin solu-
tion did not produce glycosuria in cats, even where the quantity
used would be considered large in the case of normal animals. The
action of adrenalin becomes negative at the maximum development

THE THYROID APPARATUS 69

of the acute symptoms which follow extirpation, and the reduction
of the adrenalin glycosuria keeps pace with the development of
the symptoms characteristic of suppression. According to
Ritzmann, this is not the result of suppression of the thyroid
function, but is due to a change of conditions which arises while
the organism is adapting itself to the absence of the thyroid
function.

The relationship between the thyroid gland and the
metabolism of the carbohydrates, suggests that this correlation is
dependent upon the agency of an organ of the highest importance
to the metabolism of the carbohydrates, that, namely, of the
pancreas. Lorand was the first to suggest a relationship between
the thyroid gland and the pancreas, and he endeavoured to support
his theory by histological and experimental investigation. He
pointed to the fact that after extirpation of the thyroid in dogs
from which the pancreas has been removed, the sugar disappears
from the urine; and that where the pancreas is extirpated and the
thyroid spared, the colloid contents of the latter increase. Licini,
more recently, describes the histological signs of increased thyroid
activity, and Falta and Bertelli found that, after thyroidectomy,
there was a distinct hypertrophy and increase in the number
of the islands of Langerhans.

The results of the experiments undertaken by Eppinger, Falta
and Rudinger \vith the object of determining the relationship
between the thyroid and the pancreas may be summed up as
follows :- ,

I. — If the thyroid is removed seven to thirteen days before
extirpation of the pancreas, the resulting diabetes will be charac-
terized as follows :-

(a) The metabolism of albumin in the fasting state is slightly
more than that of the control animal ; but if the pancreas only is
removed, the metabolism of albumin will be increased three- or
four-fold.

(b) The quotient D :N (Dextrose: Nitrogen) is considerably
higher than after extirpation of the pancreas alone. In the latter
case it oscillates regularly between 2.8 and 3, but after removal
of the thyroid it rises to 3.5. These figures apply both to animals
in the fasting state and those fed on flesh.

(c) The reduction in weight of dogs in the fasting state is
comparatively slight.

II. — If the pancreas and thyroid are removed at the same
time, the suppression of the thyroid is the first to make itself
gradually felt. On the first day after operation, there is an
increase in the decomposition of albumin in the fasting state,
which exactly resembles that following removal of the pancreas
alone. But in place of a further increase in the decomposition of
albumin, the rise is followed by a fall which, in this case also,
raises the quotient D :N above the normal.

7O INTERNAL SECRETION

These results led Eppinger, Falta and Rudinger to the
conclusion that the thyroid and the chromaffine system, together
with, as Falta and Berterelli discovered later, the infundibular
portion of the hypophysis cerebri, constitute a group of vascular
glands which augment and accelerate the processes of metabolism.
The balance is maintained by the antagonistic activity of those
other vascular glands which, like the pancreas and the
parathyroids, exercise a retarding influence upon metabolism.

Now as these two groups of internal secretory glands possess
physiological interrelationships with one another, the extirpation
of a vascular gland is followed by two different sets of phenomena.
In the first place, there are the direct results, due to suppression
of the specific secretion ; in the second, there are the indirect
results, due to derangement of other glands, the functions of
which, under normal conditions, were either stimulated or
inhibited by the activity of the suppressed gland. The thyroid is
believed to promote the activity of the chromaffine system and to
inhibit that of the pancreas. The direct results of thyroidectomy
consist in reduction in the metabolism of albumin, fat and salt.
The indirect results are, on the one hand, the absence of
stimulation of the chromaffine system, and on the other, a hyper-
activity of the pancreas due to the removal of the inhibitory agent.

Eppinger, Falta and Rudinger believe that the nervous system
is the agent by which the interactivities of the vascular glands
are affected, and by means of which they are enabled to influence
the processes of metabolism.

The relationship of these organs to the vegetative nervous
system is two-fold. In the first place, each gland is innerved by a
definite portion of the vegetative nervous system ; and in the
second, the internal secretion of each gland reacts upon the
condition of irritability of the nerve by which it is supplied. That
group of internal secretory organs which promotes metabolism has
a sympathetic innervation and stimulates the sympathetic nerves,
at the same time exercising an inhibitory effect upon the
autonomous nerves. The group which retards metabolism, on
the other hand, possesses an autonomous innervation and, while
stimulating the autonomous nerves, inhibits the sympathetic.
The thyroid gland possesses a double function ; being furnished
with both an autonomous and a sympathetic innervation, it is able
to affect both portions of the vegetative nervous system.

The suppression of the thyroid is followed by a decreased
irritability of the sympathetic nerve, and this is manifested in a
sluggishness of the circulation and in certain trophic disturbances.
Adrenalin exercises a direct influence upon the sympathetic nerve,
but, after thyroidectomy, its exhibition is not followed by
glycosuria and it provokes only an inconsiderable rise in blood-
pressure. At the same time, the athyrosis produces a decreased
excitability of the autonomous nerves, as shown in the sluggish-

THE THYROID APPARATUS 71

ness of intestinal peristalsis, the insignificant effects produced by
pilocarpin, and the intensified action of atropin upon the eyes
(Asher).

That thyroidectomy has an effect in reducing the metabolism
of fats has been proved by experiments.

With regard to the metabolism of salts, Falta, Tedesco, and
Bolaffio found that dogs which had been thyroidectomized some
time previously did not show a decreased assimilation during the
first few days of the fasting state. Cases have been described,
however, where the excretion of the chlorides and the amount
of calcium, phosphorus and magnesia present in the urine were
decreased after thyroidectomy, while the amount of calcium and
phosphorus in the faeces and of magnesia in the urine became
increased after the exhibition of thyroid preparations (Falta).

These results would seem to show that the suppression of the
thyroid function reduces the metabolism of salts in the same
way as it does that of albumin, though the two processes do not
proceed parallel to one another.

ATHYROSIS AND HYPERTHYROSIS IN MAN.

Sir William Gull (1873), under the title of " Cretinoid State
in Adult Life in Women," described a symptom-complex which,
later, was termed " myxcedema ' by W. Ord (1877), and
" cachexie pachydermique " by Charcot (1879), and which was re-
garded, by both these authors, as a separate clinical entity. Curling,
at an earlier date, described the atrophy or absence of the thyroid
gland in sporadic cretinism ; and the pathogenetic significance of
the thyroid gland in myxcedema was suspected even at that date.
But until the publications of both Reverdin and Kocher in
1882-1883, the clinical conditions which follow suppression of
the thyroid were either unknown or were unappreciated. These
authors, writing independently of one another, described the
symptoms which are observed after the total extirpation of a
degenerated thyroid gland. Reverdin named this condition
Myxosdeme postoperatoire ; Kocher called it Ccichexia strumipriva.

OPERATIVE ATHYROSIS.

The most constant symptom of thyroid insufficiency in the
young growing individual, in man as in animals, is a remarkable
disturbance of the processes of growth. This takes the form of a
retardation of the growth in height, the growth in breadth con-
tinuing very much as in the normal (v. Bruns). The arrestation
of development produces a dwarf-like appearance of the individual,
due to imperfect endochondral ossification. The unclosed
epiphysial lines may be seen in skiagrams, and post-mort&m
examination shows that the ossification of the ends of the

72 INTERNAL SECRETION

epiphyses is extremely deficient, while the periosteal bone forma-
tion is undisturbed. But the changes are not in the skeleton only ;
the entire organism shows signs of arrested development. The most
marked of these is the infantilism of the sexual organs, in conse-
quence of which puberty is either very retarded, or is absent
altogether. Of the other organic changes, the most important is
the enlargement and degeneration of the hypophysis cerebri, first
described by Schonemann. The enlargement is easily seen in
life by means of skiagrams. In addition to the somatic changes,
there is a very marked arrestation of mental development. As
this shows itself in a decreased locomotion and an impaired
intelligence, the clinical picture presented by such thyroidless
children is very suggestive of that of cretinism.

In adults, where the signs of arrested growth are absent, the
most conspicuous symptoms are those of nervous derangement.
There are fatigue and pains in the limbs, followed by pronounced
lethargy, and in spite of the fact that the muscular structure is
well developed, there is a remarkable deficiency in muscular power.
This is followed by a reduction in mental activity and power.
Of the somatic signs, the most important are the changes in the
skin, from which the disease myxcedema derives its name. The
skin is remarkably white and wax-like ; it is thickened and puffy,
yet at the same time dry. There is a peculiar cedematous swelling
which appears first in the face and afterwards in the extremities ;
it yields very slightly to pressure and gives a peculiar awkward-
ness to the body and a fixed expression to the face. The
circulation of the blood and the nourishment of the skin are both
much impaired. The coldness to the touch, and pallor of the
skin are objective signs, as the persistent sensation of chilliness
is the subjective sign, of the reduced cuticular circulation. The
dryness and scaling of the skin, the chronic eczema and secondary
pigmentation, and the blanching and loss of hair, are all signs
of trophic disturbance. The visible mucous membranes of the
tongue, the uvula and the nose, all show signs of cedematous
swelling. The changes in the function of the sexual organs are
very remarkable. In women, menorrhagia is an unfailing
accompaniment of athyrosis. Should pregnancy occur, as it
sometimes does, the signs of athyrosis will be greatly intensified.
Markedly cachectic men are sterile. The blood-changes consist
in a somewhat high degree of anaemia, a very great reduction
in the number of red corpuscles, accompanied by a proportionate
increase in the number of the leucocytes and, more especially, of
the mononuclear cells.

In the absence of the thyroid gland it is possible, according
to Kocher, for man to live for seven years, though in a condition
of pronounced cachexia. Apart from the supervention of com-
plicating conditions, he may die as the result of the cachexia.

Symptoms of suppression occur in 70 per cent, of the cases

THE THYROID APPARATUS 73

of total extirpation. Where these do not appear, either the gland
was not removed in its entirety, or accessory thyroids are present.
Symptoms of cachexia may appear after partial extirpation of
goitrous glands. In such cases, however, the symptoms are
much milder and the condition is one of mitigated cachexia
thyropriva, analogous to Hertoghe's spontaneous " chronic
benign hypothyroidism."

The evil consequences of treating goitre by the surgical
method may be largely avoided, if a proportion of the glandular
tissue is allowed to remain in situ. It is hardly possible to define
the exact quantity. Kocher thinks that, in the case of diffuse
goitres, at least a quarter of the gland must be preserved if
dangerous symptoms are to be avoided.

There is sometimes spontaneous recovery from the symptoms
of suppression which follow total extirpation of the thyroid.
These coincide with the growth of a so-called "goitre relapse,"
and the improvement is explained by the fact that the new
formation is not of goitrous tissue, but is a hyperplastic develop-
ment of remains of normal glandular tissue which were left in situ.
These cases are instances of autotransplantation. On the other
hand, cachexia may develop after partial extirpation of a goitre,
the phenomena in this case making their appearance at the
moment when goitrous degeneration appears in the remains of
the lobe, or in the lobe of the other side. As Kocher points out,
there are goitres and goitres. In one case, goitre may be the
result of hyperplasia of functionally active thyroid tissue; in
another, it may mean a degenerative process leading to sup-
pression of the normal thyroid function.

TRUE ATHYROSIS AND HYPERTHYROSIS.

Having given an account of the results which follow the
operative removal of the thyroid gland, it is fitting that those
genuine clinical conditions which are brought about, to the best
of our knowledge, by the suppression of its function should next
be described. The first of these is myxoedema adultorum,
generally known as myxoedema. It is not necessary to describe
the symptoms of this condition, for to do so would be to repeat
the clinical description of cachexia strumipriva. The identity of
the symptoms justifies the name of " operative myxoedema,"
which is sometimes given to cachexia strumipriva. Moreover,
though the post-mortem findings in true myxcedema are somewhat
scanty, they show that this condition, like cachexia strumipriva,
owes its origin to the suppression, or to the conspicuous reduction,
of the activity of the thyroid gland. The thyroid is invariably
much reduced in size and occasionally completely atrophied;
it is pale in colour, and, under the microscope, shows obliteration
of the glandular parenchyma together with proliferation of the

74 INTERNAL SECRETION

interstitial connective tissue. We are still, even at this date,
entirely in the dark in regard to the etiology of this slow, pro-
gressive atrophy of the thyroid tissue. We only know that women
are far more frequently affected than men (80 per cent.) ; that
the disease is frequently associated with disturbance of sexual
function, and occasionally with acute infective conditions; and
that it occurs with much greater frequency in countries where
goitre is not endemic (Great Britain, Belgium).

The abortive forms of true myxcedema, to which Hertoghe
gave the name of Hypothyroidie benigne chronique, resemble the
myxcedema postoperativum frustrum which appears after partial
thyroidectomy.

These cases, which have latterly received a good deal of
attention, generally show only isolated, though characteristic,
secondary symptoms of myxcedema; such are trophic and
vasomotor disturbance of the skin, absence of perspiration, falling
of the hair, and, occasionally, oedema. Functional disturbances of
the sexual organs, such as menorrhagia, also occur. The manner
in which these cases respond to treatment with thyroid extract
shows that the condition arises from a reduced thyroid activity, or
hypothyreosis.

Another clinical condition which ought to be included in
this group is Adiposis dolorosa, or Dercum's disease, but its
pathogenetic relationship to the thyroid gland is by no means
fully established. In 1888, the American neurologist, Dercum,
described a condition in many respects resembling myxcedema,
but characterized by the appearance in the connective tissue at
different parts of the body, of circumscribed and very painful
fatty tumours. In addition to the localized fatty tumours, there
are also diffuse fatty deposits and, at times, a remarkably obese
bodily habit. Side by side with this, there is usually pronounced
muscular weakness, the patients performing only the most
necessary voluntary movements on account of the pain induced
by muscular action. The will-power is generally unimpaired,
though there is sometimes an apathy reminiscent of that of
myxcedema, and more rarely a condition of psychic exaltation. No
information concerning the metabolism of the condition is forth-
coming; in some cases glycosuria has been observed. A
remarkable feature of the condition is the absence of eosinophile
leucocytes from the blood. Six cases have come under post-
mortem examination, and of these five showed more or less far-
reaching pathological changes of the thyroid gland. In one case,
described by Dercum and MacCarthy, the thyroid was normal, but
there was adeno-carcinoma of the hypophysis cerebri.

The pathological anatomical findings appear to point to the
thyroid as the originating cause in adiposis dolorosa. But the
hypophysis undoubtedly plays a part in the genesis of this con-
dition, and it is probable that the sexual glands also are concerned,
as in such cases they are frequently atrophied.

THE THYROID APPARATUS 75

Certain French authors (Fere, Kaplin, and Fedoroff) are of
the opinion that this condition is an obesity due to hysteria, and
that the thyroid is without pathogenetic significance.

The exhibition of thyroid gland in adiposis dolorosa has
occasionally been attended with success, but, in many cases, it
has been entirely without result.

A special pathogenetic significance is ascribed to thyroid
insufficiency in the changes which occur in later life, and which
are included in the term cachexia of old age, or senile
degeneration. The foundation for the theory that old age results
from changes in the thyroid gland lies in the fact, commented upon
by Horsley, that in old age the thyroid becomes atrophied, its
follicles shrink and retrogressive changes take place in the
epithelial cells. This is reinforced by the fact that there is a
profound analogy between the signs of advanced old age and those
of myxoedema. The falling of the hair and the dropping out of
the teeth, the dry and wrinkled skin, the lowered temperature of
the body, the diminished perspiration, the indolent digestion and
consequent emaciation, the reduced metabolism and consequent
primary deposit of fat, followed by emaciation, the atrophy of
the sexual organs, the decrease of mental power, and the
diminution of the activity of the entire nervous system — these are
all symptoms which characterize chronic myxoedema. Horsley
holds the view, which is even more emphatically expressed by
Vermehren, that senility is due, at any rate in part, to
degeneration of the thyroid gland, while myxoedema may be
described as a condition of premature senility.

Premature decay, called progeria by Gilford, was regarded
by Rummo and his pupils as a separate clinical entity and was
described by them under the name of senilismus or geroderma
genitodistrofico.

This condition is characterized by the appearance, in youth,
of senile changes in the skin and a defective development of the
sexual apparatus; it is believed to depend upon changes in the
thyroid gland and is regarded as a form of myxoedema frustrum.

Lorand recently advanced the view that old age, or senile
involution, has an etiological relationship, not with the thyroid
only, but with all the organs which possess an internal secretory
function. He points out the similarity between the changes of
senile decay and the symptoms of myxoedema, and he lays par-
ticular stress upon the reduction of metabolism, the trophic
changes in the skin, the general increase of connective tissue,
and the cessation of sexual activity, all of which are symptoms
characteristic of both conditions. He believes that the atrophy
of the thyroid is the result of retrogressive changes in other
internal secretory organs (hypophysis, suprarenals).

There is, however, one point in connection with this theory
which must not be overlooked. We have no proof that there is

76 INTERNAL SECRETION

an etiological relationship between the symptoms of senile
cachexia and the retrograde changes which, in this condition, take
place in the internal secretory organs. The possibility suggests
itself that these changes are not the cause, but the consequence,
of the general nutritional disturbance which occurs in old age.
As Ewald rightly points out, the atrophy of the intestinal tract,
which is an invariable and characteristic feature of senile cachexia,
is absent in myxoedema.

We have not sufficient grounds for the assumption that senile
decay results from the suppression of function of internal secretory
organs other than the thyroid gland. The pathogenesis of this
condition offers a wide field for investigation.

We are very much better informed in regard to the patho-
logical consequences of thyroid insufficiency in youth.

In addition to myxcedema, conditions occur in young growing
individuals as a result of suppression of the thyroid function,
which, like those which follow operative athyrosis, are charac-
terized by derangement of the processes of growth and serious
mental deficiency. Owing to the similarity which these cases
bear to those of endemic cretinism, they are generally included
under the heading of sporadic cretinism. Out of the medley of
these cases, Pineles, with considerable penetration, distinguished
two distinct clinical entities, namely, congenital myxoedema,
which he calls thyroplasia, and infantile myxcedema. In addition
to myxcedematous signs, both conditions present symptoms of
derangement of the processes of growth, though these are not as
severe in the latter condition as in the former.

Infantile myxcedema appears at or after the fifth year; it
resembles adult myxcedema in its distribution and in its clinical
course, but more particularly in the fact that it is never congenital,
but always acquired. In both cases the condition is due to patho-
logical changes leading to atrophy of an already completely
formed thyroid gland.

But in congenital myxcedema the case is otherwise, and we
have to do with a congenital thyroid deformity, a thyroidaplasia,
in fact. From evidence afforded by the literature of the subject,
Pineles drew the conclusion that the complete absence of the
thyroid, the parathyroids being present intact, is not the secondary
result of a previous pathological condition, but is a congenital
defect of development; it is, in fact, true spontaneous thyroid
suppression. The clinical picture, as in operative athyrosis, is
one of extreme severity ; there are pronounced dwarfism, extreme
idiocy, and marked symptoms of myxcedema, all of which are
present from earliest childhood.

Congenital myxcedema, the symptoms of which closely re-
semble those of endemic cretinism, differs from the latter condition
in the sporadic nature of its occurrence. Moreover, endemic
cretinism is never, and goitre very rarely, found in the antecedents

THE THYROID APPARATUS 77

of congenital myxcedema, while goitre is almost invariable in
the antecedents of endemic cretinism.

Hypothyrosis in children also includes the condition known
as infantilism.

Infantilism, as defined by Lasegue, is a disturbance of
development, the salient feature of which is the persistence, in
both the mental and physical state, of infantile characteristics.
The chief clinical signs of this condition are the small size of
the bones and internal organs, the defective development of the
sexual glands and accessory sexual organs, and the childishness
of the mental state.

The term infantilism was afterwards made to include those
cases of arrested development which result from nutritional de-
rangements and from diseases of the vessels, the brain, £c. This
form is known as infantilismus dystrophicus or typus Lorrain,
and its etiology is to be sought in a number of widely different
originating causes. It may appear, as the result of hypoplasia
of the vascular system (Virchow), in hereditary syphilis ; after
alcoholism and other forms of chronic poisoning in the parents;
in primary cerebral disease; as the result of infective diseases
contracted in early life (tuberculosis, pellagra) ; metabolic derange-
ments (chlorosis) ; cardiac disease (pulmonary and mitral insuffi-
ciency) ; and finally, as the result of unhygienic surroundings
and insufficient nourishment in early childhood.

A closer study of infantile myxcedema and cretinism, and
the recognition of the pathogenetic significance of the thyroid
gland in these conditions, led Brissaud, and after him a number
of French scientists (Meige, Thibierge, Hertoghe, £c.), to in-
vestigate the close relationship which exists between the abortive
forms of myxcedema and certain forms of infantilism. Brissaud
named these conditions infantilismus myxcedematosus, or myx-
infantilisuius, and he believed that both the dystrophic and the
myxcedematous types were thyrogenetic in origin.

Many authors, especially Hertoghe, ascribe all forms of
infantilism to disturbance of the function of the thyroid. But
there are others (De Sanctis, Ferranini, Anton) who lay stress
upon the fact that, in many cases of infantilism both slight and
severe, the thyroid is comparatively normal. Brissaud's type is,
however, well known, and its pathogenetic relation to the thyroid
is very generally conceded.

Since the discovery of the interactivity of the internal secre-
tory organs and of the influence which certain of these organs
(hypophysis, suprarenals, generative glands) exercise upon
physical and mental development, we are accustomed to ascribe
those forms of infantilism which are not dystrophic in their origin
to an arrest of development consequent upon the abnormality of
one or more internal secretory organs.

These developmental disturbances must not be confused with

78 INTERNAL SECRETION

those of another group, which are also characterized by insufficient
sexual development and sometimes by mental deficiency. The
latter are recognized as more or less clearly defined clinical entities.
Of these the most important is true dwarfism, the nanismus,
microsomia, or nanosomia of Virchow. The pathological, as
distinguished from the ethnological, aspect of true dwarfism has
been minutely studied by A. Paltauf. D. v. Hansemann dis-
tinguished between two distinct forms of nanosomia. In the one,
the individual at some stage of his development ceases to grow
(nanosomia infantilis) ; in the other, the lack of size may be
traced back to the earliest beginnings of foetal life (nanosomia
•primordialis). Individuals belonging to the latter group are very
small when born and remain, through life, smaller than normal
individuals of the same age, but they attain to a definite comple-
tion of their development. The epiphysial cartilages ossify,
sexual maturity supervenes, and the characteristic signs of in-
fantilism are absent. In infantile nanosomia, on the contrary,
the individual is normal in size when born, but at some point
in his history he ceases to grow. This cessation takes place
gradually and in spite of the fact that the epiphysial synarthroses
remain unclosed during life (Schaafhausen, Joachimsthal).
But here also, the proportions of the body are maintained and
the mental development is usually normal. Bayon describes these
individuals as having the appearance of normal people when seen
through the wrong end of an opera-glass. It is possible to
mistake true drawfism for infantilism in those cases only where
there is idiocy combined with anomalous formation of the bones,
probably the result of rickets, though the latter condition is rare.

Achondroplasia (chondrodystropliia liyperplastica fostalis,
rachitis fcetalis, micromelia after Kassowitz) also presents cer-
tain clinical signs which resemble those of infantile myxcedema.
Achondroplasia presents no mental symptoms, however, and is
characterized by a lack of proportion between the shortness of
the extremities and the extreme length of the head and trunk,
which sufficiently distinguishes it as a distinct clinical type. The
condition represents an arrest of the processes of longitudinal
growth, caused by the absence, at the points of apposition, of
the vertical cell groups of the cartilages of the long bones.

The differential diagnosis between sporadic myxcedema and
so-called mongolism is a more difficult matter. Mongolism is an
arrest of the natural processes of longitudinal growth, accompanied
by abnormality of the structure of the skull ; depression of the
bridge of the nose; open fontanelles ; thickened tongue; defective
development of the sexual organs; and especially mental derange-
ment, which at first takes the form of apathy and somnolence,
and finally passes into insane desire for movement. According
to Kassowitz, mongolism is distinguished from infantile myx-
cedema by the absence of myxcedematous cuticular changes, by

THE THYROID APPARATUS 7Q

the oblique angle of the eyelids, by the normal development of
the epiphyses and the centres of ossification of the short bones,
and more especially by the fact that the exhibition of thyroid is
attended by negative results. In mongolism the thyroid gland
is usually normal, and suppression of its function cannot be re-
garded as pathogenetic in this condition. Alt and Schuller are
of the opinion that mongolism results from an affection of the
sexual glands and is, in fact, a primary dysgenitalism.

A condition resulting from thyroid insufficiency, which is of
far greater clinical and social significance than those which have
been described, is endemic cretinism. Its distribution alone makes
it of importance. In 1883, the number of cretins in Italy was
12,882, and in Austria west of the Leitha, 12,815. In France in
1873, there were 120,000 cretins, distributed over Savoy, the
Maritime Alps, and the Pyrenees.

Endemic cretinism is characterized by clinical signs similar
to those which have been repeatedly described as resulting from
athyrosis. Of these, the most noticeable is the disturbance of
the processes of growth of the skeleton and soft parts, which is
well seen in the more or less characteristic changes which take
place in the face. Owing to the premature cessation of develop-
ment of the base of the skull, the root of the nose is broad and
sunken; the stature is dwarf-like; and the development of the
genitals remains at the infantile stage. The texture of the skin
and the cuticular trophic changes are similar to those of myx-
cedema. But the most characteristic symptoms are arrest of
mental development, idiocy, and disturbances of the sensorium.
Of the latter, deaf-mutism is the commonest manifestation.

The thyroid gland plays an important part in endemic cre-
tinism, though its responsibility in this direction has been
variously defined. Several authors describe cases in which the
thyroid was absent altogether and, according to v. Wagner, this
occurs in 10 per cent, of the cases of typical cretinism. But this
finding is purely clinical, and post-mortem evidence of a thyroid-
aplasia, or of the total atrophy of an already developed thyroid,
is not as yet forthcoming. Congenital absence of the thyroid
comes under Pineles' definition of congenital myxcedema. As a
general rule, the post-mortem finding in cretinism is goitrous
degeneration and, more rarely, atrophy of the thyroid (v^ Eisels-
berg). Histological investigation shows either goitrous hyper-
trophy, or simple or chronic inflammatory atrophy of the thyroid
parenchyma, though both conditions are occasionally present in
the same subject. W. Scholz lays special stress upon the fact,
however, that in all his cases as well as in some of those of his
predecessors, a proportion of normal, active thyroid tissue re-
mained.

Both the origin and the nature of endemic cretinism have
formed the subject of a multiplicity of hypotheses. As early as

80 INTERNAL SECRETION

1867, St. Leger mentioned forty-two different theories, propounded
by 378 different authors, concerning the genesis of goitre and of
cretinism. These possess at this date no interest other than a
historic one.

The attitude which is now universally adopted towards the
results of thyroid insufficiency, finds its expression in the theory
advanced by Kocher and v. Wagner. They maintain that the
cause of cretinous degeneration is to be sought in a disturbance
of function of the thyroid gland, a chronic athyrosis ; or, in other
words, where the thyroid is normal cretinism is impossible
(Ewald).

Whether, however, endemic cretinism is identical with athy-
rosis, and whether the pathological condition of the thyroid gland
is the primary cause of all the symptoms, or is itself the outcome
of other general degenerative processes, are questions upon which
opinions differ.

W. Scholz adopts the view that cretinism and athyrosis are
not identical conditions. He bases his conclusion upon his find-
ing of active thyroid tissue in cretins, and upon the different
effects upon metabolism and general condition produced by
thyroid exhibition in cretins and in thyroidless subjects. In
Scholz's opinion, endemic cretinism is "a goitrous degenera-
tion, accompanied by cerebral disturbances of unknown origin,
to which the inhabitants of certain localities are subject."

The demonstrable differences between the results of partial
and total thyroid insufficiency and those of endemic cretinism,
are commented upon with varying emphasis by different authors.
Ewald lays great stress upon the fundamental difference in the
growth of the bones. Athyrosis gives rise to a general and equal
retardation of endochondral ossification, which results in
dwarfism. In the cretin, however, skiagrams show that there is
unequal retardation of ossification and deformity of the bony
structure, which may be accompanied in isolated cases by pre-
mature synostosis. There is, moreover, an unmistakable differ-
ence in the clinical course, for cretins may live to old age, the
condition after a certain time remaining stationary; but myx-
cedema, in all its forms, is progressive and leads ultimately to
death.

An even more important factor is that furnished by the
difference in the etiology of the two conditions. In endemic cre-
tinism, as the name implies, certain territorial factors are operative
and we have to assume the existence of an endemic noxa, the
nature of which is at present unknown. It is possible that this
harmful agent does not affect the thyroid gland only; it is even
probable that it does not affect it primarily. Ewald concludes that
endemic cretinism " is a condition of chronic physical and mental
degeneration, which is dependent upon local causes, in combina-
tion writh a more or less pronounced degeneration of the thyroid

THE THYROID APPARATUS 8 1

gland. As the latter factor develops under the influence of the
former, a distinct clinical type is evolved, which is to be regarded
as the resultant of both the operating causes."

There is undoubtedly a close etiological relationship between
endemic cretinism and endemic goitre. Virchow pointed out that
" true endemic cretinism always appears in goitre areas, and we
do not know of a single spot on the inhabited earth where true
endemic cretinism occurs which is not also the seat of endemic
goitre." In addition to this territorial relationship, there is a
large number of facts which point to a close etiological connection
between the two conditions. The most suggestive of these is the
fact, mentioned by Fodere in 1800 and since repeatedly confirmed,
that in the greater number of instances of cretinism, the parents
are either cretinous or goitrous, but that goitre is invariably
present in the antecedents. From these observations Fodere con-
cluded that goitre was the first stage of a degenerative process,
the last stage of which was cretinism. This view is supported by
the large majority of observers, and is now very generally
accepted.

The results of recent investigations supply certain factors of
indisputable importance in the etiology of endemic goitre and
endemic cretinism. The occurrence of both conditions is confined
to specific localities. These are the higher mountainous districts
in Europe, more particularly the region of the Central Alps;
in Asia, the Himalayas; in Central America, the Cordilleras; in
Africa, all the mountainous regions. A comparison of the con-
ditions shows that the distribution of these endemics is dependent
neither upon climatic nor meteorological factors, but upon the
composition of the soil. Bircher's investigations led him to con-
clude that endemic goitre and cretinous degeneration occur only
upon the marine deposits of the Palaeozoic (Devonian, Silurian,
coal, dyas), Triassic and Tertiary periods ; while the crystalline
formations of volcanic origin of the Archaean period, the sedi-
mentary deposits of the Triassic, Cretaceous and Quaternary
periods, as well as all fresh-water deposits, are free from goitre.
Kocher found that this classification required a certain amount
of modification, but he agrees with Bircher that the causal factor
lies, not in the mineralogical composition of the soil, nor in the
chemical composition of the rocks, but in a certain definite con-
tamination inherent in the soil, as the result of its geological
formation. The direct causative agent of goitre and cretinism is
water, derived from certain geological formations, and rendered
impure by specific by-admixtures.

The etiological importance of drinking-water cannot be
doubted when we remember that goitre may be developed in a
short time by drinking from so-called "goitre springs"; while,
on the other hand, even in districts where goitre is endemic,
persons who refrain from drinking the "goitre water" are free

6

82 INTERNAL SECRETION

from the disease. Conclusive experiments were conducted on a
large scale at Bozel in the Tarantaise and at Rupperswil in
Aargau, to which localities a fresh water supply was brought from
goitre-free soil. In both districts goitre and cretinism were
formerly rife, but since the institution of the new water supply
these conditions have, in the space of twenty years, entirely dis-
appeared. Further observation, and especially the discovery that
goitre may be prevented by boiling and filtering the water, seems
to point to the conclusion that the diseases are originated by one
or more living agents. The chemical composition of the water
and the presence or absence of certain substances, such as iodine,
phosphates, lime or magnesium salts, can hardly be taken into
account.

Though it seems highly probable that goitre and cretinism
are chronic infective diseases, the originator of which is to be
found in the drinking water, there is as yet no entirely satisfactory
proof of this. Moreover, we have no conclusive proof that the
diseases are due to a living agent. Kolle, who employed the
most perfect of modern methods, was unable to prove the presence
of a specific originator in either the intestinal flora, the goitrous
thyroid gland, or in blood taken from goitrous subjects. He also
endeavoured to prove' the presence of specific substances by means
of immunization and immunity reactions, as well as by anaphylac-
tic reactions, but without success. Attempts to transmit goitre
by surgical means were also negative in their result.

Animals in goitre districts frequently develop goitre, and
though certain experiments have been undertaken with the object
of producing the condition artificially, the material at our dis-
posal is very scanty. Lustig and Carle found that they were able
to produce a slow progressive enlargement of the thyroid in a
horse and a young dog (the only one out of 13) by means of
goitre water from the Val d'Aosta. The enlargement disappeared
when the animals were given filtered water.

Grassi and Munaron found that the results of their
experiments varied considerably. In certain dogs brought from
goitre-free localities to localities where goitre was endemic, goitre
developed even after the food and drinking-water were boiled ;
while others, which wTere given goitre-water and the sediment
obtained by filtering such water, remained free from goitre. But
dogs which were kept in enclosures in which there was a
quantity of damp earth and rotting material obtained from districts
where goitre was endemic, developed unmistakable goitre. Grassi
and Munaron conclude from this that goitre and cretinism result
from toxins produced by a specific microbe, which does not inhabit
the organism, but lives free in the outer world, always in damp
material and preferably in the soil. These toxins enter the
organism by way of the alimentary canal, to which they are
conveyed in different media, of which the drinking-water is
probably one.

THE THYROID APPARATUS 83

v. Wagner and Schlagenhaufer were unable to produce goitre
in young dogs by means of sediment obtained from the water
of a goitre-spring in Zeltweg (Styria).

McCarrison affirms that goitre can be produced in man by
the exhibition of the residuum left after filtering goitre-water.

Interesting experiments, intended to throw light on the
etiology of goitre, were latterly undertaken by Wilms and
E. Bircher. They found that it was possible to produce both
nodose and parenchymatous goitres in apes and dogs, and, more
particularly in rats, by giving them water from certain springs.
Moreover, when filtered by means of a Berkefeld filter, this water
invariably produced goitrous degeneration of the thyroid gland,
while the deposit was inactive. From these results the authors
conclude that goitre is of toxic, not miasmatic, origin.

v. Wagner and Schlagenhaufer were unable to confirm the
results described by Halsted, Lanz, Marine and Lenhart, namely,
that the descendants of female animals with reduced thyroid
activity frequently show goitre, thyroid insufficiency and stages
of cretinism.

v. Wagner and Schlagenhaufer supply some interesting facts
•concerning endemic cretinism in animals. Goitres are of by no
means rare occurrence in certain species (pig, calf, dog), but
cretinism in animals appears to be extremely rare. v. Wagner
and Schlagenhaufer give descriptions and very instructive
drawings of five cretinous dogs which came under their notice.
The conspicuous symptoms were clumsiness of shape, broad short
skull, dry, scaly skin, hairless tail, defective sense of hearing,
.apathy, indolent and clumsy movements, lack of appetite, and
retarded metabolism. Microscopic examination revealed a peculiar
change in the skin, namely, considerable deposits of a substance
which, when treated with ruemotoxylin-eosin, coloured blue.
The same substance was found in the skin of thyroidectomized
goats. The thyroid gland of these cretinous animals varied in
.size but slightly from the normal, and showed no histological
changes worth mentioning. The colloid contents were large, the
follicular epithelium scanty, but there were no symptoms of
degeneration. The thymus showed signs of premature involution.
Both the clinical symptoms of cretinism and the cutaneous changes
disappeared after the exhibition of thyroid gland, to reappear,
however, as soon as the treatment was suspended.

SUBSTITUTION THERAPY.

The results which have been obtained from time to time by
the substitution of the thyroid gland have a clinical, as well as a
physiological, importance. Schiff was the first (1884) to whom
the idea occurred of overcoming the symptoms of suppression
by means of transplantation. He transplanted fresh thyroid
glands into the peritoneal cavity of thyroidectomized dogs, and

84 INTERNAL SECRETION

found that the animals remained alive for a considerable time.
Later, by means of very exact experiments, v. Eiselsberg showed
that the implanted glands will heal into place and will remain
active. Prompted by the success which attended Schiff's experi-
ments, Kocher attempted thyroid transplantation with the human
subject, but with negative results; while Bircher (1890) obtained
a transitory relief of the symptoms by the same means in the
case of a woman with cachexia strumipriva. Horsley next pro-
posed the implantation of thyroid glands from sheep, not only
in post-operative myxcedema, but in true myxcedema and in
cretinism. The attempt was made by several surgeons and was
followed by favourable results, which lasted for a varying period
of time. Operative transplantation is, however, a comparatively
difficult and not altogether a harmless undertaking ; hence the
introduction of a method of substitution by means of thyroid
extract marked an important advance in technique. Moreover, the
results of this method have added considerably to our knowledge
of the functions exercised by the thyroid apparatus.

In 1891 Vassale, who was soon followed by Gley, discovered
that the symptoms which follow thyroidectomy may be aborted by
the intravenous injection of the watery thyroid extracts. In those
days, the tetanic symptoms were believed to be the most important,
if not the only, signs of suppression, and it was just these
symptoms which were relieved by the treatment. Tetany and
cachexia were at that time still regarded as identical clinical
conditions. But we now know that the acute nervous derangement
which follows extirpation of the thyroid apparatus is due to the
removal, not of the thyroid, but of the parathyroids ; and it is
obvious that the results of the older substitution experiments,
whether by transplantation or by exhibition of thyroid extract, are
much in need of revision.

The results obtained in tetany by transplantation of the
parathyroids and by the exhibition of thyroid extract have already
been fully discussed. It is proposed to quote here only those
results which have been obtained by the transplantation of the
thyroid gland itself.

The experiments of Schiff and v. Eiselsberg were followed
by numerous others (Carle, Ribbert, Ferratti, Fano and Zanda,
Zuccaro, Bourchard, Lamari and Sgobdo, Cannizzaro, Ughetti,
Ferrari, Sultan, Pantaleone, Enderlen), and every method of
auto- and hetero-transplantation, with subjects of a great variety
of species, was attempted. The site of implantation was usually
the preperitoneal or subcutaneous tissue. Payr preferred the
spleen on account of the peculiarly favourable circulatory con-
ditions. Kocher proposed the cancellous tissue of the hollow
bones, bordering the epiphysial line — the metaphyses of the tibia
—as sites of implantation, and the results of such implantation
are described by Sermann. Salzer (1909) described the results of
peritoneal transplantation in rabbits.

THE THYROID APPARATUS 85

Nearly all authors are agreed that the healing-in of the
transplanted organ is preceded by a degenerative process, slight
at the periphery, but becoming more intense towards the centre,
where it culminates in complete necrosis. Soon blood-vessels find
their way from the periphery into the interior of the organ, which
shows a comparatively healthy peripheral zone passing into a
granulation zone, and a necrosed centre. Regeneration starts
in the peripheral follicles, and groups and rows of epithelial cells
appear, which are transformed into follicles. The granulation
tissue is replaced by glandular substance, while the necrosed
centre becomes a connective tissue scar. Finally, as the organ
becomes completely healed in and the vascularization improves, it
shows a structure precisely similar to that of the normal thyroid.

Christiani showed, and his results were confirmed by those
of Salzer, that the healing-in of the implanted gland does not
take place in the same way in thyroidectomized as in normal
animals. After extirpation, the process is more rapid and
vascularization proceeds so quickly that about three weeks after
transplantation the gland is large in size and proliferates actively ;
a condition which, in the normal animal, is not reached until
seven to eight weeks after transplantation. Some degree of
difference is apparent for five to six months. It is obvious
that the rapid healing-in of the transplanted thyroid in
the case of the thyroidless animal is due to the more rapid
vascularization. Thus it appears that an early physiological
demand upon the function of the organ promotes its
rapid healing-in. Christiani also found that portions of
thyroid implanted into the ear of normal rats, healed in well ;
while in the case of animals to which thyroid tabloids were given,
only cicatricial tissue with no trace of glandular structure was
found at the site of implantation. He concludes from this that
the physiological demand of the organism upon the thyroid
function facilitates and hastens the reorganization of the trans-
planted tissue, and he agrees with Salzer that the large healthy
implanted gland of the thyroidectomized animal is an instance
of vicarious hypertrophy.

The rapid healing-in of the implanted thyroid is accompanied
by equally favourable results in regard to its function. Imme-
diately after transplantation, the implanted organ is merely &
chemical storehouse of active thyroid substances ; with increasing
regeneration, however, it is gradually enabled to fulfil the com-
plete function of the normal thyroid gland. For this reason,
animals having one implanted lobe, but which are otherwise
thyroidless, may live for months without showing symptoms of
suppression. Payr found that after extirpation of the spleen,
into which the thyroid had been transplanted, several animals
developed not only post-operative tetany, due to removal of the
parathyroids, but also cachexia (emaciation, roughness of the
coat, falling of the hair).

86 INTERNAL SECRETION

Payr describes one case of remarkable interest, that of a
child of 6 with extreme infantile myxcedema. The child was given
thyroid gland for 3^ years without result, but the implantation
in the spleen of a large portion of thyroid tissue taken from the
mother was followed by a marked improvement in both the
physical and mental conditions.

Under certain conditions, and more particularly where the
exhibition of thyroid extract is negative, the transplantation of
healthy thyroid tissue has a distinct therapeutic value. As Salzer
conclusively shows, the site best suited for implantation is the
'subcutaneous or preperitoneal tissue, for here the colloid secretion
is adequate, while the vascularization is certainly as profuse
as when the thyroid occupies its normal site, if not more so.
Moreover, as Christian! points out, in order to obtain a thera-
peutic result, it is frequently necessary to repeat the implantation,
and for this reason alone the subcutaneous or preperitoneal tissue
is preferable to the spleen or the bone.

There is, however, but a limited field for surgical intervention,
the medical method supplying, in the great majority of cases, a
thyroid substitution which is not only of equal reliability, but
is far safer.

The results of the treatment, by means of extracts and other
preparations of thyroid gland, of the pathological conditions
which follow the suppression of the thyroid function are not only
of profound interest, but they have a very important practical
application. The experimental material, though considerable, is
largely valueless, owing to the fact that substitution was almost
invariably attempted with a view to its effects in post-operative
tetany. It is certain that neither the exhibition of thyroid
preparations nor of the fresh thyroid gland can permanently
replace the complete thyroid apparatus ; that is to say, thyropara-
thyroidectomized animals cannot be kept alive by this means.

There is a small amount of material forthcoming concerning
the beneficial effects of thyroid extract upon the pathological
changes, and especially the changes in growth in young animals,
which follow the suppression of the thyroid. Pick and Pineles
found that, in the case of thyroidectomized goats, the pathological
signs disappeared after the animals were given thyroglobulin and
the thyroid glands of swine.

According to Coronedi, the functions of the thyroid and
parathyroids may be replaced by artificial organic halogen com-
pounds, fats containing biniodide and dibromide of stearic acid,
as well as by the iodine compounds contained in the thyroid
itself. Animals which are treated with these fats before thyro-
parathyroidectomy are said to be immune for a certain time from
its results. For instance, the hypertrophy of the hypophysis,
otherwise a constant feature, is not observed under these
conditions.

THE THYROID APPARATUS 87

According to Pick and Pineles, the secondary peptones
obtained from pig's thyroid after a forty-eight hours' digestion
by pepsin and hydrochloric acid, have very little influence upon
the pathological symptoms of suppression. The primary
albumoses, and the products of prolonged pepsin and trypsin
digestion, are also inactive. They found, moreover, that
iodothyrin was inactive, which appears to contradict the view
that iodothyrin is the only active principle of the thyroid secretion.

There is a large amount of evidence in favour of the clinical
value of substitution. Since the really surprising results obtained
in myxcedema by Murray (1891) with subcutaneous injections of
sterile glycerine thyroid extract, and by Howitz, Mackenzie and
Fox with thyroid gland given by the mouth, thyroid extract has
become an indispensable factor in the management of certain con-
ditions. The thyroid substances are specific remedies in all
those pathological conditions which arise from absence or
insufficiency of thyroid function.

Brilliant results were obtained by Kocher in cachexia
strumipriva. The uninterrupted administration by the mouth of
thyroid extract will prevent the appearance of cachexia, and may
for years completely replace the function of the absent thyroid.
Moreover, the treatment may be continued for any length of
time without fear of ill-effects. Such subjects are as capable of.
work as those who are " the happy possessors of a thyroidin
factory in their own bodies." But pathological symptoms make
their appearance if the treatment is suspended, even for one day.

The results of thyroid extract are no less striking in myx-
cedema; sometimes the symptoms disappear almost immediately,
sometimes not until after months of treatment. As a general
rule, the exhibition of thyroid extract is followed by a reduction
of the cuticular swelling and the patients lose their puffy appear-
ance. The sweat-glands begin to secrete and the hair grows
again upon the proper places. The temperature rises to the
normal, sexual activity is renewed, and, in women, menstruation
returns. The apathy and lack of interest disappear, and the
whole personality changes to such an extent that the patient
seems to be a different person. In infantile myxcedema and in
cretinism, there is a remarkable promotion of the vertical processes
of growth, and this may be seen in cretins even at a comparatively
advanced age. Suspension of the treatment is followed, first, by
a cessation of improvement, and, later, by a return of the
pathological symptoms.

The systematic treatment of endemic cretinism by thyroid
extract is warmly advocated by v. Wagner. His experiments
extend over a period of at least five to six years, and the results
show that every degree of cretinism is favourably influenced,
even at an advanced age, by thyroid treatment. The slighter
forms may completely recover and, provided that the treatment

88 INTERNAL SECRETION

is continued for a sufficient length of time, the improvement will
be maintained. In the severer forms, where the cases do not
come under treatment until very late, the improvement is confined
to certain symptoms. The administration of over-doses of
thyroid may, however, be a cause of failure (W. Scholz). The
state treatment of cretinism in Styria by means of thyroid extract
has been followed in every case since 1907 by satisfactory results
(v. Kutschera). In 85.7 per cent, of the cases, the growth was
in excess of the normal growth proportionate to the age ; in
42.8 per cent, there was a considerable improvement in all the
cretinous symptoms; and in 48.6 per cent, there was a distinct
improvement in certain symptoms.

Thyroid treatment has also been employed in the manage-
ment of a large number of pathological conditions which are be-
lieved, frequently upon no very clear grounds, to have an
etiological connection with insufficiency of the thyroid. Such
are : Trophic oedema, scleroderma, several skin affections,
osteomalacia, obesity, £c.

THE METABOLIC CHANGES IN HYPOTHYROSIS
AND THE MANNER IN WHICH THEY ARE
INFLUENCED BY THE EXHIBITION OF THYROID
EXTRACT.

The metabolic changes in hypothyrosis in man are minutely
described by Magnus-Levy. In this condition, the entire energetic
output (Kraftwechsel) of the organism is reduced, and patients
increase in weight, even with a very small amount of nourish-
ment. The diminution of the energetic output (Gesamtumsatz)
is not entirely due to physical indolence, but is largely the result
of the enormous reduction in the amount of the physiological
turnover (Grundumsatz) — the physiological expenditure of the
resting body. This falls to 50 to 60 per cent, of the normal,
a figure unknown in any other chronic condition. The low
metabolism of myxcedema is accompanied by a proportionate
decrease in assimilation and in the metabolism of albumin. The
daily excretion of nitrogen amounts to only 8 or 9 grammes. An
increase in the amount of nourishment, and especially in the
amount of albumin, may add to the amount of nitrogen.

This remarkable reduction of metabolism in myxcedema
disappears as soon as the condition yields to treatment with
thyroid gland. The gas metabolism reaches the normal and may,
indeed, exceed it. Under the ordinary treatment, with one to
three tabloids a day, this change is completed in three to four
weeks. If the treatment is then suspended, the expenditure of
oxygen will be again reduced, only to increase again as soon
as the treatment is recommenced. In slight cases of myxcedema,

THE THYROID APPARATUS 89

where the gas metabolism approaches the normal, thyroid treat-
ment increases the amount up to 15 per cent. The use of thyroid
preparations produces a complete change in the conditions
governing the metabolism of albumin. As a consequence of the
improvement in appetite, the amount of albumin ingested is much
larger, and the excretion of nitrogen becomes very much in-
creased; consequently, there is an appreciable loss of nitrogen
which is counteracted only by raising the entire caloric supply.
The larger part of the N-excretion is derived from pathological
deposits, which, at the same time, disappear. The increased
supply of albumin may, at a later stage, occasion a deposit of
albumin as tissue.

Scholx concludes that the metabolic conditions of cretinism are
singularly like those of myxcedema. But the effect of thyroid
extract upon the metabolism of nitrogen is not the same in
cretinism as in myxcedema. In the former condition it closely
resembles that seen in Graves's disease. Nevertheless, Scholz
does not conclude from this that myxcedema and endemic cretinism
are opposed conditions ; he is of the opinion that, as far as
metabolism is concerned, cretinism is a similar condition to
myxoedema, but is more advanced.

THE PHYSIOLOGICAL EFFECTS OF THYROID

SUBSTANCES.

Of the physiological effects of thyroid extract, the first to be
considered is the effect which it produces upon the circulatory
system. Oliver and Schafer (1894) pointed out that the injection
of watery or glycerine thyroid extracts into the veins was followed
by a reduction in blood-pressure, the cardiac activity remaining
unchanged. This is confirmed by the observations of many
others (Haskovec, Georgiewsky, Guinard and Martin, Feny-
vessy, Ocana, Patta, v. Fiirth and Schwarz, Farini and Vidoni).
Certain authors (Heinatz, Livon, Patta) noticed that an increase
in blood-pressure was brought about by thyroid extract. Farini
and Vidoni found that, during artificial circulation through the
hinder extremities of cats and rabbits, the effect wras vaso-contractor,
never vaso-dilator. Though Schafer declares that the cardiac
rhythm is unaffected by thyroid extract, yet Haskovec, Guinard
and Martin, and Svehla all found that the decrease in blood-
pressure was accompanied by a marked acceleration of the heart's
action. Others, again, report a definite slowing of the pulse.

The effects of iodothyrin and of iodothyroglobulin upon the
circulatory apparatus were tried by v. Cyon and Oswald. They
found that, when injected into the veins of dogs and rabbits, these
substances produced a fall in blood-pressure, together with a
stronger and slower heart action, and that these phenomena
persisted after resection of the vagi and after administration of

QO INTERNAL SECRETION

atropine. v. Cyon believes that iodothyrin has a powerful effect
upon the irritability of the terminals of the vagi and of the
depressors, and that it also has an antagonism for atropine. v.
Cyon's findings have been confirmed by those of others (Boruttau,
Ocana, Besmertny, Kraus and Friedenthal, Coronedi), but
Harnack casts a doubt upon the antagonism of iodothyrin to
atropine and ascribes the restoration of vagal irritability to the
rapid passing of the effects of the atropine. Further investigation
showed (Fenyvessy, Isaac and van der Velden, v. Fiirth and
Schwarz) that the irritability of the apparatus which inhibits
cardiac activity is not affected by iodothyrin. v. Fiirth and
Schwarz also proved that the fall in blood-pressure which follows
the exhibition of thyroid extract is not specific. As they point
out, the thyroid gland, in common with many other organs
(suprarenals [Lohmann] ; brain [Vincent and Cramer] ; spleen,
thymus, lymph glands, intestinal glands, kidney, ovary, pancreas
[Gautrelet]), contains choline, a substance which is concerned in
the composition and decomposition of the lecithins and other
lipoid substances ; and it is probable that the reduction in blood-
pressure which follows the exhibition of thyroid extract is due
to the presence of this substance. They believe, moreover, that
this effect of thyroid extract has no relationship to the physio-
logical activity of the thyroid gland.

The direct and characteristic effect of iodothyrin upon the
circulatory apparatus is absent in dogs and rabbits, but is seen
to a very marked extent in cats. The intravenous injection of a
quantity of iodothyrin corresponding to 0.2 to 0.3 mg. iodine
is followed by a fall in pressure and by large slow vagus beats,
lasting for several minutes. These " Aktionspulse," as they are
called, result from stimulation of the vagus centre in the medulla.,
for they disappear after resection of the vagi. The reduction in
pressure is due, not only to stimulation of the peripheral vessels
but, as oncometric experiments show, to a direct action upon the
heart itself. Further study of these phenomena shows, however,
that they are not specific to the action of iodothyrin, but are also
observed after the intravenous injection of iodized albuminoids,
v. Fiirth and Schwarz conclude that iodothyrin is a condensation
product of melanoid nature obtained by the action of acids from
the iodine albumin of the thyroid; and that its effects upon the
circulatory apparatus do not in any way suggest a specific activity
of the thyroid gland.

In addition to the immediate effects of thyroid extract, there
are certain other phenomena which are produced by its continuous
exhibition. Hyperthyroidism has been frequently produced
experimentally, with a view to ascertaining its effects upon the
circulatory system, and a more or less marked tachycardia appears
to be the almost invariable result, v. Fiirth and Schwarz pro-
duced considerable tachycardia in dogs and cats by the sub-

THE THYROID APPARATUS 9 1

cutaneous injection of large quantities of iodothyrin, but the result
was by no means invariable. In many cases, in spite of flooding
with iodothyrin, there was neither tachycardia nor any other sym-
ptom of thyroid poisoning. They believe that the production of
tachycardia is not specific to the thyroid gland, but that it is
common to iodothyrin and to certain other iodized derivatives of
albumin. In the case of thyroid extract, they explain the effect
by the large amount of iodized albumin which the thyroid gland
contains.

Coronedi regards thyroid extract as a physiological diuretic.
He bases his view upon results obtained with thyroparathyroidec-
tomized animals having a reduced activity of the kidneys. A very
marked diuresis was produced with thyroid extract in cases where
the usual diuretics had failed.

The effects of thyroid extract upon metabolism are constant.
It has already been shown that the exhibition of thyroid substances
in myxcedema and other conditions arising from suppression of
the thyroid gland, is followed by an enormously increased meta-
bolism. Similar changes, though less marked in character, are
produced in normal subjects, both man and animals, although the
physiological turnover (Grundumsatz) is very little affected by
thyroid extract. If, however, thyroid extract or iodothyrin are
given continuously for two to three weeks, the amount of the CO2
excretion will be increased by 15 to 25 per cent. The nitrogenous
interchanges, however, are invariably disturbed by the exhibition
of thyroid extract. The increased decomposition of albumin is
expressed by an increased excretion of nitrogen, hence the nitrogen
balance is a negative one. By increasing the caloric food supply
the nitrogen losses may be avoided. In obesity, owing to the
large reserve, the loss of albumin is not as great as in the normal
subject.

Thyroid preparations have been largely employed in the
therapeutics of obesity and, in many instances, with success.
Magnus-Levy thinks that the increase in oxidation during the
resting state (Ruhegaswechsel) is not sufficient to account for the
reduction of adipose tissue which follows the exhibition of thyroid.
He believes that the result is largely due to an increased expendi-
ture; for the effect of thyroid extract is to increase the capacity
for nervous reaction and, as a consequence, these otherwise
phlegmatic people display a greater energy in movement. There
is a good deal of evidence to show that thyroid extract has an
effect in reducing constitutional obesity, but that it has very little
influence upon obesity due to overfeeding; and this seems to point
unmistakably to the conclusion that, in this case also, we have
to do with a " substitution," by means of thyroid extract, of the
diminished function of the normal thyroid gland.

With regard to the metabolism of salts, Falta, with Bolaffio
and Tedesco, showed that the administration of thyroidin produced

92 INTERNAL SECRETION

in dogs in the fasting state a marked increase in the quotient
N :P2O5, which is expressed by a rise in the amount of nitrogen
and a fall in the amount of phosphorus excreted in the urine.
Thyroidin also brings about a considerable increase in the amount
of calcium excreted in the fasces, the calcium carrying off with it
a large proportion of phosphorus. Scholz had previously shown
that the exhibition of thyroid extract produces in man an increase
in the amount of phosphorus excreted in the fasces.

EXPERIMENTAL HYPERTHYROIDISM.

The continued exhibition of the expressed juice of the thyroid
gland, or of thyroid extract, is followed in animals by a number
of pathological symptoms, though the appearance of these is by
no means constant or to be relied on. The tachycardia of hyper-
thyroidism has already been described. There are, however, other
and various changes both in the body generally and in individual
organs ; such are : derangement of metabolism (emaciation, in-
creased oxidation, increased requirement of albumin, polydypsia,
polyphagia, polyuria, glycosuria) ; derangement of digestion
(diarrhoea, intestinal haemorrhage) ; trophic disturbances (cedema-
tous swelling of the connective tissue) ; changes in the thyroid
gland itself ; and a large number of symptoms which point to
a change in the activity of the nervous system. Kraus and
Friedenthal found that the intravenous injection of thyroid juice
almost invariably produced in rabbits enlargement of the palpe-
bral fissures, projection of the eyeball, retraction of the membrana
nictitans, and enlargement of the pupil. Hoennicke succeeded in
producing exophthalmos in rabbits by the continued exhibition
of thyroid juice. Eppinger, Falta and Rudinger then showed that
it is possible to produce adrenalin mydriasis in both normal and
thyroidless dogs by continued treatment with thyroid juice or
thyroid preparations, exclusive, however, of iodothyrin. These
authors regard the symptoms seen in hyperthyroidism as the
expression of an increased hypersensibility of the sympathetic
nerve. Certain symptoms point, however, to an influence affect-
ing the autonomous nervous system, and indeed the symptom-
complex of hyperthyroidism is so extremely varied that it can
only be explained by the assumption of a polyvalency of the
thyroid secretion.

HYPERTHYROIDISM IN MAN.
As PRODUCED BY THE EXHIBITION OF THYROID GLAND.

Since the introduction of the thyroid preparations into clinical
medicine, instances of artificially produced hyperthyroidism have
frequently come under observation. The continued employment
of thyroid extract, even in small medicinal doses, is frequently

THE THYROID APPARATUS 93

followed by various symptoms of derangement, such as a sensation
of heat, increased perspiration, palpitation and, sometimes, by
glycosuria. The most remarkable are those cases where toxic
symptoms appear after a single large dose or the prolonged
administration of moderate doses. In isolated instances a single
large dose has failed to produce any evil effects ; such is the case
of a child of n, who swallowed 100 tabloids of 0.3 grm. each.
But Boinet and Ferranini found that the prolonged administration
of six to eight tabloids a day provoked serious symptoms of
intolerance. Conditions of psychic exaltation, sleeplessness,
violent trembling, extreme emaciation and anaemia, digestive dis-
turbances, extremely unpleasant subjective sensations, deranged
cardiac activity, and tachycardia, are all described as symptoms
of thyroid intolerance, v. Notthaft describes a case of artificially
produced Graves's disease. A man, aged 43, suffering from
obesity, w*ho took nearly 1,000 thyroid tabloids in five weeks,
presented all the symptoms of true Graves's disease ; these
gradually disappeared, however, after the thyroid was suspended.
These cases suffice to show the enormous influence which the
thyroid substances exercise upon the organism. It is obvious that
their employment as therapeutic agents must be in rigid conformity
to the clinical indications, the pathological conditions, and the
idiosyncrasy of the subject.

CONDITIONS WHICH MAY BE CLASSED AS THOSE
OF TRUE HYPERTHYROIDISM.

Of the pathological conditions arising from a disturbance of
function of the thyroid gland, the most important is undoubtedly
Graves's disease or exophthalmic goitre. Karl v. Basedow, in
1840, first pointed out that the combination of exophthalmos,
goitre and tachycardia constituted the syndrome of a definite
clinical condition. To these three, other more or less characteristic
secondary symptoms have from time to time been added, and the
clinical definition of Graves's disease is now made to include the
so-called forme fruste and the condition lately described by Stern
as " Basedowoid."

The nature of Graves's disease has formed the subject of
various conflicting hypotheses. The older neurogenic theory,
which regarded the condition as an affection either of the sym-
pathetic (more particularly the vago-sympathetic) nerve or of the
medulla, was based upon inconclusive experiments and isolated
and contradictory post-mortem findings. The thyrogenic theory,
as first propounded by Gautier and ably confirmed by Mobius,
produced a revolution in the point of view regarding the patho-
genesis of this condition, though individual authors still continued
to support the bulbar theory. Tedeski, for instance (1902), be*

94

INTERNAL SECRETION

lieved that his experiments pointed to a lesion of the anterior
portion of the restiform body as the originating factor of Graves's
disease, but that the symptoms are manifested by the agency of
the thyroid gland. The later attempts to prove the neurogenic
origin of the disease were based upon a more complete knowledge
of the innervation of the thyroid gland. Experiments to this end
were undertaken by Briau at Morat's laboratory and they show
that the sympathetic nerve of the neck contains fibres which act
as vaso-dilators to the blood-vessels of the thyroid. Wiener has
recently expressed the view, based upon his discoveries concerning
the innervation of the thyroid, that the thyroid derangement is not
the primary feature of Graves's disease, but is a secondary con-
dition brought about by abnormal innervation of the gland.

Whether the thyroid affection is primary or is a secondary
feature of nervous origin, one thing is universally conceded, and
that is, that the thyroid gland is the pathogenetic centre from
which the symptom-complex of Graves's disease proceeds. A
rational explanation of the condition is offered by the assumption
of a functional anomaly on the part of the thyroid gland. The
grounds for this assumption are as follows : (i) The invariable
occurrence of a pathological enlargement of the gland— the
anatomically and histologically characteristic goitre ; (2) the
coincidence of the first clinical symptoms with the swelling of the
gland, especially as seen in those instructive cases (acute inflamma-
tion, syphilitic changes, metastases of neoplasms) where the
sudden affection of the gland is attended by the immediate appear-
ance of the clinical signs; and (3) the remarkable therapeutic
results by which partial extirpation is invariably attended.

The thyrogenic theory of the origin of Graves's disease
receives remarkable support from the antagonism, described by
Moebius, between the clinical symptoms of athyrosis as manifested
in myxcedema and in Graves's disease. This is well seen in
A. Kocher's comparison of the symptomology of Graves's disease
with that of cachexia thyropriva.

CACHEXIA THYROPRIVA.

Absence or atrophy of the
thyroid gland.

Slow, small, regular pulse.

Absence of vascular congestion
and coldness of the skin.

Indifferent expression, lacking
in movement and vitality.

Narrowed eyelids.

GRAVES'S DISEASE.

Swelling, generally diffuse, of

the thyroid gland, hyper-

vascularization.
Rapid, frequently tense, jerky,

occasionally irregular pulse.
Extreme excitability of the

vascular nerves.
Anxious, roving glance which

appears angry when fixed.
Wide open eyelids, exophthal-

mos.

THE THYROID APPARATUS 95

CACHEXIA THYROPRIVA. GRAVES'S DISEASE.

Retarded digestive and excre- Abundant excretion, generally
tory processes, small appe- abnormal appetite, in-

tite, slight need for food. creased need for food.

Slow metabolism. Increased metabolism.

Thick, opaque skin, dry or Skin thin, transparent, finely

scaly. injected, moist.

Short, thick fingers, frequently Long, slender fingers, with

broadened at the tips. pointed tips.

Sleepiness and desire for sleep. Insomnia and restlessness dur-
ing sleep.
Retarded sensation, perception Intensified sensation, perception

and action. and action.

Mental vacancy and indiffer- Mental whirl, excitement to the
ence, lack of emotion. point of hallucination,

mania, melancholy.
Awkwardness and slowness of Perpetual restlessness and

movement. haste.

Stiffness of the extremities. Tremor of the extremities, in-

creased mobility of the
joints.

Retarded skeletal growth, Slightly built skeleton, occa-
short, thick, frequently sionally soft or thin bones,

deformed bones.

Constant chilliness. Unbearable sensation of heat.

Difficult and slow respiration. Superficial respiration, slight

expansion of the thorax in
inspiration.

Increase in weight. Loss of weight.

Senile appearance, even of Youthful, luxuriant develop-
young people. ment, at least in the earlier

stages.

The antagonism between the principal symptoms of the two
conditions is very marked, though occasionally in severe cases of
Graves's disease symptoms appear which bear a close resemblance
to those of cachexia strumipriva.

Other momenta, such as the deleterious effects of the exhibi-
tion of thyroid extract in Graves's disease and the artificial pro-
duction of the symptoms of Graves's disease by hyperthyroidism,
are to be regarded, not as direct proofs of the thyrogenic origin
of this condition, but as powerful arguments in its favour.

We will now pass to a consideration of the symptoms and
organic changes characteristic of Graves's disease.

The thyroid enlargement — the goitre — is one of the constant
symptoms of the condition. Cases where the thyroid changes are
absent are, in the opinion of all observers, extremely rare. The

96 INTERNAL SECRETION

enlargement of the thyroid is not, as a rule, very considerable,
and is generally readily distinguishable from other forms of goitre.
Histologically, the goitre of Graves's disease is defined as a
parenchymatose hypertrophy of the gland, with profuse vascu-
larization. In addition to the active new formation of tissue there
are retrogressive processes ; and side by side with young follicles,
formed by epithelial proliferation, old follicles are seen to be
breaking up by means of cell desquamation. In older goitres
there is also a marked increase of interstitial connective tissue.
The goitre of Graves's disease is differentiated from all other
goitres by the nature of its histological changes. But it must be
borne in mind that the signs of an increased secretory activity
are the same as in the colloid goitres.

Erdheim regards certain young cell formations with fat
granules as characteristic of the goitre of Graves's disease ; while
according to Lobenhoffer, the acidophile granules in the proto-
plasm, which must be regarded as the secretory product of the
epithelial cells of the thyroid, are increased in exactly the same
way in Graves's disease as in colloid goitre.

Of the pathological anatomical findings in Graves's disease,
hypertrophy of the thymus is among the most frequent (Thor-
becke, v. Hansemann, Boit, Monkeberg, Gierke, Capelle, Rossle).
The enlargement of the thymus is a centra-indication for
thyroidectomy, for after operation such cases frequently get
worse, owing, it is believed, to thymogenic auto-intoxication
(Gierke). The thymus hypertrophy is said to arise from a
vicarious endeavour on the part of the thymus to make good the
deficiency in the amount of secretion elaborated by the hyper-
trophied thyroid (Rossle). But the persistence or enlargement of
the thymus may be explained by the fact that the victims of
Graves's disease are frequently of lymphatic constitution; and
the presence of the thymus as well as the hypoplastic arrest of
development of the genitals, like the frequent swelling of the
lymph glands and the formation of lymphatic deposits in the
thyroid gland, may only be the signs of a status thymicolympha-
ticus.

The heart shows all the clinical signs of hypertrophy; more
rarely, there is dilatation of the left ventricle with fatty degenera-
tion or brown pigmentation of the muscle fibres. According to
Askanazy, an interstitial lipomatosis of the voluntary muscles,
which develops variously with the severity and age of the case,
is a constant finding.

The other organic changes, and particularly the pathological
changes in the central nervous system, are not constant.

The origin of the exophthalmos, which is almost patho-
gnomonic of Graves's disease, has always been the most difficult
problem in connection with the disease.

The exophthalmos consists in an enlargement of the palpebral

THE THYROID APPARATUS 97

fissure, which may be due to contraction of the levator palpebrum
muscle, together with a protrusion of the eyeball, brought about
by contraction of Miiller's protrusor bulbi muscle, the existence
of which in man has been proved by Landstrom. The latter
muscle has a sympathetic innervation, while the levator palpebraj
muscles are innerved by the autonomous oculomotor nerve. The
irritation of the sympathetic at the neck causes a protrusion of
the eyeball, in the course of which the space between the lids
undergoes a certain amount of secondary mechanical enlarge-
ment. The exophthalmos is undoubtedly a symptom of the in-
creased irritability of the sympathetic nerve, and this view is
supported by the adrenalin mydriasis which O. Lowi saw in
persons with Graves's disease. The enlargement of the space
between the lids, which sometimes takes place independently of
the protrusion of the eyeball, and Grafe's symptom, which con-
sists in the absence of synergy between the movements of the
eyeball and of the upper lid, are both signs of irritation of the
autonomous system (Eppinger and Hess).

Tachycardia is also a constant symptom in Graves's disease,
though, as Chvostek points out, of very varying clinical signifi-
cance. The results of experimental research point to the sym-
ptom as a sign of increased irritability of the sympathetic nerves.
An irritation of the nervus accelerans, which hastens the heart's
action and belongs to the sympathetic system, suggests itself in
this connection. Experimental systematic hyperthyroidization
almost invariably produces tachycardia, and there is ground for
the belief that the acceleration of the pulse due to the increased
activity of the sympathetic nerve, is an effect of the increased
amount of thyroid substances circulating in the blood. The
hypertrophy of the cardiac muscle is sufficiently explained by its
continued hyperfunction.

Other signs of the increased activity of the sympathetic
system are to be found in the greater vasomotor excitability,
the increased secretion of the sweat glands, the tendency to a
heightened temperature, and the increased production of heat.
The increased amount of adrenalin in the blood points to the
same conclusion. Kraus and Friedenthal discovered that the
serum of persons with Graves's disease caused the pupil of an
enucleated frog's eye to dilate, and later A. Fraenkel, by exact
biological experiments with the uterus removed from the living
body (" iiberlebend "), found that the blood of persons with
Graves's disease contained a very much increased amount of
adrenalin.

Eppinger and Hess brought together a variety of symptoms
which they believe to be signs of irritation of the autonomous
nervous system. In addition to the enlargoment of the palpebral
fissure and Grafe's symptom, they include derangement of the
respiratory rhythm and diarrhoea among the symptoms of an

7

98 INTERNAL SECRETION

increased vagal activity ; they also attribute (though somewhat
arbitrarily) the increased perspiration, the congestions and the
circumscribed oedema to irritation of the autonomous nerves.
These authors divide their cases of Graves's disease into two
groups ; one, in which the symptoms of sympathetic excitement
predominate, they describe as sympathetico-tonic ; while the other
is described as vago-tonic, from the fact that here the most
marked symptoms are those proceeding from the autonomous
nervous system. Falta, Eppinger and Riidinger assume a poly-
valency of the thyroid secretion and they regard the hyper-
thyroidism of Graves's disease as the outcome of a simultaneous,
though probably independent, stimulation of both the sympathetic
and autonomous nervous systems.

A special interest attaches to the metabolic changes of
Graves's disease. In simple goitre, the metabolism is in no way
different to the normal, and it is affected by thyroid extract in a
manner precisely similar to that of other persons with normal
thyroids. In Graves's disease, on the other hand, the metabolic
changes are so characteristic of the condition that they constitute
important diagnostic criteria. The metabolism of Graves's disease
is characterized by an increased expenditure of energy. The
respiratory interchange of gases shows an increase of 50 per cent.,
and even 70 to So per cent., in the amount of oxygen
consumed (Magnus-Levy, Salomon), and these results are
confirmed by Steyrer, who continued his experiments over
a long period of time. The increased consumption and the
increased and remarkably fluctuating caloric production, is
partly the result of the augmented cardiac and respiratory
activity; in part, and to an even greater degree, it is due
to the nervous excitement and motor unrest, more particularly
the tremor. But, after making due allowance for the operation
of these factors, it will be found that in complete muscular repose
there is still a large increase in the interchange of gases. When
we remember the effect of thyroid extract upon metabolism, it
seems obvious that this augmentation is only to be accounted
for by a hypersecretion of the thyroid gland. That the caloric
production may be still further increased by the exhibition of
thyroid extract, has not as yet been proved (Magnus-Levy,
Steyrer). It may be noted here that the administration both of
rhodagen and of Moebius's anti-thyroidin serum is not followed
by any demonstrable effect upon metabolism. This applies also
to treatment with thymus extract, at one time much vaunted for
its curative effect in Graves's disease. The enormously increased
metabolism accounts for the emaciation, which is often very
extreme. The increased caloric explains the subjective sensation
of heat, the profuse outbreaks of perspiration, and the tendency,
commented upon by Charcot, to a heightened temperature. That
the increased caloric does not produce hyperpyrexia or even fever

THE THYROID APPARATUS 99

is probably due to an adequate degree of activity on the part of
the apparatus which regulates heat production. The rise in tem-
perature which occurs shortly before death (Kocher) is probably
due to failure on the part of this apparatus.

The increased production of heat is frequently associated with
an augmented demand for, and consumption of, albumin, together
with a negative N-balance, though the latter is not invariable. The
metabolism of nitrogen varies with the fluctuating course of the
disease and may, for longer or shorter periods, approximate to
the normal. The albumin losses and the toxic decomposition of
albumin may be counteracted, even when the disease is at its
height, by a diet containing albumin, or by a diet containing
carbohydrates but free from nitrogen (Riidinger). The fats also
undergo decomposition. In connection with the metabolism of
the carbohydrates, it must be borne in mind that the assimilation
of the carbohydrates is reduced in Graves's disease, and that for
this reason an alimentary glycosuria is easily provoked (Ludwig
and F. Kraus). The feature which characterizes the metabolism
of Graves's disease is the increase in the total amount of oxidation.

An increased metabolism of mineral salts has not as yet been
proved, though A. Kocher describes an increase in the excretion
of phosphorus. Investigation in this direction has recently been
undertaken by Scordo and Franchini.

Certain features of Graves's disease are the clinical opposites
of those seen in myxcedema. These are : the thin, soft, smooth,
moist skin ; the general nervous excitability ; the restlessness and
haste ; the tremor ; the exaggerated reflexes ; and the mental
exaltation and psychic changes, which may even amount to
psychosis.

There are certain symptoms wrhich are common to both
Graves's disease and cachexia strumipriva as, for instance : trophic
disturbance of the skin; oedema; dryness, falling and blanching
of the hair; friability of the nails; abnormal pigmentation; and
increased salivary and lachrymal secretions.

The changes in the blood are the same in both conditions.
There is an increase of mononuclear leucocytes and a remarkable
increase in the eosinophile cells. And in both conditions there are
changes in the activity of the sexual glands, which are shown, in
women, by a cessation of the menstrual processes.

It is interesting to note, in this connection, that symptoms
resembling those of Graves's disease are associated with other
pathological conditions. Such are the forme fruste seen in
chlorosis (Chvostek) ; the pseudo-chlorosis, encountered in
goitrous districts, and characterized by swelling of the thyroid,
increased cardiac activity, mental excitement, fatigue, and pallor,
without, however, chlorotic changes in the blood (F. v. Miiller) ;
and, finally, the symptoms resembling those of Graves's disease,
which are seen at the climacteric (Gluzinski). On the one hand,

100 INTERNAL SECRETION

therefore, hyperthyroidism leads, as in Graves's disease, to
changes in the function of the ovaries; on the other, primary
changes in the activity of the sexual glands may exercise a
secondary influence upon the thyroid, and as a result, symptoms
resembling those of Graves's disease are produced.

The brilliant results obtained by modern surgery in the
treatment of Graves's disease illustrate very clearly the etiological
connection between this condition and the thyroid gland. The
operative method is based upon the view that a reduction in the
volume of the gland, together with a decrease in, or prevention
of, its abnormal vascularization, must reduce its secretory activity
and so abolish the results of hypersecretion. The methods em-
ployed are : the ligature of one or more enlarged thyroid arteries ;
the extirpation of one-sided vascular goitres; and the resection
or excision of more than one half. Kocher found that these
measures were followed, in 76 per cent, of his cases, by complete
cure, and in another 14 per cent, by improvement. Similar
results are described by others. But there is a strong feeling
in many quarters that not all cases are suitable for operative
treatment, and that success largely depends upon the constitution
of the patient and, most important of all, upon conditions affecting
the thymus. Surgical treatment is accompanied by certain
dangers per se, and in a certain percentage of cases (3 to 4.7 per
cent.) operation has resulted in death.

Another method of limiting the secretion of the goitrous
gland and perhaps, also of destroying the hypertrophic
parenchyma, is by means of the Rontgen rays (Gorl,
Stegmann, Holzknecht, &c.). Up to the present, however, no
very conclusive results as to the therapeutic value of this method
have been forthcoming.

The results of organo-therapy in Graves's disease are
interesting only in so far as they furnish direct evidence against
the assumption of a hypothyrosis in this condition (v. Cyon,
Oswald). The effect produced by thyroid extract is, invariably,
the aggravation of the disease.

Attempts to treat Graves's disease with extracts of the thymus,
ovary and suprarenal capsule, have a certain theoretic interest, but
are of no practical significance.

The serum-therapy, first tried by Ballet and Enriquez, and
afterwards developed by Moebius, is founded upon the belief
that the surplus secretion formed by the hypertrophied thyroid
of Graves's disease can be employed to neutralize the toxins
contained in the serum of thyroidectomized animals. It is thought
that in this way the surplus is removed from the tissues which
have a specific affinity for the thyroid secretion, the reaction of
which would otherwise be manifested by pathological disturb-
ances. The serum of thyroidectomized animals, known as
Moebius's antithyroidin serum, and rhodagen, which, upon the

THE THYROID APPARATUS IOI

assumption that the toxins pass into the milk (Lanz), was pre-
pared from the milk of thyroidectomized goats, were at one
time very widely employed, and, it is said, with good result.
But the earlier enthusiasm for this method appears to have some-
what abated; at least, very little has latterly been heard of it.

Isolated attempts have also been made to treat Graves's
disease by means of thyrotoxic immune serum (Thompson,
Stradiotti).

From the nature of the evidence before us, the etiological
relationship between Graves's disease and the thyroid gland cannot
any longer be doubted. The further question, as to whether the
etiological factor is to be found in a quantitatively increased
secretion, a hyperthyrosis, or in a qualitatively altered secre-
tion, a dysthyrosis, is not so easily answered. Although the
greater number of facts appear to be in favour of hyperfunction,
yet the absence of any histological signs of an increased secretion,
the failure of all attempts to produce a complete clinical picture of
Graves's disease by means of experimental hyperthyroidization,
and more particularly, the not infrequent occurrence of symptoms
of thyroid insufficiency in Graves's disease, are factors not readily
explained by a theory of hyperfunction. According to Moebius's
theory, the thyroid secretion of Graves's disease is not only
increased, but it is also perverted.

Nevertheless, an increased knowledge of the nature of thyroid
secretion and, more particularly, of its chemical composition
and physiological activity, together with a more accurate analysis
of the clinical symptoms and of their significance, renders the
probability of a dysthyroidism in Graves's disease more and more
remote. As Kraus points out, this is a problem which, for the
present at any rate, cannot be explained beyond a certain point.

The evidence in favour of a qualitative change in the nature
of the thyroid secretion is becoming gradually less significant.
The absence of any signs of hypersecretion, more particularly
the small amount of iodine present in the goitres of Graves's
disease, is sufficiently explained by the assumption of an
abnormally small capacity on the part of the gland for the fixation
of iodine, and by the over-rapidity with which the active substance
is expended (Kocher, Kraus). The failure of hyperthyroidization
to produce the entire symptom-complex of Graves's disease in
animals, can scarcely be regarded as unequivocal evidence, when
we remember that by the methods employed, only very imperfect
imitations of the clinical conditions as seen in man were repro-
duced. The positive results of experiments with animals have a
much greater value in their relation to individual cardinal
symptoms. With regard to the symptoms of thyroid insufficiency
sometimes encountered in Graves's disease, it must be remembered
that similar phenomena are seen in pathological affections of other
internal secretory organs as, for instance, the hypophysis and the

IO2 INTERNAL SECRETION

sexual organs, signs of hyper- and hypo-function occurring some-
times side by side. There is a possibility that the continued
increased activity gives rise to a temporary functional insufficiency,
which may, later, find anatomical expression.

It is possible to account for all the symptoms of Grav.es's
disease by the continuous circulation in the blood of thyroid sub-
stances in abnormally large quantities. For it must be borne in
mind that, not only do the extent and intensity of the symptoms
depend upon the degree of thyroid affection, but they also depend
upon the modifying effect which the thyroid secretion itself exer-
cises upon the different organic tissues and functions. As Eppinger
and Hess with justice point out, the symptoms of derangement
will vary according to whether the subject is sympathetico-tonic
or vago-tonic.

Graves's disease is the direct outcome of the flooding of the
organism with thyroid substances. These exercise an elective
stimulating effect upon the sympathetic, and partly also upon the
autonomous, portions of the vegetative nervous system ; and they
also influence the activity of those other internal secretory organs
which have functional interrelationships with the thyroid gl-and
(thymus, hypophysis, suprarenals, sexual glands). The question
now arises as to whether the primum movens of Graves's disease
is to be sought within the thyroid or without it. The etiology of
the condition is still shrouded in darkness. The remarkable
incidence of the disease in women, and the frequency with which
its occurrence is associated with functional changes of the sexual
glands, are undoubtedly factors of significance. Moreover, the
comparative frequency \vith which Graves's disease occurs in
persons with status thymicolymphaticus is probably something
more than coincidental. A more complete knowledge of the
innervation of the thyroid gland suggests the possibility that the
cause of the anomalous secretion is to be sought in a primary
affection of the sympathetic nerve, or of the nervous areas in which
it takes its rise. Thus we arrive at a neurogeno-thyrogenic theory
of the origin of Graves's disease.

Another pathological condition which is associated with
clinical hyperthyrosis, is simple goitre. Goitre is a latent swelling
of the thyroid gland, unaccompanied by inflammation.
Anatomically, the degenerative process consists in hypertrophy
and hyperplasia of the gland, by which different parts of the
tissue may be affected in a varying degree. The functional dis-
turbances arising from a derangement of the internal secretion
are, however, comparatively unimportant. The profound meta-
bolic changes produced by the hyperfunction of Graves's disease
are absent in simple goitre, and up to now, an appreciable de-
parture from normal metabolism has not been observed. More-
over, the etiological connection between the pathological signs of
the disease and a change in the function of the thyroid, is very

THE THYROID APPARATUS 103

slight. At a first glance, it might appear that the cardiac and
respiratory disturbances were referable to this cause. But more
careful investigation shows that the respiratory disturbance
results, partly from stenosis of the trachea due to pressure, and
partly from mechanical injury of the nerves of the larynx. The
cardiac derangement consists, anatomically and clinically, in
hypertrophy and dilatation, more particularly of the right heart.
It is brought about, partly by mechanical injury of the venous
circulation (Rose's goitre heart), and partly by the difficulty of
respiration (Kocher's goitre heart with dyspnoea) ; compression of
the nerves of the heart may also be a contributing factor.

The cardio-vascular symptoms are the only ones which can
be regarded as of hyperthyrotoxic origin. These are : palpitation,
some tachycardia, slight cardiac enlargement, glittering of the
eyes, slight tremor, liability to perspire, and dermographism
(Kraus's goitre heart).*

There is undoubtedly an analogy between the symptoms of
Graves's disease and those which are experimentally produced in
animals by hyperthyroidization. Moebius describes a pathological
sequence, commencing with simple goitre, the evidences of Graves's
disease afterwards developing one by one, until the complete
clinical picture of that condition is reproduced. Kraus, however,
does not consider that there are sufficient clinical grounds to
justify such a sequence. For, in the great majority of cases,
the characteristic signs of Graves's disease are absent in simple
goitre, and this applies very particularly to the typical metabolic
changes, a fact of primary importance.

The functional aspect of simple goitre is not identical with
that of hyperthyroidism, and the hyperfunction suggested by
the anatomical conditions is most undoubtedly absent from the
clinical signs. But it must be remembered that the goitrous
degeneration of the thyroid gland represents the anatomical
diagnosis only ; that hypersecretion is not always demonstrable,
even histologically ; and that, though some portions of the gland
are hyperplastically changed and are more actively secretory,
others again are degenerated in such a way that their function
is reduced or even abolished. That "goitre" and "goitre," as
Kocher points out, "are not always identical," is proved by the
fact that, after thyroidectomy, symptoms of suppression may be
in some instances provoked, in others abolished, by the
development of a goitre from a portion of the gland left in situ.
That the anatomical hypertrophy of the thyroid may be
associated either with slight symptoms of hyperfunction or

* E. Bircher (March, 1910) has recently shown that in rats with
parenchymatous goitres produced by means of goitre water, there is in-
variably an enlargement of the heart, shown by the increased weight and
the thickened walls. Bircher believes that the noxa of goitre has a direct
influence upon the heart.

104 INTERNAL SECRETION

severe symptoms of reduced function, is illustrated by endemic
goitre and endemic cretinism, the etiological relationship between
which is well known.

THEORY OF THE THYROID FUNCTION.

We now proceed to utilize the foregoing descriptions of the
results of hypo- and athyrosis, of the activity of thyroid extract,
and of the appearances which accompany hyperthyrosis in man
and animals, as material for a more detailed account of the
functional activity of the thyroid gland.

The thyroid gland was the first organ to be credited with an
internal secretory function, and it was in connection with the
thyroid that the two-fold aspect of this function was first sug-
gested. On the one hand, we have to do with a positive pro-
ductive activity on the part of the gland ; and, on the other, with
its neutralizing activity, or negative secretory function. Thus
two theories regarding the function of the internal secretory
organs arose, the one advocating a positive and metabolic activity,
the other what may be called a negative or antitoxic activity.
Both theories derived a measure of support from the neutralizing
function of the thyroid gland. And, to-day, it is very generally
believed that the secretion elaborated by the thyroid gland serves
to neutralize the toxic products which are formed in the course
of normal metabolism, or which are believed to be formed
abnormally, either qualitatively or quantitatively, upon sup-
pression of the function of the organ. The two theories are
opposed only in regard to the actual place where the process of
neutralization occurs. The secretion theory assumes that this
process takes place in the blood-stream, \vhile the antitoxin theory
places the seat of operation within the thyroid gland itself.

With an improved knowledge of the results which follow sup-
pression of the thyroid function and, more particularly, of the
acute nervous symptoms induced by thyroidectomy, it was very
natural that the idea of an auto-intoxication should present itself.
It was not until the discovery of the presence in the thyroid
gland of a body containing iodine, that its secretory activity
assumed a physiological significance. The results of a sub-
stitution therapy were, however, invariably regarded as due
to a neutralizing and antitoxic action on the part of the thyroid
extract. This view is still so widely accepted that it is expedient
to enter into a more detailed consideration of it.

The antitoxic theory was first propounded by Notkin, and
was afterwards developed by F. Blum. It can have but few
supporters at this date among scientists whose views are based
upon their own clinical or experimental experiences. It is as well,
however, that the theory should be reviewed, because it was ad-
vanced by Blum in opposition to the views which he formerly

THE THYROID APPARATUS 105

held, and which he himself declared to be erroneous; and it
constitutes, in a sense, an attack upon those views.

Blum failed to recognize that the thyroid apparatus is not a
single organ. According to his theory, the " thyroid gland is
not a secretory gland, but is a neutralizing organ, which acts
by withdrawing certain toxins from the blood-stream, which are
neutralized within the gland, the process serving, more par-
ticularly, to protect the central nervous system." The toxins
(entero-toxins) are supposed to be formed within the intestines,
and to be largely derived from flesh foods ; they become fixed
in the thyroid gland, and are there gradually neutralized. In
the course of this process, intermediate products (thyrotox-
albumins) are formed and these, when completely neutralized, are
eventually discharged from the gland in the form of harmless
excreta.

The serious pathological disturbances which follow the sup-
pression of the thyroid function — the acute tetany, with
degenerative changes of the central nervous system, the cachexia,
idiocy and mental derangement, the interstitial nephritis and
grave ocular troubles — these can all, according to Blum, be inter-
preted only as manifestations of a toxic condition. The influence
which diet has upon post-operative symptoms, commented upon
by Horsley, is regarded by Blum as proof of the activity of a
toxic agent which, under normal conditions, would be retained
and neutralized by the thyroid gland. Neutralization is supposed
to take place by iodization of the toxic albuminoid, whereby an
unsaturated thyrotoxalbumin, containing iodine, is formed as an
intermediate product. This body has a toxic influence upon the
heart and upon metabolism. In view of the fact that the amount of
iodine contained in the iodized albuminoid of the thyroid gland
varies very considerably, and that the amount of organically fixed
iodine may be increased by iodide of sodium given by the mouth,
it must be assumed that a continuous process of iodization goes
on in the gland. The process of iodization is continued to the
point of saturation, the saturated iodized albuminoid being non-
toxic. Blum assumes a specific property of isolating iodine — an
iodasis — on the part of the thyroid gland, and he believes, further,
that the iodine stored up in the gland does not again leave it.
He was unable to find the smallest trace of iodine in the lymph
of the thoracic duct of animals which had been given iodide of
potassium in large quantities. As Magnus-Levy points out,
however, a careful examination of the quantitative condition robs
this result of its significance, for the amount of lymph analysed
by Blum was only 100 c.cm., and it \vas certainly not all derived
from the thyroid. Moreover, Gley and Bourcet found that iodine
was a constant constituent of the blood, and their finding is
confirmed by Bonninger.

Blum maintains that iodine is retained in the thyroid gland;

106 INTERNAL SECRETION

for he found iodine in considerable quantities in the thyroid gland
of dogs which had, for months, been given food which contained
no halogens. If the thyroid furnished a continuous supply of
iodine to the blood, it would in time, under these conditions, part
with the whole of its supply. But, as Kraus points out, this
argument is not convincing, for, judging by the analogy of other
substances which are present in the organism in small quantities
only, it is by no means improbable that the iodine which leaves
the thyroid gland is again returned to it by the agency of the
blood-stream. Further, Baumann, and also Miwa and Stoltzner,
showed that, under conditions similar to those described by Blum,
the amount of iodine present in the gland is actually reduced.

If Blum were right in his original assumption that the thyroid
gland supplies a vital principle to the blood-stream, we should
expect the ligature of the veins and lymphatics leading away from
the gland to be followed by symptoms of suppression. Not only is
this'not the case, but Blum found that this operation was followed
by an increased oxidation, a stimulated cardiac activity,
destruction of the red blood-corpuscles, and serious lesion of the
liver, the bile pigment passing into the urine. He deduces from
this that the ligature of the vessels leading away from the gland
causes obstruction, and consequent overflow, of its contents ;
that this produces a partial insufficiency of the organ, which gives
rise to appearances similar to those which follow the exhibition of
thyroid juice. But the results of these experiments contain no
proof that an incomplete, and therefore toxic, toxalbumin proceeds
from the gland. It is much more probable that, under the changed
circulatory conditions, which do not, however, completely arrest
the flow of blood from the gland, the amount of the normal active
substance which passes into the blood-stream is very much
reduced.

That Blum was unaware of much that has recently been
discovered concerning the nature and function of the thyroid
gland, is suggested by the fact that he speaks of the parathyroids
as bodies composed of undeveloped thyroid tissue, which con-
tribute nothing of importance to the general economy. He draws
his conclusions from his own and Kishi's experiments with dogs,
which lived for a considerable time after extirpation of the para-
thyroids, a small proportion of thyroid tissue having been left
in situ. Blum describes the post-mortem findings as follows :
" After a certain time, the remains of the thyroid showed a
remarkable increase in the number of the interior cells, which
produced a certain resemblance to the parathyroids. The follicles,
with occasional isolated exceptions, had entirely disappeared, and
the colloid substance was absent. Closer investigation showed that
the cell-agglomerations formed a tubular structure, similar to that
seen in true glands." After a comparison of this description with
the plates reproducing the microscopic findings, it is not possible

THE THYROID APPARATUS. 1 07

to repress a suspicion that the " remnants of the thyroid gland '
left in situ were not thyroid tissue at all, but were the actual para-
thyroids themselves.

Blum also claims that he was able to cure, or at any rate very
much ameliorate, acute tetany by means of a milk diet. In the
chapter on tetania parathyropriva, instances were given of the
effect upon this condition of certain forms of diet ; a more careful
investigation of this point is very desirable. As far as we can
see, however, Blum's observations do not furnish grounds for
the assumption of an auto-intoxication. They may add to our
knowledge of the function of the parathyroids, but they cannot
be said to supply any evidence as to an antitoxic activity on the
part of the thyroid gland.

The pathological conditions which follow affections of the
thyroid gland result, according to Blum's theory, from the
interruption of the steady procedure of the process of
neutralization. As soon as, owing to suppression of the thyroid
gland, the fixing of the free poison ceases, tetany, cachexia,
strumipriva, myxcedema, and other thyroid affections make their
appearance. If the entero-toxins are fixed, but are not sufficiently
quickly, or not completely, neutralized, the thyroid becomes over-
loaded". This gives rise to those forms of goitre which are favour-
ably influenced by iodine — the neutralizing agent of the thyroid
gland.

If, however, the fixation of the toxin continues uninter-
ruptedly, but the toxin, as thyrotoxalbumin, passes into the blood
before it is completely neutralized, a partial thyroid insufficiency
results, similar to that produced experimentally by the exhibition
of thyroid gland or by ligature of the vessels and lymphatics, and
identical with the clinical picture presented by Graves's disease.
Blum advances this as the clinical ground for the treatment of
Graves's disease by means of an absolutely flesh-free diet, as
opposed to operative treatment.

It must be evident from the preceding pages, that Blum's
theories concerning the thyroid gland are not only insufficiently
grounded, but that they are not adequate either to explain the
physiological and pathological phenomena with which we are
already acquainted, or to pave the way for further knowledge.
Blum's theories offer no explanation of the undoubted effects of
"substitution'1 in conditions arising from thyroid insufficiency,
and he himself must admit the possibility of the neutralizing pro-
cess being performed by the thyroid substances themselves. For
the increased oxidation, by which Blum explains the beneficial
effects obtained with thyroid extract in myxcedema, is the result of
an activity on the part of the thyroid substance, which takes
place externally to the gland, and is not, therefore, dependent
upon the presence of the thyroid cells. Moreover, Blum takes no
account of the significance of the suppression of the parathyroid

IOS INTERNAL SECRETION

function in the causation of tetany. For this reason, his doctrine
represents a step backwards, and, though the risk of post-operative
tetany is now, happily, much less than formerly, the acceptance
of Blum's theory might very conceivably add to the seriousness
of that risk.

The arguments which have been brought forward, and the
observations which have been described, demonstrate very clearly
the erroneous nature of Blum's theory of the antitoxic activity of
the thyroid gland. At the same time, these results show that the
function of the thyroid gland is, by means of its internal secretion,
to supply a chemically active substance to the economy. What is
the nature of the specific activity of the thyroid secretion ? The
theory advanced by Baumann and his pupils and, more par-
ticularly, by Oswald, is based upon the assumption that the
specific activity of the colloid present in the thyroid secretion is
directed to the neutralization of toxic substances, and that this
neutralization takes place within the blood-stream. This is a
combination of the theories of secretion and of neutralization. All
attempts to obtain this toxin from the blood of thyroidless animals
has, however, been attended by as little success as the search
for the toxin of tetany.

The evidence in favour of a neutralizing function on the
part of the thyroid gland is wholly indirect. It has been pointed
out that thyroidectomized animals have a smaller resistance to
inorganic poisons (calomel, according to Perrin and Jeandelize)
than normal animals, and that experimentally induced tuberculous
and post-tuberculous processes are favourably influenced by pro-
longed exhibition of thyroid extract (Frugoni and Grixoni).

The most important evidence in favour of an antitoxic activity
on the part of the thyroid gland and the thyroid substances, is
supplied by Reid Hunt's investigation of the neutralization of
cyanmethyl (acetonitril, CH3CN). He showed that, after the
exhibition of a minimal quantity (i/io mg. of the dry gland) of
thyroid extract by the mouth, the resistance of white mice to the
subcutaneous injection of acetonitril was increased from two- to
ten-fold. Thyroid gland which is free from iodine exercises a
certain amount of influence in this direction, but as a general
rule the neutralizing activity of thyroid extract increases in direct
proportion to its Iodine contents. It is, however, hardly possible
that the process of neutralization consists in a chemical com-
bination of the cyanogen components with the sulphur present
in the gland. For, in the first place, the thyroid substances do
not neutralize the other cyanogen compounds, such as hydro-
cyanic acid and sodium nitrocyanide ; and in the second place, the
amount of acetonitril neutralized bears no relationship to the
amount of thyroid substances.

Reid Hunt himself points out that the results of his
experiments cannot be regarded in any sense as proofs of the

THE THYROID APPARATUS

neutralizing activity of the thyroid gland. He thinks that these
results are sufficiently explained by the changes in metabolism
produced by the thyroid substances. And, certainly, the evidence
in favour of a neutralizing activity on the part of the thyroid
gland cannot yet be regarded as sufficient, seeing that such
activity is manifested only in regard to acetonitril, and only in
mice. Moreover, the resistance of animals, including mice, to
other toxins, as, for instance, morphine, is not only not increased,
but is appreciably lowered by thyroid extract. It is interesting
to note in this connection that the blood of persons with Graves's
disease produces the same increased resistance to acetonitril in
mice as thyroid extract. This may be regarded as evidence in
favour of a hyperthyrosis in Graves's disease.

It is evident, then, that direct proofs of the neutralizing
function of the thyroid gland are not forthcoming, and that the
indirect proofs advanced by Reid Hunt are capable of another
interpretation. Such being the case, the hypothesis of an anti-
toxic thyroid function must be allowed to remain sub judice.
At the time when the symptoms of thyroid suppression were re-
garded as manifestations of an acute auto-intoxication, this
hypothesis was obvious and perhaps even necessary. To-day, it
not only appears unproven, but, in the light of our present know-
ledge of the function of the thyroid gland, it is in reality
superfluous.

All the known phenomena, both physiological and patho-
logical, associated writh the activity of the thyroid gland, are
sufficiently accounted for by the following interpretation of the
thyroid function.

The thyroid gland is a secretory organ, the end-product of
the secretory activity of \vhich is supplied to the blood in the
form of an iodized albuminoid. Inasmuch as it modifies the
activity of distant organs, this substance behaves as a hormone.
As far as we know at present the thyroid secretion, by promoting
katabolism and increasing normal function, plays the part of
disassimilatory hormone to a large number of tissues and pro-
cesses. This disassimilatory activity principally affects the
metabolic processes, the cardiac activity, some portions of the
sympathetic system, and certain of the internal secretory organs
(hypophysis, suprarenals). Certain phenomena in other parts of
the body suggest, however, that the thyroid secretion also
possesses an inhibitory function and contains, therefore, an
assimilatory hormone. The promotion of skeletal growth, the
development of the sexual glands, and the limitation of the internal
secretory function of the pancreas, are instances of such assimila-
tory activity.

The question arises as to whether this two-fold and
antagonistic activity on the part of the thyroid secretion is due
to the action of two different hormones ; or whether the results

HO INTERNAL SECRETION

are brought about by a single homogeneous hormone capable of
producing two opposite sets of effects, according to the apparatus
influenced. The nervous system supplies the only field for such
activity, and so the further question suggests itself : Is the
hormonic activity of the thyroid gland direct, or is it effected
only by the agency of the nervous system? That it is possible
for an organ to send out chemical stimuli which, in different parts
of the body, produce entirely different results— in one part pro-
moting assimilation and in another inhibiting it — cannot be
doubted. It must further be taken into account that the end-
results will also be different in cases where the influence upon
the end-organ is not direct, but is effected by the agency of
another internal secretory organ. Thus, for instance, the changes
which take place in the sexual organs after suppression of the
thyroid might easily result, not directly from the absence of an
assimilatory thyroid hormone, but indirectly and as secondary
results, due to a change in the function of the hypophysis. The
solution of these problems demands a far more complete know-
ledge of the interactivities of the internal secretory organs than
we at present possess.

The second theory, which explains the antagonistic activities
of the thyroid gland by a single thyroid hormone, acting primarily
upon the nervous system, demands serious consideration. Certain
phenomena seem to point to the conclusion, that the changes in
organic function brought about by the agency of the thyroid
secretion, are, in reality, only the physiological expression of a
changed condition of irritability of the vegetative nervous system.
Although the thyroid secretion principally stimulates the sym-
pathetic system, it does not affect it alone, for it also stimulates
certain portions at least of the autonomous system ; moreover, the
sympathetic and autonomous innervation is, certainly in many
parts, antagonistic. This antagonism is sufficiently explained by
the assumption of a single homogeneous thyroid hormone, which
exercises a disassimilatory effect upon the vegetative nervous
system — in other words, increases its functional activity. But it
is very important to remember that our knowledge of the manner in
which the nervous system acts upon the processes of metabolism,
and especially upon the new formation of tissue and the processes
of growth, is extremely meagre. Investigation of recent date,
especially that undertaken by the Vienna school of scientists, has
been concerned solely with the chemistry of metabolism, while the
morphological aspects of these, processes have up to now received
but little attention.

THE THYMUS GLAND.

THE thymus (German : Briesel) develops in man as a paired
sac-like diverticulum of the ventral portions of the third and
fourth, and perhaps also partly from the second, pharyngeal

THE THYMUS GLAND I I I

clefts. It proliferates into the pleural space until it reaches the
heart, at the same time becoming gradually separated from
the branchial clefts. This sac-like primordial beginning of the
thymus is entirely epithelial in structure; the lumen is very small
and the cortex is composed of several layers of epithelial cells.
Branch-like processes are early thrown out from the lower edge,
the organ in man assuming a lobular structure at the second or
third month of foetal life. Connective tissue and blood-vessels
now begin to form and the communication between the central
lumen and the pharyngeal cleft closes up. At birth, the two
halves are grown together in the median line, and the thymus
lies between the sternum, the pericardium and the great vessels,
with the upper end extending upwards into the region of the
neck.

The complete thymus is a greyish-red organ composed of
lobes and lobules, the lobules being surrounded by a delicate
sheath of connective tissue. The change which, in the course of
development, takes place- in the length and breadth of the organ,
is accompanied by changes in its histological appearance, and
the original epithelial organ develops into a structure resembling
the lymph glands.

There are two theories as to the manner in which this
histological change takes place. According to the one, the trans-
formation theory, the epithelial cells divide and subdivide, be-
coming smaller and smaller so as to resemble leucocytes. Accord-
ing to the other, the theory of pseudon'orphosis, the epithelial
beginning of the primordial thymus is, with the exception of a
small portion, entirely replaced by elements from the central
germinal layer. From investigations carried out with a large
number of animals of different species, Hammar concludes that
the reticulum — the supporting and stellate cells, believed to be
derived from the central germinal layer — is in reality also of
epithelial origin. He regards the reticulum as the most important
element of the thymus parenchyma.

Development is accompanied by changes in the epithelial
thymus, both regenerative and degenerative in nature. In the
human embryo, signs of involution appear in the course of the
fourth month, the flat, horny epithelial cells becoming transformed
into the concentrically disposed layers of Hassal's corpuscles. At
the same time, leucocytes pass from the blood-vessels for the pur-
pose of absorbing the broken-down medullary masses. According
to Stoehr, the earlier view of the thymus as a lymphoid organ is
no longer tenable. And he also points out that the so-called
lymphocytes, upon the existence of which the analogy of the
thymus with the lymph glands rests, are of epithelial origin and
are epithelial in their permanent characteristics.

In many animals, the complete thymus is apparently entirely
composed of lymphoid tissue, the epithelial cells having almost

112 INTERNAL SECRETION

completely disappeared. In man, the medullary substance con-
tains larger or smaller groups of epithelial cells, which are studded
with leucocytes. The thymus also differs chemically from the
lymph glands. Ivar Bang showed that the thymus cells have a
different chemical reaction to that of the leucocytes, the bone-
marrow cells, and the cells of the spleen. That the thymus cells
are not identical with those of the lymph glands is proved by
the fact that the amount of the nucleinates, the substances which
are characteristic of the nuclear structure of the true glands, is
at least five times as large in the thymus as in the lymph glands.
The older idea, that the thymus was the seat of origin of the
leucocytes (Beard), is disproved by the investigations of Stoehr.

INVOLUTION OF THE THYMUS.

The thymus is an organ which maintains its structure (as
described above) for a certain period of life only, and its function
is necessarily exercised only during that period. After a short
period of progressive development and growth which, according
to Friedleben, lasts in man until about the second year of life,
retrogressive changes set in, which lead eventually to a complete
disappearance of the parenchyma. The adenoid tissue is gradually
replaced by adipose tissue, the original lobulated formation being
retained until old age, and the fatty substance frequently enclos-
ing small remnants of true thymus tissue. Involution of the
thymus in man coincides normally with adolescence.

Hammar shows that, in addition to the involution of adoles-
cence, there is also an accidental involution, which may occur
at any period of life and leads to a rapid reduction in the size
of the gland. He found that the thymus gland of rabbits in
the fasting state fell, during the first three days, to one-half its
normal weight, and that toxic influences operated in the same
direction. This accidental involution is characterized histo-
logically by a diminution in the lymphocytes of the cortex, a
reduction in the bulk of the lobes, a disappearance of the dif-
ferentiation between cortex and medulla, and a remarkable richness
in blood. In the involution of adolescence, the microscopic
changes are very similar, though the process sometimes affects
certain portions only of the parenchyma and these may be of
varying extent. The formation of adipose tissue takes place in the
interlobular or vascular connective tissue.

The process of involution may, however, be arrested at any
age, and a remarkably large and well-preserved thymus, the so-
called persistent thymus, is sometimes seen in man. In these
cases, according to Schaffer, the original organ is not preserved,
but there is a new formation of thymus tissue, the original medul-
lary substance assuming a fresh cortical layer. Friedleben and,
latterly, Basch, found that after partial extirpation of the thymus,
there was hypertrophy of the remaining portions.

THE THYMUS GLAND 113

The normal weight of the thymus in man is shown by the
following table (Hammar) :-

At birth 13.26 grammes.

Between the ages 1-5 ... ... 22.98 ,,

,, ,, ,, 6-10 26.1 ,,

.. 11-15 37-52 M

,, 16-20 ... 25.58

,, ,, ,, 56-65 ... 16.08 ,,

,, ,, ,, 66-75 6.0 ,,

At a more advanced age the organ is principally composed
of adipose tissue.

The size of the thymus in the dog is estimated by Baum as
follows : At birth, the weight of the thymus is to the body as
i 1250. In the first two weeks the proportion changes to i 1170.
Involution now begins, and in the course of the first two to three
months, the proportion falls to i :i2oo, or i : 1600. Remnants
of the thymus are found in dogs up to the second or third year.
Basch found that the most frequent proportional figures were :
in dogs in the third to fourth week, i : 300; and in rabbits in the
third week, i :5oo or 600. According to Basch, the development
of the thymus in dogs, during the same period, is at least twice
as favourable as in rabbits and cats, and for this reason, dogs
are more suitable subjects for experimental extirpation.

According to Noel Paton and A. Goodall, guinea-pigs are
the best subjects for this purpose. In these animals the thymus
appears in the form of two flat lobes; it is situated in the neck
upon both sides of the trachea and does not extend into the
thoracic cavity. In new-born animals, its average weight is
0.19 grm. to about 80 grm. of body weight, and the \veight of the
organ continues to increase until the weight of the animal is
about 300 grm., which occupies about two months. At this age
the animal becomes sexually mature and retrogressive changes in
the thymus begin to take place; in animals weighing 400 grm.
and over, its average weight is only 0.03 grm.

According to the investigations of Soederlund and Backmann,
the thymus of rabbits attains its maximum relative weight at the
end of the third week after birth ; and its greatest absolute weight
during the fourth month, while the organism is preparing for
spermatogenesis. The involution of the thymus seems to coin-
cide, in rabbits as in guinea-pigs, with the completion of the
development of the sexual organs.

PHYSIOLOGY OF THE THYMUS.

In 1858, a monograph by Friedleben appeared, entitled " The
Physiology of the Thymus Gland in Health and in Disease."
8

114 INTERNAL SECRETION

This work was based upon the results of experimental investi-
gation and clinical experience, and it must still be regarded as
the text-book upon the subject. It not only brings together all
that was previously known about the thymus, but it contains
descriptions of the author's anatomical, physiological and chemical
experiments, together wdth an account of his clinical experiences.
He tested the physiological significance of the thymus by means
of experimental extirpation, and he mentions that he was antici-
pated in this method by Restelli who, in 1845, experimentally
removed the thymus from sheep, dogs and calves. The greater
number of Restelli 's animals died after a short period of fever.
Friedleben operated upon twenty dogs and three goats, his method
of procedure being first to expose the jugular fossa, then to open
the apex of the pleura, thus bringing the thymus into view. After
this it was an easy matter to remove the organ, either whole or
in portions, by inserting the forceps on the inner surface of the
manubrium sterni. Friedleben found that none of his animals
died, and he concludes from this that extirpation of the thymus
does not affect the life of the organism any more than extirpation
of the spleen. He describes metabolic changes, however, affecting
the amount of albumin contained in the blood, the respiratory
interchange of gases, and the products of decomposition found
in the urine. But these results do not stand the test of the more
perfect methods of our day, and the only findings of Friedleben 's
which can be regarded as really important are the changes which
he noticed in the bones of thymectomized dogs (profusion of
blood, pronounced tendency to bend, retarded growth).

It is not until thirty-five years later that we hear of the next
attempt at experimental extirpation of the thymus. Langerhans
and Sawaliew removed the thymus from rabbits three to six weeks
old and found that this wTas not followed by symptoms of sup-
pression. In 1894, Gluck described the results of extirpation of
the thymus after complete resection of the sternum, the animal
remaining perfectly healthy. According to Ambrosini, Thiroloix
and Bernard found that total extirpation of the thymus of young
rabbits was followed by progressive emaciation, the animals dying
three or four weeks later with symptoms of hyperthermia and
convulsions.

Tarulli and Lo Monaco (1894-1897) describe the results of
thymus extirpation in young dogs and young hens, and they
conclude that, in the dog, the thymus is not an organ which is
essential to life. They found that in very young dogs its removal
was followed by nutritional disturbances; reduction in muscular
power; reduction in the volume of the blood, in the number of red
blood-corpuscles, and in the quantity of haemoglobin ; derange-
ment of the growth of the bones; and rickets-like changes in the
skull and bones of the extremities. The changes were, however,
quite transitory, and disappeared as the animals grew bigger.

THE THVMUS GLAND 115

In young hens, operated upon when two to five days old, there was
weakness of the legs, tremor of the entire body, and, finally, a
somnolent condition ending in death. The removal of one lobe
only of the thymus was followed by a transitory weakness, from
which the birds quickly recovered. In birds of more than a week
old, the removal of the whole of the gland, like that of one lobe,
was not followed by pathological signs.

Abelous and Billard (1896) describe the remarkable results
which follow extirpation of the thymus in the frog. According to
these authors, frogs live from three to, at the outside, fourteen days
after total extirpation ; death is accompanied by intense muscular
weakness, trophic disturbances of the skin (pallor, ulceration),
changes in the nature of the blood (decrease in the number of
red blood-corpuscles, leucocytosis) and general oedema. Removal
of one lobe of the thymus is not dangerous to life, but extirpation
of the portion left in situ is followed by the symptoms described.
If the remaining portion is not removed until fifteen to twenty
days after extirpation of the first, it will show a certain amount
of hypertrophy.

Camia is the only author who is able to confirm these results.
The careful investigations of S. Vincent, ver Ecke and, more
particularly, of Hammar, led them to different conclusions,
Hammar found that, during an observation period of twelve to
fifty-nine days after total thymectomy, his frogs showed no
symptoms of pathological disturbance. It seems probable from
Pari's experiments, that the symptom-complex seen by Abelous
and Billard was due to the accidental infection of their subjects.
Moreover, Hammar and ver Ecke found that removal of one side
of the thymus was not followed by compensatory hypertrophy
of the other side; on the contrary, owing to reduced nutrition,
there was a more or less clearly defined accidental involution.
Hammar concludes that the thymus is not more necessary to life
in the frog than it is in mammals.

Experiments with mammals are described by Carbone, Ghika,
Ventra and Angiolella. Carbone found that thymectomized
rabbits and a thymectomized dog did not differ in their develop-
ment from control animals of the same litter, and that they
showed only a passing reduction in the number of their red blood-
corpuscles. Ghika removed the thymus from eight cats and
thirteen rabbits; he found that in the first few days there was
emaciation and arrest of development which lasted for weeks,
though in some of his animals the losses were afterwards made
good. In his opinion, the thymus is concerned in the formation
of blood and the promotion of growth. Ventra and Angiolella
saw cachexia, similar to that which follows extirpation of the
thyroid, in young animals after thymus extirpation.

In 1903, K. Basch first published the results which he
obtained by experimental extirpation of the thymus ; he added

Il6 INTERNAL SECRETION

to these results later, and in 1906 published a detailed account
of his investigations. Before discussing his discoveries in detail,
however, it will be well briefly to describe the results obtained by
means of extirpation by certain other authors.

Cozzolino removed the thymus from young rabbits weighing
300-400 grm. and, in the first two months after operation, was
able to find no change in their condition. In a second com-
munication, however, he describes crookedness of the legs, arrest
of growth, swelling of the tendons, and progressive cachexia
in an animal upon which he had operated three months previously.
The histological changes were : irregular proliferation of the
cartilage in the region of the epiphyses, which were swollen, and
considerable new formation of vessels in the bones.

S. Vincent did not observe any change in the condition of
guinea-pigs after extirpation of the thymus.

Noel Paton and Goodall found that extirpation of the thymus
produced no effect upon the growth and development of new-born
guinea-pigs. The number of the red blood-corpuscles was un-
changed, but up to the age of 2 months there was a reduction
in the number of all kinds of leucocytes. Thymectomized animals
showed the same leucocytosis, inflammatory conditions and
artificial infections in pregnancy as normal animals ; their resist-
ance to the diphtheria toxin was normal, but to streptococci and
staphylococci it was slightly reduced.

Noel Paton arrived at some remarkable results concerning
the behaviour of the sexual glands after thymectomy. That the
removal of the sexual glands of rabbits is followed by hypertrophy
of the thymus, was discovered by Calzolari in 1898. J.
Henderson next showed that early castration is associated in
cattle with a stimulation of the processes of growth and a retarded
atrophy of the thymus. The normal atrophy of the thymus,
which begins at the age of puberty, may be considerably hastened
in cattle by using the young bulls for stud purposes and by
allowing the heifers to become pregnant. Paton found that the
atrophy of the thymus was arrested in guinea-pigs after castration.
He also made the interesting discovery that if thymectomy is
performed on guinea-pigs before they reach the age of puberty,
the operation is followed by a rapid development of the testicles.

U. Soli found that the weight of the thymus in capons was
much larger than in cocks; in the latter it averages 0.6 grm. to
each kilogramme of body weight; while in the capon its weight
is 1.16 grm. to each kilogramme of body weight. In Soli's
cocks, the removal of the thymus produced a reduction in the
weight of the testicles.

It seems probable from these results that the thymus exercises
an inhibitory influence upon the development of the testicles, and
the appearances seem to show that the involution of the thymus
is consequent upon the maturity of the sexual glands.

THE THYMUS GLAND 1 17

The results obtained by R. Fischl from his experiments with
goats, rabbits and dogs were purely negative, and he concludes
from this that the removal of the thymus has no effect upon the
development of the subject. Basch, however, is of the opinion
that Fischl 's experiments were carried out under quite wrong
conditions, and for this reason cannot be regarded as con-
clusive.

Basch points out that the method of extirpation practised by
Friedleben, and by the greater number of investigators after him,
that, namely, of removing the thymus by way of the suprasternal
fossa, is not a good one, at any rate in the case of dogs. He
preferred a median section of the sternum, and was careful to
assure himself before finishing the operation that every particle of
the thymus had been removed. Post-mortem examination some
time after operation does not yield the same results as the
exploration of the living animal. The almost inevitable pneumo-
thorax does not, in his experience, produce unfavourable results.
Of the animals upon which he operated (frogs, doves, rabbits,
cats, guinea-pigs, dogs), dogs are most sensitive to the removal
of the thymus. As in dogs the thymus continues to develop only
during the first weeks after birth, and, at the second month
undergoes rapid involution, Basch always employed suckling dogs
for his experiments, from the same litter as control animals. In
seventeen out of twenty litters, he succeeded in keeping at least
one subject and one control animal alive for longer than four
weeks. He destroyed the greater number of the animals operated
upon in the second month after extirpation ; a few were kept
for a longer period and, in one instance, the animal was kept for
six months.

The most important changes which Basch observed in his
thymectomized dogs were those affecting the skeleton. From the
second to third week after operation the bones were generally
distinctly softer and more pliable than in the control animals, and
the thymectomized animals were more straddling and awkward in
their gait. The hinder part of the body was weaker and more
emaciated, and the upper and lower legs were turned outwards ;
there was less liveliness of movement than in the control animal,
the thymectomized animal mostly sitting upon its haunches. A
few weeks later, the front legs also became bandy ; there was a
broadening in the region of the lower radial epiphysis ; and the
animal walked on the flat of its feet. The animals were backward
in development as compared with the control animals, and some-
times showed a change in the mental condition ; there was less
movement and less intelligence. There was, moreover, in the
course of the first and second months, a distinct backwardness
in weight.

In order to test the conditions of ossification, Basch fractured
a leg-bone at the same time and under similar conditions in both

Il8 INTERNAL SECRETION

the thymectomized and the control animals. He found that the
amount of strength required to break the bone was much less in
the case of the thymectomized than in that of the control animal.
Five to seven days after the fracture the callus in the control
animal was large, and felt more like a spindle-shaped swelling
of the bone; in the thymectomized animal it was ring-shaped and
considerably smaller. The difference in the development of the
callus was perceptible for several weeks. The changes in the
bones were well shown in skiagrams. In the thymusless animal,
the periosteal apposition at the seat of the fracture was slight, the
change of the soft parts into bone being only indicated. The
difference in the formation of the callus was best seen in
suckling puppies, more particularly in cases where the fracture of
the bone took place three to four weeks after the extirpation of
the thymus. This seems to show that the change in the re-
generative processes of the bones does not make itself felt until
after a certain time has elapsed. The changed character of the
bones is most clearly seen in the hollow long bones, especially in
the tibia and femur, and after them in the humerus and the fore-
arm bones ; the ribs and the bones of the hand and the foot are, in
general, much less affected.

The examination of anatomical preparations also revealed a
distinct backwardness in the development of the bones. In the
animals from which the thymus had been removed, the bones
were slighter and smaller than in control animals, while the
epiphysal lines were frequently broadened and irregular. In
two cases there were pronounced changes similar to those seen in
the spontaneous rickets of dogs. Microscopic examination showed
the changes typical of retarded ossification. In the thymectomized
animal, the bone-compact is narrower and contains less lime than
in the control animal ; and the bony trabeculas are more fragile
and contain a larger proportion of the original cartilaginous
formation. There is a larger proportion of cartilaginous tissue
at the epiphysal diaphysis line than in the normal animal. The
cartilaginous coating of the epiphyses is thicker and more
voluminous, and the ossified bony portion is smaller. The long
bones of the thymectomized animal take longer to develop;
calcification progresses slowly, and this causes the retardation of
growth, the softness of the bones, and the imperfect apposition of
the periosteal bony layers after fracture.

Basch does not regard the changes which follow extirpation
of the thymus as being in any way related to rickets. He is much
more inclined to look upon them as disturbances of the develop-
ment of the skeleton, more especially affecting the calcification
of the bones, and having an etiological connection with the
suppression of the thymus gland. The thymus function being
only temporary in its nature, it follows that the changes brought
about by its suppression are temporary also. Basch believes

THE THYMUS GLAND 119

that the changed conditions of ossification resulting from the
suppression of the thymus may be the forerunners of rickets.

Basch endeavours to find an explanation of the changes
in the bones, in the metabolic conditions which obtain in
thymectomized animals. As C. Bracci pointed out (1905), the
removal of the thymus of rabbits causes a reduction of Ca in the
bones and other tissues. Basch investigated the amount of cal-
cium salts excreted in the urine; he found that, during a period
of eight days and under precisely similar conditions, the
thymectomized animals excreted more than twice the amount of
calcium excreted by control animals. This difference disappeared
some considerable time after extirpation.

In contrast to this, however, Sinnhuber found that neither
the extirpation of the thymus nor the exhibition of thymus gland
was followed by an increased excretion of lime in the faeces or
the urine. Basch explains this discrepancy with his results by
a difference in the conditions under which the experiments were
performed, Sinnhuber's control animal being taken from a
different litter to that from which the thymectomized animal was
taken ; and, moreover, the control animal had previously suffered
from a serious nutritional disturbance characterized by exception-
ally high excretion of lime.

Basch also describes a litter of puppies, a few weeks old, in
which the development of the bones was proportional to the
growth of the thymus, while there was no apparent modification of
the development of either the thyroid or the testicles.

He also found that, where a portion of the thymus was left
in situ, there was less difference in the formation of the callus and
that, in some instances, it was quite normal. In one such case
he observed a hypertrophy of the remaining lobe of the thymus.

U. Soli also found that thymectomy was followed in young
rabbits by changes in the development of the skeleton, these
changes affecting the hollow long bones and the ribs.

Sommer and Floerken (1908) described the results of
thymectomy and transplantation of the thymus in both dogs and
cats. The thymus was removed from the animals at the age of
two months ; they lived for six to seven months, and differed from
the control animals of the same litter in awkwardness of shape,
clumsiness of movement, and roughness of coat. Skiagrams
showed that the long bones were much shorter and clumsier than
those of the control animals. In the case of animals in which
a thymus had been implanted, the long bones showed, on the
contrary, an increase in the processes of longitudinal growth.

Ranzi and Tandler (1909) showed some dogs from which the
thymus had been removed by a median section of the sternum.
To prevent pneumothorax, this was done in Sauerbruch's
negative-pressure chamber. Three and a half months after
operation the animals weighed less than control animals from

120 INTERNAL SECRETION

the same litter ; their bones were remarkably soft ; they had a
peculiar straddling walk; and they had not lost their milk-teeth.
There was no enlargement of the testicles.

The implantation of the thymus in young dogs was followed
by contradictory results. The continued subcutaneous injection
of an extract of the thymus glands of sheep, produced in sheep a
backwardness in development and in weight. Ranzi and Tandler
assert that when applied to the enucleated eye of frogs, thymus
extract produces enlargement of the pupil.

With regard to the influence of thymus extirpation upon the
nervous system, Basch (1908) proved that, in young dogs, the
well-known galvanic excitability of the peripheral nervous system
is distinctly increased after extirpation of the thymus. In animals
before thymectomy, or in control animals of the same age, the
kathodic closure contraction takes place at i to 2 milliamperes,
the kathodic opening contraction at over 5 milliamperes; after
thymectomy, the kathodic opening contraction figures gradually
fall, reaching their lowest, 3 to 4 or even 1.5 to 2 milliamperes, in
the third week, and at this they remain for several weeks. In two
cases there was an increased irritability at the cortex of the
brain of the motor-points affecting the anterior extremities.

The hypersensibility of the nerves to electric stimulus is less
intense after thymectomy than after thyroparathyroidectomy, and
for this reason only a small proportion— about one-tenth — of
thymectomized dogs die of convulsions.

According to Sabatini, and his view is confirmed by Basch,
in normal animals the direct application of soluble calcium salts
reduces the irritability of the cortex of the brain ; in thymectomized
animals, the subcutaneous injection of these salts produces a
distinct reduction of peripheral hyperirritability, and their re-
peated injection may even restore the kathodic opening contraction
to its normal figure.

In normal animals, the injection of thymus extract is believed
to increase the sensibility of the peripheral nerves; in
thymectomized animals, both thymus extract and suprarenal ex-
tract rather reduce this sensibility.

According to Basch, the thymus gland is physiologically
associated with a definite reaction of the motor apparatus to the
electric current. He is of the opinion that the causative factor
of infantile tetany lies, not only with the parathyroid glands,
but with the entire group of branchiogenic organs, of which the
thymus is probably the most important ; for not only is it very
sensitive in its reaction to general disturbances, but it is
functionally active in the first years of life only.

Now that we know that, in many species of mammals, the
thymus gland contains accessory parathyroids (Pepere), it seems
probable that the latent tetany associated with Basch 's experi-
ments wras purely parathyroprive in origin, and not in any
way due to suppression of the function of the thymus.

THE THYMUS GLAND 121

EFFECTS OF THYMUS EXTRACT.

Svehla (1896) found that the watery extract of the thymus of
man and of certain animals (pig, dog, ox), when injected into the
veins of dogs, produces an acceleration of the pulse and a re-
duction of arterial tension. The fall in pressure is the expression
of an enfeebling, or of a paralysis, of the vasoconstrictors, while the
acceleration of the heart's action is the result of the direct influence
of the extract upon the cardiac muscles themselves, and not upon
the nervous apparatus which accelerates cardiac activity. The
arrest of respiration and of cardiac activity which sometimes
follow large closes of thymus extract, are secondary results of the
peripheral vaso-motor paralysis.

Svelha showed further that this specific substance is not pre-
sent in the thymus of the human embryo, but is formed after
birth. Its activity apparently becomes stronger with time and,
even at the age of 40, the thymus in man still retains its specific
activity. Both the toxicity of thymus extract and its influence in
reducing pressure have been confirmed by other investigators
(Basch, Livon, Vincent and Sheen). Vincent and Sheen, how-
ever, emphasize the fact that substances with similar depressant
effects are obtained from many tissues besides the thymus. Farini
and Vedoni also describe the depressant action of thymus extract ;
they found that blood containing thymus extract, when circulated
by artificial means through the hinder extremities, did not produce
a vaso-dilation, but a vaso-contraction, which lasted, however,
only a short time. R. Popper (1905) discovered that the marked
reduction of blood-pressure which, together with suffocation and
heart failure, follows the intravenous injection of homologous
thymus extract, is not the result of a specific toxic activity of the
thymus extract upon the circulatory apparatus, but is due to a
property common to all tissue extracts, that, namely" of producing
intravascular coagulation and so giving rise to circulatory disturb-
ances. He found that, in rabbits which died after the injection
of thymus extract, there were extensive areas of coagulation in
the vascular system and in the heart ; dogs, however, usually re-
covered, the formation of thrombi being confined to single vessels.
If the coagulation of the blood is prevented by means of extract
of leeches, the action of the thymus extract ceases to be toxic, and
the reduction in blood-pressure appears only after very large
doses, and then in a very slight degree.

Thymus extract remains active after boiling, and this shows
that its active principle is not, in itself, a ferment, but that it is a
substance which causes the formation of a ferment having the
property of coagulating blood.

122 INTERNAL SECRETION

MORS THYMIA AND THE STATUS THYMICO-

LYMPHATICUS.

The laryngeal spasm of infants was termed asthma thymicum
by the older physicians, and its sudden fatal termination was
supposed to result from changes in the thymus. After very care-
ful investigation, Friedleben came to the conclusion that " neither
the normal nor the hypertrophied thymus is able to provoke laryn-
geal spasm, and that there is no such thing as asthma thymicum."
This view was, at first, very generally accepted. The fact, how-
ever, that in many cases of sudden death, post-mortem examina-
tion showed a distinct hyperplasia of the thymus, led Grawitz to
conclude (1888) that, in such cases, death was due to suffocation
from a mechanical compression of the trachea, and this explana-
tion is still, in many instances, held to be rational and sufficient.

Another explanation was, however, offered by Arnold Paltauf
(1889). He insisted upon the existence of a specific constitutional
anomaly, suggested in Rokitansky's text-book (1861), and which
Paltauf describes as follows :

"Pallor of the skin; well-developed panniculus adiposus ;
hyperplasia of different parts of the lymphatic system, the
lymphatic glands of the neck, axilla, mesentery; enlargement of
the follicles of the naso-pharyngeal cavity, the intestinal walls,
the base of the tongue and the spleen ; the thymus larger than the
average. This finding points to a general pathological condition
of the body which is generally termed the lymphatic constitution.
The hyperplasia of the thymus and its abnormally prolonged
duration are not the causes of death, but are symptoms of the
general nutritional derangement, which is further evidenced by
the enlargement of the lymph-glands, tonsils, &c."

Svehla next concluded, from the effects of thymus extract
upon the heart and the vessels, that the mors thy mica of children
is due to hyperthymization ; that is, to the action of a substance
circulating in the blood, which is supplied in an increased quan-
tity by the hyperplastic thymus.

The fact that the effects of thymus extract are not specific,
withdraws from Svehla's theory its most important support. And
yet Hart, writing quite recently, considers the theory of an accu-
mulation in the organism of the toxic products of metabolism as
the result of thymus hyperplasia, to be quite plausible. He
tions, there was paresis of the hinder extremities, " the cardiac
persistent thymus, rubbed down and prepared under sterile condi-
tions, there was paresis of the hinder extremities, " the cardiac
activity was much accelerated, the animals sat forward and stiffly
upright, as if in cardiac distress, in which attitude, after a few
moments, they died." Post-mortem examination showed that,
apart from hyperasmia, all the organs were healthy ; the supra-
renals showed signs of extreme hypera?mia with some ha^mor-

THE THYMUS GLAND 123

rhages. Calf's thymus, rubbed down and prepared under sterile
conditions, produced negative results when injected into the peri-
toneum of control animals.

Wiesel ascribes sudden death in the status thymicolym-
phaticus to a hypoplasia of the chromaffine system, as seen in the
post-mortem finding of changes in the suprarenals. He thinks that
the secretion of the chromaffine system, which raises blood-
pressure and stimulates the heart and the vessels, is supplied in
insufficient quantity, and that, in such individuals, slight noxae
may cause paralysis of the vessels and heart failure.

It is evident, then, that sudden death in children and adults
as the result of laryngospastic convulsion, .as well as those cases
where death takes place at the commencement of chloroform
anaesthesia, the post-mortem findings frequently being negative,
are referable to a status thymicolymphaticus. The investigations
of Richter, as well as those of v. Sury, show, however, that great
caution should be exercised in identifying sudden death in child-
hood with mors thymica. Richter points out that an acute capil-
lary bronchitis, unrecognized during life, may easily be the cause
of sudden death.

We have, as yet, no sufficient explanation of the pathogenetic
significance of the thymus in mors thymica, or of the manner in
which this is brought about. And the part played by the thymus
in the production of the so-called status thymicolymphaticus is
equally unexplained.

Bartel recently interpreted the status thymicolymphaticus as
one of the symptoms of a more or less general hypoplastic constitu-
tion. He describes the post-mortem findings in over 100
cases. The superficial fascia was in all cases well developed;
the height was frequently above the average for the
sex and age; there was marked swelling and hyper-
plasia of the lymphatic glands, the lymphatic deposits
of the mucous membranes (tonsils, lymph follicles of the
tongue, stomach and intestines) and the follicles of the spleen ; the
bone marrow was frequently red, and there was, in the very large
majority of instances, a much enlarged thymus. The average
weight of the thymus considerably exceeded the average figures
given by Paitauf and Mettenheimer, namely : from 15 to 25 years
of age, 22.1 grm. ; from 25 to 35, 3.1 grm. Bartel's figures
do not differ greatly from those of Hammar, which are, however,
remarkably high. Bartel also found congenital smallness in the
lumen of the aorta and of the peripheral vessels, remarkable small-
ness in the size of the heart, comparatively large brain (hyper-
trophia cerebri), colloid degeneration of the thyroid gland and
fragile structure of the bones. The only details needed to com-
plete the clinical complex of the hypoplastic constitution are :
hypoplasia of the genitals, defective growth of pubic hair; in the
female, narrow vagina, infantile uterus, usually abnormally large

124 INTERNAL SECRETION

and smooth ovaries, menstrual anomalies and frequently
anomalies of pregnancy ; in the male, deficient growth of pubic
hair and smallness of the external sexual organs.

Out of 15 cases of Addison's disease, Hedinger found 7 with
marked status thymicolymphaticus, 5 in whom the condition was
not so marked, and 3 in whom it was uncertain.

The pathological significance of the constitutional anomalies
presented by the status thymicolymphaticus is shown, in the first
place, by the greater sensitiveness of such individuals to harmful
disturbances of all kinds (Laub). Their greater vulnerability is
shown by the fact that more than half of these subjects die early
in life (14 to 25) of infective diseases. Of these the most frequent
is tuberculosis, but nephritis, eclampsia and diabetes are all to
be met with ; and suicide is a not infrequent termination to these
lives (Bartel).

The older pathologists regarded this condition as a pre-
disposition to tuberculosis and to certain other infective diseases ;
this view is confirmed by the results of modern investigators
(Kundrat, Ort, Bartel).

THE SUPRARENAL SYSTEM.

THE INTERRENAL AND ADRENAL SYSTEMS.

HISTORICAL.

THE suprarenal capsules were first recognized as separate
organs by Bartholomeus Eustachius Sanctoseverinatus, the great
anatomist of the Renaissance, in the year 1563. It is commonly
believed that these organs are mentioned in different passages in
the Bible, but the notion is an erroneous one arising, as Blanchard
points out, from incorrect translation of the Vulgate.

The manner in which our knowledge of the suprarenals has
grown is interesting from many points of view. This is fully
described in another place, the present intention being to give
only a very brief summary of the more important historical data.

The work of Eustachius was followed up by a number of
authors, who made exhaustive investigations into the anatomy and
functions of the suprarenal capsules. It is nevertheless curious
to find that many anatomical and medical works of the iyth and
i8th centuries contain no mention of these organs (Vesalius,
Fallopius, Fabricius, Aquapendente and van Swieten).

In 1716, the Academic des Sciences of Bordeaux offered a
prize for an answer to the question : " Quel est Tusage des glands
surrenales?" The judge was Montesquieu, then 29 years of age,
who found himself unable to award the prize to any of the con-
flicting and, in some instances, very extraordinary theories offered
in solution of the problem. He closed his searching criticism of
these theories with the words : " Le hazard fera peut-etre quelque
jour ce que tous les soins n'ont pu faire."

THE SUPRARENAL SYSTEM 125

This fortunate chance was a long time in coming. In 1819,
Caillau made Montesquieu's judgment public, at the same time
reviewing the work of the century following it, and his summary
was this: " Les anatomistes n'ont pas pu decouvrir 1'usage des
glandes surrenales . . . Nous ne sommes pas plus avances
aujourd'hui sur les glandes dont il est question que du temps du
fameux Eustache qui en parle le premier."

Caillau's view was right in so far as it concerned the function
of the suprarenals; but it must not be forgotten that the iSth cen-
tury added largely to our knowledge of the anatomy of these
organs. In 1752, J. B. Winslow published an exact description
of the anatomy of the human suprarenals, and at the beginning of
the i gth century (1806) J. F. Meckel's comparative anatomy of the
suprarenals appeared, a work the importance of which it is difficult
to over-estimate.

In the course of the next fifty years, important additions were
made to the morphology of the subject. In 1846 A. Ecker gave
an exact description of the minute structure of the suprarenals as
revealed by the microscope. Leydig's work in comparative mor-
phology (1851-1853) and A. Kolliker's epoch-making description
of the histological structure of the suprarenals (1854) \vere of the
highest importance to the later development of our knowledge of
the subject.

The year 1855 marks both a turning-point and the commence-
'ment of a new era in suprarenal research. All that had gone
before served merely as the foundation for a profound and far-
reaching doctrine concerning the physiological and pathological
significance of these organs, a doctrine which to-day is,
in certain directions, still awaiting completion. At that
date, the work of nearly three centuries had supplied
all that was to be known macroscopically of the anatomy of
the suprarenals; there was a certain small amount of knowledge
of the embryology, teratology and pathological anatomy
of the subject ; the keen research of the fifty previous
years had supplied important data in the department of com-
parative anatomy; whilst as much was known of the minute
structure as the means of that day permitted. But the physiology
of the suprarenal capsules was a sealed book. The older authors,
it is true, formulated vague and generally insufficiently grounded
hypotheses concerning the functional significance of these organs;
more modern observers, basing their views upon the results of
investigation in comparative anatomy and histology, arrived at
more or less well-founded suppositions; but in no case did either
observation or experiment bring to light a single fact concerning
the functional activity of these organs in any direction whatsoever.

It was in 1855 that Thomas Addison published his book
" On the Constitutional and Local Effects of Disease of the Supra-
renal Capsules ' —a work in which a clinical condition observed

126 INTERNAL SECRETION

in man was, upon pathologico-anatomical grounds brought into
relationship with a disturbed condition of the suprarenals.

Addison described the condition, which was afterwards named
after him, as an idiopathic anaemia, associated with extreme
apathy and adynamia, disturbances of the digestive tract and of
the nervous system, and a bronze-coloured pigmentation of the
skin and mucous membranes ; whose course was chronic ; which
presented all the features of a progressive cachexia, frequently
accompanied by violent symptoms, such as uncontrollable diar-
rhoea, coma and convulsions; and with a termination which was
always fatal. In every case examined, the post-mortem findings
showed serious disease, generally tuberculous in character, of the
suprarenals, and Addison concluded from this that both the patho-
logical condition and its fatal termination were due to suppression
of the suprarenal function.

Addison's observations supplied the first contribution, from
clinical experience, to the physiology of the suprarenals ; they
showed that these organs are essential to the life of the individual ;
and they furnished certain inferences as to the nature and method
of their functional activity.

Addison's discovery gave an immense impetus to research
which, for the first time in the history of this subject, was con-
ducted upon physiological lines; that is to say, by means of ex-
periment with the living animal. It \vas believed that extirpation
of the suprarenals of animals — planned earlier by various investi-
gators (Ecker, Meckel) but never carried out — would supply the
much desired information as to the function of these organs.
Moreover, this method alone could decide whether the clinical
condition observed by Addison in man, could be induced in
animals by the experimental destruction of their suprarenals.
These expectations were, however, not fulfilled. Although a
large number of communications were forthcoming \vhich con-
firmed the coincidence of the classical symptom-complex — pig-
mentation of the skin, muscular weakness, gastro-intestinal de-
rangement, anaemia, — with a disease of the suprarenals in man,
yet in no case was it possible experimentally to reproduce a similar
group of symptoms in animals. All that experimental investiga-
tion was able to achieve, was a definite answer to the question as
to w'hether animals could survive after extirpation of the supra-
renals— in other words, as to w'hether or not the suprarenals \vere
essential to the life of the animal.

The first accounts of such experiments were published in the
year 1856. The results described were capable of various inter-
pretations and led to a vast amount of discussion which, helped on
by numerous experiments, lasted until about the middle of the
'sixties. It seemed at that time that the part played by the supra-
renals in the animal economy was not a vital one.

The interest of physiologists was, however, permanently

THE SUPRARENAL SYSTEM 127

aroused, and the suprarenals have since formed a constant subject
of investigation. A strong impetus was furnished by the new
doctrine of the internal secretions and, more particularly, by the
discovery of the remarkable physiological activity of the watery
extract of suprarenal.

Since 1896 a large number of publications have appeared
(Brauer, Diamare, Fusari, Giacomini, Grynfellt, Kohn, Kose,
Pettit, Poll, Soulie, Srdinko, Vincent, Wiesel) in which the
suprarenal question is treated from the genetical and from the
comparative morphological points of view.

COMPARATIVE MORPHOLOGY AND EMBRYOLOGY.

The study of the comparative morphology and of the embry-
ology of the suprarenals led to a complete revision of the older
theories, and created a new physiological foundation. The results
of these investigations are, briefly, as follows :

Neither morphologically and genetically, nor physiologically
and pathologically, are the suprarenals homogeneous organs, but
they are the result of the combination of two different and inde-
pendent organic systems. The suprarenal complex is derived,
not from the whole of these systems, but from different larger
portions of them.

The earlier view, which regarded the suprarenals as inde-
pendent homogeneous organs, having a topographical relationship
to the kidneys, was a perfectly justifiable one, for it was based
upon purely anatomical data obtained from man and the higher
mammals. That the physiology and pathology of the suprarenals
are largely derived from this anatomical standpoint and continue
to be affected by it, is readily comprehensible; but that this is a
cause of much of the haziness by which the subject is surrounded
cannot for a moment be doubted.

The conception of the suprarenals as homogeneous organs,
early underwent a certain amount of modification ; for in addition
to the principal organs, other structures were frequently observed
to be present, sometimes associated with the principal organs and
sometimes isolated from them, which could only be regarded as
accessory suprarenals. Although the presence, position and
structure of these bodies is subject to considerable variation, yet
they occur so frequently that they must be regarded as normal
structures. The fact that their existence has so often been ignored
and their physiological significance insufficiently understood, has
been a very fruitful source of error.

If the conception of the suprarenals as homogeneous organs
was shaken by the discovery of these accessory bodies, a con-
sideration of their structure served to shatter the theory entirely.
Section of the suprarenals shows, even to the naked eye, that they
are composed of two sharply defined portions, differing from one

128 INTERNAL SECRETION

another both in colour and consistency. This difference was
recognized by the earlier investigators, by whom the two portions
were distinguished as the " medulla " and the " cortex." These
terms are not merely topographical, but possess a histological
significance. The microscopic examination of the more minute
structure shows that the medulla and the cortex of the suprarenals
are composed of two different tissue formations.

The cortex is composed of rows and columns of cells contain-
ing a varying quantity of shining granules, which are partly
double-refractive. The characteristic reactions of these granules
show that they contain fat or are closely related to lecithin, and
for this reason they are known as lipoid granules. They colour
strongly with the specific analine dyes for fats (alkanet, sudan III,
scarlet R.); they stain black with fluids containing osmium; and
they are more readily soluble than fats in fat-dissolving agents
(chloroform, xylol, ethereal oils).

The medulla consists of a tissue well furnished with nerves
and vessels, and composed of spheroid or cord-like cell-agglomera-
tions, the cells of which possess a specific affinity for chromium
salts. The contents of these cells are very evanescent, but they
may be preserved in chromic acid and solutions of the chromic
acid salts, by which they are coloured a light yellow to dark brown
(Henle, 1865). The finely granular cyptoplasm has a marked
affinity for the specific stains for nuclei (carmine, hasmatoxylin,
safranin) and colours a black-green with ferric chloride.

Thus, the anatomically homogeneous suprarenals consist his-
tologically of a peculiar combination of two different tissues, the
cells of one being characterized by their lipoid contents and those
of the other by their chromaffinity.

This differentiation is not sufficient, however, when we come
to the anatomical comparison of the homologous organs of the
different classes of animals. It is only in the higher mammals
that well-defined paired organs are met with which, from their
position and partly also from their structure, can be identified as
suprarenals. In birds these organs consist of the two characteristic
kinds of tissue, but the topographical arrangement of medulla and
cortex is absent. It is rather the intimate interweaving of two
nets of cell-columns of which one — the system of principal
columns — has all the histological characteristics of the suprarenal
cortex, the other — the intermediary system — presents those of the
chromaffine medulla. The conditions in reptiles are essentially
the same, but it is worth noting that here the tissue with lipoid
cell-contents is largely predominant; it is only in the hydro-
sauria and chelonia (crocodile and tortoise) that these cortical '
threads are interwoven with fine medullary threads. In the lepido-
sauria (lizards and snakes), isolated balls of medullary substance
are scattered in a ventral direction in the cortex, and the greater
part of the chromaffine tissue occupies a dorsal position.

THE SUPRARENAL SYSTEM 1 29

This, at least anatomically, isolated suprarenal of the
am n iota is absent in the anamniota, where it seems to be replaced
by a number of small bodies, partly connected and partly entirely
separate. The amphibia represent, to a certain extent, the tran-
sition stage between the higher and lower vertebra?. In the anura
(frogs, toads), the yellow bodies which represent the suprarenals
are united to form a thin plate which is attached ventrally and
medially to the kidneys ; in the gymnophiona (blind worms), they
are united at least at the head end to form a largish mass, and
the cordal part only is broken up into separate portions; in the
urodela (salamander, newts), they are divided into numerous small
islands, situated close to the kidney and along its entire length.
The histological relationship between these organs of the amphibia
and the suprarenals of the amniota is shown by the fact that, in
addition to the larger portions, composed of rows of cells with
lipoid contents, chromaffine tissue is also present in isolated
groups of cells and cell-masses which, in the anura, form an inter-
communicating network of intermediary columns.

In all vertebrates lower than the batrachians, the suprarenals
are replaced by two topographically separate systems of small
bodies.* The only exception is the amphioxus, in which no
cell-groups of a structure similar to suprarenal tissue have as
yet been found.

The one system includes the entire body, described in the
Selachii under the name of " interrenal body," lying between the
caudal end of the kidneys ; in the Teleostii, the so-called
' corpuscle of Stannius " ; and in the Ganoidei, the corpuscles dis-
tributed throughout the whole kidney, likewise described by
Stannius; as well as the small structures which, in cyclostomata,
are attached to the walls of the posterior cardinal veins and
extend from the region of the pronephros (head kidney) to the
tail. Histologically, all these bodies are exclusively composed
•of cells arranged in vesicles or tubules. The cells contain lipoid
granules and their structure is therefore similar to that of the
suprarenal cortex.

The second system is chromaffine in character and comprises
those paired bodies, associated with the sympathetic ganglia and
lying dorsally to the kidneys in the caudal rump-part of the body,
which, in the Selachii, are called the suprarenal organs. But as
this terminology is liable to lead to confusion (the German

* The question as to whether or not the invertebrates possess organs
•equivalent to the suprarenals was first propounded by Leydig. He observed
peculiar cells with yellow granular contents against the nerve fibres and
ganglia of Paludina, Pontobdella and Mermis, and regarded these as the
counterparts of the suprarenals. Poll and Sommer found chrome-brown
cells in the central nervous system of leeches, and Poll 'found similar cells
in the abdominal ganglia of Hirudo, Aulastoma, Placobdella, and Xephelis.
I myself found that the extract of the abdominal ganglia of Hirudo
mcdicuialis and Lumbricus terrcstris contained adrenalin, and this may be
proved by biological methods.

9

130 INTERNAL SECRETION

Nebennieren being called in English " suprarenal bodies "), it is
expedient to call them, from their histological characteristics,
chromaffine or phasochrome bodies; or, from the nature of their
function, they may be termed adrenal organs.* In the Teleostei
and Ganoidei, these adrenal bodies are situated in the walls of the
cardinal veins. In the Cyclostomata, the adrenal system extends
from the neighbourhood of the second pair of gills to the tail ;
it takes the form of bands, which are situated between the aorta
and the cardinal veins, and are intimately associated with the
blood-vessels.

Comparative anatomy shows that the two fundamental tissues,
which in mammals are distinguished as cortex and medulla, are
present in all vertebrates, and are therefore to be regarded as
structures which are component parts of the vertebrate body. In
fish, the two kinds of tissue appear as two different organic
systems, anatomically separate from one another, and known as
the interrenal and adrenal systems. The interrenal system includes
all the structures which, like the suprarenal cortex, are composed
of cells with lipoid contents; the adrenal system comprises all
tissues the cells of which, like those of the medullary portion of
the suprarenal, are characterized by their chromaffinity.

In the higher vertebrates, however, these systems have, to a
differing extent, lost their independence, and have also become
very much reduced in size. A partial amalgamation of both
systems is seen in the amphibia, the independent portion of the
adrenal system here forming isolated cell-agglomerations, which
are intimately connected with the sympathetic system. In reptiles
and birds, the association between the two systems is more
intimate ; though independent portions of the adrenal system are
found, in the form of chromaffine bodies, throughout the sympa-
thetic system in birds, while in reptiles they lie along the great
abdominal vessels. In mammals, the amalgamation of the two
systems is complete. This is the result of the topographical
arrangement by which the adrenal system becomes the medullary
portion, while the interrenal system becomes the cortical portion,
of the suprarenal capsules. But even here, a considerable pro-
portion of the adrenal system remains independent. It is
distributed along the sympathetic system, partly in the form of
isolated pha?ochrome cells and larger or smaller chromaffine
bodies, and partly in the form of larger structures, invariably
found at the bifurcation of the carotid artery and at the abdominal

* The terms " chromophile " (Stilling), "chromaffine" (Kohn), " phzeo-
chrome " or " chrome-brown " (Poll) tissue, indicate a special histological
characteristic; the term " paraganglia," suggested by Kohn, has an etiological
significance; while the term "adrenal system," in so far as it is not a
topographical description but is used as a synonym for " adrenalin-
producing organs," expresses the functional significance of these glands.
The chrome-brown cells are very aptly termed " cellules adrenalogenes " by
Bonnamour.

THE SUPRARENAL SYSTEM 13!

division of the aorta and named respectively the carotid gland and
Zuckerkandl's accessory organs of the sympathetic system.

The greater number of \vhat are usually called accessory
suprarenal organs are rather, from their histological structure,
free portions of the interrenal system, and should by rights be
called accessory interrenal bodies. They are found in the neigh-
bourhood of the suprarenals ; in the substance of the kidneys ;
and distributed through the whole of the retroperitoneal space
and extending downwards into the pelvis, in women chiefly in
the ligamentum latum, in men in the vicinity of the spermatic
cord and the testicles.

A homogeneous suprarenal is found only in the higher verte-
brates, and even here it is only certain portions of the two systems,
varying in different classes, which combine to form the apparently
homogeneous organ. The suprarenal of mammals, with its cortical
and medullary parts, represents a combination of portions of
the adrenal and interrenal systems. The terms " cortex " and
" medulla ' merely represent the topographical conditions in
mammals; in reptiles and birds the systems are differentiated
into "principal" and "intermediary columns"; in the lepido-
satirii and amphibia a portion of the " medullary substance " lies,
not in the interior, but upon the surface of the " cortex." As
histological definitions, 'cortex' and ''medulla" are synony-
mous with interrenal and adrenal tissue, but being only parts of
these systems, they can never be employed to describe the
systems as a whole.

It has been shown by means of comparative anatomy and
histological investigation that the bodies of vertebrates contain
two different and independent systems, certain portions of which
combine to form the suprarenals of the higher orders. This is
confirmed by the results of comparative embryology. In all
orders of vetebrates during organogenesis, two independent and
autonomous organic systems are evolved from two different
primordial beginnings. These are the adrenal and interrenal
organs which, according to the further development of their tissue,
maintain their independence either wholly or in part (as in cyclo-
stomata and fish). In the course of histogenesis, and after mani-
fold changes, large portions of each system combine to form either
a number of small bodies, as in the amphibia, or a single homo-
geneous organ, such as the suprarenals of the amniota.

The interrenal system is the direct descendant of the meso-
derm. It is developed from the ventral portion, that part which
forms an epithelial sheath, covering the lateral plates of the ccelom
in the so-called interrenal zone. At about the time when the
sexual glands first begin to appear, thickenings of the peritoneal
epithelium are formed by means of mitotic cell-proliferation at
circumscribed areas. These thickenings take the form of buds,
the cells of which early acquire a characteristic appearance. Later

132 INTERNAL SECRETION

on, the buds become detached from the parent membrane and
assume the status of interrenal organs which, in the form of
isolated cell-agglomerations, lie free in the supporting tissue and,
by their change of position, acquire fresh topographical relation-
ships to the surrounding organs. At the same time, as growth
continues, processes of degeneration and of coalescence take place,
leading, in the former case, to a reduction in the length of the
system, which originally extended over comparatively large por-
tions of the body of the embryo ; and in the latter, to the partial
or complete negation of the primary discontinuity of the system.
Thus, vigorous growth and the coalescence of separate buds is the
primary origin of the principal organs, while accessory organs are
primarily the result of imperfect involution. Accessory bodies
may, however, be formed secondarily at a later date by fission of
the principal organs.

The embryonal interrenal cells undergo further histological
and cytological differentiation until the specific structure is
assumed. In cyclostomata and in fish, the interrenal system
remains in this condition of independence.

The adrenal system is derived from the ectoderm ; it shares its
primordial beginning with the sympathetic system and develops
as a part of it. In the course of the histogenesis of the sympathetic
ganglia, two different cell-types are formed from the apparently
homogeneous and undifferentiated seat of origin of the primitive
ganglia. Of these, one is the prototype of the sympathetic nerve-
cells, while the other includes certain specific elements of a peculiar
character which are the first chromaffine cells (phueochromoblasts).
The latter occur either singly or in larger or smaller groups in the
midst of the nervous tissue and not divided from it. The
apparently homogeneous primitive beginning may, however,
divide into t\vo in such a manner that the chromaffine tissue lies
within or near a sympathetic ganglion, and may occasionally be
separated from it by a sheath of connective tissue. In the Selachii,
the elements of the adrenal system remain stationary at this stage
of development, and are represented by the so-called suprarenal
bodies of this order. Finally, there may be a complete topo-
graphical separation of the adrenal elements from the sympathetic
system, the chromaffine bodies, as soon as they become separate
structures, showing only very slight traces of their genetic asso-
ciation with the sympathetic. Separation of all three kinds is
seen in amniota and in amphibia. In these orders the adrenal
system consists of depositions of chromaffine tissue within the
sympathetic ganglia and plexuses; of deposits of chromaffine
bodies attached to the sympathetic; and of relatively autonomous
structures like the so-called accessory organs. The slight dis-
position to a separate existence by which the organs of the adrenal
system in general are characterized, is also shown by the fact that
portions of this tissue associate themselves at an early develop-

THE SUPRARENAL SYSTEM 133

mental stage with other heterogeneous tissues, such as the carotid
gland and the interrenal tissue.

The development of the suprarenal represents a later chapter
in the history of both systems; it is the last genetic event in which
a combination of interrenal and adrenal tissue takes place. It is
seen for the first time in the amphibia, where groups of character-
istic cells, released from the sympathetic ganglia, wander along
the wall of the aorta in a ventral and median direction, finally
reaching the interrenal bodies, which are already fully formed
and clearly defined. In the gymnophiona, these cell-groups place
themselves by the side of the interrenal cell-bodies, but in the
urodela and anura they become either partially or wholly inter-
mingled with them. The result is the formation, not of a supra-
renal, but of a number of small suprarenals.

In reptiles and birds the process is analogous. At the begin-
ning, the interrenal system consists of isolated buds; at a later
period, sympathetic elements associate themselves with the meta-
morphosed and well-defined interrenal body and, in the course of
histogenetic development, this association becomes more intimate.
Almost the entire interrenal system is used up in the formation of
the suprarenal bodies, and the accessory interrenal bodies, which
are rare in these orders, are probably formed by secondary division
of the principal organ.

In mammals, at the time when the interrenal system has be-
come clearly defined and histologically differentiated, which in
the human embryo is at about the fifth week, undifferentiated sym-
pathetic elements wander from the principal mass of the abdominal
plexuses to the cell-columns of the interrenal bodies. These cells
break through the capsule upon the median side and make their
way between the cell agglomerations and columns of the interrenal
tissue, at the same time keeping their structural relationship with
the abdominal sympathetic. In the external mass, a differentia-
tion between nerve-cells and chromaffine cells is soon perceptible;
but the cells which made their way into the interior remain for a
long time in their primordial state. This intrusion of sympathetic
elements is continued during the whole of fcetal life, the interrenal
tissue becoming entirely interwoven with these elements, as seen
in the completed suprarenal of birds. It is not until later, when
the histological and cytological transformation of interrenal tissue
into the three-layered suprarenal cortex is complete, that the inter-
polated sympathetic elements become, in a topographical sense, the
suprarenal medulla. At about the beginning of the fourth month,
they acquire the chrome-brown colour which is their chief histo-
logical characteristic. That in mammals, as in the other higher
orders of vertebrates, the whole of the interrenal tissue is not used
up in the formation of the suprarenals, is shown by the fact that
accessory suprarenals frequently occur which contain no trace of
chromaffine tissue. These structures, which should rightly be

134 INTERNAL SECRETION

termed "accessory interrenal bodies fl (Beizwiscbennieren), may
be formed primarily by the persistence and after-growth of isolated
interrenal buds placed in a caudal direction ; they may also be
formed secondarily by fission of the principal organ, due either to
interproliferation of the sympathetic elements, or to circumscrip-
tion of growth and consequent division as the result of connective
tissue formations.

It is obvious that wherever, in the course of embryonal
development, portions of the interrenal and adrenal systems come
into close topographical relationship, true "accessory suprarenals"
(Beinebennieren) may be formed ; that is to say, organs composed
of a cortex and medulla with a structure the exact counterpart of
that of the suprarenals. The accounts of such bodies are, how-
ever, very scanty. In 1884, d'Ajutolo found a true accessory
suprarenal in the plexus pampiniformis of a newly-born boy ; and
Delamare found one in 1904, in the solar plexus. Aschoff (1903)
describes chromaffine bodies and interrenal structures lying side
by side in the paradidymis and parovarium of newly-born children.

Comparative embryology supplies etiological proof of the
existence within the body of animals of two independent supra-
renal systems ; it also shows .how, in the course of philogeny, these
systems tend to an increasing and more perfect unification. The
question arises as to whether this coalescence results in an organ
the homogeneous character of which is purely morphological, or
whether this combination of the two heterogeneous systems is the

o *

expression of an intimate functional relationship of the two, the
suprarenal being perhaps functionally a higher organic entity.

But physiology, whose province it is to solve this problem,
was from the beginning confronted with an anatomically homo-
geneous suprarenal and, up to the present, has occupied itself
solely with the suprarenal function.

The following tables illustrate the suprarenal systems as
they occur in all the animal classes. Table A shows all that is
at present known concerning the invertebrate animals and the
vertebrates up as far as the bactrians inclusive. In addition to
the permanent conditions affecting the interrenal system, it shows
those which obtain in the embryonal interrenal. Table B includes
all vertebrates higher than the bactrians ; it illustrates the condi-
tions which govern the embryonal interrenal, those affecting the
free portions of both the interrenal and adrenal systems, and the
conditions governing those portions of both systems which unite
to form true accessory suprarenals.

PHYSIOLOGY OF THE SUPRARENALS.

EXPERIMENTAL EXTIRPATION.

It has already been pointed out that Addison's epoch-making
discovery of the results which, in man, arise from the suppression

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138 INTERNAL SECRETION

of the suprarenal function, was followed by a large number of
experiments, undertaken with the object of discovering whether or
not the suprarenals are essential to the life of the organism. The
lack of a sound anatomical basis was, however, a great bar to
physiological investigation. It was not until after nearly fifty
years of experimental work of the most searching kind, that the
conflicting evidence was reconciled and a satisfactory solution of
the problem finally discovered.

A brief review of the evolution of the subject is not without
interest.

As the result of his experiments with animals, Brown-Sequard
came to the conclusion that the removal of both suprarenals, or
even of one, as he originally believed, resulted in death within a
very short time (average 34 hours), and that death in such cases
was due to suppression of the suprarenal function. It was not
long, however, before this view was disputed upon many sides.

It was pointed out by Gratiolet, Philipeaux, Berrutti and
Perusino, and Harley that the death of the subjects might easily
result from secondary affections, such as surgical shock ; the lesion
of numerous nerves and plexuses, the semilunar ganglion
more particularly; hepatitis and peritonitis. But more impor-
tant than this was the fact that numerous accounts were given by
different authors (Martin-Magron, Berrutti and Perusino,
Philipeaux, Harley, Chatelain, Schiff) of cases where animals, as
mice, rabbits, cats, dogs, horses, and especially rats, lived with-
out pathological signs for weeks and months after extirpation of
both suprarenals.

With this negative solution of the problem of the vital im-
portance of the suprarenals, general interest in the subject
declined, and to such an extent that between 1863 ar>d 1879 no
publication dealing with the experimental side appeared.

Nothnagel's experiments in 1879 supplied a fresh stimulus
to investigation. He, together with other scientists both of his
own and of a somewhat later day (Foa, Burg, Russo-Giliberti
and Di Mattei, Tizzoni, Alezais and Arnaud), endeavoured
by means of lesions of the most varied description (crushing,
cauterization, £c.) to produce chronic inflammatory processes of
the suprarenals, in the hope of obtaining experimentally the
clinical complex of Addison's disease, as seen in man. These
experiments were of little value in determining the vital import-
ance of the suprarenals, for, in the large majority of cases, there
is no proof that by the methods employed the whole of the supra-
renal tissue was removed. It is much more probable, and the
experimental evidence points directly to it, that where the animals
lived for some time after operation, portions of suprarenal tissue
had been left in situ, and that, as a result of regenerative pro-
cesses, these remnants became enlarged later. This accounts also
for the statement that animals will live for some time after sup-

THE SUPRARENAL SYSTEM 139

pression of both suprarenals, provided that they are destroyed
separately, several weeks being allowed to elapse between the two
operations.

From the results of his experiments with dogs and rabbits,
Tizzoni came to the conclusion that the destruction of one or both
suprarenals is followed by death. He believed that death may
occur soon after operation or. that it may be postponed for weeks
and even months, and that it occurs as the result of serious changes
of the central and peripheral nervous systems. He describes far-
reaching disturbances of the nerve-fibres and ganglion-cells,
accompanied by pronounced congestion, changes in the vessel
walls, haemorrhages, and leucocyte infiltration into all parts of
the nervous system. Tizzoni 's experiments do not prove that the
suprarenals are essential to life, for his animals sometimes sur-
vived experiment for months and even years. Moreover,
definite proof of a relationship between the operative procedure
and the post-mortem findings would have to be forthcoming.
Such proof is lacking; and, in view of the method of operation
employed, by which total extirpation of the suprarenals has rarely
been accomplished, Tizzoni's experiments seem rather to show
that animals with even serious lesion of the suprarenals may live
for a long time without pathological signs, provided that these
organs are not entirely destroyed.

Tizzoni's statement that, whether one suprarenal or both were
extirpated and, in the latter case, whether they were removed
together or singly, the results were in all cases the same, is a
proof of the unreliability of his conclusions. This statement
was challenged by H. Stilling in 1890. Stilling found that
young rabbits, in which the left suprarenal had been destroyed,
lived for several months to over a year without showing signs of
disturbance.

Stilling was able to show that, after extirpation of the one
suprarenal, the other became very much larger, and in fact
showed compensatory hypertrophy. This is a discovery of the
greatest importance in determining the functional significance of
the suprarenals.

According to Stilling, the weight of both suprarenals in the
rabbit is on an average o.i grm. to 1,000 grm. of body
weight, but after extirpation of the left gland he found that in
six cases the right gland weighed 0.17 to 0.43 grm. per kilo of
body weight. He also found that after the removal of both supra-
renals, the remnants of tissue which it is almost impossible to
avoid leaving upon the right side, may by proliferation of the
undamaged cells, become as large as the normal suprarenal.
Stilling, like Canalis, found accessory suprarenals in normal rab-
bits in two cases out of forty, and in every case where the principal
organs had been removed; he makes the interesting statement
that, after extirpation of one suprarenal, accessory suprarenals are

140 INTERNAL SECRETION

very frequently found in the vicinity of the vena cava and
vena suprarenalis. In his view, the suppression of the suprarenal
function causes a strong proliferation of the isolated suprarenal
bodies which, in the embryonal stage, split off from the main
organs. This proliferation produces a compensatory hypertrophy
which may end by completely replacing the suppressed suprarenal
function.

Stilling's suggestive work contains the important statement
that these newly-formed, accessory suprarenals possess a structure
resembling that of the cortical substance, and that they contain no
medullary tissue. Stilling, moreover, was the first to describe cells
structurally similar to those of the suprarenal medulla. These
cells stain brown with the chromium salts ; and they are found,
sometimes singly and sometimes formed into small bodies with a
structure similar to that of the medulla, in the ganglia of the
abdominal sympathetic and in the intercarotid ganglion.
Stilling thinks that, owing to the presence of these cells, a pro-
portion of medullary substance is present in animals from which
both suprarenals have been removed. This, in combination with
the fact that the cortical substance is always built up again by
accessory suprarenals, explains the impossibility of completely
destroying the suprarenals and of producing the clinical complex
of Addison's disease experimentally in animals. The Addison's
disease of human pathology is due to the destruction of the
suparenals, and perhaps also of the structures by which the
suprarenal function may be replaced. Enlargement of the
accessory suprarenals and of the chromophile bodies would
explain the occurrence of suprarenal derangement unaccompanied
by Addisonian symptoms.

Stilling's work did not receive the recognition which it
deserved. It appeared at a time when physiologists were first
beginning to understand the importance of the blood glands.
Brown-Sequard had introduced his theory of the internal secre-
tions, and had expressed his conviction of the necessity of the
suprarenals to the life of the organism. Stilling's discoveries
seemed to contradict this view.

In Richet's physiological laboratory, a number of experi-
ments were undertaken with the object of determining the essential
character of the suprarenal function. Special attention was
devoted to the technique of these experiments, and the removal of
the suprarenals was effected according to the most approved rules
of modern surgery.

Abelous and Langlois (1891) next showed that, in frogs, the
destruction of one suprarenal is not attended by results ; but that
the destruction of both glands invariably causes death, winter
frogs living for twelve to thirteen days and summer frogs dying at
the end of forty-eight hours. The animals also die after partial
destruction of both suprarenals, unless at least a quarter of each

THE SUPRARENAL SYSTEM 141

organ is left intact. In such cases the animals live the same length
of time as after one-sided extirpation.

Albanesi and Gourfein obtained similar results. The latter,
however, was unable to confirm the difference in the duration of
life in summer and winter frogs.

Experiments with tritons showed that one-sided suprarenal
extirpation was borne without ill-effect, while the removal of both
organs invariably caused death at the end of a few days. When,
however, a portion of tissue the size of a pin's head was left
in situ, the animals lived from eighteen days to nine weeks.

Abelous and Langlois obtained similar results from their
experiments with guinea-pigs, and Langlois with experiments
upon rabbits. Removal of one suprarenal was attended by
transient emaciation only ; removal of both was followed within
quite a short time, nine to twelve hours, by death. The animals
lived for a few hours longer if an interval of one to twro weeks was
allowed to elapse between the removal of the glands. Donetti
found that guinea-pigs lived from fifteen to forty-eight hours.

Somewhat later (1897) Langlois published the results of a
large number of experiments with dogs. He found that, after
total extirpation, the maximal length of life was forty to fifty-
two hours ; where an interval was allowed to elapse between the
removal of the glands, the average length of life was twenty-eight
hours, and still shorter where both glands were removed at once.
There is some diversity of opinion as to the length of life in dogs
after total suprarenal extirpation. De Domenicis (1893) gives it as
two to four hours; Szymonowicz (1896) gives an average of fifteen
hours; Thirololois (1893) gives twenty-five to forty hours; Kuclin-
zew (1897) gives eighteen to twenty-four hours. Soddu (1899)
and, more recently, Mariani (1906) describe experiments on dogs
where the animals lived one to two days.

From the results of their experiments with dogs, Pal (1894)
and Santi Rindome Lo Re (1895) disputed the essential character
of the suprarenal function in the life of the organism. Pal found
that of eight dogs from which the suprarenals had both been re-
moved, three lived for two to three days; two lived for six days;
and one lived for four months and eight days. He was unable to
discover in this animal either remnants of suprarenal tissue or, at
least within the area of operation, accessory suprarenal bodies.

One of Santi Rindone's dogs lived for thirty-six days after
total extirpation.

Numerous reliable extirpation experiments upon dogs, cats,
and rabbits are described by E. O. Hultgren and O. A. Andersson
(i8g8).

They found that extirpation of one suprarenal together with
partial destruction of the other, was followed by a passing
emaciation, but that the animals did not die. The removal of
both suprarenals at the same time was followed, in cats, by death

142 INTERNAL SECRETION

after an average of sixty-eight hours ; where the suprarenals were
removed in two sittings, death followed after 134 hours; and
where by three, in eighty-eight hours. In rabbits, after removal
of both organs at the same time, death followed in five to six days ;
where, however, the organs were removed separately, with a long
interval between the operations, the animals remained alive for
months. These authors also state the remarkable fact that previous
castration doubles the length of life of such animals. According
to Krychtopenko (1906), rabbits frequently survive the total
extirpation of their suprarenals.

From the results of their very careful experiments, H. Strehl
and O. Weiss (1901) concluded that all animals, from which
both suprarenals have been removed, die. The following table
shows the results of their experiments :

Length of Life after Number

Species Operation; in hours of Animals

Dogs

Dogs

Cats

Cats

Rabbits

Guinea-pigs

Rats

Mice

Hedgehog

Weasel

22-75 7

75-138 3

15-28 15

28-47 2

8-14 ... 26

4-9 20

15-19 4

8-13 10

14 t

21 ... ... I

Frogs 22-45 25

One cat lived for a week after operation without showing
signs of pathological disturbance. After death, a suprarenal of
about the size of a pea was found attached to the spermatic
vein. The other animals died in every case, and the post-
mortem finding was negative.

Where the suprarenals were removed separately, with an
interval of a month between the operations, the animals lived
longer. Thus, four dogs lived 109 to 214 hours; five cats 30 to
170 hours; nine rabbits 21 to 76 hours; twenty-one frogs from 30
to 66 hours. In every case the suprarenal which was removed
last was enlarged.

My own method of extirpation, and one which I have
practised on numerous dogs, cats, and rabbits, differs from those
of the earlier investigators in certain important particulars. In
each case, I first performed a lumbar section by which I was
enabled to dislodge the suprarenals in a dorsal direction. Leaving
the glands attached by means of the blood-vessels, I sewed them
in between the cuticle and the muscular structure of the back.
In this way they remained alive, and were readily accessible
without the necessity of opening the peritoneum. Three or four
days later, they were exposed by cutting through the cuticle ;
the vessels were ligatured, and the organs removed in the easiest

THE SUPRARENAL SYSTEM 143

manner possible. Many animals bore the extirpation of one
gland without any sign of derangement, and lived for months
afterwards. After the removal of both glands death invariably
followed within two to four days. In two rabbits which lived
respectively sixteen and twenty-eight days, there were accessory
suprarenals of about the size of a pea, situated close to the vena
cava, below the renal veins.

These experiments undoubtedly prove that the suprarenals
are essential to the life of the organism. For not only was the
extirpation of the dislodged organs followed shortly by death,
but the operation was performed in such a manner that there
were no secondary lesions, and there was no danger of infection.

The results of experimental extirpation of the suprarenals in
rats and guinea-pigs require to be discussed separately. It
must be remembered that, in the first accounts which were given
of animals which survived the extirpation of both suprarenals, the
subjects of the experiments were rats (Harley).

In a large number of his publications, Boinet lays particular
stress upon the fact that grey rats will live for one to six months
after extirpation of both suprarenals, whether these are removed
separately or simultaneously, though many animals die a fewr
days after operation. Abelous and Langlois explain this peculiar
state of things by the fact that, in ten rats out of eleven, two
to three accessory suprarenals are present in the neighbourhood
of the principal organs and the hinder surface of the renal
vein. Boinet next tried the effect of removing these accessory
structures as well as the principal organs; he found that, out of
twelve animals, seven survived the operation, and of these some
lived for several months. He concluded from this that the
vicarious function of these accessory organs is generally over-
estimated, and he emphasizes the fact that these accessory supra-
renals contained no medullary substance.

Wiesel found that accessory suprarenals without medullary
substance, or, as they would now be termed, accessory interrenals,
were present in about 50 per cent, of the rats which he examined.
They were situated between the testicles and the lower pole of
the epididymis, and he found that, after removal of the
suprarenals, these structures undergo compensatory hypertrophy.
We shall again refer to the significance of this finding
in the light of the remarkable frequency with which rats
survive double extirpation of the suprarenals. It must, however,
be pointed out that, contrary to the opinions of H. and A.
Christiani — who found that, after total extirpation of both supra-
renals, rats died in ten to twenty hours (out of twenty-nine animals
only three survived) — white rats, especially male animals which
have attained sexual maturity, in the greater number of cases,
bear the removal of their suprarenals without evil results. It is
evident from this that results obtained from experiments with rats

144 INTERNAL SECRETION

do not furnish conclusive evidence as to whether or no the supra-
renals are essential to the life of the animal organism.

A peculiar interest is attaching to the guinea-pig as the
subject of experimental epinephrectomy, owing to the fact that
there is no record of any instance where guinea-pigs survived the
removal of both suprarenals ; moreover, it is generally believed
that accessory suprarenals are never present in these animals.
A. Velich has devoted special attention to the study of the
guinea-pig, and he found that, out of 100 animals over the age
of six months, only five possessed accessory suprarenals. In each
case the structure was extremely small, about 1.5 mm. in diameter,
and was placed, in four cases upon the right and in one case upon
the left, of the vena cava, at the spot where the renal vein opens into
it. He also found that, in young guinea-pigs, after extirpation
of one suprarenal there was not only a compensatory hypertrophy
of the other together with partial regeneration of the tissue
left behind from the extirpated organ, but that accessory supra-
renals, 2-3 mm. in diameter, were invariably formed at the right
of the vena cava, and that these new structures were entirely
composed of cortical tissue. The further development of the
minute accessory suprarenals — which frequently consist only of
isolated cortical elements — after the partial extirpation of the
principal organs, shows that even these structures are capable of
compensatory activity. They are not able, however, entirely to
replace the complete suppression of the principal organ, and for
this reason total extirpation of both suprarenals of guinea-pigs
invariably results in death.

Experiments have been undertaken quite recently which aim
at the destruction of the suprarenals by means of specific cyto-
toxins. Several investigators (Bigart and Bernard, Abbot, Yates,
Sartirana, Gildersleeve, Van Calcar) have endeavoured to pro-
duce an epinephrotoxin or suprarenolysin, but their attempts
have been principally confined to a description of the pathological
changes which take place in the suprarenals, and little has been
added to our knowledge of the function of these organs. A,
Bogomolez recently obtained a suprarenolytic serum from rabbits
with the suprarenals of dogs, and from dogs with the suprarenals
of cats; he found that the injection of this serum was followed
by a marked increase in blood-pressure, a stronger cardiac impulse,
an acceleration of the pulse and of the respiration, and later, by
a period of prostration, which was, however, transient. He
regards these symptoms as the result of the increased activity of
the suprarenals and their consequent exhaustion, and of the
medullary substance more particularly. Histological examination
showed profound changes in the suprarenals of animals which had
been treated with injections of suprarenolytic serum. The proto-
plasm of the cells of the medulla had become markedly spongy
and vacuolized, and was, in parts, entirely dissolved. Amorphous
deposits of basophile substance, which the author regards as

THE SUPRARENAL SYSTEM 145

the products of secretion, were not present in the medullary cells.
With the exception of moderate enlargement of the vessels, the
cortical substance presented no signs except those of an increased
secretory activity.

L. della Vida employed immune serums obtained separately
from the cortex and medulla of the suprarenals of guinea-pigs.
He states that the action of the medulla-serum was toxic to his
animals and produced hyperaemia of all the organs, together
with degenerative changes in the suprarenals, kidneys, and liver.
It is more than probable that the cytotoxic sera employed by
della Vida were strictly specific in vitro, but that at the same time
they were more or less haemolytic in their activity ; this renders
it difficult to distinguish the toxic effects of the haemolysis from
any specific disturbances which may have taken place in the
suprarenal tissue.

From the results which have been obtained by extirpation of
the suprarenals the following conclusions may be drawn :-

(1) From the fact that it is followed by no pathological signs,
the removal of one suprarenal must be regarded as negative in
its effect upon the organism. The compensatory hypertrophy
which invariably takes place in the remaining organ and in any
accessory organs which may be present, shows that this negative
effect is not due to an absence of functional significance, but to
the fact that the suppressed function is replaced by the vicarious
activity of the remaining organ and of other similar tissues. This
hyperfunction is expressed anatomically by hypertrophy.

(2) Extirpation of both suprarenals is as a rule followed by
the death of the animal, whatever its species, within a very short
space of time (hours or a few days). That this is not due to the
severity of the operation or to secondary causes, such as infection,
&c., but occurs solely as a result of the suppression of the func-
tion of the organs, is shown by the constancy of the result ; for
death follows even in those cases where, the organs having been
previously dislodged, the operation is a slight one. It is evident
then, that the suprarenals are not only important to life, but that
they" are essential to it.

(3) Whether the suprarenals are removed together or singly,
with a longer or shorter interval between the operations, the final
result of complete epinephrectomy will be the same. But where
both the organs are removed at once, the duration of life is much
shorter, and it would appear from this that the sudden suppression
of the suprarenal function is not compatible with a continuation
of life. That the duration of life is longer where the suprarenals
are removed separately is explained by the fact that, in the
interval, any accessory suprarenal tissue which may be present
undergoes compensatory hypertrophy and, after removal of the
second suprarenal, does what it can to replace the suppressed
function, though necessarily to an insufficient extent.

10

146 INTERNAL SECRETION

(4) In certain exceptional cases, where animals have survived
the extirpation of both suprarenals and where the result is not due
to imperfect extirpation, it arises from special anatomical con-
ditions. In some animal species, as the dog and cat, such excep-
tional cases are extremely rare; in others, as in the rabbit, they
are of more frequent occurrence ; in rats, they are rather frequent,
and extremely rare in the case of guinea-pigs. In these cases the
survival of the animals is doubtless connected \vith the presence
of accessory organs.

These structures are very rare in dogs and cats ; they occur
in about 15 to 20 per cent, of rabbits; in nearly 50 per cent, of
rates; in guinea-pigs, at the most, 4 per cent.

(5) Partial destruction of the suprarenals, either by the removal
of one and large portions of the other, or by partial destruction
of equal portions of both, may be borne without results, or it
may cause death. Survival depends, in the first instance, upon
the amount of tissue destroyed.

Repeated experiments have been made with the object of
discovering the amount of suprarenal substance necessary to life.
Mathematically precise results were hardly to be expected.
Langlois found that, in the case of rabbits and dogs, one-sixth to>
one-eleventh of the total weight was sufficient. I myself found
that cats, rabbits, and dogs always survived if, after the removal
of one suprarenal, one-quarter of the second was left in situ —
that is to say, one-eighth of the whole amount of suprarenal sub-
stance. In isolated cases even smaller quantities sufficed. H.
and A. Christiani found that, in the case of rats, the extirpation
of one suprarenal together with half of the other, \vas born&
without ill-effects. If more than half of the second suprarenal
was removed, they found that some animals survived, while others
died. These authors are of the opinion that a very small quantity,
less than one-quarter of the total weight, of suprarenal tissue may
suffice to support life.

THE RESULTS OF THE EXTIRPATION OF THE
CORTICAL AND MEDULLARY SUBSTANCES.

I found in the course of my experiments that partial supra-
renal extirpation was followed by certain phenomena, which led
me to the conclusion that the amount of tissue left in situ is not
the only factor of importance, but that the part of the organ from
which the remnant is derived is also of considerable significance.
Experiments undertaken with the object of determining whether
or not the suprarenals as homogeneous organs are necessary to
animal life, served also to determine the significance of the
different parts and the vital importance of the interrenal and
adrenal systems.

The question as to whether it was the cortex or the medulla

THE SUPRARENAL SYSTEM 147

which rendered the suprarenals necessary to life, seemed at first to
have already received an answer. The specific physiological effects
of suprarenal extract, to which we shall refer later, were known. It
was also known, or at any rate suspected, that the active principle
of the extract was derived from the medullary substance, and that
this essence passes intra vitam into the blood-stream by way
of the suprarenal veins.

In view of the known physiological activity of the medullary
substance, the conclusion seemed obvious that animals from
which both suprarenals had been removed, died from the lack of
an essence, elaborated by the suprarenal medulla, which is neces-
sary to the performance of a large number of bodily functions.
According to Cybulski, this essence maintains in a state of
normal tonus, the activity of those nervous centres which control
the cardiac and vascular muscles, the respiratory musculature,
and perhaps the muscular tissue of the entire body. After re-
moval of the suprarenals the animal dies, because, in the absence
of perpetual stimulus, these nerve centres, the activity of which
is essential to the life of the organism, cease to act.
The evidence in support of this theory is that, in dying animals
from which the suprarenals have been removed, the blood-
pressure is extremely low, while interference with respiration, as
by occlusion of the trachea, does not produce either a dyspnceic
increase in blood-pressure nor dyspnceic cramps. The injection
of suprarenal extract is followed by an increase in blood-pressure
accompanied by a certain improvement in vitality, and the
dyspnceic blood produces the usual symptoms of suffocation.

These experiments have no great value as evidence, especially
when we consider that, in all moribund animals, there is a low
arterial blood-pressure and a slight reaction to dyspnceic stimuli,
and that the injection of suprarenal extract into moribund animals
is always followed by a rise in blood-pressure and a certain return
of vitality.

What seems to be more reliable proof of the part played by
the medullary substance in death from suprarenal suppression,
is the fact that extirpation of both suprarenals is immediately
followed by a considerable reduction in arterial tension. Strehl
and Weiss attribute this fall in blood-pressure to the cessation
of the supply of the substance which stimulates blood-pressure.
Their views are founded upon the results of the following experi-
ment with rabbits.

If, after removal of one suprarenal, the vein leading from
the other is severed or ligatured, in certain cases, " though in a
small minority only," there will be a marked fall in blood-pressure.
If the ligature is released, the blood-pressure will rise to the
normal. Young and Lehmann performed a similar experiment
upon dogs; they found that the ligature of both suprarenals
gradually produced a slight reduction in arterial pressure, and

148 INTERNAL SECRETION

that the loosening of the ligatures was followed, in from ten to
thirty minutes, in three out of eight cases, by a distinct rise in
blood-pressure.

The results of Strehl and Weiss's experiment, though in-
teresting, have in my opinion been very much overrated. The
experiment really only shows that the specific substance elaborated
by the suprarenal is perpetually conveyed into the blood-stream
by the blood from the suprarenals. If, after complete extirpation
of the suprarenals, death is due to the absence of this substance,
or rather to the reduction in blood-pressure caused by its absence,
we should expect the operation to be immediately followed by
a somatic sinking of the animal, accompanied by a continued
fall in blood-pressure. The fall in blood-pressure described by
Strehl and Weiss was, however, only transient, the authors
describing it as lasting several seconds. Lewandowski found
that thirty minutes after extirpation of both suprarenals the
blood-pressure was normal.

I myself found that, after removal of the suprarenals from
•the extraperitoneal situation in which I had placed them, there
was a fall in blood-pressure lasting fifteen to thirty minutes,
except in cases when the animal was much affected by the opera-
tion and the anaesthetic. At the end of that time the blood-
pressure gradually rose and, by the next day, had reached the
normal. Where the anaesthesia is more profound and the supra-
renals are removed by laparotomy, the blood-pressure becomes
very much reduced and in some instances there is no recovery.
As a general rule, however, where the method of operation is
technically above reproach, animals from which both supra-
renals have been removed usually appear to be perfectly well,
with normal blood-pressure for two or three days, after which
they die (Hultgren and Andersson). This applies more particu-
larly to cases where the suprarenals have previously been dis-
lodged, the ultimate removal taking place extraperitoneally. A
few hours before death there is a distinct gradually increasing
fall in blood-pressure, though the same phenomenon is observed
in all moribund animals. As neither ligature of the veins nor
removal of the suprarenals is followed by an appreciable decrease
in blood-pressure, there is no actual proof that death is due
solely to the suppression of the agent which stimulates blood-
pressure. The cause of death after complete extirpation of the
suprarenals is, at present, unknown.

The assumption that death after total suprarenal extirpation
may, in some measure, be due to intervention of the cortical
portion — or, in other words, that the interrenal tissue is
essential to life — is justified upon various grounds.

It has been repeatedly proved that the accessory organs
which, after removal of the suprarenals, suffice to maintain life,
are entirely composed of cortical tissue, or, in the terminology

THE SUPRARENAL SYSTEM 149

of the present day, belong exclusively to the interrenal system.
There is also undoubted proof that, after extirpation of the supra-
renals, this tissue undergoes compensatory hypertrophy. These
are the two points upon which 1 base my assumption that the
interrenal tissue has a vital significance in the economy of the
organism.

In the course of my investigations into the question of the
amount of suprarenal tissue necessary to the maintenance of
existence, I found that mammals (rabbits and dogs) would live
with one-eighth, or less, of their suprarenal substance, provided
that the portion left behind was composed of cortical tissue.
Further experiment showed that, after removal of one suprarenal
in toto together with the medullary substance of the other, more
or less of the cortex being left in situ, the animal not only
continued to live, but showed no signs of pathological disturbance.
I found in one of five surviving rabbits two small accessory inter-
renal structures situated to the right of the vena cava. In a
number of other instances, the destruction of the medullary por-
tion, in so far as this was possible by operative means, was
entirely negative in its results ; but I have never succeeded in
keeping animals alive after removal of the cortex and preserva-
tion of the medulla, no matter how carefully the operation was
carried out.

These results are not, however, confirmed by those of Vassale
and Zanfrognini (1902). They found that the complete destruc-
tion of the medulla was followed, in cats and rabbits, by death
in exactly the same way as total extirpation of both glands ; while,
after partial destruction of the medulla, the animals lived for
three weeks and then died, showing signs of pronounced cachexia.
This fatal termination was ascribed by these authors to the
absence of the medullary tissue, while in those cases where the
animals survived, they attribute the result to the presence of
extracapsular chromaffine bodies.

H. and A. Christiani concluded from their experiments with
rats, that in the case of these animals very minute portions of
suprarenal tissue suffice to support life, always provided that the
remnant contains a sufficiency of sound medullary tissue. Larger
portions, if composed wholly of cortical substance, will not pre-
vent a fatal termination.

Without a knowledge of the method of operation, it is very
difficult to judge of the value of the results obtained by Vassale
and Zanfrognini. The experiments of H. and A. Christiani,
though apparently free from objection, are of little value in the
present connection, owing to the fact that accessory interrenal
structures are frequently present, especially in the testicles, of
the species which they employed as subjects. Rats always
possess a large amount of interrenal tissue and in some recent
experiments I found that these animals, especially adult males,

1 50 INTERNAL SECRETION

very frequently survive the removal of both suprarenals. This
shows that the remnants of tissue left in situ by Christiani have
no appreciable functional significance. A. Kohn, who emphasizes
the physiological importance of the chromaffine tissue and lays
special stress upon its importance to life, is inclined to doubt
the value of the last-mentioned experiments. He says : The
complete destruction of the medullary substance is supposed to
cause death. But in many mammals, such as cats and rabbits, a
considerable quantity of chromaffine tissue lies externally of the
suprarenals upon the ventral surface of the abdominal aorta.
Why is it that these structures do not prevent death, if a small
portion of medullary tissue when left in situ is able to do so?"
According to Kohn, it is even more difficult to reconcile this
view with the results of experiments on amphibia. " In the
amphibia, the amount of extracapsular chromaffine tissue in the
sympathetic is considerably in excess of the medullary substance,
and yet after complete destruction of the suprarenals, frogs and
newts (tritons) invariably die. How is it that the large amount
of extracapsular chromaffine tissue which remains after operation,
does not prevent the death of these animals, if a minute propor-
tion of suprarenal tissue, which may not even contain chromaffine
cells, is able to maintain life for many weeks?" My answer to
this question is : That the animals will survive without medullary
tissue, for, in the free portions of the adrenal system they possess
a sufficiency of extracapsular chromaffine tissue. If it were
possible to extirpate all the free portions of the adrenal system,
which is, of course, technically impracticable, then and then only
should we be justified in referring the death of the animal to
suppression of the function of this system.

The specific activity and physiological significance of the
adrenal system, together with that of its subdivision, the supra-
renal medulla, cannot, in face of the evidence, be doubted. That
it is important and even essential to the life of the organism we
know, but the proof of this is not supplied by the results of
experimental extirpation. These experiments tend rather to show
that the cortex, or more correctly the interrenal tissue, is necessary
to the life of the animal.

EXPERIMENTAL EXTIRPATION WITH FISH.

During my stay at the zoological station at Naples, in 1899,
I undertook a series of experiments with the object of determining
the vital importance of the interrenal tissue in fish. The most
favourable conditions appeared to me to be provided by the topo-
graphically separate interrenal and adrenal organs of the Selachii.
I was compelled at the outset, however, to abandon all attempts
at extirpation of the adrenal system on account of its intimate
association with the cardinal veins. Even the first pair of large

THE SUPRARENAL SYSTEM 151

adrenal bodies, formerly called the "axillary heart," cannot be
removed. Conditions relatively more favourable for extirpation
.are offered by the interrenal system.

The interrenal body of sharks (Squalidas) is a long narrow
band, situated between the kidneys and partly covered by
them ; it is continued towards the cranium as a detached band, or
in separated dot-like bodies. The interrenal body is exposed by
raising the kidneys from the dorsal abdominal wall. In some
species of Squalidae, the interrenal body is embedded in the sub-
stance of the kidney and is only visible in preparations. I em-
ployed small specimens of Scyllium cattulus and Scyllium canicula
.as subjects for my investigations, and in twelve cases I succeeded
in removing the interrenal body. Of these, one lived for eight
and one for ten days, while the remaining animals lived for three
weeks, after which they were destroyed. Anatomical examination
of the first two animals showed an entire absence of interrenal
tissue. In all the other cases, post-mortem examination showed
remnants of interrenal tissue of a varying size, which upon histo-
logical examination were found to be hypertrophied.

Experiments with Raiidas (skates and rays) were more in-
structive, and the anatomical conditions were decidedly more
favourable. In most Raiido?, round or oval paired bodies are
found to right and left of the middle line between the kidneys ;
occasionally they are united by a bridge of varying width. In
the species which I employed (Torpedo marmorata, T. occellata,
Raia batis, R. punctata, R. clavata), there is generally a largish
interrenal body, situated either to right or left, generally at the
caudal point of union of the kidneys; while upon the other side,
more in a cranial direction and at the medial border of the
kidneys, a row of smaller bodies is sometimes found. For anyone
who is acquainted with the anatomical conditions it is possible to
remove the whole of the interrenal tissue ; care must be taken, how-
ever, to avoid any isolated interrenal bodies which may be present.

In t\venty-seven cases out of thirty-two, post-mortem examina-
tion revealed no trace of interrenal tissue; in one case there was
a portion of about the size of a grain of millet seed, and in four
cases portions as large as a pea. Animals which died within
forty-eight hours were excluded, for these cases always showed
changes which sufficiently explained the cause of death. Apart
from violent haemorrhage and destruction of the renal tissue, the
severing of the abdominal sutures and consequent prolapse of the
viscera was the most frequent cause of death. In successful cases,
for the first three to four days after operation, there was no
appreciable change in the condition of the animals, the first sym-
ptoms making their appearance at about the seventh or eighth day.
The animals first showed a loss of liveliness and readiness to move
about ; spontaneous swimming about the aquarium became less
frequent; and, compared with control animals in the same

152 INTERNAL SECRETION

aquarium, they were much paler in colour ; fourteen to eighteen
days after operation they had become so weak muscularly that they
could scarcely be induced to swim at all ; their colour was very pale ;
and they lay all day in a corner of the aquarium, refusing all
food. Their reaction to stimuli almost entirely disappeared, and
at the latest, three weeks after operation they died with all the
symptoms of general prostration. Post-mortem examination re-
vealed no definite cause of death ; the stomach was invariably
empty and the blood pale in colour.

Of the five fish in which portions of interrenal tissue were
accidentally left behind, one lived for over four weeks without
symptoms of muscular weakness. It was finally destroyed, and
was found to possess an interrenal body the size of a pea. Both
in this case and the other four, all of which showed symptoms
of suppression of the interrenal function, there was distinct
histological proof of hypertrophy of the interrenal tissue left in
situ.

In my opinion, these experiments incontestably prove that
the complete destruction of the interrenal tissue is incompatible
with the continuation of life; and that death occurs under condi-
tions similar to those which follow extirpation of the suprarenals.

The results of my experiments with cartilaginous fish appear,
however, remarkably antagonistic to those obtained by Pettit and
by S. Vincent with osseous fish. Both these investigators found
that eels lived for months after extirpation of the suprarenals and
showed no change in their general condition. They considered
that the suprarenals of osseous fish were represented by the cor-
puscles of Stannius, situated upon the ventral or dorsal surface
of the kidneys and composed exclusively of interrenal tissue. These
experiments with eels appeared to contradict the results which I
obtained with Selachii, and the discrepancy seemed to me the
more significant in view of the careful methods adopted by both
Pettit and Vincent and the remarkable unanimity of their results.
I was unable to detect the slightest inaccuracy either in their
methods or observations, and for this reason it seemed that a
repetition of their experiments was hardly likely to yield fresb
results. For some time, I was unable to find an explanatioa of
this difference in the behaviour of Teleostii and Selachii, but
Giaconimi's recent anatomical work has explained the mystery
in the most satisfactory manner. Giacomini shows that in the
eel, in addition to Stannius's body and the interrenal tissue dis-
tributed in its vicinity, which he calls the posterior or caudal
interrenal organ, an anterior cranial interrenal system is also
present, composed of isolated bodies situated at the anterior edge
of the head kidney and attached to both the anterior and posterior
cardinal veins. The wide distribution of this anterior interrenal
system, together with the large amount of interrenal tissue present,
makes it very certain that the removal of Stannius's corpuscles

THE SUPRARENAL SYSTEM 153

alone supplies no evidence as to the essential character of the
interrenal tissue in the economy of the organism. The large
amount of tissue remaining in the system explains why eels
invariably survive the removal of their suprarenals.*

SYMPTOMATOLOGY OF SUPPRESSION OF THE
SUPRARENAL FUNCTION.

The symptoms which, in different animal species, follow the
removal of the suprarenals, have been variously described. This
is chiefly due to the fact that the duration of life after operation
is so short, that it is difficult to determine which symptoms arise
from suppression of the organ, and which are complications result-
ing from the operative intervention. The clinical complex pre-
sented by suprarenal suppression is by no means uniform, and
is, moreover, so ill-defined in character that its classification as
a clinical entity is impossible. Where operation is immediately
followed by pronounced muscular weakness, extreme nervous
depression which may amount to a paralytic condition, reduced
cardiac and respiratory activity, and a lowered temperature, the
idea which inevitably presents itself is that we have to do with the
after-effects of serious surgical disturbance.

If, however, the suprarenals are removed by less drastic
surgical means, the operation is not followed by any of the above
symptoms, the animals appearing quite normal a few hours after
their recovery from the anaesthetic. Where the suprarenals have
been previously dislodged, they may be removed from their
position under the skin of the back without an anaesthetic, and
the animals will remain free from symptoms for one to two days.
Upon the second day in some cases, though usually not until the
third, there is loss of appetite. About twenty-four to forty-eight
hours before death, which occurs four to six days after operation,
the animal becomes spiritless and wears a pathetic look; it ceases
to move about and refuses all food. The apathy and muscular
weakness increase and there is considerable stiffness and uncer-
tainty of movement of the hind legs. Extreme prostration follows,
the animal becoming too weak to move ; it has a flaccid paresis
of the hind legs and lies in a peculiar position, flat on the
abdomen with the extremities extended. At this stage the tem-
perature is very low, respiration becomes increasingly difficult and
laboured, the heart's action is irregular and weak, and the animal
soon dies. Immediately before dissolution, single muscular con-
tractions are sometimes observed and, though more rarely, con-
vulsions.

* In a recent publication (Ascher-Spiro, Ergebnisse der Physiologic,
Qth year, IQIO, p. 537) S. Vincent compares his experiments with eels with
mine with Selachii, and he concludes that the cortex of the suprarenal is
not essential to the life of the organism. It is evident from this that
Giacomini's anatomical work (1908) has not come to Vincent's notice.

154 INTERNAL SECRETION

Let us take these symptoms singly and examine them more
closely.

The initial symptom, a reduction of 2-4° in temperature
immediately after operation, has very little clinical significance.

This fall in temperature is quite transient, the figure becom-
ing again normal twenty-four hours after operation. Personally,,
I have never observed the initial fall in animals operated upon
by my method. In cases, however, where the results of operation
are complicated by haemorrhage, prolonged narcosis, &c., the
initial fall in temperature may be continued and progressive. As
a general rule the temperature begins to drop forty-eight hours
before death, after the asthenic symptoms have appeared. From
then onwards the reduction is progressive. The normal rectal
temperature of 39° C. drops to 34° C., and immediately before
death to 30° C. and under. Hultgren and Andersson regarded
this abrupt fall in the temperature curve before death as charac-
teristic of animals from which the suprarenals had been removed.

The emaciation which follows removal of the suprarenals may,
with greater justification, be regarded as characteristic of the con-
dition. There is a considerable reduction in \veight immediately
after operation, and thus reduction is slowly progressive. The
loss is undoubtedly partly due to the lack of appetite, the animal
in the later stages refusing all food. That a relationship exists
between the emaciation and the suppression of the suprarenal
function is proved by the fact that the removal of the suprarenal
from one side only is followed by a considerable loss of weight.
This lasts from two to three weeks, when an increase in weight
takes place. It is an interesting fact that intestinal derangements
and diarrhoea are not usually associated with the condition.

Investigation of the metabolic conditions and systematic
examination of the urine of animals from which the suprarenals
have been removed, has rarely been undertaken. According to
Alezais and Arnaud, the amount of phosphates in the urine of
rabbits is increased after extirpation of the suprarenals. Noth-
nagel considers that the indican reaction, sometimes afterwards
observed in the urine of rabbits, is due to secondary conditions.
Many authors report polyuria.

Investigation of the metabolism of albumin was first carried
out with rabbits and cats after both single and double suprarenal
extirpation by Hultgren and Andersson. They found that there
was no change in the metabolism of albumin. Where the animals
were able to take nourishment, food containing a large proportion
of carbohydrates possessed the same property of storing up
albumin as in normal animals. Where the animals refused to
take food, the decomposition of albumin was the same as in the
normal fasting animal.

Interesting information concerning the metabolism of the
carbohydrates in suprarenalless animals has recently been pub-

THE SUPRARENAL SYSTEM 155

lished. Bierry and Malloisel (1908) describe hypoglyca^mia in
dogs. O. Forges found that, a few hours after double suprarenal
extirpation, the sugar contents of the blood are subnormal. He
also found that, in three cases of Addison's disease in man, the
sugar contents of the blood were below the average. Frank and
Isaak, who experimented with rabbits, deny that there is a con-
nection between hypoglycsemia and suprarenal suppression, but
their experiments cannot be regarded as conclusive.

Eppinger, Falta and Rudinger showed the phlorizin pro-
duces only slight glycosuria in suprarenalless dogs. They also
found that, in certain cases of Addison's disease, the toleration of
sugar is remarkably high ; while L. Pollak was unable to produce
glycosuria with 2 mg. adrenalin in a case of Addison's disease.
Similar doses when" exhibited in normal people invariably pro-
duced glycosuria.

Andre Meyer describes his failure to obtain results by means
of adrenalin injections; his results are confirmed by those of
Kahn.

It appears from the foregoing that the regulation of the
sugar contents of the blood is a function of the suprarenal, or
rather of the adrenalin-secreting, tissue.

In a communication dated December 17, 1909, O. Schwarz
describes certain appearances which follow extirpation of both
suprarenals. He found that in sexually mature male rats, which
it is well known live without any symptom of disease for long
periods after removal of both suprarenals, phlorizin exercised
its full glycosuric action ; but that it produced toxic effects which,
under certain conditions, were counteracted by the exhibition of
adrenalin. Rats deprived of both suprarenals also showed a
marked reduction in the amount of glycogen, an increased decom-
position of albumin, and, in spite of these factors, an increase in
weight.

These findings of Schwarz have a peculiar interest, but in
my opinion they represent the results, not of suprarenal suppres-
sion, but of the suppression of a portion of the adrenal system.
It is probable that many symptoms should properly be ascribed
to a decreased function of the interrenal system ; this applies parti-
cularly to the remarkable change in the behaviour of rats, wild
and ferocious animals frequently becoming tame and quiet after
operation. Schwarz thinks that, o\ving to the frequency with
which accessory interrenals occur in white rats, these animals are
not suitable subjects in which to study the functions of the supra-
renal as a whole. Rats which have been deprived of their supra-
renals are not in reality suprarenalless, they merely possess a
more limited adrenal system than normal animals. Moreover,
they cannot be regarded as suffering from the absence of adrenalin,
but — and perhaps only temporarily — merely from scantiness of it.
We know from the experiments of v. Haberer and Stoerk that
adrenal tissue may undergo a very high degree of hypertrophy.

1 56 INTERNAL SECRETION

In connection with these findings of Schwarz's, O. Forges
reports that he found a diminution in the quantity of glycogen in
dogs without suprarenals.

These results, when taken in conjunction with observations
to be described later of the glycosuric activity of adrenalin, point
to the fact that the internal secretion of the adrenal system affects
the mobilization of the sugar in the blood as \vell as the new
formation of glycogen in the economy.

The most conspicuous symptoms of suprarenal suppression
are undoubtedly the muscular weakness, asthenia, and apathy,
which increase to complete paralysis shortly before death. The
extreme indolence of the muscular movements is very conspicuous
in frogs ; it makes its appearance upon the second day after
operation and in the case of the hinder extremities passes ulti-
mately into paralysis. Abelous and Langlois compare the condi-
tion with the effects of curare poisoning, for they found that the
sensibility of the muscles to indirect electric stimulus by way of
the nerves disappeared shortly before death, while the sensibility
to direct stimulus remained. These results were not confirmed
however by later investigators (Gourfein, Hultgren and Anders-
son, Biedl) with either frogs or warm-blooded animals. It is
very important to remember that the clinical picture presented by
suprarenal suppression bears not the slightest resemblance to that
of curare poisoning, either at the beginning, when the condition
is characterized by extreme muscular weakness and prostration,
or later, when total paralysis has made its appearance. On the
other hand, a liability to fatigue, first pointed out by Albanese,
and an extreme sensitiveness to violent muscular exertion, are
undoubted characteristics of all animals with suprarenal in-
adequacy. To compel such animals to extreme muscular effort is to
greatly shorten their lease of life, and, in many cases, the animal
falls dead while making the muscular effort.

The blood of animals which have lost their suprarenals is
said to possess a peculiar toxicity. According to Brown-Sequard,
the blood of such animals shortens the life of animals of the same
species which have likewise lost their suprarenals, while the life
of the latter is prolonged by the blood of normal animals. Abelous
and Langlois found that symptoms of exhaustion were produced
in frogs, guinea-pigs and dogs, and, in the case of epinephrec-
tomized animals, death was hastened, not by the blood only of
animals which had lost their suprarenals, but also by alcoholic
extracts of their muscles, especially of tetanized muscles ; similar
effects were produced by extracts of tetanized muscles of normal
animals. The intravenous injection of these extracts into healthy
animals produced transient symptoms of poisoning. These find-
ings are confirmed by Boinet and Mariani. Boinet also found
that the viscera of epinephrectomized animals was markedly toxic,
while Mariani found that there was an increased toxicity of the
urine.

THE SUPRARENAL SYSTEM 157

Mariani affirms that the increase in blood-pressure, which is
induced by the exhibition of suprarenal extract, is immediately
abolished by the blood of epinephrectomized animals. According
to Strehl and Weiss, there are certain data which point to the
conclusion that the toxic action of the blood of suprarenalless
animals may be counteracted by means of suprarenal extract.
These findings, together with those of Soddu concerning the
favourable effects of blood-letting and saline infusion upon supra-
renalless animals, would seem to show that the peculiar prostra-
tion of such animals and their eventual death is due to an
accumulation, more particularly in the muscular structure, of the
harmful products of metabolism. These results supply the foun-
dation for the theory that it is the function of the suprarenals to
render innocuous certain toxic products of metabolism, the
chemical nature of which is as yet unknown. According to
Charrin and Langlois, the suprarenals exercise this neutralizing
activity upon other toxins also, such as nicotine and the bacteria
toxins. This is a point, however, wThich we shall have occasion
to discuss more fully later.

To return to the signs of suprarenal suppression ; there still
remain the conditions governing the morphological elements of
the blood, and the question as to the deposition of pigment after
suprarenal extirpation.

Brown-Sequard's original view was that death followed
epinephrectomy as the result of an accumulation of pigment in the
blood, whereby emboli and haemorrhages were produced in the
brain. This view did not find favour with later authors. Boinet
alone held the opinion that, after removal of the suprarenals, a
black pigment accumulated in many organs and tissues, and for
this reason he employed the term "experimental' Addison's
disease. Pigmentation of the skin and mucous membranes of
rabbits was observed by Nothnagel in three cases, by Tizzoni in
thirteen (twelve cases of single and one of double suprarenal
extirpation). F. and S. Marino-Zucco found that fourteen to
twenty-four days after the removal of one suprarenal from rabbits,
slate-grey patches the size of a linseed appeared upon places
where the skin had been shaved. These patches at first increased in
size, but at the end of two months had entirely disappeared. Similar
patches were seen in rabbits which were not albinos after inocu-
lation of the suprarenals with Pfeiffer's pseudotubercle bacilli and
Eppinger's cladothrix, as well as after the subcutaneous injection
of neurin. But it has been pointed out by many that these
pigmented patches are quite accidental, and are frequently
observed in rabbits which are not albinos. Of the later investi-
gators, no one has been able to record anomalies of pigmentation
in animals after removal of one or both suprarenals.

The blood of epinephrectomized animals presents no analogy
with the anomalous conditions seen in Addison's disease in man.

158 INTERNAL SECRETION

Szymonowicz found that removal of the suprarenals was followed
by an increase in the number of the red blood corpuscles, while
Bornet describes a decrease in the red and an increase in the white
blood cells. But Hultgren and Andersson found that after very
exact experiment they were unable to show any change in the
haemoglobin contents of the blood and in the number of its cellular
elements.

SUPPRESSION OF THE SUPRARENAL FUNCTION

IN MAN.

Complete suppression of the suprarenal function may occur
in man as the result of the congenital absence of these organs.
The accounts of the older authors of the absence, believed to be
congenital, of the suprarenals from the cadavers of adult persons
are entirely valueless, and are, in any case, very scanty. More
recently such a finding has been described in the case of one
person, aged 40, who had died of phthisis (Martini), and in one
boy aged 6 (Averbeck) ; but in these instances no account was
taken of the probable presence of accessory suprarenals. The
absence of one suprarenal which, as experiment seems to show, is
by no means dangerous to life, is of the rarest occurrence.

With regard to hypoplastic infantilism of the suprarenals,
many instances of malformation have been described by J. F.
Meckel. Weigert, Lomer, Zander, point to the hypoplasia of the
suprarenals as a frequent occurrence in certain disturbances in
the embryological development of the brain, more especially in
anencephaly and hemicephaly. According to Zander, a reduction
in the size of the suprarenals is to be expected in cases where, at
a certain stage of embryonal development, the anterior portions
of the cerebral hemispheres have perished. Czerny found that, in
the five cases of congenital hydrocephalus which he examined,
there was complete absence of the medullary substance of the
suprarenals, the cortex remaining intact.

Total aplasia of the medulla in adults has been occasionally
described as an accidental finding (Ulrich, Klebs). In these
cases the suprarenals were atrophied, and consisted only of cortical
substance. The condition of the extracapsular chromaffine tissue
was not described.

vSpecial interest is attaching to Wiesel's findings of hypo-
plasia of the chromaffine system. One case was that of a girl of
eighteen with posteriolateral curvature of the spine, who died of
cardiac insufficiency. The second was in a case of sudden death
after heat stroke, and the third was in a youth of eighteen with
status thymicolymphaticus. Hedinger describes hypoplasia of
the chromaffine system in a number of cases of sudden death in
the status thymicolyphaticus.

Acute suprarenal suppression is not infrequently brought

THE SUPRARENAL SYSTEM 159

about in man by haemorrhage into the organ. Such suprarenal
haemorrhages are seen in still-born children, and these may per-
haps occur intra partum. Sudden destruction of the suprarenals
may, however, take place in later life as a result of haemorrhage or
suppuration of the organ.

The symptom-complex of this form of suprarenal disease was
first described by Virchow. There are very severe nervous
symptoms, together with peritonitis, and these end rapidly in
death. Post-mortem examination shows that, in the greater number
of these cases, the haemorrhage is due to trauma, emboli, or
thrombi ; in rare cases, acute suppuration was found. Acute
suprarenal suppression to a certain extent resembles the condition
produced in animals by the extirpation of both suprarenals. In
subacute cases pigmentation of the skin is rarely absent.

The cases of chronic suprarenal suppression which have been
described have a greater significance. Bittorf has recently
classified chronic suprarenal insufficiency under two headings.
The first group includes those cases in which the disease is primary
and is due to atrophy, hypoplasia, or cirrhosis of the organ. The
second comprises those cases where the suprarenal insufficiency
is secondary, and occurs as the result of tuberculosis, syphilis, or
tumours. In the literature of the subject, Bittorf found accounts of
forty-seven cases of primary atrophy, and to these he added five
cases which came under his own observation, and of which two
were clinical only. Anatomically, these were all cases either of
simple atrophy or of chronic, inflammatory, connective tissue cir-
rhosis. The degenerative changes were not confined to any particu-
lar portion of the organ. In some instances the cortex only was
affected ; in others the medulla only ; but in the majority of cases
both portions were affected, though unequally. Clinically, all
these cases were characterized by more or less clearly marked
symptoms of Addison's disease; the pigmentation of the skin,
in particular, was always present, though in a varying degree.

Primary disease of the suprarenals is of comparatively rare
occurrence, secondary conditions such as those which form the
groundwork of Addison's disease being of far greater frequency.
The typical anatomical finding in Addison's disease is tubercu-
losis of both suprarenals, which may be the sole finding, or it may
be associated with a tuberculous condition of other organs. As a
general rule, there is complete, or nearly complete, caseation and
fibrous induration with chalky deposits or caseous softening.
More rarely, syphilitic processes and tumours have been
observed.

This extreme and very typical suprarenal degeneration is,
however, not present in all cases. As early as 1885, Lewin col-
lected 381 cases of typical Addison's disease, and of these the
suprarenals were affected in only 281 cases, in 37 they were
intact. In a later communication he describes 316 fresh cases,

l6o INTERNAL SECRETION

and in 25 of these the suprarenals were sound. The occurrence of
cases which present all the clinical signs of Addison's disease with
anatomically sound suprarenals, when taken in conjunction with
certain pathological changes which have been observed in the
sympathetic system, suggest that the pathogenetic factor in this
condition does not lie with the suprarenals, but is to be sought
in the sympathetic system itself. Nevertheless, a critical con-
sideration of the material at his disposal compelled v. Kahlden
(1896) to adopt the view that the changes in the sympathetic
system, and especially in the spinal cord, generally slight in
character, though occasionally severe, are without any patho-
genetic significance in this condition.

The nervous or sympathetic theory assumed that Addison's
disease originated in a pathologically demonstrable affection of the
nervous system, but in its original form this theory is no longer
tenable. A certain measure of etiological responsibility is ascribed
to the sympathetic system by Neusser, who regards Addison's
disease as a systemic affection which may take its rise in any
portion of the chain — in the spinal cord, the sympathetic nerves, or
the suprarenals. Neusser's view is supported by a fact which I
have proved, namely, that certain fibres of the splanchnic nerves
act upon the suprarenals as vaso-dilators, while others may exer-
cise an influence upon suprarenal secretion.

Owing to the advances which have been made in anatomy and
embryology, the sympathetic theory has necessarily changed
in form, but in certain directions it receives a measure of support
from Wiesel's recent publications. Wiesel does not find, how-
ever, that the cause of Addison's disease lies with the nervous
system itself, he believes that it is to be sought in the adrenal
system, so intimately connected with the nervous system
genetically, anatomically, and functionally. He describes six
cases in which there was serious degeneration and even destruction
of the chrome-brown cells, not in the medullary substance of the
suprarenals only, but also in the free parts of the adrenal system
in the neighbourhood of the sympathetic. In one case, that of
severe double tuberculosis of the suprarenals unaccompanied by
symptoms of Addison's disease, not only was there no absence of
the chrome-brown tissue, but there was distinct hyperplasia of
it. If these findings show that Addison's disease is due to a
pathological condition of the chrome-brown tissue, then all the
earlier observations of cases of " Addison's disease with sound
suprarenals " lose their significance. For those observations were
founded upon an imperfect knowledge of anatomy, the adrenal
system being at that time little understood. Moreover, there was
always the possibility that in such cases the intracapsular portion
of the adrenal system, the suprarenal medulla, had at first remained
sound, the free portions only being primarily or more severely
affected. On the other hand, cases of " suprarenal affection un-

THE SUPRARENAL SYSTEM l6l

accompanied by symptoms of Addison's disease " are to be ex-
plained, in the light of our present knowledge, by a pathological
condition of the cortex only. Where, however, there were demon-
strable changes in the medullary substance, the functional activity
of the adrenal system might be carried on by its extracapsular
portions.

Wiesel's findings are confirmed by those of Beitzke, but
both v. Hansemann and Karakascheff are opposed to his views.
The latter even goes so far as to ascribe Addison's disease to a
pathological condition, not of the chromaffine tissue, but of the
cortex of the suprarenals. He describes a case in which, notwith-
standing complete caseation of both suprarenals, the symptoms of
Addison's disease were absent. But in this case there was an
accessory suprarenal consisting only of cortical substance — an
accessory interrenal. Bittorf and Beitzke are of the opinion,
however, that not only does Karakascheff's case prove nothing
against Wiesel's theory, but that it does not establish his own,—
that, namely, of the paramount importance of the cortex in the
etiology of Addison's disease. Bittorf believes that the patho-
genesis of Addison's disease does not lie solely with the
chromaffine system. He bases his view upon the localization in
the suprarenals of the atrophic disturbances described above; and
upon one case in which distinct symptoms of Addison's disease
were present, in spite of the fact that the chromaffine tissue
was intact, the suprarenals being only partially destroyed by
hypernephrometastases. As Karakascheff and Bittorf pointed
out, the chief evidence against Weisel's theory lies in certain
findings by him and Hedinger of extreme hypoplasia of the
chromaffine system, unaccompanied by any symptoms of
Addison's disease.

It is still more difficult to account by Wiesel's theory for
those typical cases of Addison's disease where there is either
complete disorganization of the suprarenals or pronounced
destruction of the cortex, the medulla being comparatively sound.
In the latter class of case, considerable portions of the medullary
substance and of the extracapsular chromaffine tissue may still be
intact. Wiesel explains these cases by the assumption that, owing
to the intimate topographical relationship between medulla and
cortex and the fact of their common circulatory system, the
affection of the cortex is a secondary condition resulting from the
primary disease of the adrenal system. But until very definite
grounds upon which to base such an assumption are forthcoming,
the only tenable theory concerning the pathogenesis of Addison's
disease is that which refers it to the suprarenals as a whole, and
not to certain portions of them. From such a point of view, whether
the medulla or the cortex is the part primarily affected is
immaterial, for the functional disturbance of one part is invariably
followed by that of the other ; and it is the disease of the entire
ii

1 62 INTERNAL SECRETION

organ, whether the destructive process is partial or entire, which
produces the typical symptom-complex of Addison's disease.

Bittorf, like Neusser, adopted the view that derangement of
suprarenal function may be caused, not only by disease of the
organ itself, but also by a pathological condition of the secretory
nerves which regulate its function. Those cases of Addison's
disease in which the suprarenals were apparently sound, are
readily explicable by the assumption of a primary affection of the
secretory nerves. Moreover, as Bittorf points out, and his view
is confirmed by Beitzke, the recent literature of the subject con-
tains no conclusive accounts of cases such as these, and he believes
that the frequency of the findings is in an inverse ratio to the
accuracy with which the cases were observed.

Cases of one-sided partial destruction of the suprarenals
unaccompanied by Addisonian symptoms, are readily explained
by the presence, either of functionally active suprarenal tissue in
larger or smaller quantities, or of accessory suprarenals. It is
a more difficult matter to account for those cases where one-sided
suprarenal disease is accompanied by symptoms of Addison's
disease. Neusser believes this to be due to trie transmitted
influence of the diseased organ upon the sound one, but Bittorf
believes that the influence is rather chemical. He regards as
analogous the " transmitted " anuria which, with other symptoms
characteristic of total suprarenal suppression, is seen in one-sided
suppression ; and he points moreover to those cases of one-
sided suprarenal tuberculosis, \vhere the removal of the diseased
capsule is followed by complete cessation of all symptoms of
Addison's disease.

This theory derives no support, however, from the results of
experimental pathology. One-sided suprarenal suppression is
not attended here by symptoms of a deranged organic function,
and there is no insufficiency of the half of the pair which
remains intact. On the contrary, there is rather a functional
hyperactivity, which may ultimately be expressed by anatomical
hypertrophy, of the sound capsule. It is evident from this that
the pathogenesis of Addison's disease, where associated with the
destruction of one suprarenal capsule, is in need of further
investigation.

We are in a more favourable situation in regard to those
cases, formerly so much discussed, in which, though the clinical
signs of Addison's disease are absent, post-mortem examination
shows a more or less complete destruction of both suprarenals.
As Bittorf with justice points out, these are usually cases where
the clinical observation has been faulty, the absence of the
pigmentation of the skin in many instances being regarded as
sufficient ground for the exclusion of Addison's disease, other
clinical signs passing unnoticed. The clinical observation of
these cases, if it is to be of value, requires to be scrupulously exact.

THE SUPRARENAL SYSTEM 163

Moreover, it must be borne in mind that, though the destruction of
the suprarenals means the suppression of a considerable portion
of an organic system, the suprarenals form a portion only of that
system, the probability being that the adrenal system is not
appreciably affected by such suppression. Moreover, consider-
able portions of interrenal tissue, which vary in size in individuals,
may be present as accessory interrenals.

A critical survey of the facts which we possess concerning
the pathogenesis of Addison's disease leads inevitably to the
conclusion that Addison's theory, according to which the clinical
complex presented by the condition is the result of an anatomical
disease of the suprarenals, explains the large majority of cases,
and that the instances in which the functional derangements are
not associated with appropriate anatomical findings are excep-
tional. But the pathological anatomy of Addison's disease is as
yet unable to explain the physiological and pathological signifi-
cance of the different parts of the suprarenal system. We are
not at present in a position confidently to assert that the
suppression of a definite suprarenal system is the cause of the
condition, and we are even less justified in forming conclusions
upon the homogeneity of the suprarenal function from the
pathological-anatomical conditions as seen in man.

THE SYMPTOMATOLOGY OF ADDISON'S DISEASE.

Addison's description of the clinical symptoms of chronic
.suprarenal derangement is so significant and comprehensive that,
though the exhaustive clinical investigation of the last fifty years
has strengthened and defined his view, it has added little to the
symptomatology of the condition.*

Experimental pathology has not as yet provided a satisfactory
explanation of the genesis of individual symptoms. As we have
already pointed out, the destruction of the suprarenals is not
followed in animals by a symptom-complex analogous to that seen
in man ; such an analogy, as we know, exists in the case of
thyroid suppression. The well-defined and characteristic signs of
Addison's disease as seen in man are represented in animals by
'vague and ill-defined symptoms of acute suprarenal suppression.
This difference is most easily accounted for by the radical differ-

J f'

ence in the two subjects in the duration of functional suppression.
It seems almost as if, in the case of the animal, there was not
sufficient time after acute destruction of the suprarenals for the
•development of symptoms of chronic disease. Owing to the fact
that partial destruction of the suprarenals gives rise to regener-
ative processes and to the vicarious activity of the sound portion,

* A comprehensive description of the clinical appearances in diseases
of the suprarenals is given in a monograph by Bittorf, and also by v. Neusser
and Wiesel.

164 INTERNAL SECRETION

it is not possible to produce chronic progressive suppression of
the suprarenal function experimentally and, by this means, acquire
a more intimate knowledge of the consecutive symptoms.

Moreover, as the results of extirpation of the suprarenals do
not in any way resemble the clinical symptoms of Addison's
disease, our reference of the individual symptoms of the latter
condition to a suppression of the suprarenal function is, neces-
sarily, more or less hypothetical.

What is known of the physiological activity of the internal
secretion of the adrenal system makes it easy to understand that
the reduction or suppression of the function of that system should
be followed by hypotonus, reduction in blood-pressure, and the
consecutive symptoms of cerebral anaemia. There was also at one
time a disposition to explain the adynamia — the extreme
muscular weakness so characteristic of Addison's disease, which
has been demonstrated objectively by Langlois by means of
Mosso's ergograph — by a lack of the tonic suprarenal secretion.
But a better acquaintance with the physiological effects of
adrenalin shows that there is no justification for ascribing to this
substance a controlling influence upon the tone of the striated
muscles. As we shall see later, adrenalin affects the sympathetic
nerve-endings only. The muscular asthenia of Addison's disease
is to be explained only by the most complicated hypotheses. The
most tenable theory is that, adrenalin being essential to the
metabolism of the carbohydrates, its reduction is attended by a
loss in the metabolism of glycogen, glycogen being essential to
the performance of muscular function.

The asthenic symptoms and the gastro-intestinal disturbances
are by many authors attributed to the antitoxic activity of the
suprarenal cortex. The sole symptom wrhich invariably follows
suppression of the suprarenal function in both man and
animals, is emaciation. Up to the present, however, we have
no knowledge of the metabolic changes in animals to which
this emaciation is due. The information which we possess con-
cerning the metabolic changes in Addison's disease in man is of
too scanty a nature to supply an answer to the problem.

The origin of the pigmentation of the skin and mucous
membranes, the typical bronze skin (melanoderma) of Addison's
disease, is very difficult of explanation. Once again let it be
said that, up to the present, no one has succeeded in producing,
under experimental conditions free from objection, a pigmentation
of the skin in animals. The pigmentation of the skin is a fairly
constant, and frequently a very early, symptom in Addison's
disease. It first shows itself in the face and hands, then it affects
the neck and arms and, finally, spreads to the trunk and lower
extremities. The parts of the skin which are normally pigmented
are usually attacked first and acquire a deeper colour. The distri-
bution is affected by external conditions, such as exposure to-

THE SUPRARENAL SYSTEM 165

strong sunshine, pressure, and friction. Even more characteristic
than the discoloration of the skin, is the affection of the mucous
membranes of the cheeks, lips and gums, and of the conjunctiva.
Anatomically, the pigment is principally deposited in the cells of
the rete Malpighii, and, as far as we know (v. Kahlden, Riehl,
Schmorl) is conveyed there from the blood-vessels of the cutis by
means of wandering cells (chromatophores). It is almost
exclusively deposited in the lower epithelial layers, the upper cefls
generally remaining free from pigment.

The pigment is free from iron, but nothing further is known
regarding its chemical constitution, though, as far as we can
judge, it is identical with that of other cuticular pigments. Its
formation is generally believed to be associated with a colourless
pre-stage in the blood, though certain observers consider that it
may be formed autochthonously within the epithelium. It has
also been referred to the increased destruction of blood corpuscles
in Addison's disease, together with the retarded flow of the stream
due to the decrease in blood-pressure, but there is no ground to
warrant such an assumption.

The effects of adrenalin upon the pigment of Addison's
disease have recently been investigated. v. Furth and H.
Schneider found that, when tyrosinase was added to tyrosin, the
latter acquired a red, then a violet, and finally an ink-black
coloration. Neuberg next discovered that the extract of a
melanotic suprarenal tumour acted upon adrenalin in such a
manner that pigment was formed; and he discovered a ferment in
the ink-bag of Sepiidas which converted adrenalin into a black
product of oxidation. Adami supports the view advanced by
Halle and Frankel that tyrosin is the matrix of adrenalin, and he
believes, further, that in suprarenal disease the matrix (tyrosin and
allied bodies) is unable to form adrenalin, and therefore accumu-
lates in the tissues. Where the skin is exposed, these substances
become converted by the action of oxydases into a black-coloured
pigment. The entire question of pigmentation in Addison's
disease is urgently in need of further investigation.

SUPRARENAL SUBSTITUTION.

Numerous experiments have been undertaken with the object
of counteracting the results of suprarenal suppression in animals
by means of a substitution therapy. This has been attempted by
two methods, the one by the exhibition of the organic extract
(organo-therapy), the other by transplantation.

ORGANO-THERAPY.

Speaking generally, experimental organo-therapy has not
been attended by satisfactory results. Abelous and Langlois
attempted, but without success, to keep frogs, from which both

1 66 INTERNAL SECRETION

suprarenals had been removed, alive by means of watery supra-
renal extract obtained from animals of the same species. They
obtained better results with guinea-pigs, and succeeded in pro-
longing the lives of these animals for a few hours by means of
injections of suprarenal extract, given immediately after removal
of the second capsule. In a later publication, Abelous asserts
that he succeeded in keeping suprarenalless frogs alive for as
long as twelve days, by the injection of alcoholic extract of the
suprarenals of dogs. At almost the same moment, Brown-
Sequard communicated the fact that the injection of suprarenal
extract will produce a marked improvement in the condition of
moribund epinephrectomized guinea-pigs.

Numerous accounts are forthcoming of the favourable effects
of organotherapy upon both the general condition and individual
symptoms, in animals reduced to extreme prostration after extir-
pation of their suprarenals. Many authors lay special stress upon
the fact that the intravenous injection of suprarenal extract raises
the low blood-pressure and improves the much impaired respir-
atory activity. Hultgren and Andersson found, in addition, ftiat
the subcutaneous injection of suprarenal extract prevented the
terminal fall in temperature, that it improved the general condition,
and to a certain extent relieved the extreme muscular weakness.
But in face of what is now known of the physiological activity of
suprarenal extract, these results cannot be regarded as in any way
establishing a specific substitution therapy. The results which
follow the exhibition of suprarenal extract in suprarenalless
animals are identical with those observed in normal animals and
in dying animals, whatever the cause of death. To establish the
value of a suprarenal substitution therapy, it is not sufficient to
point to the results observed after a single exhibition
(Einverleibung) of suprarenal extract. In my opinion such a
conclusion would be justified only if it were possible to show, as
in the case of substitution by the other organic extracts, that the
exhibition of suprarenal substance is able to prolong the lives of
suprarenalless animals. The material which is forthcoming does
not, however, provide any such proof. Langlois's epinephrectom-
ized rabbits and Hultgren and Andersson 's epinephrectomized
cats lived, after treatment with suprarenal extract, for at the most
twenty-four hours. Strehl and Weiss were able to keep the
animals which they treated with suprarenal extract alive for
only nine hours longer than the control animals. I have
treated a large number of animals, by feeding them with
suprarenal tabloids previous to epinephrectomy, for periods
varying from a few days to several weeks, the treatment being
continued after operation by means of subcutaneous injections of
the watery extract of suprarenal. But in spite of the flooding of
the organism in this manner with suprarenal substance, there
was little difference after operation in the condition of these

THE SUPRARENAL SYSTEM 167

animals from that of the control animals. Also, the average length
of life of the animals under treatment was very little longer than
that of the control animals. From the results which I obtained I
was led to conclude that suprarenal substitution is not practicable
by these methods.

Seeing that the exhibition of suprarenal extract is attended
by doubtful results in experimental suprarenal suppression, it is
not surprising that in Addison's disease the method has not
accomplished all that was at first expected of it. Charrin and
Langlois were probably the first to attempt the treatment of this
condition by means of subcutaneous injections of the glycerine
extract of suprarenal, obtained from dogs and horses. Since then
the effects of organo-therapy in Addison's disease have been tried
by many.

According to Gilbert and Carnot, the clinical material may
be classified, according to the results obtained, in four groups.

(1) Those cases in which organo-therapy was attended by
harmful results, the general condition becoming aggravated and
the fatal termination hastened (Rendu, Foa and Pellacani, Zucco,
Pitres, Posselt). Boinet, more particularly, has drawn attention
to the symptoms of intolerance which follow treatment with
organic extract in Addison's disease. He found that prolonged
treatment produced nervous symptoms, the most frequent being
a tremor similar to that of Graves's disease.

(2) The large group of cases in which the results of treat-
ment were negative (Langlois, Chauffard, Grainger-Stewart,
Murrel, Darier, P. Marie, Galliard, Allaria and Varanini, Bendix,
Turner, Trevithick, Box, Huismans, Christomanos, Lange,
Bockhaus, Osier, Ringer and Phear, Sibley, Bittorf).

(3) Those cases in which an improvement in certain sym-
ptoms was observed. The most frequent signs were a diminution
of the muscular asthenia, improvement of the digestive derange-
ments, and an increase in weight (Langlois, Mahe, Maragliano,
Dieulafoy, Marie, Schafer, Rolleston, Osier, Vidal, Hayem,
Yollbracht, Dupaigne, Spillmann, Edel, Faisans, Anderodias,
Althaus, Byrom-Bramwell, Gullau, Vernescu, Foster, Raven,
Decks, Engelhardt, Ebstein, Sellier and Verger, Posselt).

(4) Those rare cases in which complete recovery is reported.
Schilling found that, in the case of a patient 16 years old, a three-
months' treatment with suprarenal (^ to i suprarenal capsule per
day) was followed by the disappearance of all previous Addisonian
symptoms, namely, the asthenia, anorexia, diarrhoea, and even
the pigmentation of the skin and mucous membranes. The
weight rose from 69 to 99 Ibs. Some time after recovery the
patient died suddenly from pneumonia, and the post-mortem
examination showed that there was sclerosis and softening of both
suprarenals.

Beclere, Hirtz, Lambotte, and Androdias also describe cases

1 68 INTERNAL SECRETION

of recovery from Addison's disease. Kinnicut publishes the
statistics of forty-eight cases of Addison's disease which were
treated by organo-therapeutic measures. Of these, in two cases
there was aggravation of the condition ; in eighteen, the condition
remained unchanged; in twenty-two, there was an improvement;
and in six cases there was complete recovery.

It is evident from this that the treatment of Addison's disease
by means of suprarenal extract is very variable in its results. The
few cases of recovery are nullified by those where an aggravation
of the condition ensued. In the large majority of instances the
treatment produced negative results or the amelioration of single
symptoms only. The muscular weakness and the digestive
derangements appear to be the symptoms most favourably
influenced.

That suprarenal extract, when given by the mouth, should
affect the reduced cardiac activity, and the lowered blood-pressure
is hardly to be expected. Nevertheless, Griinbaum asserts that,
although suprarenal extract, when given by the mouth, does not
raise the blood-pressure of normal subjects, it does have that
effect when given to persons suffering from Addison's disease.
Falta has recently shown that in man, the subcutaneous injection
of adrenalin brings about a rise in blood-pressure.

The symptom which is least affected by this method of treat-
ment is undoubtedly the pigmentation.

The foregoing accounts of the effects of suprarenal extract in
Addison's disease suggest certain definite ideas. Of these, the
most important concerns the influence of adrenalin upon the
symptoms. But a certain measure of efficacy must be ascribed to
other substances present in suprarenal extract, and notably those
which are derived from the suprarenal cortex. Experiments with
animals seem to suggest that the exhibition of suprarenal
substances in Addison's disease provokes hypertrophy of the
portions of the organ which, in this condition, undoubtedly
remain intact, and that by this means the functional inadequacy
of the organ is reduced in a quantitative sense. The negative and
harmful effects of suprarenal treatment are probably seen in those
cases where the suprarenals have become completely destroyed.

TRANSPLANTATION OF THE SUPRARENALS.

The second method of suprarenal substitution is that of the
surgical transplantation of the organ. In 1887 Canalis attempted
the implantation in the kidney of small portions of suprarenal
tissue, but the results which he obtained were purely negative,
the implanted portions becoming necrosed and undergoing
resorption. The experiments of Abelous, and later those of
Abelous and Langlois, with frogs were equally unsuccessful.
Courfein implanted the suprarenals of frogs and guinea-pigs in

THE SUPRARENAL SYSTEM 169

the lymph-sac of frogs, but in all his cases the implanted organ
perished. Boinet implanted suprarenals intraperitoneally in
rats and found that the implanted organ became atrophied and, in
some instances, resorbed. De Dominicis removed the left supra-
renal of dogs, leaving the vascular stem intact, and implanted the
organ below the kidney ; he found that, at the end of nine to
ten days, there was no change. Jabulay implanted fresh
suprarenals from dogs in two patients suffering from Addison's
disease, and in each instance death followed after twenty-four
hours. Hultgren and Andersson implanted suprarenals in three
cats, in each case without result.

There is a special interest attaching to H. Poll's transplanta-
tion experiments. He removed the left suprarenal of rats and
implanted it under the skin, or in the muscles of the back, of the
same animal or another of the same species. By this means he
was enabled minutely to follow the histological changes in the
transplanted organ.

Poll found that, during about the first week, regressive
changes preponderated. A largish necrosed focus appeared in the
centre of the implanted suprarenal. In addition to the central
medullary tissue, the zona reticularis of the cortex and the inner
portions of the zona fasciculata underwent degenerative changes,
and were destroyed.

During the second week, a large part of the necrosed tissue
became gradually resorbed, giant cells being formed in the
process. At the same time the cells of the zona glomerulosa and
the external portion of the zona fasciculata became destroyed,
while peculiar, light, transparent cells, filled with vacuoles, were
formed in the cortical tissue, which afterwards disappeared, leav-
ing a pigmented scar.

From the third week onwards, signs of progressive new
formation appeared. Minute regenerative foci were formed which
lay, partly internally and partly externally of the thickened con-
nective-tissue capsule. They developed into largish bodies,
shaped like the segment of a sphere, with cord-like arrangement
of cells. Later on, these cell agglomerations assumed the exact
appearance of cortical substance.

The regeneration of the cortical tissue and the degeneration
of the medullary tissue were observed by Christiani in experi-
mental transplantation performed on rats. And Stilling found
that, when the suprarenals of rabbits were transplanted in their
testicles, they showed typical cortical tissue for as long as one
and a half to three years.

Further information concerning the results of transplantation
is given by Imbert. He implanted the suprarenals of dogs in their
kidneys and found, in one instance, a pseudolipoma, in another, a
cyst, at the site of implantation. Strehl and Weiss sewed the
suprarenals into pockets between the muscular structure and the

1 70 INTERNAL SECRETION

abdominal cavity; they also placed them free in the abdominal
cavity; and they implanted them in vascular organs, such as the
kidney and liver. But in every instance the implanted organs
perished. Small portions of implanted suprarenal tissue did not,
in the vast majority of cases, heal in.

Better results were obtained by Schmieden, who implanted
small portions of suprarenal tissue in the kidneys of rabbits and,
in a large number of cases, these healed in. But he does not
believe that these implanted portions are likely to remain alive
for any length of time, and his experiments seem to show that
one year is the maximal period.

Payr used the spleen with considerable success as the site
of implantation for the thyroid, but in the case of the suprarenals
the choice of this locality was followed only by transient healing
in, no permanent results being obtained (Coenen, Kreidl, Biedl).
Shiota found that a suprarenal, when transplanted into the spleen
or kidney of rabbits and cats, contained adrenalin during the
first forty-eight hours only, the substance disappearing at the end
of this time. Although the cortex will remain in a fairly healthy
condition for from ten to seventeen weeks, the medullary substance
ceases to slain with chromium twenty-four hours after implanta-
tion.

The admirable experiments of v. Haberer and Stoerk resulted
in successful suprarenal transplantation with complete functional
activity. Their method was to remove the suprarenal without
severing its vascular peduncle and to implant it in the kidney.
De Dominicis had already dislodged the left suprarenal without
cutting through the peduncle (his experiment has been described
in a previous chapter) and I had removed the suprarenals to an
extra-peritoneal position, leaving their vascular stalk intact. These
results undoubtedly showed that, if the normal nutritional con-
ditions were maintained, the transplanted organ would preserve its
functional activity. In 50 per cent, of their cases, v. Haberer and
Stoerk succeeded in producing permanent results which were
functionally, as well as anatomically, demonstrable. In the un-
successful cases, the result was invariably attributable to insuffi-
cient nourishment of the .implanted organ.

Microscopic examination of these successfully transplanted
suprarenals showed that in no case did the organ retain its original
structure, but that, in addition to sound and hypertrophied tissue,
it invariably contained regressive and necrosed substance. In the
first few days after transplantation with preservation of the
peduncle, there is a regressive metamorphosis of the organ which
is occasionally so widespread that the only part which remains
alive is that in the immediate vicinity of the peduncle. Com-
paratively soon after operation, generally in the first week, active
proliferation commences at this spot, the proliferating parenchyma
spreading into the regressive or necrosed portions of the organ.

THE SUPRARENAL SYSTEM iyi

From this a chaotic mixture of living and hypertrophied, and
regressive and necrosed tissue results.

The hypertrophied tissue may in a later stage again become
regressive and, in some cases, even necrosed. This interchange
of proliferation and regression goes on for some time, and
necrosed tissue may be observed for as long a period as three
months. The newly-proliferated cell agglomerations may assume
the structure characteristic of the normal suprarenal ; or there may
be a re-arrangement, not only in the cells of the cortex, but also
in the relative position of the cortex and medulla. The medullary
substance frequently breaks through the cortex and forms en-
closures between the cortical cell complexes ; or these enclosures
may be placed sub-capsularly, and even extra-capsularly. In
many instances the regenerated cortex, when complete, assumes
a form similar to that of suprarenal adenoma. It was formerly
believed that, in successful transplantation, the cortex only re-
mained intact, but it is now certain that the medullary substance
also retains its vitality and its capacity for regeneration, and that
it undergoes hypertrophy in the same manner as the cortex.

About five months after transplantation, the alternation of
regenerative and degenerative processes ceases and the conditions
become more stable. In the majority of cases an entirely new
suprarenal has been formed ; by proliferating into the old structure
and becoming regeneratively hypertrophied, the newr cortical and
medullary tissue crowds out the regressive, necrosed tissue and
replaces it.

The tests which have been made of the functional capacity of
the transplanted suprarenal yield the following results : In experi-
mental one-sided transplantation — and this applies to cases where
the histological findings are unequivocal — it is not possible to
pronounce upon the functional activity of the healed-in organ, for
there is always the possibility of the function having been under-
taken by the sound one of the pair. One-sided implantation is
usually borne without symptoms by dogs, rabbits and cats,
v. Haberer describes a control-experiment with a dog, in which
one-sided suprarenal extirpation was accompanied by distinct
symptoms of suppression, namely, pronounced spastic paresis of
the hind extremities, failing appetite and general depression. The
dog died at the end of eight days, the post-mortem examination
showing that the second suprarenal was slightly hypertrophied.

In a second group of experiments, both suprarenals were
transplanted into the kidney, each capsule being transplanted
separately and a varying length of time allowed to elapse between
the two operations. In many cases, where the first suprarenal
had become necrosed or atrophied and had ceased to function
while the preliminary regressive changes were still in progress in
the second, the animals died as the result of suprarenal inade-
quacy. This group of experiments also brought the interesting

1 72 INTERNAL SECRETION

fact to light that after suppression of one capsule, the condi-
tion of the second does not render it more favourable for trans-
plantation ; it does not, as a priori assumption would suggest,
become hypertrophied but, on the contrary, it almost completely
perishes.

The functional capacity of a transplanted suprarenal is tested
by removing the second capsule some time after the first. In
cases where there was pronounced necrosis of the implanted supra-
renal, the animals lived for a short time only after the second
operation. In nine cases, animals with only one transplanted
suprarenal remained alive for many days and even for months.
Subsequent microscopic examination revealed, in these cases, a
splendid healing-in of the implanted capsule with new formation
and reconstruction of the suprarenal tissue, together with com-
plete degeneration of the original peduncle and a new vascular
system derived from the kidney. As accessory suprarenals were
in no case present, it is certain that these animals continued to
live with their only suprarenal implanted in their kidney and
that they showed no pathological signs. But these cases, as well
as those of double transplantation, supply another remarkable
fact, namely, that the animal has a better chance of life if an
interval of about eleven to sixteen days is allowed to elapse be-
tween the transplantation of one suprarenal and the extirpation
and implantation of the other. Where the interval is longer, the
results are frequently unsuccessful. The impression conveyed is
that the suprarenal function is so completely taken over by the
sound capsule, that the regenerative processes in the second,
damaged capsule are retarded. If the sound capsule is injured
or removed at a moment when the regenerative process in the
second organ is at its height, the new formation of tissue will
receive an additional stimulus.

Yet another group of experiments comprises those in which
the transplantation of both suprarenals is undertaken separately,
and one kidney, together with the suprarenal implanted
in it, is removed by means of a third operation. Of eleven
animals experimented upon, six died after the third operation as
the result of suprarenal inadequacy. In each of these cases, how-
ever, it happened that the suprarenal removed was well healed in
and hypertrophied, while the condition of the second, as seen
post mortem, was regressive. Five dogs lived for years after the
third operation and showed no pathological signs, and in these
instances the extirpated transplanted suprarenal was also hyper-
trophied.

The degree of functional activity of the transplanted supra-
renal has been further tested, by examination of its adrenalin
contents by means of blood-pressure experiments and experiments
with frog's eyes. The results showed a complete agreement be-
tween the microscopic structure and the adrenalin contents.

THE SUPRARENAL SYSTEM 173

The value of the experiments of v. Haberer and Stoerk, which
will be described more fully later, lies in the proof which they
supply that the suprarenal may be transplanted with success, both
functional and anatomical, provided its vascular stem is left
intact. Further, these experiments were the first to show that,
after transplantation, the medullary substances lives and becomes
hypertrophied in exactly the same manner as the cortical sub-
stance. The conclusion drawn by the authors from these findings,
namely, that the part played by the medulla in suprarenal function
is of equal importance with that of the cortex, is the more in-
controvertible seeing that other observations have supplied proof,
not only of the vital necessity of the medulla, but also of its
functional significance. But, in my opinion, the successful trans-
plantations of v. Haberer and Stoerk are decided evidence against
the view, that the medulla is the only part of the suprarenal capsule
which is essential to life. This theory was based upon experiments
where transplantation, though technically successful, was followed
by death, and it depended upon the fact that degeneration of the
medullary substance, together with preservation of the cortex, were
always found in such cases. All that these older experiments prove,
however, is the greater sensibility and lability of the medulla.
They show, and this is confirmed in other directions, that a
reduction in the vascular provision and a limitation of the nutri-
tional conditions invariably kills the medulla, but that the cortex
has greater powers of resistance.

Free grafting of chromaffine tissue is successful in those cases
only where this tissue is normally situated upon a free surface
as, for instance, the dorsal surface of the kidney in reptiles
(Christiani's experiments with lizards). Parodi's experiments
show that embryonal suprarenal tissue, in which the medulla lies
upon the surface, possesses very little regenerative power ; and,
in an experiment recently described by Neuhauser, the trans-
plantation of embryonal tissue into the kidney of a rabbit was
followed by a tumour-like growth.

The results of experimental transplantation, as far as they go
to-day, not only prove the internal secretory function of the supra-
renals and their vital importance to the organism, but they also
justify the hope that the clinical symptoms produced by supra-
renal suppression may be more successfully treated by surgical
means than has been possible, up to now, by organo-therapeutic
measures.

THE ACTIVITY OF SUPRARENAL EXTRACT.

Investigation of the clinical activity of extract of the supra-
renals, has effected a clearer insight into the function of these
organs.

As early as 1879, Pellacani demonstrated the toxic action of

174 INTERNAL SECRETION

subcutaneous and intravenous injections of the watery extract
of suprarenal. He did not believe that this action was specific,
for he found that similar results were produced by means of
other organic extracts. But very soon after, Ziino and di Mattei
denied the toxicity of suprarenal extract and they referred the
results which followed its exhibition to infective processes, more
particularly the influence of products of the decomposition of the
albuminoids introduced into the system with it. On the other
hand, Pellacani and Foa (1883) proved that the toxic substance
in the suprarenal cannot be identical with the fibrin ferment,
which is present even in the alcoholic extracts of these organs
and is specific to the suprarenal. Guarnieri and Marino Zucco
(1888) confirmed the extreme toxicity of the watery extracts and
they considered that the active agents were neurin and the organic
phosphorus compounds. The brothers Marino Zucco even went
so far as to believe that the symptom-complex of Addison's
disease could be produced by means of neurin injection. These
authors, together with Dutto, proved that neurin was present
in the urine of persons with Addison's disease, and,
towards the end of the 'eighties, a hypothesis arose that
the physiological function of the suprarenals consisted in
the neutralization of neurin, which was a product of the decom-
position of the nervous tissue. This doctrine seemed to find a
support in Albanese's experiments with frogs. But both Boinet
and Langlois were unable to confirm the experiments upon which
the theory was founded; while Supino further showed that the
toxic conditions which follow the injection of neurin are entirely
different from the clinical complex produced by suprarenal extir-
pation. Alezais and Arnaud, and later Tizzoni, denied the exist-
ence of a toxic agent in the suprarenal, confirming the view of
an earlier observer, namely, Alexander. They attributed the
effects of suprarenal extract to post-mortem changes in the tissues.

The discovery by Oliver and Schafer (1894) °f the specific
physiological action of suprarenal extract, drove all previous con-
clusions as to the general toxic activity of these organs into the
background. The experiments which followed were, naturally
enough, chiefly concerned with the more minute analysis of in-
dividual pharmacodynamic effects. But since the discovery that
these effects are principally due to an active substance present
in the medulla and, more particularly since the isolation of this
active principle in the form known as adrenalin, inquiry into the
general effects of suprarenal extract has somewhat languished.
The lack of any method of exact dosage is a serious drawback to
experiment.

A consideration of the material furnished by the subject shows
that there is no sufficient justification for identifying the general
effects of suprarenal extract with those of adrenalin. For, in
.addition to adrenalin, suprarenal extract contains other substances

THE SUPRARENAL SYSTEM 175

derived from the cortex, concerning the activity of which we as
yet know nothing. Moreover, therapeutic measures, especially
those aiming at substitution in the case of suprarenal suppression
in man, have been attempted almost exclusively with preparations
derived from the whole suprarenal. The fresh raw organ, the
organ dried and powdered, suprarenal tabloids, and the watery
extract of suprarenal, have all been employed in this connection.
Until something is known of the physiological activity of the
cortex, the empirical method of treatment with the whole organ
must be regarded as superior to treatment by means of the active
principle, adrenalin.

The following experiments serve to illustrate the present
position. Oliver and Shafer injected the watery extract of the
suprarenal of calves into dogs, guinea-pigs and cats without pro-
ducing toxic symptoms. In guinea-pigs and dogs, large quanti-
ties of the extract were followed by transient disturbances of the
pulse and respiration, as well as by a fall in temperature. The
subcutaneous injection of large doses into rabbits resulted, after
a few hours and in some instances after a few days, in a fall in
temperature followed by death. In frogs there were symptoms
of central paralysis.

According to Cybulski the toxic action of suprarenal extract
is seen in rabbits only after intravenous injection ; it affects the
central nervous system.

According to Gluzinski, watery glycerine extracts of the
suprarenals of cattle, calves, pigs, dogs and rabbits produce a high
degree of intoxication in normal animals. Intravenous injection
is followed by paralysis and loss of sensibility in the hinder, and
convulsions in the fore, extremities; there is acceleration of the
respiration and enlargement of the pupils, dyspnoea and wide-
spread paralysis, ending in death. Subcutaneous injection is less
deadly; the animals sicken and the- temperature becomes sub-
normal, but unless the doses are too large they recover.

Dubois found that suprarenal extract derived from rats was
very deadly. When injected in even quite small doses, it pro-
duces lassitude, paresis, and in many cases paralytic symptoms
ending in death. The degree of the toxicity of the extract varies;
it is increased if the animals are fed upon decomposing food, and
after experimental infection. Suprarenal extract derived from
rats kept in captivity is less toxic than that obtained from free-
living animals. The medullary substance contains a larger pro-
portion of toxin than the cortex. The amount of the extract
tolerated varies with individuals, and muscular fatigue previous
to injection renders the animals more sensitive to its toxic action.
According to Dubois, suprarenal extract contains at least two
substances, one of which causes general vaso-dilation and is in-
soluble in go per cent, alcohol ; while the other, which is soluble
in alcohol, produces widespread paralysis, reduced cardiac
activity, and asphyxia ending in death.

1 76 INTERNAL SECRETION

By treating watery glycerine extracts of the suprarenals of
cattle, sheep and calves with strong alcohol, Gourfein obtained
a precipitate which was insoluble in alcohol and which, when
dissolved in water, was less toxic in its action. The substance
which remained dissolved in the alcohol and which resisted heat,
produced progressive difficult respiration and weakness of the
heart-beats, but it did not produce paralysis. The autopsy showed
that the lungs were severely congested.

According to Wybauw, the extract of the suprarenal of
guinea-pigs is less toxic than suprarenal extracts derived from
other animals.

Very complete experiments are described by S. Vincent. The
extract which he employed was mostly derived from sheep, though
occasionally from oxen, dogs, cats and guinea-pigs, and was
obtained by the agency of saline solution both with and without
boiling. He found that the subcutaneous injection of this extract,
if given in sufficiently large doses (equivalent to 0.5 to 0.6 grm.
of the fresh organ) produced more or less pronounced muscular
weakness, occasional paresis with ultimate paralysis of the ex-
tremities, accelerated and shallow, followed by deep and slow
respiration, occasional dyspnceic convulsions, and a fall in tem-
perature ending in death, in all the animals experimented upon
(frogs, toads, rats, mice, rabbits, guinea-pigs). Hasmaturia and
bleeding from the nose and mouth are not infrequently seen in
rats and guinea-pigs. The injection of small doses of the extract
is followed by a partial immunity lasting several weeks. Thirst
is the first noticeable symptom in dogs, which drink water greedily
and afterwards excrete a great profusion of urine. After a short
stage of excitement accompanied by increased muscular activity
and tremor, these dogs develop paresis and finally paralysis.
The most noticeable symptom in cats is the quickened respiration,
the paralysis being less marked. Late effects, those which only
make their appearance after hours or even days, have never been
observed. The administration of the extract in sufficiently large
doses is invariably followed by symptoms within a few minutes.
According to Vincent, the symptoms take their rise in the central
nervous system, and are the outcome of the activity of the medulla,
no toxic substance being present in the cortex.

Vincent also tested the physiological effects of separate ex-
tracts derived from the interrenal and the adrenal tissues of fish.
He found that the Stannius's body of Gadus morrhua, composed
exclusively of interrenal tissue, and the interrenal body of Selachii
produced no effect when exhibited in mice, while the extract of the
suprarenal body of Scy Ilium canicula and Raia clavata, when in-
jected under the skin of mice, produced quickened respiration,
reduction in temperature, and convulsions terminating fatally
within, at most, five minutes. The toxicity of the extract of
the suprarenal bodies of Selachii, when injected into the veins of
dogs and rabbits, is confirmed by Biedl and Wiesel.

THE SUPRARENAL SYSTEM 177

The discovery that the intravenous injection of the watery
extract of suprarenal is followed by specific and well-defined
physiological results, started a new era in suprarenal investiga-
tion. This discovery was announced by Oliver and Schafer before
the Physiological Society of London on May 10, 1894. A year
later, Cybulski and Szymonowicz published their results which,
though obtained independently, coincided in the main points with
those of Oliver and Schafer. An enormous number of experi-
ments followed, which not only explored the physiological and
pharmacodynamic activity of suprarenal extract down to the
minutest detail, but utilized the facts so won to reconstruct in its
entirety the chemistry of the suprarenals.

CHEMISTRY OF THE SPECIFIC ACTIVE SUBSTANCE
PRESENT IN THE SUPRARENALS.

As early as 1856, Vulpian made the discovery that the supra-
renal contains a substance which is distinguished by its remark-
able colour reactions. It colours green with ferric chloride, and
takes on a pink to carmine-red colour when exposed to the air
and treated with alkalies or with oxydizing agents, such as
iodine-water and chlorine-water. Virchow, who confirms Vul-
pian's discovery, found that the characteristic colour reaction is
associated with the medullary substance and that it is demonstrable
in microscopic sections. According to Virchow, the chromogenic
colouring substance is identical with the substance which colours
green with ferric chloride, and is not associated with the morphotic
elements, but with the secretion, the intercellular substance. In
1885, Kruckenberg drew attention to the important fact that this
suprarenal chromogen possesses certain properties in common
with pyrocatechin, and Brunner (1892) believed that the two
substances were identical.

Oliver and Schafer ascribed the peculiar hasmodynamic action
of suprarenal extract to the medullary substance and, following
them, Moore found that the substance which produces increased
blood-pressure is identical with chromogen, but that its pharmaco-
logical properties are entirely different from those of pyrocatechin.
S. Frankel (1896) was the first to suggest that the substance which
raises blood-pressure is a derivative, containing oxygen, of the
pyrocatechin group. The experiments of v. Fiirth and Abel were
of great importance because they prepared the way for the
isolation, in a state of chemical purity, of the active principle of
the suprarenal. In 1901 Jokischi Takamine succeeded in obtain-
ing this substance in a crystalline form, and he gave it the name
of adrenalin. Almost at the same time and quite independently,
Aldrich produced the same substance from the suprarenal, also
in the form of well defined crystals.

The methods of isolating adrenalin are based upon the fact
12

1 78 INTERNAL SECRETION

that,- when alcohol or acetate of lead are added to suprarenal ex-
tract, the by-substances are released, and the addition of concen-
trated ammonia results in the precipitation of adrenalin in the form
of microscopic crystals. These are further purified by repeated
solution in acids and precipitation by means of ammonia, until
eventually, clusters of crystals composed of prismatic needles and
rhomboid scales are formed. These adrenalin crystals dissolve
slowly in cold water and somewhat more readily in hot. They
dissolve freely in diluted acids, and form salts ; their reaction upon
litmus paper is weakly alkaline. They are not readily soluble
in alcohol, and they are insoluble in chloroform, amylic
alcohol, carbon bisulphide, ether, acetone, and benzine. In
accordance with its phenol nature, adrenalin is soluble in the
caustic alkalis, but not in the alkali carbonates and ammonia. It
cannot be precipitated by means of potassium mercuric iodide,
picric acid, tannic acid, phosphoromolybdanic acid, phosphoro-
wolframic acid, or mercuric chloride ; but it is reducible by
Fehling's solution and by ammoniated solution of silver. When
exposed to the air, the watery solution colours red and after-
wards turns brown ; the addition of ferric chloride produces the
characteristic green coloration.*

Numerous experiments were undertaken by Aldrich, Bertrand,
Abderhalden and Berger, Jowett, Friedmann, v. Fiirth, Pauly,
Stolz, with the object of analysing the elements and ascertaining
the weight of the molecules, and these revealed the more intimate
characterization of adrenalin (epinephrin, according to Abel,
suprarenin, according to v. Fiirth). This substance is empirically
formulated as C9H13NO3. The following formula expresses its
constitution : —

OH

CH2NH.CH3

Adrenalin contains a benzol nucleus which is substituted in
the 2, 5, 6- position. Three hydroxyl groups (OH) are present in
the adrenalin molecule and, of these, two are placed in the vicinity
of the benzol nucleus in the 5, 6- position. The molecule contains
a methylimid group.

Stolz succeeded in obtaining a substance, by a synthetic
process, which possesses pharmacological properties exactly
similar to those of adrenalin.

If chloracetopyrocatechin — which is obtained from the action
of chloracetylchloride upon pyrocatechin — is treated with ammonia

* The preparation known as "Adrenalin Takamine " (put upon the
market by Parke, Davis and Co.) is adrenalin in combination with hydro-
chloric acid, in a solution (i : 1000) of sodium chloride and chloreton, the
latter being a derivative of chloroform and aceton.

THE SUPRARENAL SYSTEM 179

or with primary aliphatic amine, amino, methylamino-, and
ethylaminopyrocatechin are obtained according to the following
formula :

C6H3(O.H)a.CO.CHa|Cl + H| .NH2 = C6H3(OH)2.CO. CH2NH3

Aminoacetopyrocatechin

TH .NH.CH, = C6.H3.(OH)2.CO. CH2NH.CH3

Methylaminoacetopyrocatechin

TH[ .NH.C2H5 = C6H3(OH)2.CO. " CH2.NH.C2H,

Ethylaminoacetopyrocatechin

According to Lowi and Meyer, the manner in which these
bodies act is exactly similar to that of adrenalin, but the strength
of their action is very much less. By reducing these ketone bases,
Stolz obtained, by the addition of two hydrogen atoms, the
complementary secondary alcohols, namely, amino-ethanol-,
methylamino-ethanol-, and ethylamino-ethanol-pyrocatechin. In
their action these alcohol bases are not only qualitatively identical
with adrenalin, they also approach it quantitatively. Methylamino-
ethanolpyrocatechin, or orthodioxyphenylethanolmethylamin, is
chemically identical with adrenalin obtained from the suprarenal.*
This synthetic adrenalin differs only from natural adrenalin
in that it is optically inactive, while the natural substance diverts
the polarized ray of direction towards the left. This synthetic
racemic suprarenin is composed of equal parts of d- and 1-supra-
renin ; it was split up into its component parts by Flacher.

Synthetic 1-suprarenin is, both physically and chemically,
absolutely identical with the natural adrenalin obtained from
suprarenal. The experiments of Cushney, Abderhalden and his
co-workers show that the physiological action of the synthetic
substance is both quantitatively and qualitatively the same as
that of natural adrenalin.

The physiological action of d-suprarenin is in every respect
similar to that of the natural substance, but is very much less
intense ; while the racemic body, in accordance with its composi-
tion out of d- and 1-suprarenin, occupies a middle position.

The question which now arises is, of which substances is the
organic adrenalin composed? The theory that adrenalin is
formed from the waste products of muscle-metabolism (Boruttau,
Battelli) is unsupported by any known fact. The experiments of
Abelous, Soulie, and Toujans, which appear to confirm this
assumption, and which also point to the cortex as the site of
origin, will be discussed later.

The information which we possess in regard to the chemical

* The Hochster Farbwerke have recently put upon the market a i : 1005
solution of this combination, to which they give the name of " Supra-
renium hydrochloricum syntheticum." At present they supply the 1-supra-
renin only under this name.

1 80 INTERNAL SECRETION

process by which adrenalin is formed, is very scanty. As far as
its preceding stages are concerned, Friedmann supposed that
adrenalin might be derived from an oxyphenylserin or an
oxyphenylmethylserin, which substances might possibly have
been previously formed in certain albuminoids. According to
Halle and Frankel, tyrosin and phenylalamin may possibly be
waste products. The conversion of tyrosin into adrenalin is
supposed to be a combination of four chemical processes (oxida-
tion, evolution of carBonic acid, methylization of nitrogen, and a
second process of oxidation of the lateral chain in the @ position),
in the course of which para-oxiphenylethylamin is formed as an
intermediary product. This supposition is supported by the
results of experiments showing that the addition of tyrosin to an
emulsion of ox's or pig's suprarenals, is followed after six days
in an incubator by an increase in the adrenalin contents of from
14 to 33 per cent.

Neuberg found that the extract from a melanotic tumour con-
verted adrenalin in a short time into a dark brown product ; and
he also discovered that a melanin ferment obtained from the ink-
bags of cuttle fish (sepia) gives a similar melanin reaction with
para-oxy-phenylethylamin and tryptophan as with adrenalin. By
means of the tyrosinase from the fungus Prussula delica, Abder-
halden and Guggenheim obtained the same colour-reactions with
tryptophan and the derivatives of tyrosin (d-alanyl-1-tyrosin and
1-leucyl-l-tyrosin) as with 1- and d-suprarenin.

From these results it appears highly probable that the
products of the decomposition of albumin, and especially
tyrosin, are the matrix of adrenalin.

The most important chemical test of the presence of adrenalin
in liquids and tissue secretions is the characteristic colour reaction,
namely, green with ferric chloride and pink with iodine water.
The same reactions have also been employed as quantitative tests
in colorimetric experiments; ferric chloride by Battelli, and the
iodine reaction by Abelous, Soulie and Toujan. But the results
obtained by these methods cannot be regarded as by any means
exact, for they are dependent upon the operation of certain
extraneous conditions. The substance must be employed in a
state of chemical purity and with an almost neutral reaction, for the
presence of free acids and other bodies prevents the ferric chloride
reaction, which, in any case, is common to all derivatives of
orthodioxybenzol, and is not specific to adrenalin. Iodine stain-
ing is prejudiced by the fact that adrenalin solutions which are
exposed to the air and light take on a red colouring.

In the last two years a number of chemical tests for adrenalin
have been published.

The method described by G. Comessatti is based upon the
fact, first observed by Muhlmann, that the addition of sublimate
to suprarenal extract produces a red colour. A few drops of a

THE SUPRARENAL SYSTEM iSl

1-2 : 1000 sublimate solution are added to the liquid containing
adrenalin when, after one to three minutes, a diffuse red color-
ation is seen which lasts for several hours. Comessatti employed
his method also as a quantitative test of the amount of adrenalin
present in the suprarenal. In his view, the red coloration is
due to the formation of oxyadrenalin (Battelli), and is identical
with the red colour which adrenalin solutions acquire when
exposed for some time to the air. Of allied substances, pyro-
catechin gives a green reaction with sublimate, salicylic acid and
resorcin produce shades of red. According to Comessatti, this
reaction gives positive results with attenuated solutions, where
Vulpian's ferric chloride reaction is doubtful (0.0025 grm.
adrenalin : 1000; or, one drop adrenalin in twenty distilled water;
or, one drop adrenalin in 100 to 130 cm.3 tap water). On the
other hand, K. Boas found that, in the case of even concentrated
extracts, the reaction did not take place at room-temperature, but
that it made its appearance only after boiling.

Another chemical method of differentiating adrenalin is that
of Cevidalli. If hydrochloric acid is added to suprarenal extract
prepared with physiological saline solution, the albuminoids will
be precipitated; the filtrate is then rendered alkaline with NH3,
and a few drops of a concentrated solution of ferricyanide of
potassium are added, when a pinkish colour makes its appearance
which, after several hours, changes to a brownish black. By this
method, Cevidalli and Leoncini carried out a series of .investi-
gations into the amount of adrenalin present in the suprarenals
after death from various causes. They found that the " docimasia
surrenale " is sufficient to decide the medico-legal question as to
whether death has taken place suddenly, or is the outcome of
prolonged illness. In the latter case, the reaction is weak, but it
is very strong after sudden death.

The colorimetric method of A. Zanfrognini depends for its
results upon the fact that, where adrenalin is present, the brown
manganese dioxides are converted into the colourless lower oxides,
in the course of which the solution acquires a red stain. The
intensity of the colouring is proportional to the amount of
adrenalin present in the solution. The reaction is extremely
sensitive, and is clearly perceptible in a solution of i : 1,000,000;
it remains unchanged for hours ; and takes place independently
both of the reaction of the medium and the presence of
neutral salts. The reagent (3 grm. permanganate of potassium
dissolved in 24 c.cm. distilled water, with the addition of 8 c.cm.
lactic acid) is added drop by drop to the liquid containing
adrenalin, and it immediately loses its characteristic colour and
acquires a distinct pink coloration. An excess of the brown
reagent does not affect the result, the superfluity being
immediately carried off by the addition of a minimal quantity of
peroxide of hydrogen. The colorimetric result is ascertained by

1 82 INTERNAL SECRETION

progressive weakening of the liquid to be tested until a reaction
takes place, which, in regard to the intensity of the stain, is equal
to a standard adrenalin solution of i : 1,000,000.

The amount of adrenalin in the suprarenal is ascertained by
cutting the organ into small pieces and reducing it to a paste
by means of quartz sand; ten times the bulk of a 2 per cent,
acetic acid solution is added, and the mixture is allowed to stand
for about twenty-four hours ; the filtrate is then twice treated,
each time with five parts of the same acetic acid solution, in a
water-bath at 70° C., and is again filtered. The filtrate, which
still retains its brown colour, is bleached with ammonium sulphate,
and is then ready for use. According to Zanfrognini, the adrenalin
present in the human suprarenal remains unchanged for several
days after death.

S. Frankel and R. Allers describe a new and extremely
sensitive and characteristic adrenalin reaction. It depends upon
the fact that hydroidic-acid, or potassium biniodide and dilute
phosphoric acid, when added to adrenalin solution and heated,
change in such a manner as to produce an eosin pink colour in
weak solutions, and a splendid rose-red colour where stronger
solutions are used. On the further addition of ammonia, the
red colour changes to a rust-brown. The reaction is obtainable
with an n/50no- adrenalin solution, which is thus a .00365 per
cent, solution, or, in other words, contains i 1300,000. The
reaction is wholly specific to adrenalin, and none of the substances
for which adrenalin may be mistaken give a similar red stain.
The characteristic coloration is probably due to the formation of
an iodo- or an iodoso-combination on the part of the adrenalin.

As G. Bayer has shown, the adrenalin colour reactions with
ferric chloride and with chromates, as well as with the Frankel-
Allers test, may be rendered more sensitive by the addition of
aromatic amidosulphonic acids (a-naphthylaminosulphonic acid,
p-amidobenzolsulphonic acid). The sulphanil acid modification
of the ferric chloride and chrome reactions ought to have a
distinct value in microscopic and histological work. The iodine
reaction of adrenalin is intensified by alanin and by phenylalanin,
and probably also by other products of the decomposition of
albumin.

A method of testing the urine for adrenalin, recently
described by Schur, makes use of the red iodine reaction in the
following manner : an excess of tincture of iodine is added to the
liquid to be examined; the surplus iodine is then removed by
repeated shaking-up with ether, and this is continued until the
ether ceases to acquire a yellow tinge. Where adrenalin is
present the specimen stains pink, and though this colour is
permanent in pure adrenalin solutions, in urine it disappears after
some time. Adrenalin can be detected by this method in urine, in
a proportion of i : 200,000; in normal saline solution, in a proper-

THE SUPRARENAL SYSTEM 183

tion of 1:1,500,000. Pure urine frequently gives a similar
positive reaction, and Schur thinks it possible that adrenalin is
one of the constituents of normal urine. The sensibility of this
iodine reaction may also be made use of in quantitative adrenalin
tests.

The biological methods employed for the detection of adren-
alin will be discussed later.

THE PHYSIOLOGICAL ACTIVITY OF ADRENALIN.

Of the physiological effects of adrenalin, that which it exer-
cises upon the vascular apparatus is the most important and the
most characteristic. This is readily seen if a certain quantity
(about one-twentieth mg.) of adrenalin is injected into the veins
of an animal, and its blood-pressure registered by means of a
kymograph. The injection is followed almost immediately by
a rapid increase in blood-pressure which rises to a considerable
height, but this is partly concealed by the fact that, soon after
injection, the pulse becomes extremely slow. The increase in
blood-pressure lasts a short time only, from thirty seconds to two
to three minutes according to the dose, and the maximum is
obtained for a few seconds only. The retardation of the pulse
soon disappears also, and is followed by a gradual fall in
pressure, the starting point being reached in two, or at the most
four, minutes.

The increase in pressure is very much more perceptible if the
fall in the pulse-rate is avoided. This is done by eliminating, by
means either of atropine or resection, the inhibitory influence
of the vagi upon the cardiac contractions. If this is done, the
blood-pressure rises to twice, or even three times, the normal
figure. Blood-pressures reaching 250 to 300 mm. Hg. may by
this means be observed in dogs and rabbits, figures which are
not obtainable by the action of any other substance. Where
breathing is spontaneous, the respiratory fluctuations in blood-
pressure disappear during the rise and while the tension is at
its height; they reappear as the tension gradually diminishes.

A rise in blood-pressure follows the exhibition of even
minimal doses; the amount of the increase and its duration are
to a certain extent proportional to the amount of substance
injected. A typical increase in pressure of about 15 to 25 mm.
Hg. is obtainable with .0005 mg., and is certain with .001 mg.,
to every kilo of body-weight, of both the natural adrenalin and
the synthetic suprarenin. A dose of .005 mg. will raise the blood-
pressure 50 mm. Hg. ; and after .01 mg. it may be increased by
as much as So to 100 mm. Hg. An increase in the dose gradually
prolongs the period of hypertension. The maximal degree of
pressure is usually obtainable with .1 mg. adrenalin, while a
further increase of two to tenfold in the amount of the dose

184 INTERNAL SECRETION

frequently produces only toxic effects, such as fluttering or sudden
arrest of the heart, and occasionally cedema of the lungs.

These conditions militate to a certain extent against an
accurate estimation by means of blood-pressure readings, of the
quantitative value of adrenalin solutions. The presence of an
amount less than .001 mg. in i c.cm. cannot be proved with
certainty by means of animal experiments. The approximate
values of solutions containing a larger proportion of adrenalin
may be estimated by means of dilution.

The effect of adrenalin in raising blood-pressure is primarily
the result of vaso-constriction, that is to say, of a contraction of
the walls of the peripheral blood-vessels. This constriction of
the blood-vessels is clearly shown by the pale colour of the mucous
membranes. By means of oncometric experiments, Oliver and
Schafer ascertained the volume of the different organs. They
found that the abdominal viscera supplied by the splanchnic
nerve, such as the spleen, kidney, and intestine, become con-
siderably reduced in volume ; while the volume of the extremities
becomes increased, owing to the rush of blood into them from
the splanchnic region. A. Velich found by direct inspection that
there was a distinct reduction in the volume of the intestine,
kidney, and conjunctiva.

With regard to the origin of this peripheral vaso-constriction,
Cybulski and Szymonowicz assumed that it resulted from stimu-
lation of the central vaso-motor apparatus in the medulla
oblongata. But other experiments have shown that suprarenal
extract produces an enormous rise in blood-pressure after resec-
tion high up the spinal cord and destruction of the medulla (Oliver
and Schafer), after destruction of the entire central nervous
system (Biedl, Velich), and after resection of both splanchnic
nerves (Boruttau). I have kept the arterial pressure of animals
in which the central nervous system was entirely destroyed, at
140 to 160 mm. Hg. for hours at a time, by means of continuous
transfusion of a diluted solution of suprarenal extract. The rise
in blood-pressure also takes place where, as the result of profound
chloroform or chloral anaesthesia, the intervention of the central
nervous system is excluded (Gottlieb). That the vaso-motor
nerve-centres play a part in the production of the vaso-constriction
cannot be denied, if the quantitatively stronger action in the
sound animal, and the increased pressure which immediately
follows the direct introduction of adrenalin into the cerebral
circulation (injection into the carotid towards the brain, Biedl
and Reiner) are taken into account. It is probable that the
stimulation of the vascular centre is not direct, but is a secondary
effect brought about by the local anaemia.

The vaso-contraction does not affect all parts of the system
equally. The introduction of adrenalin into the general circu-
lation affects primarily those vessels whose innervation proceeds

THE SUPRARENAL SYSTEM 185

from the splanchnic nerve, and these undergo the maximum
degree of contraction. As Jonescu has pointed out, the renal
vessels are the first to contract, and this effect is produced by
doses which are too small to raise the pressure of the circulation
as a whole. If then, constriction within the splanchnic region gives
rise to a marked increase in tension, the increase in pressure will
produce a passive dilatation of the vessels in other parts of the
system, and this dilatation will be most pronounced in those
portions of the circulatory system which are not actively affected
by the constricting agent. Portions of the circulatory system
which are comparatively slightly affected by the vaso-constriction
are, apparently, the vessels of the extremities (passive increase in
the volume of the extremities has already been referred to), the
cerebral vessels and vessels of the retina, the pulmonary vessels,
and the coronary vessels of the heart.

Spina showed that the intravenous injection of suprarenal
extract produces so marked a dilatation of the cerebral vessels,
that the opening of the dura mater may be followed by
hyperagmia amounting to cerebral hernia. But Biedl and Reiner
found that the cerebral vessels may be induced to contract by the
direct application of the agent. As soon, however, as the increase
in tension becomes general throughout the circulation, this
cerebral anaemia disappears as a result of the general high
pressure. That adrenalin causes the cerebral vessels to contract
was proved by Wiggers, who allowed Locke's fluid, to which
adrenalin had been added, to stream through the brain of a dog ;
he found that the liquid, after leaving the brain, was considerably
reduced in quantity.

Velich was the first to discover the effects of suprarenal
extract upon the pulmonary circulation. He found that there was
a slight increase in pressure in the pulmonary artery, but believed
that this might be due to back pressure from the left auricle.
Direct inspection of the lungs showed that neither the intravenous
injection nor the direct application of adrenalin was followed by
the blanching observed in other organs under similar conditions.
Gerhardt also observed a slight increase in tension in the pulmon-
ary artery, and he ascribed it to the fact that, owing to the contrac-
tion of the systemic vessels, a larger amount of blood is carried to
the right heart. According to Gerhardt, the pulmonary vessels
are unaffected by suprarenal extract, and Brodie and Dixon were
unable to prove a vaso-constriction of these vessels after the
employment of adrenalin. They ascribe this result to inade-
quacy on the part of the vaso-motor innervation of the pulmonary
vessels. Plumier found that large doses were followed by distinct
vaso-contraction of the pulmonary vessels, and Petitjean arrived
at the same conclusion in regard to these vessels as Biedl and
Reiner in regard to the vessels of the brain. Petitjean believes
that adrenalin induces the pulmonary vessels to contract, but that

1 86 INTERNAL SECRETION

the contraction is very quickly counteracted by the passive
dilatation.

The effect of adrenalin upon the coronary vessels of the heart
is, in one particular, quite distinctive — it does not induce con-
traction. It will be shown later that strips cut from the
coronary vessels react to adrenalin differently from other vessels,
and the cause of this startling phenomenon will be explained.
It will, moreover, be shown upon which factor the localization of
the vascular effects depends.

The vaso-contraction produced by adrenalin may be observed,
in both warm-blooded animals (Pick, Biedl) and in frogs (Lawen),
by allowing the substance to circulate through organs removed
from the living body (iiberlebend) ; the effect is shown by the
marked reduction in the venous outflow. Lawen transfused a
liquid composed of two parts suprarenin (Hcechst) to ten million
parts Ringer's fluid, through the hinder extremities of Rana
esculenta, and he found a reduction of 87 to 96 per cent, in the
amount of the outflow; while a solution of ten times less concen-
tration produced a reduction of 50 to 81 per cent, in the outflow.
If the vessels are washed out with an indifferent liquid, they
resume their normal size. Owing to the sensitiveness of this
reaction, it is possible to employ artificial circulation through the
excised living organ both as a test for the presence of adrenalin
and as a means of estimating its physiological value.

The effect of adrenalin in producing local vaso-constriction is
well known and forms the basis of its therapeutic employment.
Adrenalin produces a high degree of vaso-contraction in very
vascular, and especially in hyperaemic, localities. It was intro-
duced into the therapeutics of ophthalmics by Bates and Darier,
who employed it as a means for the reduction of the hyperaemia
of inflamed and reddened conjunctivas. It has also been employed
to produce local anaemia in oto-rhinology and dermatology. The
work of H. Braun suggested this substance as an adjuvant to
cocaine and its congeners, and it has been largely employed in
minor surgery for the production of local anaesthesia. Adrenalin
was early employed as a styptic, more especially in paren-
chymatous haemorrhage. As early as 1895, I made use of
the vaso-contractor properties of adrenalin by employing it in
experimental surgery to reduce parenchymatous haemorrhage. I
also recommended, and with good result, tampons soaked with
sterilized suprarenal extract as a remedy in profuse uterine
haemorrhage. To-day, adrenalin is largely employed for the
reduction of hyperaemia; as an adjunct to other measures in the
production of focal anaesthesia ; for the prevention or reduction of
haemorrhage in operation ; and as a styptic.

Adrenalin is unable to penetrate the epithelial cover, hence
it produces no apparent effect upon the normal skin and mucosa as
long as these are intact. For therapeutic purposes, adrenalin is

THE SUPRARENAL SYSTEM 187

usually introduced into the tissues by subcutaneous injection ;
where, however, the mucosa are acutely inflamed and hyperasmic,
the local application, either by instillation or by painting the sur-
face, has a similar effect.

J. Baum has pointed out that the effect of suprarenal sub-
stance in producing blanching of the skin will be the more
energetic, prompt, and sustained, the more nearly the condition
of the vessels approximates to the normal. In acute inflammatory
conditions the action is marked ; where, however, the condition of
the vessels is chronically pathological, as well as in all forms of
destructive disease, the anaemia produced by adrenalin is slight
and very transient, and telangiectatic veins do not become
emptied. As soon as the anaemia passes, normal tissue regains
its normal appearance, and hyperaemia supervenes only after
repeated employment of the drug ; but where there are chronic
pathological changes in the tissue, the first application is followed
by pronounced venous hyperaemia.

Upon which part of the vessels does adrenalin act ? There
is no doubt that, in large and small arteries with muscular wrails,
adrenalin produces a contraction of the musculature. It is a
remarkable fact that, where adrenalin is employed locally, those
injections disappear first which are described as parenchymatous,
and it is more than probable that this is due to an enlargement
of the capillaries. Further, it has been observed that, where
adrenalin is applied locally to reduce parenchymatous haemor-
rhage, not only do the great vessels not contract, but, owing
obviously to the increased peripheral resistance, the great arteries
have a stronger beat. If the circulation of frogs is watched
through the microscope it will be seen that, after the introduction
of adrenalin, the circulation in the capillaries is suspended at a
moment when the blood in the arteries supplying them is still
flowing with undiminished rapidity (Bukofzer). When adrenalin
is injected into the veins, the volume of the organ decreases and
the parenchyma becomes pale, but the great arteries which supply
the organ are rather dilated than otherwise, and their beat is
stronger; this is well seen in the mesentery, after the exposure of
a loop of the intestine.

Since the contractility of the capillaries and their motor inner-
vation was proved by Steinach and Kahn, the part played by this
portion of the vascular system in the vaso-contraction produced
by adrenalin, can no longer be doubted. These authors showed
that there is a similarity of process between the contraction of
an artery and the contraction of a capillary; for, in response to
certain stimuli, the branched cells in the capillary wall (discovered
by Rouget and S. Mayer) contract, and may so reduce the vessel
as to entirely obliterate the lumen. An object eminently suited
to observation of capillary conditions is the nictitating membrane
of the living frog; if this is watched under the microscope, it

1 88 INTERNAL SECRETION

will be seen that stimulation of the isolated sympathetic is followed
by a contraction of the capillaries.

The constricting effect of adrenalin upon the veins seems to
be slight, and has, up to the present, received little attention.

The characteristic effect of adrenalin, namely, the increase in
arterial tension, is chiefly the result of an increased peripheral
resistance due to the contraction, and consequent reduction in the
size of the lumen, of the smaller arteries and the capillaries.

The enormous power \vhich suprarenal extract has of pro-
ducing vaso-contraction, forms the rationale of its therapeutic
employment in all those conditions, where the circulation
threatens failure in consequence of the sluggishness of the
stream. Of these, the most comprehensive are : vascular paralysis,
such as may be produced experimentally by destruction or
inhibition, by means of toxins (chloral hydrate, chloroform), of
the vaso-motor centres, and which is frequently seen in the last
stages of some infective diseases and in many toxic states ; and
cardiac asthenia, in which, owing to inadequacy of the heart
muscle and the vascular paralysis, those symptoms of
decreased circulation make their appearance which are known
as " shock " or " collapse."

Paralysis of the vessels and cardiac weakness both produce a
fall in arterial tension, and lead to a deficiency in the blood
supply to the vital nervous centres, as well as to an insufficient
filling of the chambers of the heart, cardiac anaemia, and ultimate
arrest of the heart's action. By producing contraction of the
engorged vessels in the splanchnic area and so raising the blood-
pressure, adrenalin effects a more favourable distribution of blood ;
it promotes the filling of the chambers of the heart and increases
the supply of blood to the nervous system. I found that, even in
cases where the nervous system was entirely destroyed, suprarenal
extract not only prevented the cessation of the circulation, but
that, by its aid, a normal circulation with a respectable arterial
tension was maintained for some considerable time. It \vas upon
the basis of these findings that, in 1895 at Professor Albert's
Clinic, I injected sterilized suprarenal extract into the veins in
two cases of cardiac and vaso-motor paralysis. In one case, the
results were negative, but here the autopsy showed that death
was due to embolism of the pulmonary artery. The second case
was one of extreme collapse with arrested respiration, the result
of chloroform narcosis, and here the effect of adrenalin was really
startling. The injection was immediately followed by deep, slow-
respirations which gradually became more frequent, and a full
radial pulse was perceptible, which was, however, somewhat slow
at first.

The resuscitating effect of adrenalin has been repeatedly
shown in a large number of animal experiments where, owing to
haemorrhage, or the arrest of cardiac and respiratory activity in

THE SUPRARENAL SYSTEM 1 89

chloroform anaesthesia, a fatal termination was threatened. Similar
results have been observed in cardiac paralysis induced by potas-
sium salts (Mankowski, Winter, Thenen).

Kothe recommends the clinical employment of an intravenous
injection of J to i c.crn. of a i : 1000 adrenalin solution in extreme
collapse ; where haemorrhage threatens a fatal termination, he
advises the addition of a few (6 to 8) drops of adrenalin to the
normal saline solution employed for transfusion. Heidenhain
observed that adrenalin in saline transfusions was attended by
favourable effects in septic peritonitis, this condition, according
to Romberg and Passler as well as Heinecke, arising from
paralysis of the vaso-motor centres.

Diluted adrenalin solution in large quantities has been em-
ployed with favourable results in the cardiac inadequacy of
diphtheritic children (Pospischil).

Quite recently, F. Meyer showed that the intravenous injec-
tion of adrenalin saline solution into rabbits poisoned with
diphtheria toxin and already moribund, was followed by a rise in
blood-pressure and in the pulse-rate, an appreciable improvement
in the respiration, and a return of the corneal reflex; death did
not supervene until seven hours later.

In addition to its effect upon the vessels, adrenalin, as we
have already seen, exercises a tonic influence upon the heart
muscle, and for this reason its exhibition is indicated in all forms
of circulatory inadequacy. Kothe's dictum : ' That adrenalin is
the most powerful analeptic which we possess ' is justified by
clinical experience (Meissl, Rothschild, Calmann, John).

In considering the other physiological effects of adrenalin, it
must be well borne in mind that this substance exercises an
intensifying influence upon a number of muscular and glandular
organs which derive their innervation from the sympathetic sys-
tem. Lewandowsky (1899) was the first to show that the intra-
venous injection of suprarenal extract into cats produces a
contraction of those muscles of the eye and orbit which have a
sympathetic innervation, and this finding was confirmed by Borut-
tau. Langley, and after him his pupil Elliott, next showed by
means of the most careful experiments, that the action of adrenalin
is wholly confined to tissues with a sympathetic innervation ; and,
moreover, that the effect of adrenalin, in any part of the body, is
identical with that produced by electric stimulus of the sympathetic
nerve supplying that part. Where the influence of the nerve is
stimulatory, exciting contraction or promoting secretion, the
action of adrenalin will also be stimulatory. Where, however,
irritation of the nerve is followed by inhibition, the injection of
adrenalin will also produce inhibition.

Before passing to a consideration of the grounds upon which
this hypothesis is founded, it is proposed to give a brief summary
of the doctrine of the innervation of the vegetative organs, as
formulated by the English school of physiologists.

1 90 INTERNAL SECRETION

THE VEGETATIVE NERVOUS SYSTEM.

It has been the custom hitherto upon anatomical and func-
tional grounds, to divide the entire nervous apparatus into two
great systems, namely, the cerebro-spinal or animal system, and
the sympathetic or vegetative system. The first, by means of
efferent nerve fibres, supplies impulses to the voluntary, striated
muscles, and, by means of afferent nerves, receives communications
from the organs of sense. The second controls all the involuntary
functions; it innervates the unstriated muscular tissue throughout
the body, as well as the secretory glands and the striated muscle
of the heart ; and it also controls certain striated muscle cells at
the beginning and the end of the intestinal tract and in the external
genitals.

From the results of descriptive anatomy it has long been
known that the two systems are not entirely distinct, and this is
confirmed by experiment. The sympathetic system is not in-
dependent, but is connected by means of numerous rami communi-
cantes with both the brain and the spinal cord. The essential
difference between the two systems lies in the fact, that communi-
cation between a striated muscle and its nervous centre is effected
by means of a single neuron, composed of a ganglion cell, a
peripheral nerve-fibre, and the terminal expansion of the latter ;
while in the case of the vegetative system, ganglia are interspersed
along the entire length of the nerve, from its source of origin
in the brain or cord to the organ where it ultimately terminates.
This arrangement is carried out, in the first place, by the ganglia
of the prevertebral chains, and, later, by ganglia of the second
and third order. These ganglia possess a special physiological
significance, for they represent breaks in the continuity of the
neuron, each ganglion cell with its nerve fibre marking the
commencement of a second neuron. Thus the vegetative system
is anatomically characterized by the presence of pre-ganglion and
post-ganglion fibres. That this distinction has a functional sig-
nificance, in other w^ords, that a change in the nature of the
stimulus takes place in the ganglion cells, is shown by the fact
that stimulation of the pre-ganglion nerve fibres before and after
inhibition of the ganglia (as the result of anaemia or of the action
of nicotine, w?hich has a specific paralysing influence upon these
ganglion cells) produces entirely different effects.

The English physiologist, Gaskell, has further drawn atten-
tion to the fact that, though all the anterior roots of the spinal
nerves supply motor nerves to the voluntary muscles, the efferent
fibres supplying the vegetative organs (which Gaskell calls the
' visceral nervous system ") do not leave the cord in an unbroken
series, but are divided into three groups, separated from one
another by the nerve roots of the plexus of the anterior and pos-

THE SUPRARENAL SYSTEM

terior extremities. The system has been variously named " vegeta-
tive," "sympathetic," "organic," and " ganglionary," but
Langley abandons these terms in favour of the more comprehen-
sive word " autonomous." Following Gaskell's division of the
system into three groups, he names them as follows : (i) the
cranio-cervical ; (2) the thoraci-columbal ; (3) the sacral. The
central portion of the thoraci-columbal system, together with the
thoracic and ventral chains and their plexuses and branches, forms
the "sympathetic" system in its more limited sense; and with
these must be included the plexuses which Anerbach and Melssner
regarded as forming a separate intestinal nervous system.

The term "autonomous nervous system," as employed by
Langley and the English authors following him, includes, then,
all those nerves by which the involuntary organs are supplied,
and according to this nomenclature the " sympathetic system " is
a subdivision only of the great autonomous system. Other later
authors, and the Germans more particularly, regard the sym-
pathetic as distinct from the autonomous system ; they include
under the former heading, the prevertebral chains, and those nerve
fibres whose roots are centred in the cord in a series extending
from the first thoracic to the fourth lumbar nerves. Under this
system of classification the autonomous system comprises : (i) the
cranio-bulbar nerve fibres, which are derived from the meso-
cephalon and the medulla oblongata, and which include the
oculomotor (III), the facial (VII), the glossopharyngeal (IX), and
the vagus (X) nerves ; (2) the sacral nerve fibres, which proceed
from the lower lumbar and sacral portions of the spinal cord, and
which combine to form the pelvic nerve.

This system of classification is based upon the fact that nearly
all vegetative organs possess a double innervation.

The sympathetic system supplies the involuntary muscles all
over the body, including those of the organs and of the vessels,
and it also innervates the glands. But an exclusively sympathetic
innervation belongs only to the sw7eat glands, the hair muscles
of the skin, and a portion of the muscular structure of the
intestinal vessels. In all other parts of the body there is, in
addition to the sympathetic innervation, a cranial-autonomous or
sacral-autonomous innervation, and in certain instances, as in the
vasodilators of the extremities, there is also a spinal nerve supply.
In many cases, the autonomous nerves are actually the physio-
logical antagonists of the sympathetic nerves, influencing the
voluntary muscles, the glands, vessels and heart in a manner
diametrically opposed to that of the sympathetic nerves. Where
the sympathetic in such instances promotes activity, the auto-
nomous nerves inhibit it.

It was at first believed that the stimulatory and inhibitory
nerves must be derived from different portions of the nervous
system, the one belonging to the sympathetic, the other to the

VEGETATIVE

Autonomous Nerves.

ACTION OF

3

5
0

COURSE

PERIPHERAL

GANGLION

EFFECT OK STIMULATION

Pilo-

carpin

Atropine

Nitrites
after
Frcihlich
and Lewi

. c

e c

£"3
<u-c
15 O
^ 0)

<J

N. Ill

N. VI

Ciliary

ganglion

Muse. Sphincter iridis ... ... F.
Muse, ciliaris ... ... ... F.
Retractor muscle of the nictitating
membrane ... ... ... I.

F.
F.

A. F.
A. F.

A. I.

•

c

N. VII
Chorda

Submaxillary
and sublin-

Submaxillary and sublingual glands :
Secretion ... ... ... ... F.

F.

A. F.

tympani

gual ganglia

Vessels (F.) and I.

A. F. (?)

A. I.

N. VII

Sphenopala-
tinoid ganglia

Mucosa of the tongue :
Secretion ... .. . F.

F.

A F

N. IX

G. oticum

Vessels ... ... ... F. and I.
Mucosa of the cheek :
Secretion ... ... ... ... F.

F.

A. F.

A. I.

e$

4^

Vessels . F.

tx

0

•1

N. X

G. vagi

Bronchial muscle ... ... ... F.

F.

A. F.

u <i
J5

Heart muscle ... ... ... I.

I. !

A. I. !

•a
u

s

I/?

3

Muscles of the gastro-intestinal canal :
CEsophagus ... ... ... ... F.

F.

A. F.

Nervus va£

Cardia ... ... ... F. and I.
Stomach ... ... ... F. and I.
Small intestine ... ... F. and I.
Gallbladder F.
Glands of the gastro-intestinal tract :
Stomach ... ... ... .. F.

F.
F.
F.

F.

A. F.
A. F.
A. F.
A. F.

A. F.

A. I.

.

Liver... ... ... ... ... F.

Pancreas ... ... ... ... F.

A. F.

r

vi

!g

*C 1-1

0 1>

Peripheral
ganglia of the
pelvis

Vessels of the rectum and anus ... I.
Muscles of the colon and rectum... F.
Muse, rectococcygeus ... ... F.
Anal sphincter ... ... ... I.

F.

F.

No A. F. !

S

^ C

V _

S rt

Urinary bladder :
Detrusor ... ... ... . . F.

F.

No A. F. !

<3 1
C/}

.- o
> rt

Sphincter ... ... ... ... I.

A. I.

0)

&.'-'

Urethra ... . . I.

A. I.

tn HH

12

^

External genitals :
Vessels ... ... ... ... I.

A. I.

.

Muscles (retractor penis) ... ... I.

A. I.

F. = Promotion of function (muscular contraction, acceleration of the heart's
I. = Inhibition of function (muscular relaxation, retardation of the heart's action,

NERVOUS SYSTEM.

Sympathetic Nerves from the Thoraco-htmbar Roots.

AcTIO^

I OK

ORIGIN

EFFECT OF STIMULATION

Adren-
alin

Ergotoxin
after Dale

Stimulation of the
sympathetic or by
adrenalin after
ergotoxin

Retractor muscle of the nictitating mem-
brane ... ... ... ... ... F.

F.

I-IIITh. I

Muscle of the eyelid ... ... ... F.
Orbital muscle ... ... ... ... F.

F.
F.

\ F. and
A. F.

Slight or no F.

I-II Th.

Muse, dilator pupilke ... ...(I.)andF.

F.

II-IV Th.

Cerebral vessels ... ... ... .. F.

F

IV-VIITh.

Vessels of the ear and head ... ... F.
Muscles of the hair of the face and neck. F.

F.
F.

A. F.

NoF.

II-IV Th.

Submaxillary and sublingual glands :
Secretion... ... ... ... ... F.

F.

A. F.

NoF.

Vessels F.

F.

Mucosa of the tongue :
Secretion ... F.

F

Vessels F.

F.

Mucosa of the cheek :
Secretion
Vessels ... ... ... ... ... I.

F. (?)

I-V Th.

Heart muscle ... ... ... ... F.

F.

A. F.

Slight or no F.

r

Muscles of the gastro-intestinal canal :
(Esophagus ... ... ... ... I.

I.

Cardia ... ... ... ... ... I.

I.

Stomach .. ... ... ... I. and F.

I.

F. and A. F.

I.

U]

Small intestine ... ... ... ... I.

I.

I.

O

O

Gall-bladder F. and I.
Gall-duct F.

I.

F. and A. F.

I.

1
J

Ileocoecal sphincter (cat) ... ... F.
Secretion of the pancreas ... ... F.

F.
F. (?)

F. and A. F.

Negative action.

II Thoracic— IV

t— *-

Vessels of the lung ... ... ... ?
Vessels of the intestine as far as the
descending colon ... ... ... F.
Vessels of the other abdominal viscera
F. and I.
Muscles of the spleen and of the ureter F.
Muscles of the internal genitals F. and (I.)
Vessels of the upper and lower ex-
tremities ... ... ... F. and (I.)
Muscles of the hair ... ... ... F.
Sweat glands . . ... F.

F.

F.
F.
F.

jr.

F. and A. F.

F. and A. F.
F. and A. F.
F. and A. F.

F. and A. F.
F. and A. F.
A. F.

L| Fall in blood
j f pressure

r'.

i.

i. ?

Negative action.

tn

4-»

O

o

Vessels of the rectum and anus ... F.
Muscles of the colon and rectum ... I.

Anal sphincter (cat) ... ... ... F.

F.

F. and A. F.

I.

1

S-<

Urinary bladder :
Detrusor ... ... ... ... I.

I.

I.

Sphincter . . ... F.

F.

1 F. and

>J

Urethra ... F.

F.

A. F.

- Negative action.

J>

HH

h- 1

External genitals :
Vessels F.

F.

-

Muscles (retractor penis) ... ... F.

F.

F. and A. F.

Negative action.

activity, vasoconstriction, secretion). A. F. = Arrest of function,
vasodilation). A. I. = Arrest of inhibition. ! = Noteworthy exceptions.

13

194 INTERNAL SECRETION

autonomous system.* Further investigation reveals the fact, how-
ever, that fibres which produce entirely opposite results are not
necessarily derived from different sources. Indeed, it has been
shown that both systems frequently send nerve fibres to the same
organ and that the function of the fibres is apparently identical ;
on the other hand, nerve fibres producing completely opposite
results appear to proceed from the same system.

We must assume that the complete nervous supply to a
vegetative organ comprises a fourfold innervation, namely: (i)
autonomous stimulatory ; (2) autonomous inhibitory; (3) sym-
pathetic stimulatory; and (4) sympathetic inhibitory. A number
of instances of such fourfold innervation are already known, but
investigation of the subject is of so recent a date that the informa-
tion which is forthcoming is necessarily very incomplete. The
conditions under which the innervation of the various vegetative
organs takes place offer a wide field for inquiry in the future.

The table upon pp. 192 and 193 shows all that is at present
known concerning the innervation of the vegetative organs. They
also show the relationship between the individual organic func-
tions and certain poisons.

The study of the action of certain toxins has brought im-
portant functional characteristics to light, and has revealed func-
tional differences between the animal and vegetative systems on
the one hand, and the autonomous and sympathetic portions of
the vegetative system on the other. These differences are for the
most part fundamental and in accordance with certain Iaw7s ; and
they depend upon the chemistry of the organs and, more particu-
larly, upon the chemical differentiation of the nerve endings.

Langley showed that nicotine has an elective affinity for
those ganglion cells, which, throughout the vegetative system, pro-
duce an anatomical break in the continuity of the neuron, and in
which a functional change in the nature of the nervous stimulus
takes place. After the intravenous injection of nicotine — and the
effect is even more marked if a diluted nicotine solution is applied
directly to a ganglion — there is a transient stimulus, followed by
paralysis, of those ganglion cells in which commutation of
stimulus takes place. Electric stimulus produces certain effects
upon nerve fibres of the vegetative system, and the results of this
stimulus, whether applied before or behind a ganglion, are
identical. But the effect of nicotine is to paralyse the obstructing
ganglion cell — and its influence is entirely confined to this cell—
with the result, that stimulus of the pre-ganglion fibre is negative,
while the post-ganglion fibre responds in the ordinary way.

* Following a system of nomenclature adopted by English physiolo-
gists, it is proposed to describe any action, whether a muscular contraction,
an increase in the cardiac function, a contraction of the vessels, or the
promotion of the secretion of an organ as motor effect or function (F.).
The prevention of function of whatever nature (muscular relaxation, cardiac
insufficiency, vasodilation) is termed inhibition (I.).

THE SUPRARENAL SYSTEM 195

It is evident from this that the effects of nicotine are confined
to the vegetative nervous system, for the efferent fibres of the
cerebro-spinal system are nowhere interrupted by ganglia. Such
being the case, nicotine may be used to determine whether certain
results are due to stimulation of the vegetative or of the animal
system ; moreover, it will decide the question as to whether or not
certain ganglia act as physiological commutators to certain nerve
fibres. Anatomical investigation shows that each vegetative nerve
contains several ganglia, but it is evident from the effects produced
by nicotine that an actual interruption in transmission occurs at
one point only in its course.

The elective action of other toxic substances upon the vegeta-
tive nervous system serves to differentiate between the activity of
the sympathetic and the autonomous nerves. The elective, and at
the same time antagonistic, effects produced upon certain organs
and organic functions, by atropine on the one hand and by the
so-called muscarine group of substances (muscarine, pilocarpine,
physostigmine) on the other, have long been recognized and have,
in a certain measure, been turned to account for therapeutic pur-
poses. The substances of the muscarine group exercise a stimu-
latory effect upon those functions which are inhibited by atropine.
Closer investigation shows that the organs influenced by these
substances are exclusively those which possess an autonomous
innervation, such as the eye, the salivary glands, and the organs
supplied by the vagus nerve, namely, the heart, the bronchial mus-
culature, and gastro-intestinal canal. The sweat-glands form a
remarkable exception, for, although they are equally affected by
the action of these toxins, their innervation, as far as we know at
present, is entirely sympathetic. Moreover, as will readily be
seen by referring to the table on pp. 192 and 193,
the stimulatory action of pilocarpine, as representative of
the muscarine group, and the inhibitory action of atropine,
do not extend to all the nervous effects produced by
the autonomous system, but are confined to those whose
influence consists in the promotion of function. Pilocar-
pine is, then, a toxin which promotes autonomous activity;
atropine is a toxin which inhibits autonomous activity. In the
case of the heart muscle, on the contrary, the action of pilocarpine
is inhibitory, while that of atropine is stimulating. Frohlich and
Lowi were able to prove that the nitrites are also inhibitory toxins
whose action is confined to the autonomous nerve endings, but
that their influence is extended solely to those whose function is
inhibition.

Adrenalin is a substance possessing an elective affinity for
the sympathetic system. The foundation for this theory will be
fully discussed in the following chapter. It will be seen from
the table given above (pp. 192 and 193) that adrenalin affects those
tissues only which have a sympathetic innervation ; and that its
effects are identical with those which may be obtained by stimu-

IQ6 INTERNAL SECRETION

lating the sympathetic nerve fibres of certain organs. The in-
variable effect of adrenalin upon the sympathetic nerve fibres is
to intensify their activity, whether the nature of that activity be
stimulatory or inhibitory.

With regard to the two last columns of the table, the follow-
ing facts must be borne in mind. The column before the last
shows the effects of ergotoxin upon the sympathetic system, while
the last column shows the effects of stimulation, by electricity and
by adrenalin, upon a sympathetic system which has been poisoned
by ergotoxin. Dale has shown that the toxic influence of pre-
parations of ergot, and especially of ergotoxin, produces a stimu-
lation, followed by inhibition, of the sympathetic nerve endings,
this toxic influence being solely confined to their function-pro-
moting activity, their function-retarding activity remaining un-
changed. An injection of adrenalin given under these conditions
produces, therefore, a paradoxical result. The conclusions to be
drawn from these phenomena will be discussed later.

THE PHYSIOLOGICAL EFFECTS OF ADRENALIN
UPON THE SYMPATHETIC SYSTEM.

The Vessels. — The striking effect which the active principle
of the suprarenal has in producing contraction of the vessels,
naturally suggested the question : Is this result due to the direct
action of the substance upon the contractile elements of the
vessel walls ; or is it a secondary result, the outcome of the
stimulation of peripheral structures included in the sympathetic
system ?

Oliver and Schafer at first assumed a direct action upon the
muscular tissue, and among the proofs which they advanced in
support of this theory was the effect produced by suprarenal
extract upon the heart and upon the striated muscles.

Support is given to the theory of a direct action of the sub-
stance upon the vessel walls by the fact that, at a developmental
stage when nervous elements are not demonstrable in the vessel
walls, a distinct contraction of the vessels may be produced in the
embryo chick by the direct application of a drop of suprarenal
extract (Konigstein).

By the artificial circulation of adrenalin through the hinder
extremities of dogs, I discovered that the contraction of the
vessels, which is shown by the decrease in the venous outflow,
will also take place if the animal is first paralysed by means of
large quantities of curarin, or if curarin has been previously added
to the blood circulating through the extremities. Tillie proved
that curarin produces paralysis of the vaso-constrictor nerve
terminals, and these experiments of mine go to show that the
effect of the substance in producing vaso-constriction is due, at
least in part, to a direct action upon the muscular structure. I

THE SUPRARENAL SYSTEM 197

found that the effect of suprarenal extract is much stronger be-
fore than after the exhibition of curarin, and it seems certain from
this that the peripheral nervous elements play the chief part in
the production of vaso-constriction.

Langley found that, in the case of the submaxillary gland,
even where the post-ganglionary fibres had undergone degenera-
tion, the intravenous injection of suprarenal extract was followed
by constriction only of the vessels, and he believed that the action
of the substance was, in all probability, directly muscular. He
emphasizes the fact, however, that the effects of suprarenal extract
vary in different parts of the vascular system, and he draws atten-
tion to the parallel between the action of this substance and the
effects of electric stimulus upon the sympathetic nerves.

According to Brodie and Dixon, the fact that the influence of
adrenalin upon the pulmonary vessels is negative, is a sufficient
proof that this substance affects the sympathetic nerve endings
and these only, and has no influence whatever upon the unstriated
muscles.

In order to test the effects of adrenalin upon the nerve ter-
minals, these authors first induced, by means of cocaine, curarin,
or apocodein, a paralysis of the systemic vaso-constrictor nerve
fibres. They were unable to obtain satisfactory results with
cocaine, but they found that, after curarin, the action of adrenalin,
although not entirely neutralized, was very much slighter in effect.
Lawen, on the other hand, found that the effects of suprarenin,
when introduced into the circulation of frogs previously treated
with curarin, were in no way diminished; he concludes from this
that there is not a direct antagonism between curarin and supra-
renin, and he believes that suprarenin exercises a direct action
upon the muscular structure of the vessels.

Dixon 's experiments with apocodein bring an even more
certain proof of the effects of adrenalin upon the nerve terminals
of the vessels of both the heart and the intestine. Dixon showed
that apocodein, which is an alkaloid obtained by dehydration from
codein, when given in moderate doses, affects the sympathetic
nerve cells in exactly the same way as nicotine. A moderate dose
of apocodein causes vaso-dilation with consequent hypotension ;
it accelerates the heart's action ; and it intensifies the autonomous
movements of the unstriated muscles of the intestine. Apocodein
in moderate doses does not in any way affect the physiological
action of adrenalin.

When given in large doses, apocodein produces a paralysis
of the nerve terminals of the striated muscles, similar to that
caused by curarin ; a paralysis of the vagus terminals in the
heart, similar to that produced by atropine ; and a complete para-
lysis of the vaso-motor nerve endings. At this stage of apocodein
poisoning, adrenalin does not provoke a rise in blood-pressure
nor does it affect the portions of the intestine which have a sym-

igS INTERNAL SECRETION

pathetic innervation. Substances such as barium, which exercise
a direct influence upon the unstriated musculature of the vessels,
produce an increase in blood-pressure even under these condi-
tions. Dixon concludes from this that adrenalin acts on the
sympathetic nerve endings.

That the effect of adrenalin upon the blood-vessels is identical
with that produced by stimulation of the sympathetic nerves could
not be doubted if proof were forthcoming that, where the sym-
pathetic innervation is inhibitory and therefore vaso-dilator, the
effect of adrenalin is also to produce vaso-dilation.

Dastre and Morat point out that the sympathetic system fur-
nishes vaso-dilator fibres to the bucco-facial region, and R. Brad-
ford discovered that it also supplies vaso-dilators to the kidneys.
Elliott was unable to obtain a primary vaso-dilation by means of
adrenalin in any part of the body; upon the principle that the
vaso-dilator nerves react to very slight stimuli, he reduced his
doses to the minimum, but was still unsuccessful. Sollmann and
Pari observed an occasional dilation of the renal vessels after
adrenalin, while Jonescu has recently pointed out that minimal
doses are followed by a constriction of the renal vessels.

Elliott and Dale were successful in proving the vaso-dilator
properties of adrenalin by means of chrysotoxin. After the intra-
venous injection of 100 mg. of chrysotoxin, stimulation of the
splanchnic nerve is followed, not by a rise, but by a fall in
blood-pressure. Under similar conditions adrenalin also produces
a fall in pressure, which lasts for about the same length of time
as the rise which takes place under normal conditions. This fall
in blood-pressure, whether brought about by the agency of
adrenalin or by electric stimulus, is probably due to stimulation of
the vaso-dilator nerve endings.

The vaso-dilator effect of adrenalin may also be seen in the
coronary vessels of the heart. It has long been known that
adrenalin rather increases than diminishes the circulation of blood
through the heart, and this result has been attributed to the in-
creased cardiac activity. Elliott showed that adrenalin will
produce an increased circulation in a portion of ventricle flooded
with Locke's fluid.

Owing to the fact that portions of arteries respond actively
to the influence of adrenalin after their removal from the living
body, a great deal of information has been obtained concerning
the effect which adrenalin has upon the vessels and its dependence
for this effect upon the nature of their innervation. The experi-
ments of Bayliss, MacWilliam and v. Frey show that isolated
blood-vessels, if suitably treated, will remain alive and sensitive to
stimulus for days. Prompted by the results of these experiments,
O. B. Meyer succeeded in working out a method by which the
influence of different drugs upon the vessels might be studied. A
circular strip is cut from an artery and suspended lengthwise in

THE SUPRARENAL SYSTEM 1 99

some Ringer's solution, which is kept at the temperature of the
body and through which oxygen is allowed to circulate ; the altera-
tions in the length of the specimen are recorded graphically by
means of a lever. The walls of the large arteries of cattle become
appreciably shortened by the addition of adrenalin, and the degree
of the contraction is, up to a certain point, proportionate to the
amount of adrenalin added. The concentration necessary to pro-
duce an effect was found to be .000015 mg. to 15 c.cm. Ringer's
solution (1:1000 million); by increasing the concentration, the
amount of contraction was increased ; and maximal results were
obtained with a concentration of i : 50,000.

Owing to its sensitiveness, this reaction is a reliable biological
test both for the presence and the quantity of adrenalin.

Meyer proved the presence of adrenalin in defibrinated bul-
lock's blood or serum by this method. We shall consider later
the extent to which Meyer's method may be employed as a test
for the presence of adrenalin in the heterogeneous blood serum.
I have proved the sensitiveness of the reaction in numerous experi-
ments. I was able, by this means, to detect adrenalin in the
ganglia of the ventral nerve-cord of leeches; and I found that an
extract, obtained from the fresh ganglion chains of ten leeches
in 2 c.cm. of normal saline solution, produces a vascular con-
traction equal to that obtained with io-8 to io-7 adrenalin con-
centration. In this instance, the ferric chloride reaction was un-
certain. Fraenkel's adrenalin test with the uterus taken from a
living rabbit (to be described later) gave results almost identical
with those which I obtained with portions of arteries.*

Meyer proved by his method that, not only does adrenalin
act upon the customary preparations from the carotid and the
subclavian arteries of bullocks, but that it also reduces the length
of sections taken from the pulmonary artery and of longitudinal
strips from the jugular vein. He also found by this method that
there is an antagonism between the effects of adrenalin and those
of atropin, curarin, and cocaine, and he assumes, therefore, that
adrenalin affects the nerve terminals. As further proofs in sup-
port of his theory, he adduces the following : (i) That adrenalin
is active in low concentration and within certain temperature limits
only ; (2) that it ceases to affect preparations which are a few days
old, at a stage when they are still sensitive to muscular electric
stimulus; and (3) that adrenalin stimulates the vascular muscles,
while it inhibits the contraction of intestinal muscles which have
been removed from the living body.

O. Langendorff obtained conclusive proof, by Meyer's method,

* The statement which appears in a monograph by v. Neusser and
Wiesel, to the effect that " according to Wiesel " the physiological activity
of the ganglia of the ventral cord of invertebrates exactly coincides with
that of the chromaffine tissue of vertebrates, is the result, Wiesel informs,
me, of a mistake in the name of the author.

2OO INTERNAL SECRETION

that the effect of adrenalin upon the vascular muscles depends
upon their vaso-motor innervation. The treatment, with adrenalin,
of portions taken from the coronary vessels of the ox is followed,
not by shrinking, but by a distinct lengthening of the specimens.
In this instance, therefore, adrenalin does not provoke contraction
but dilation. This result is explicable if we take into consideration
the fact that the sympathetic innervation of all peripheral vessels
is constrictor, while, according to P. Maass, the sympathetic
nerves supplying the coronary vessels of the heart (which include
the first thoracic ganglion and the ansa Vieussenii) contain only
dilator fibres, the contractors being conveyed by the pneumo-
gastric nerve.

It may be noted in passing that the antagonism, which
Langendorff discovered between the cardiac vessels and the other
peripheral vessels, is demonstrable by means of substances other
than adrenalin. Eppinger and Hess found that, unlike adren-
alin, pilocarpin, physostigmin and cholin hydrochlorate (Merck)
produce a shrinking — that is to say, a contraction — of portions
taken from the coronary vessels, while in the case of the peri-
pheral vessels, they induce dilation as shown by the increase in
length. Certain substances influence both sets of vessels in the
same manner, barium chloride, calcium salts and the digitalis
bodies producing contraction, while atropine, ergotin and the
nitrites produce dilation. According to Pal, pilocarpin contracts
the coronary, mesenteric and femoral arteries and dilates the renal
artery.

The observations described above justify the conclusion that
the site of the influence of adrenalin is to be sought, not in the
muscular structure of the vessels, but in those apparatuses which
are in communication with the sympathetic nerve endings.

The Heart. — As we now know, the full effects of adrenalin
upon the heart are to be seen only after the inhibitory vagal
nerve endings have been paralysed by means of atropine. If the
vagi are allowed to remain intact, the predominant effect will be
the slowing of the rhythm, due to the increased arterial tension.
Even the resection of the vagi at the neck does not entirely over-
come the tendency to a retarded rhythm, interrupted by single
arhythmic beats. The slowing of the pulse and the extra-systolic
arhythmia are sufficiently explained by the increased venous ten-
sion and consequent impossibility of completely emptying the left
ventricle.

The full action of adrenalin may, however, be observed in
the mammalian heart in situ after the vagal terminals have been
paralysed with atropine. There is, as a rule, a further accelera-
tion of the contractions and there is, especially, a stronger ventri-
cular systole which is well seen by registering the contractions
or by means of a plethysmograph. This increased cardiac activity
is the result, not of improved circulatory conditions arising out

THE SUPRARENAL SYSTEM 2OI

of the heightened blood-pressure, but of the direct action upon the
heart of the substance itself. Thus, the intravenous injection of
suprarenal extract will bring back life into an animal poisoned
with chloral, in which the action of the heart is almost or entirely
obliterated. The injection is followed by a progressive increase
in the rapidity and power of the contractions ; the blood-pressure,
which had fallen almost to nothing, rises ; and, after a second
injection, the heart resumes its normal activity which is main-
tained. A similar result may be obtained after poisoning with
potassium salts, which bring about a cessation of diastole and
thus are typical cardiac poisons (Gottlieb).

The resuscitating effect of adrenalin upon the heart — the man-
ner in which it hastens and strengthens cardiac contraction — is
undoubtedly an important factor in the analeptic action, already
described, which this substance has in conditions of collapse due
to paralysis of the vessels or to temporary cardiac insufficiency.

The action of adrenalin mav also be observed in hearts

j

which have been removed from the living body. Oliver and
Schafer experimented with isolated frogs' hearts through which
normal saline solution was allowed to circulate. They found that
suprarenal extract produces spontaneous contraction in a motion-
less heart ; in the case of a feebly beating heart, the beats become
stronger and more rapid, the irregularity disappears, and rhythm
is restored.

The tonic influence of adrenalin upon the isolated mammalian
heart when flooded by Langendorff's method is very clearly
shown by the acceleration and remarkable increase in power of
the contractions (Gottlieb, Hedbom, Braun and Mager, Cleg-
horn). Weakness of the heart's action, arising from prolonged
deprivation of the nutrient fluid or from the action of toxins, is
invariably corrected by the application of adrenalin, and it is not
until after the method has been continued for some time that the
reduced cardiac activity again becomes apparent in the guise of
arhythmia and reduction in frequency. Hering-Bock found that
an increase in the pulse-rate and a stronger cardiac contraction
also followed the employment of adrenalin in the isolated cardio-
pulmonary circulation.

Gottlieb endeavoured to discover with isolated frogs' hearts,
whether suprarenal extract acts directly upon fhe cardiac muscles
or upon the ganglia. The action of the ventricle was arrested by
means of the first ligature of Stannius between the sinus venosus
and the auricle ; by the injection of a small quantity of suprarenal
extract, it was next induced to contract rhythmically in the same
manner as after the so-called second ligature of Stannius. After
the application of the second ligature of Stannius, however, the
ventricle, which was then entirely deprived of its ganglia, failed
to contract even in response to injections of suprarenal extract,
and it responded to mechanical stimulus with a single contraction

202 INTERNAL SECRETION

only. These results led Gottlieb to the conclusion that supra-
renal extract is a powerful stimulant of the vaso-motor ganglia of
the ventricle.

The question as to whether the effect produced by adrenalin
upon the heart represents a direct muscular action, or is due to an
affection of the sympathetic nerve endings which reaches the
heart by way of the nervi accelerantes, has formed the subject of
much recent discussion. The following results are advanced as
evidence in favour of the latter hypothesis.

According to Elliott, the cardiac action of adrenalin is not
observed in all animal species. The heart of invertebrates, as
the crab, does not appear to react to it in any way.

Gaskell's experiments go to show that, in the heart of turtles
and birds, the auricle is provided with augmentary fibres, while
the ventricle possesses neither stimulatory nor inhibitory fibres.
Elliott found that, in the turtle, the effect of adrenalin is to
strengthen and accelerate the contractions of the auricle only,
the ventricle remaining entirely unaffected. When the heart is
undamaged, the acceleration probably affects the ventricular
rhythm only, though this has the effect of shortening the contrac-
tions. The isolated hearts of birds (pigeons) become very much
stimulated if adrenalin is added to the fluid circulating through
them. After separation of the auricles, the ventricular beat is
suspended for a time and adrenalin produces no effect upon the
activity of the ventricles, but portions of the auricle respond to-
the action of adrenalin by accelerated contractions. As a general
rule, those parts of the heart react more readily to adrenalin which
are innervated, either wholly or in part, by the sympathetic
system ; thus the auricles react better than the ventricles.

The effect of suprarenal extract upon the hearts of fish is to
produce a much stronger contraction of the ventricles. This is
clearly shown in the experiments which I carried out in 1899 with
the object of finding the curve of the cardiac activity of torpedoes.
The rhythm of the heart when in situ is rather retarded than other-
wise. The blood-pressure, which was taken at a branchial artery,,
rose to very nearly twice the normal figure. A similar effect was
obtained \vith extract of the suprarenal bodies of animals of the
same species.

By means of experiments with isolated hearts, Gatin-
Gruzewska and Maciag have recently discovered that the hearts
of cold-blooded animals are much less sensitive to adrenalin than
those of warm-blooded animals. The effect of adrenalin upon the
former is to increase the duration of systole and this is followed
by a slowing of the rhythm ; while in the case of hearts taken from
rabbits, the use of minimal doses is followed by stronger and
more rapid contractions.

In the case of the embryonal heart, the effect of adrenalin
seems to depend upon whether or not it possesses a separate

THE SUPRARENAL SYSTEM 2OJ

sympathetic innervation. Scott Macfie found that the cardiac
movements of an embryo chick, two to three days old, were
entirely unaffected by adrenalin. According to Kuliabko, the heart
of the human embryo is very little influenced by this substance.
Quite recently, I found that the heart of the embryo chick is
insensitive to adrenalin at a time when the vessels of the vascular
area contract readily in response to this substance. Upon the
fifth to seventh day, when the intrusion of sympathetic elements
has already taken place and a substance which, upon the ground
of its biological reactions, is assumed to be adrenalin, is present in
embryonic extract, the response of the heart to adrenalin stimulus
is clearly shown in the acceleration of the contractions and in
single arhythmic beats.

Dixon's experiments with apocodein supply definitive in-
formation concerning the actual site which adrenalin affects in
the mammalian heart.

The immediate effect of apocodein is to produce a paralysis
of the inhibitory vagal nerve endings in the heart. At this stage,
adrenalin acts in the same manner as upon a heart in which the
vagal terminals have been paralysed by means of atropine ; that
is to say, it brings about an increase in the rate and the volume
of the beats. Further doses of apocodein have the effect of entirely
neutralizing the action of adrenalin. The increase in the pulse-
rate (from 93 to 211 a minute) produced by adrenalin almost en-
tirely disappears (93 to 101), and a still further application of
apocodein is followed by an actual fall (87). Even when used
in large doses, adrenalin fails to either accelerate or strengthen
the systole. The effect of apocodein is to paralyse the acceleratory
nerve endings, upon which adrenalin exercises a stimulating
influence.

These results seem to show that the action of adrenalin
consists in a stimulation of that portion of the sympathetic
apparatus whose function it is to promote cardiac activity.

This assumption is confirmed by certain phenomena, recently
observed after intravenous adrenalin injection by means of the
electrocardiograph, by R. H. Kahn, some of which phenomena
are also obtainable by means of strong artificial stimulation of
the vagus nerve. Such are the prolonging of the refractory
period, the heart-block, and the automatic and weakened
ventricular beat. The phenomenon which is specific to adrenalin
is the disassociation of the auricular and ventricular beats, which
is continued for some time, and in the course of which the
ventricular beat gives normal electrograms. After resection of
both vagi, all these phenomena disappear, and the rise in blood-
pressure is recorded without important changes in the electro-
cardiogram.

The Digestive Tract. — Strips cut from the cesophagus or
stomach of frogs, when fresh, possess considerable tone, but

204 INTERNAL SECRETION

after they are wetted with suprarenal extract they become
relaxed, cease to contract spontaneously, and are less sensitive to
electric stimulus (Boruttau, Botazzi). The inhibitory action
which adrenalin has upon the rhythmic contractions of the
stomach-ring of frogs or eels, is observed with a concentration as
low as i :io-G (O. B. Meyer).

Langley found that the intravenous injection of adrenalin
into rabbits was followed by an immediate relaxation of the
cardia, in consequence of which a fluid present in the oesophagus
was permitted to pass. In no case was there a contraction of
the oesophagus muscles, and even the spontaneous contractions
disappeared. The action of adrenalin is the reverse of that of
the vagus, for peripheral irritation of the vagus is followed by
a contraction of the gastric sphincter. If the stomach is
exposed, it will be seen that the action of adrenalin is to produce
inhibition of the spontaneous movements. As soon as the
relaxation of the cardia ceases, rhythmic contractions of the
stomach take place ; thus the effect of suprarenal extract resembles
that of irritation of the splanchnic nerve. Elliott was also able
to show that the spontaneous movements of the stomach are
inhibited in the same manner, by both the action of adrenalin
and by stimulation of the splanchnic nerve, the entire muscular
structure becoming relaxed; irritation of the vagus, on the other
hand, produces contraction of the stomach and peristaltic move-
ments. The pylorus, in rabbits, contracts in response to adren-
alin in the same way as after stimulation of the splanchnic nerve.

The effect of suprarenal extract upon the small intestine is
shown by inhibition of the peristaltic and oscillatory movements,
though after a few minutes these reappear (Boruttau, Pal).
According to Kuliabko and Alexandrowitsch, adrenalin improves
the tone of the intestinal muscles, and gives rise to oscillatory
movements.

The inhibitory action of suprarenal extract is even more
marked in the case of the large intestine. In the rabbit there is
relaxation of the internal anal sphincter and blanching of the
mucosa. In the cat and the dog there is a contraction of the
sphincter similar to that produced in these animals by irritation
of the sympathetic nerve-fibres.

The similarity of the effects produced by adrenalin and by
stimulation of the sympathetic are demonstrable along the entire
length of the gastro-intestinal tract. With the exception of the
three sphincters (pyloric, ileo-cascal, internal anal), which con-
tract, there is a general muscular relaxation.

This similarity of result persists in the intestines of birds
and amphibians, in spite of the fact that here the innervation
conditions are not the same. The oesophagus of frogs and
turtles relaxes, and the stomach contracts in response both to
adrenalin and to stimulation of the sympathetic. In fowls,

THE SUPRARENAL SYSTEM 205

adrenalin produces a tonic contraction of the duodenum and, to
a certain degree, of the rest of the small intestine; the large
intestine relaxes, and the ileocascal and internal anal sphincters
contract. Irritation of the vagus produces the reverse effects;
and irritation of the spinal roots of the sympathetic produces
results identical with those of adrenalin.

The Urinary Bladder. — Lewandowsky found that the
intravenous injection of suprarenal extract was followed by a
relaxation of the detrusor fibres, which was shown by a reduction
of the internal pressure. Langley found that the results which
he obtained were similar to those produced by stimulation of
the inferior mesenteric ganglion or of the hypogastric nerve.
The local application of suprarenal extract produces blanching
accompanied by local contraction, which is, however, followed
by relaxation.

Elliott investigated the innervation conditions of the bladder
and urethra in different varieties of mammals, and he found that
the effect of adrenalin upon the muscular structure of the bladder
was in all cases coincident with a sympathetic innervation.

In all mammals, sympathetic fibres proceed from the lumbar
spinal roots to the urinary bladder by way of the hypogastric
nerve, and autonomous fibres pass to it from the sacral roots by
the agency of the pelvic nerve (errigens). Electric stimulation
of the hypogastric nerve is followed, in cats, by a brief contraction
of the bladder, which principally affects the fundus, and this is
succeeded by considerable relaxation of the bladder accompanied
by a violent contraction of the urethra. The intravenous injec-
tion of adrenalin immediately provokes a short contraction of
the fundus and of the urethra, together with a complete relax-
ation of the body of the bladder. While the effect of adrenalin
lasts, stimulation of the pelvic nerve fails to produce contraction.

In the ape (Macacus rhesus), the effect both of adrenalin and
of hypogastric stimulation is to produce a slight relaxation of
the bladder. In the rabbit, irritation of the hypogastric produces
a slight increase in internal pressure and contraction of the
urethra, similar effects being obtained with adrenalin. The
urinary bladders of the guinea-pig, the hedgehog, and the rat
do not react to adrenalin. In the dog, stimulation of the
hypogastric produces only very slight contraction of the fundus,
and the influence upon the muscular structure is equally insig-
nificant. In the ferret (Mustelus putorius, var. domestica),
irritation of the hypogastric is followed by complete contraction
of the bladder. It is a remarkable fact that, in this animal, the
motor innervation of the bladder is derived from the sympa-
thetic system and the inhibitory innervation from the sacral
autonomous system. A small quantity of adrenalin given intra-
venously is also followed, in this animal, by violent and
prolonged contraction of the bladder. The remarkably strong

206 INTERNAL SECRETION

peristaltic movements of the ureters are not influenced either by
adrenalin or by stimulation of the sympathetic. In spite of the
close relationship between the Mustelides and Herpestes mungo,
the bladder of the latter does not react to adrenalin. The urinary
bladder of goats and of the Indian civet-cat (Viverra zibetha)
responds in the same manner as that of the ferret.

This difference in the innervation of the bladder in mammals
serves to show very clearly that adrenalin may exercise an
inhibitory action upon unstriated muscles, if these muscles receive
an inhibitory innervation from the sympathetic. The muscular
inhibition produced by adrenalin is entirely independent of the
blanching provoked by this substance ; for, in the cat, the latter
effect is almost entirely absent, while the relaxation of the
muscles is perceptible in every part of the bladder, and may be
produced by direct local application.

That the specific action of adrenalin is, in the case of certain
tissues, independent of the blanching process, is also seen in the
heart, where the coronary vessels remain uninfluenced, while
the rapidity and strength of the contractions is considerably
increased. The direct effect of adrenalin independently of the
blood supply, namely, relaxation and cessation of spontaneous
movements, may also be observed in a portion of living intestinal
wall after its removal from the body.

The External Genital Organs. — After the intravenous injec-
tion of suprarenal extract, these organs become blanched and
•contract in a manner similar to that which follows stimulation of
the lumbar sympathetic (Langley and Anderson). The tunica
dartos of the testicle has a different reaction — it does not contract
in response to suprarenal extract. According to S. Lieben, the
intravenous injection of adrenalin provokes relaxation of the
tunica dartos.

The Internal Genital Organs. — Langley observed a high
degree of contraction and marked blanching of the vagina and
cornua in rabbits and cats, after the intravenous injection of
.adrenalin in small doses. In male animals, there was a contrac-
tion of the vas deferens.

The similarity between the effects of adrenalin upon the uter-
ine muscles, and those of stimulation of the sympathetic, will be
fully discussed later. For the present purpose, the following
will suffice.

The effect which adrenalin has upon the uterus is among
the most perfect and startling of the phenomena which this
remarkable substance calls forth. The blanching and contrac-
tion are well seen in the virgin uterus, but these appearances
are nothing short of astonishing in the uterus of the pregnant or
puerperal animal observed in a normal saline bath. The
intravenous injection of adrenalin produces a degree of uterine
.anaemia and a violence of contraction, not obtainable by the

THE SUPRARENAL SYSTEM 207

agency of any other substance. I found that, in pregnant
animals, the intravenous injection of adrenalin was frequently
followed by abortion. If, in the later stages of pregnancy, a prem-
ature birth is obtained by artificial means, it is usually accom-
panied, at least as far as my experience goes, by serious, or
even incurable, haemorrhage. The intravenous injection of
.1 mg. adrenalin will, however, immediately arrest such haemor-
rhage. It will be seen by direct inspection that adrenalin pro-
duces a high degree of contraction of the uterine muscles as well
as of the vessels, and this is sufficient to account for the
cessation of the haemorrhage. Adrenalin not only produces
uterine contractions, but it increases the excitability of the organ
to such a degree, that it reacts to direct or nervous stimuli to
which it was previously insensitive.

The specific action of adrenalin upon the uterine muscles was
turned to account by Neu in the therapeutics of obstetrics. He
recommended the direct injection of adrenalin into the substance
of the relaxed and enlarged uterus. By this means the desired
contraction was obtained, while the possible ill-effects of intra-
venous injection were avoided. I have found from personal
experience that the method is free from objection.

The action of adrenalin upon the living uterus is also seen
after the removal of that organ from the body. Acconi, and
after him Franz, proved the effects of certain pharmacological
reagents upon both the automatic movements of the uterus, and
upon portions of extirpated uterine tissue obtained from man and
animals. Kurdinowsky next discovered that it was possible to
prolong the life of the uterus of a rabbit for days at a time by
the transfusion of Locke's fluid into the aorta. He found that
adrenalin, even in very weak solutions, acts more powerfully upon
the uterus than any known substance. By adopting Magnus's
method with the intestine, Kehrer obtained graphic tracings of
the spontaneous movements of the uteri of rabbits and cats.
Still more recently, A. Fraenkel employed the uterus removed
from the living body of rabbits as a quantitative test of adrenalin.
He found that adrenalin solutions reacted upon portions of the
uterus in such a manner as to produce a specific change in the
curve of the spontaneous contraction-waves. The lever rises
rapidly and very decisively to a point above the summit of the
highest normal wave; it remains in this position for several
minutes, oscillating slightly; and then falls slowly to the abscissal
line, at the same time making wide oscillations. The curve
produced by the action of adrenalin is the expression of the
transitory maximal contraction effected by this substance. This
contraction takes the form of a tonic stimulation, starting promptly
and increasing slowly until, in some instances, a tetanic condition
obtains. According to Fraenkel, and I am in a position to
confirm his results, the uterus of rabbits responds to an adrenalin

208 INTERNAL SECRETION

solution of i :2O million. The amount of contraction is
dependent, within certain limits only, upon the size of the dose.
When employing this method as a quantitative test, the degree of
contraction must not be taken as the standard ; the latter is
obtained by accurate estimation of the degree of concentration
which will produce a typical tonic increase. Of the biological
tests for adrenalin, registration of the uterine contraction is
undoubtedly the most effective.

The Hair Muscles. — As Lewandowsky pointed out, supra-
renal extract produces a contraction of the erector muscles of the
hair in cats, and an erection of the quills in sea-urchins. Langley
next discovered that, in the cat, the erection of the hair of the
head takes place in the same wray after extirpation of the superior
cervical ganglion and degeneration of the post-ganglionary
fibres. Taking this finding in conjunction with the fact that all
the pilomotors are included in the sympathetic system, he con-
cludes that suprarenal extract exercises a direct influence upon
the unstriated muscle-fibres of the hair.

The unstriated muscles of the skin show a remarkable
departure from the phenomena usually associated with the action
of adrenalin and the results of sympathetic stimulation. The
back and tail hairs of cats stand up immediately in response to
stimulation of the corresponding sympathetic fibres, but they
react only slightly and tardily to the injection of even large doses
of adrenalin. In the ape, the hairs are observed to move upon
the temples and forehead only. In the dog, the injection of
adrenalin is followed by the erection of the hairs of the neck,
and in Herpestes mungo by prompt erection of the tail hairs.

Elliott believes that the difference in the behaviour of the
erector muscles of the hair is attributable to differences in the
demand made upon them under normal conditions. The English
domestic cat rarely puts up its hair, while the hair of the mongoose
rises in response to every passing emotion. Thus, in the latter
species, adrenalin acts very promptly upon the hair. The
feathers of birds have a sympathetic innervation, and adrenalin
causes erection in this case also ; it is best seen in the cock,
and is less clearly marked in hens and pigeons. Elliott found
in the case of his own skin, the hair muscles of which normally
possessed a very sensitive reaction, that subcutaneous injection
of .03 mg. adrenalin produced a stronger effect upon the hair
muscles than upon the vessels.

The Bronchial Muscles. — According to Einthoven, Beer,
Brodie, and Dixon, the involuntary muscles of the bronchi receive
their innervation from the vagus nerve. Stimulation of this
nerve produces a contraction of the bronchi, and consequent
contraction of the bronchial tubes. According to Roy and
Brown, and also to Sandemann, the vagus contains fibres which
cause the bronchial muscles to expand. As far as we know at

THE SUPRARENAL SYSTEM 2OQ

present, then, the innervation of the bronchial muscles is
autonomous in the sense of motor stimulation, while the presence
of a sympathetic innervation has not, up to now, been demon-
strated. From Dixon and Brodie's careful experiments, it seems
as if suprarenal extract exercised very little effect upon the
bronchial muscles. Small doses do not produce either contraction
or expansion of the bronchioles, while large doses have been
followed in isolated cases by transient contraction. These
findings are confirmed by my own experiments with adrenalin.
In anaphylactic shock (Auer and Lewis) in guinea-pigs, as well
as after the intravenous injection of peptone (Biedl, Kraus), there
is acute cramp of the bronchial muscles which is promptly
relieved by atropine, the action of which is to paralyse the vagus.
In cases such as these, the intravenous injection of adrenalin is
negative in its result. According to Jagic, bronchial asthmatic
spasm in man may be checked by the subcutaneous injection of
i c.cm. adrenalin. Eppinger and Hess explain this result by the
assumption, that the stimulation of the sympathetic by adrenalin
overpowers the muscular cramp arising from the increased stimu-
lation of the vagus. In view of these divergent findings,
further investigation of the innervation conditions of the
bronchial muscles and of the effect which adrenalin has on them,
appears to be imperative.

The Eye. — The intravenous injection of adrenalin provokes
retraction of the nictitating membrane, elevation of the eye-lid,
exophthalmos, and dilation of the pupil. Thus, the musculus
palpebras tertius, the unstriated muscles of the eye-lid, the
musculus protrusor bulbi, and the musculus dilatator pupillas, are
all induced to contract in the same manner as after electric stimula-
tion of the sympathetic nerve in the region of the neck.
Adrenalin produces effects which are similar and even more
powerful, after extirpation of the superior cervical ganglion and
consequent degeneration of the post-ganglionary fibres (Lewand-
owsky, Langley). It seems certain from this that the site
directly affected by adrenalin is peripheral.

The effect which adrenalin has in enlarging the pupil was
next studied, and from two points of view. In the first place, it
has been turned to account as a test for adrenalin and as a
method of determining its physiological significance. Wesseley,
and later Meltzer and Auer, found that, when applied to the eyes
of frogs, adrenalin produced mydriasis, and the latter authors
suggested (1904) the frog's eye as a suitable adrenalin reagent.
They pointed out that the reaction takes place even after enu-
cleation of the bulb. Ehrmann next showed that, when preserved
in isotonic fluid, the enucleated frog's eye is considerably more
sensitive than the bulb in situ, and upon these findings he based
his quantitative adrenalin test. Ehrmann found that adrenalin
reacts upon the dilator muscles of the pupil in a solution of i :2O

14

2IO INTERNAL SECRETION

million ; in other words, the dilation of the pupil demonstrates the
presence of adrenalin in a quantity as small as .000025 m§"-
This mydriasis of frogs' eyes was subsequently employed as a
test for adrenalin in liquids of the most varied description (blood,
urine), but the results were not in all cases unequivocal ; that is
to say, they were not characteristic of adrenalin only.

It has since been discovered that, in addition to adrenalin,
a large number of substances provoke dilation of the pupil of
isolated frogs' eyes. Waterman and Boddaert produced this
effect with weak watery solutions of pyrocatechin, with salicylic
acid, hydrokinone, and resorcin ; they think the reaction is
dependent upon pyrocatechin. Ehrmann found that acetic acid
and ammonia produce irregular dilation of the pupil, but that
the pupil also contracts in response to these reagents. According
to Pick and Pineles, tyrosin and phenylalanin produce mydriasis
of the frog's eye ; Cramer, Borchardt and Pal attribute the same
effect to pituitary extract; Ranzi and Tandler to thymus extract.
Pick and Glaessner obtained a mydriatic reaction with the pan-
creatic juice of man and of dogs, which was particularly marked
where - these subjects had been previously fed upon meat.
According to Comessati and Diem, the mydriasis of frogs' eyes,
when employed as a test for the presence of adrenalin in urine-
or in concentrated saline solutions, has very little value.

We shall have occasion to speak later of the mydriatic action
of the blood serum, and of the theories which have arisen concern-
ing the presence of adrenalin in the plasma under both normal and
pathological conditions. For the present, it is sufficient for us
to notice the fact that the mydriasis of frogs' eyes is, in itself,,
not a conclusive proof of the presence of adrenalin in the blood
serum ; this test should always be reinforced by other biological
and chemical reagents.

The action of adrenalin has also been put to practical use
in another direction. Lewandowsky was the first to discover
that the instillation of suprarenal extract into the conjunctiva is,
in the case of both man and animals, without effect upon the
pupil. Melzer and Auer next showed that, after extirpation of
the superior cervical ganglion of both rabbits and cats, the
instillation of adrenalin produces a considerable enlargement of
the pupil. We know that the sympathetic contains fibres which
promote contraction of the dilator muscles of the pupils. If,
therefore, stimuli which are inactive or only slightly active in
the case of normal eyes, react strongly upon eyes which have
lost their ganglion, we must assume the presence of sympathetic
inhibitory fibres which take their rise in the ganglion and by
which the peripheral irritability is reduced. O. Lowi assumed
that the occurrence or non-occurrence of mydriasis after adrenalin
instillation, was an expression of the functional activity of the
sympathetic inhibitory nerves. He therefore endeavoured to find

THE SUPRARENAL SYSTEM 211

out whether mydriasis takes place under certain special conditions,
in which a suppression of the sympathetic inhibition is assumed.
He found that, after the instillation of adrenalin into the con-
junctiva, enlargement of the pupil was invariable in dogs and
cats from which the pancreas had been removed ; that it was
occasional in artificial pancreatic insufficiency; and that it was
present in many clinical instances of diabetes and Graves's
disease. Lowi assumes from this that the inhibition of certain
organs with a sympathetic innervation is a normal function of
the pancreas. He regards the mydriasis produced by adrenalin
in Graves's disease as the expression of an increased irritability
of the sympathetic, brought about by hyperthyroidism. This
increased irritability is as readily attributable to a suppression
of the inhibitory nervous function, as to an increase in thf>
stimulatory nervous function. Eppinger, Falta and Rudinger
succeeded later in producing adrenalin mydriasis in normal and
thyroidectomized dogs by continuous treatment with thyroid
extract.

The Glands. — Langley found that, when suprarenal extract
is given in moderately large doses, it provokes a profuse secre-
tion on the part of all the salivary glands, as well as of the
mucous glands situated in the mouth, oesophagus, and trachea.
This increased secretion becomes apparent a little later than the
rise in blood-pressure, it quickly reaches the maximum, and then
gradually subsides. Hence the irritability of the cervical sym-
pathetic and of the chorda tympani is not by any means reduced,
that of the latter being, in fact, rather augmented. That the
secretory stimulus does not proceed from the central nervous
system, is shown by the fact that it continues unchanged after
resection of the superior cervical ganglion and of the chorda
tympani. It is the outcome of peripheral stimulation, and it
remains constant, "though somewhat diminished in intensity, after
comparatively large doses of nicotine. Moreover, atropine, in
a quantity sufficient to paralyse the fibres of the chorda, does
not inhibit the increased secretion, though this disappears in
response to atropine in large doses. It is evident, from these
results, that suprarenal extract stimulates those elements — whether
nerve terminals or glandular cells — which are inhibited by the
action of atropine. Adrenalin excites the secretion of saliva even
after extirpation of the ganglion and degeneration of the post-
ganglionary fibres, and this makes it certain that the effect cannot
be due to stimulation of the sympathetic nerve terminals.

Under the influence of adrenalin, the vessels of the sub-
maxillary gland contract and the gland blanches; after an interval
of thirty seconds it becomes increasingly red until its colour is
deeper than before the injection. The blanching is less than
after stimulation of the sympathetic, the flushing less intense
than after stimulation of the chorda. Here also, vaso-constriction

212 INTERNAL SECRETION

takes place after degeneration of the post-ganglionary fibres and
must, for this reason, be regarded as the outcome of the direct
action of suprarenal extract.

The intravenous injection of suprarenal extract produces an
increased secretion on the part of the lachrymal glands, and this
persists after removal of the superior cervical ganglion.

Suprarenal extract increases the secretion of bile. This result
is not apparent, however, unless the cystic duct is occluded ;
otherwise the relaxation of the gall bladder permits the gall to
escape down it.

According to Langley, adrenalin does not apparently induce
pancreatic secretion, but it does promote the activity of a secret-
ing pancreas. In large doses, adrenalin inhibits pancreatic
secretion (Bendicenti, Glasener and Pick).

According to a communication by Yukawa, the gastric
secretion increases under the influence of adrenalin.

As we know, the blood supply to the kidney is very much
affected by the action of adrenalin. Minimal doses produce an
appreciable reduction in the volume of the organ, consequent
upon the contraction of the vessels; this is succeeded by pro-
nounced vaso-dilation and increase in volume. The experiments
of Bardier and Fraenkel show that the urinary secretion is in-
fluenced in such a manner that there is, first, a reduction in the
amount of urine excreted by the ureters, or there may even be
complete cessation of the flow ; this is followed by marked
polyuria which lasts for some considerable time. These authors
found that, in those cases where vaso-constriction is absent, the
primary reduction in secretion also fails to appear, and it seems
evident from this that the changes in renal secretory activity
which are brought about by the agency of adrenalin, are largely
attributable to changes in the circulatory conditions.

According to Schlayer, adrenalin, when given intravenously,
acts under certain conditions as a diuretic upon animals con-
taining much fluid.

Biberfeld found that the subcutaneous injection of suprarenin,
in doses of 1.5 to 2.5 mg. per kilo, produced a marked diuresis
in rabbits, together with a considerable decrease in the sodium
chloride contents of the urine.

The manner in which the suprarenals themselves react to
the influence of adrenalin has, up to now, received but little
attention. As far as the suprarenal circulation is concerned, I
found that the intravenous injection of suprarenal extract pro-
duced an increase, followed by a decrease, in the venous outflow.
These changes in the circulation are due only in part to the
altered hamiodynamic conditions. In part, they represent the
results of the action of the extract upon the vessels themselves,
and they are comparable to those effects, partly constrictor and
partly dilator, which are obtained by stimulation of the sym-
pathetic nerves supplying the organ.

THE SUPRARENAL SYSTEM 21$

The increase in the amount of lymph excreted from the
thoracic duct which, according to Camus, follows the intravenous
injection of adrenalin, is in all probability largely due to changes
in the circulatory conditions. It cannot be denied, however, that
adrenalin may possibly exercise an effect upon the formation of
the lymph itself.

After the subcutaneous injection of adrenalin, oedema fre-
quently appears at the site of injection, and the lymphatics lead-
ing away from it are sometimes found to be full. If the same
quantity of adrenalin is employed, but in a very dilute solution,
the cedematous swelling becomes much more marked and may
last for some time. These phenomena must be largely due to a
reduction in resorption, brought about by a local constriction of
the vessels at the site of injection. This accounts for the fact
that the subcutaneous injection of adrenalin produces so little
effect upon the blood-pressure ; to a certain extent, the substance
blocks the way of its own resorption.

The gradual resorption of the adrenalin in minimal quantities
explains why it is that the subcutaneous injection of even large
doses does not produce a rise in blood-pressure, but is followed
by considerable periodical changes in pressure (Biedl). Lowi
and Meyer found that when methylaminoketone, which is closely
related to adrenalin, is injected subcutaneously in large doses,
the blood-pressure becomes elevated and will continue so for
over an hour. This result is explained by the fact that methyl-
aminoketone is considerably less active than adrenalin, hence
the possibility of its better resorption. Meltzer and Auer found
that the intramuscular injection of adrenalin produced an increase
in blood-pressure ; but Patta pointed out that, whether given intra-
muscularly or subcutaneously, the injection of adrenalin is not
followed by a rise in blood-pressure in animals, unless the sub-
stance is introduced by accident into a blood-vessel. In man,
the subcutaneous injection of adrenalin produces an increased
blood-pressure (Falta).

A. Exner showed that the intraperitoneal injection of
adrenalin is followed by a reduced resorption on the part of the
lymphatics of the peritoneum. For it is not only those toxins
which enter the system by way of the blood-vessels, which under-
go a tardy resorption after the introduction of adrenalin into the
peritoneum or into the stomach; the same is seen in the case of
substances which, owing to their physical properties, reach the
blood-stream through the agency of the lymphatics.

Langley found that the sweat glands of the cat were un-
affected both by the intravenous injection of adrenalin and by
its subcutaneous introduction into the ball of the paw. Elliott
found that a subcutaneous injection of .025 mg. of adrenalin did
not provoke secretion of the sweat glands in the palm of the
hand in man ; on the contrary, owing to the extreme local anaemia,

214 INTERNAL SECRETION

secretion at, and surrounding, the site of injection was rather
diminished than otherwise.

The failure on the part of adrenalin to stimulate the secretory
activity of the sweat glands is undoubtedly a very remarkable
phenomenon, for it is quite certain that these glands are fur-
nished with a sympathetic innervation.

Adrenalin stimulates the sweat glands of the frog to active
secretion. After the injection of small quantities of adrenalin into
the dorsal lymph space, the entire body of the animal becomes
covered with secretion. If the secretory process in the glands of
the nictitating membrane is observed under the microscope
(Strieker and Spina), it will be seen that the introduction of
adrenalin is followed by progressive enlargement of the glandular
epithelium and by the extrusion of drops of secretion, in exactly
the same manner as after stimulation of the sympathetic nerves
(Drasch).

S. Lieben found that adrenalin produced marked contraction
of the pigment cells of the skin of frogs, a dark-coloured frog
becoming light in the space of ten minutes. This effect of
adrenalin upon the pigment cells is not brought about by the local
anaemia, nor is it a reflex effect ; it is the result of the direct
action of the substance. According to Gaup, the pigment cells
are controlled by the sympathetic.

Adrenalin exercises a similar agglomerating effect upon the
pigment granules in the pigment epithelium of the retina of frogs,
but this is seen only after local application. This agglomerating
action may even, to a certain extent, inhibit the migration of the
pigment in response to the stimulus of light, and where this for-
ward movement has already taken place, a further agglomeration
of the pigment granules will be produced in a varying degree by
the action of adrenalin (Klett).

Among the physiological effects of adrenalin, those must be
included which this substance produces in the composition of the
blood. According to Foa, adrenalin reduces the alkalinity and
produces acidity of the blood. Falta and Berterelli found that the
injection of adrenalin is followed by an increase in the specific
gravity ; by hyperglobulia with isolated erythroblasts ; and by
marked leucocytosis affecting the neutrophile polynuclear cells, the
eosinophile cells being very much reduced. In dogs with
hypereosinophilia of about 12 per cent., the injection of adren-
alin is followed by a reduction to .3 per cent. Eppinger and Hess
discovered that the physiological eosinophilia of rabbits is reduced
by the action of adrenalin. The morphological structure of the
blood is influenced by adrenalin in a manner the reverse of that
of pilocarpin which, it is well known, produces lymphocytosis and
eosinophilia in both man and rabbits (Neusser).

Metabolism. — The influence which adrenalin exercises upon
metabolism demands special consideration. The investigations of

THE SUPRARENAL SYSTEM 215

Kraus and R. Hirsch, as well as those of Quest, show that there
is little alteration in the metabolism of nitrogen in healthy dogs
after the intravenous or subcutaneo.us injection of adrenalin. The
slight increase in N-metabolism is explicable by the glocosuria
which is coincident with it, as well as by the necrosis of the skin
which follows subcutaneous injection. Eppinger, Falta and
Rudinger found that, in starving animals, adrenalin caused a
marked increase in the metabolism of albumin ; feeding with fatty
foods still further increased the effects of adrenalin. The increased
excretion of nitrogen which, in starving animals, immediately
followed the injection of adrenalin and which was also observed
by Underbill and Closson, cannot in the nature of things be re-
ferred to necrosis of the skin. Eppinger, Falta and Rudinger
regard the increase in the metabolism of albumin and of fats as
the expression of an improved thyroid function.

According to the investigations of Ealta, Bolaffio and
Tedesko, adrenalin excites an increase in the metabolism of salt.
The amount of phosphorus excreted in the urine may be increased
to three times, that of potassium and sodium to four times, the
normal. With regard to the metabolism of purin, Falta declares
that the excretion of uric acid and of allantoin are both consider-
ably increased.

This effect which adrenalin has in accelerating metabolism is
regarded by authors of the Viennese school as an expression of the
condition of increased excitability which this substance produces
in the sympathetic system.

That aspect of metabolism which, it is conclusively proved,
lies within the province of the sympathetic system, is the
metabolism of the carbohydrates. The influence which adrenalin
exercises upon these conditions has, therefore, a special interest.
When Blum, in IQOI, made the important discovery that the
experimental subcutaneous or intravenous injection of suprarenal
extract produces glycosuria, which follows with equal certainty in
both starving animals and those deprived of the carbohydrates,
there was a general inclination to regard this result as the mani-
festation of a toxic activity on the part of suprarenal extract.
It formed the subject of keen and very minute investigations, and
these have revealed the fact that the glycosuria which follows the
exhibition of adrenalin, is the expression of a physiological action
on the part of this remarkable substance.

Blum's discovery was tested and confirmed in many direc-
tions. It soon became evident that the glycosuria makes its
appearance after the exhibition both of the extract of the supra-
renal and of adrenalin, its active principle. For this reason, it
was very generally believed that glycosuria is one of the physio-
logical effects of adrenalin. The sole author \vho opposed this
view wras Landau, who ascribed the glycosuria to a substance
derived from the suprarenal cortex.

2l6 INTERNAL SECRETION

The following facts concerning adrenalin glycosuria may be
regarded as proved. The glycosuria makes its appearance after
the exhibition of comparatively small doses (.01 to .1 mg.) of
adrenalin, and is, on the whole, more readily provoked by subcu-
taneous or intraperitoneal, than by intravenous, injection (Lowi).
The cause of this remarkable phenomenon will appear later. The
subcutaneous introduction of i to 2 mg. adrenalin is followed
after half an hour, at the latest after two hours, by a glycosuria
lasting about three hours. The repeated injection of similar
doses into the same animal is not, however, followed by the
regular appearance of the glycosuria. One day the urine will
contain a large quantity of sugar, the next day perhaps none at
all, and in the end the glycosuria may entirely disappear.

It has been observed by several authors that the glycosuria
which follows the exhibition of adrenalin is accompanied by hyper-
glycsemia. The increase in the amount of sugar in the blood
was proved by Bierry and Gatin-Gruzewska, and by Noel Paton,
in the case of rabbits and dogs. These authors also showed
that when given to starving animals, adrenalin diminished the
amount of glycogen present in the liver and muscular structure,
and may indeed be regarded as a certain method of eliminating
glycogen from the system. Drumont and Noel Paton were unable
to produce changes in the glycogen of the liver of well-fed rabbits
by means of small doses of adrenalin, such changes being brought
about by doses large enough to produce acute toxic symptoms.
Later investigations have proved beyond any manner of doubt,
that the glycogen largely disappears from the liver and muscles
where the adrenalin action is very intense (Agadchanianz, Doyon,
Morel, and Kareff). L. Pollak recently pointed out that, after
previous feeding with glycose or levulose, the glycogen
stored up in the liver may be induced completely to disappear by
means of large doses of adrenalin. Small doses of adrenalin differ
considerably in their effect, according to whether the glycogen
accumulated in the liver is formed from glycose or levulose.
Levulose-glycogen is markedly the more resistant.

Since Blum's first communication it has been definitely proved
that, after prolonged fasting, glycosuria is present in all animals.
Pollak's experiments testified to the remarkable fact, that the
repeated exhibition of adrenalin in fasting rabbits and in rabbits
which have been rendered absolutely free from glycogen by means
of strychnine, is followed, not only by sugar in the urine, but by
the accumulation of glycogen in the liver. The amount of
glycogen which collects in the liver is as large as that which is
usually seen only in animals fed with carbohydrates. It has been
shown (Underhill and Closson, Eppinger, Falta and Rudinger)
that adrenalin causes a very considerable increase in the metabol-
ism of albumin in starving animals, and the remarkable phenom-
enon described above is probably attributable to the storing-up of

THE SUPRARENAL SYSTEM 2iy

glycogen as a result of this increase in albumin-metabolism.
Pollak is not inclined to explain the large quantities of glycogen
which he found, solely by the theory of an increased metabolism of
albumin ; he is disposed to leave the question open for the present.
In answer to the question as to why the intravenous injection
of adrenalin is not invariably followed by glycosuria, and why
the repeated subcutaneous injection provokes signs of tolerance,
frequently expressed by the absence of glycosuria — Pollak dis-
covered that, though the intravenous injection of adrenalin invari-
ably causes hyperglycasniia, this is not sufficiently marked to
produce glycosuria, seeing that there is, under these conditions,
an invariable reduction in diuresis. Where, however, simul-
taneously with the adrenalin injection, measures are adopted with
the object of promoting diuresis, sugar is invariably present in
the urine. After subcutaneous injection of adrenalin, the hyper-
glycasmia is so pronounced that glycogen will be present in the
urine apart from artificial promotion of the diuresis. The repeated
subcutaneous injection of adrenalin produces a high degree of
hyperglycasmia, such as is usually observed only in cases where
there is no simultaneous diuresis. As, however, the glycosuria is
not always present, it must be assumed that, either the kidneys
acquire a tolerance of their large glycogen contents resulting from
the continued employment of adrenalin, or that they are subjected
to some specific influence.

W. Straub and his pupil, H. Ritzmann, have done much to
further a more detailed knowledge of adrenalin glycosuria.
Kretschmer discovered that the remarkable absence of constancy
in the effect of adrenalin upon the vessels, depends upon the
readiness with which adrenalin undergoes oxidation, and that a
permanent adrenalin action upon the tone of the vessels is to be
obtained only by a permanent employment of the drug. Ritzmann
next showed that the glycosuria lasts for exactly the same length of
time as adrenalin is present in the blood. If adrenalin in very
weak solution is allowed to enter a vein and to flow continuously
into the blood stream, it will be found that an adrenalin solution
of a concentration of i :2 million, introduced at a velocity of about
c.cm. to the minute, does not provoke glycosuria. Sugar does
not appear in the urine until the velocity reaches 3 to 4 c.cm.
per minute. Within certain limits, there is a direct proportion
between the concentration of the adrenalin in the blood and the
amount of sugar excreted in the urine ; so that, other things being
equal, each velocity of a solution of given concentration provokes
a glycosuria which invariably yields the same amount of sugar
within a given space of time. The glycosuria does not make its
appearance immediately, but is preceded by a prolonged latent
stage, which is probably accounted for by the fact, that a certain
amount of time is required for the completion of the chemical
process by which the sugar is set free. There is, moreover, an

2 1 8 INTERNAL SECRETION

intimate connection between the glycosuria and the amount of
glycogen present in the economy. In animals which have a large
amount of glycogen in their economy, half the usual dose of
adrenalin will produce an excretion of sugar quantitatively equal
to that provoked in normal animals by the full dose. Where,
however, the animal economy is poor in glycogen, similar results
will be obtained only by the agency of much larger quantities of
adrenalin.

According to Ritzmann, where experiments are undertaken
with the object of studying the physiological processes by which
adrenalin glycosuria takes place, it is essential that the adrenalin
should be introduced directly into the blood stream ; for the
method of introducing it into the economy by a single subcu-
taneous injection does not reproduce the natural conditions. It
has, moreover, been proved that, where adrenalin is injected
subcutaneously, the quantity required to produce certain glyco-
suric effects is considerably larger than in cases where the
substance is introduced by continuous intravenous transfusion.
For example, in one case, a subcutaneous injection of 2 mg.
adrenalin was required to produce 0.64 grm. sugar in the
urine, while the same result was obtained by means of intravenous
transfusion with a diluted solution containing 0.4 mg. adrenalin.
Thus of the 2 mg. which were injected subcutaneously, 1.6 mg.
or So per cent, were destroyed without producing glycosuria.

It is evident from Pollak's experiments described above, that
the glycosuria produced by the intravenous exhibition of adrenalin
is dependent upon the diuresis. And Ritzmann mentions that, in
several of his experiments, the diuresis entirely ceased, and the
animals died without excreting any part of the fluid which had
been introduced into their economy. Even where adrenalin is
introduced continuously into the blood stream, a velocity which
is at first active becomes inactive after a time (this effect being
the reverse of that demonstrated by Kretschmer in the case of the
blood-vessels), and the glycosuria is restored only by increasing
the concentration of the solution. This phenomenon is explained
by a transitory exhaustion, either of the sugar supply or of the
ultimate products of the sugar.

From the results of these investigations into the mechanism
of adrenalin glycosuria, it seems highly improbable that adrenalin
directly affects the formation of sugar in the urine. It is far more
likely that it influences the process of the distribution of sugar
in the blood. We know that, in its influence upon the
blood-vessels, the effect of adrenalin is equal to that of
stimulation of the sympathetic ; and it is also well known
that the diabetes produced by Claude Bernard's puncture is the
outcome of hyperirritation of the sympathetic. The analogy
between the mechanism of the glycosuric and the vaso-constrictor
effects of this substance, suggests the hypothesis that the actual

THE SUPRARENAL SYSTEM 2 19

site of the direct action of adrenalin is to be found in those fibres
of the sympathetic, the central irritation of which produces effects
similar to those of puncture of the fourth ventricle. Through the
agency of the sympathetic system, adrenalin increases the tone
of the vessels, and in a similar manner it increases the sugar-tone
(Zuckertonus) — that is to say, it increases the concentration of the
sugar in the blood, so producing hyperglycasmia, which is
followed by glycosuria.

Blum first pointed out the similarity which exists between the
effects of Claude Bernard's puncture and the glycosuria produced
by adrenalin, and he suggested that the former is expressed
through the agency of the suprarenals. A. Meyer next showed
that puncture of the floor of the fourth ventricle does not produce
glycosuria in rabbits from which the suprarenals have been
removed; and more recently, Waterman and Smit found that
puncture of the floor of the fourth ventricle, similarly to stimu-
lation of the sympathetic, increases the amount of adrenalin
present in the blood. The far-reaching analogy between the effects
of puncture of the fourth ventricle and experimental adrenalin
glycosuria, is still further confirmed by the experiments of
Eppinger, Falta, and Rudinger. These showed that, if the
thyroid gland is extirpated, in neither condition does glycosuria
result ; but that a mobilization of carbohydrates takes place, as
shown by the decreased excretion of nitrogen, and that this is
consumed by the agency of the now hyper-active pancreas. A
further similarity between the two conditions is shown by the
behaviour of dogs from which the pancreas has been removed.
These animals showed increased glycosuria and hyperglycaBmia,
both after puncture of the fourth ventricle (Hedon and Kaufmann),
and after the exhibition of adrenalin. The authors conclude from
these results, that the excretion of sugar after puncture of the
fourth ventricle represents a discharge from the chromaffine
system .

The difference in the processes by which glycosuria and hyper-
glycasmia result from puncture of the fourth ventricle and from
the exhibition of adrenalin, lies in this : that, in the case of
adrenalin, the results are brought about by peripheral stimulation
of the sympathetic ; after puncture of the fourth ventricle they are
due to stimulation of the sympathetic centres.

L. Pollak found that, after resection of the splanchnic nerve,
adrenalin invariably produces glycosuria; while the experiments
of Claude Bernard and Eckhard show that, after such resection,
puncture of the fourth ventricle is not followed by glycosuria. In
the case of puncture of the fourth ventricle, irritation of the sugar
centre in the medulla is conveyed by way of the sympathetic
(splanchnic nerve) to the liver, where it excites that organ to part
with its glycogen. Resection of the splanchnic nerve breaks the
communication between the centre and the sugar-forming organ,

220 INTERNAL SECRETION

thus hyperglycagmia becomes impossible. Adrenalin, on the
other hand, affects the peripheral sympathetic nerve-terminals in
the liver in exactly the same way as it does those of other organs,
and for this reason, the glycosuria is uninfluenced by the resection
of the communicating nerve.

Observation of experimental adrenalin-glycosuria has revealed
the intimate relationship which subsists between the action of
adrenalin and the internal secretory activity of the pancreas. That
adrenalin-glycosuria is in some way related to pancreatic diabetes
is evident from the results obtained by Herter and Wakeman.
These authors discovered that, if the pancreas is painted with
adrenalin, the resultant glycosuria is more intense than that which
follows the application of adrenalin to other organs. Vosbourgh
and Richards obtained marked hyperglycasmia by the same means.
Herter and Wakeman assume that, whatever the site at which
adrenalin is applied, its glycosuric action reaches the pancreas
and reduces the capacity of that organ for the oxidation of sugar.
If this view is correct, adrenalin should not produce an increase
in the glycosuria present in animals which have lost their pan-
creas ; and results obtained by Lepine, as well as by Bierry and
Gatin-Gruzewska, seem to point in this direction. Velich, on the
other hand, found that though extirpation of the pancreas is not
followed by glycosuria in well-nourished frogs until after several
days have elapsed, it may be brought on immediately after
operation by means of adrenalin. Noel Paton produced glycosuria
by this means in geese and ducks after the removal of the
pancreas ; while Doyon, Morel, and Koreff found that the injection
of adrenalin was followed by an increase in the sugar contents of
the blood of dogs which had lost their pancreas.

It is very evident from the results of these experiments that
the theory that adrenalin glycosuria is a form of pancreatic
diabetes, is insufficiently grounded.

Zuelzer adopted a different theory. He found that, in dogs
without pancreas, if adrenalin was prevented from entering the
blood stream by ligature of the suprarenal veins, the glycosuria
was minimal. He succeeded in preventing glycosuria in rabbits
by injecting them with pancreatic extract, and he concluded that
Minkowski's " pancreatic diabetes ' is in reality a positive
' adrenalin diabetes."

In experiments which I undertook with Offer, we succeeded
in producing both inhibition of the adrenalin glycosuria and
inhibition of the adrenalin mydriasis of frogs' eyes, with chyle
from the thoracic duct.

These experiments were based upon some observations (to be
described later) which I carried out in 1898, and which showed
that chyle contains a substance which influences the amount of
the sugar consumption of the organism. I found that, in the
case of dogs which had become diabetic owing to the fact that the

THE SUPRARENAL SYSTEM 221

chyle was prevented from flowing into the blood stream, Lowi's
characteristic mydriasis reaction after adrenalin instillation was
not obtainable. This seems to suggest a parallel between the
origin of pancreatic diabetes and that which follows ligature
of the lymphatic duct. Upon the assumption that chyle
contains the internal secretion of the pancreas, which
is necessary to the normal metabolism of sugar, we tested the
action of chyle in adrenalin glycosuria ; we found that the subcu-
taneous injection of 80 to 120 c.cm of chyle from dogs, markedly
reduced, and even completely neutralized, the glycosuric action of
adrenalin when exhibited simultaneously. Adrenalin glycosuria
in rabbits is promptly suppressed by the intravenous injection of
hirudin, and also, as I discovered later, of the extract of the
muscular structure of crabs; it is, therefore, amenable to sub-
stances which, according to Heidenhain, are included in the group
Lymphagoga, Order I. By following up our experiments,
Tomaczewski and Wilenko found that all the Lymphagoga pos-
sess the property of suppressing adrenalin glycosuria.*

In the course of their investigations into the interactivities of
the internal secretory glands, Eppinger, Falta, and Rudinger
discovered that, in dogs without pancreas, in which the metabolic
derangement is at its height, the excretion of sugar and of nitrogen
are enormously increased by the subcutaneous or intraperitoneal
injection of adrenalin. The excretion of sugar becomes so much
increased that the proportion of the quotient D : N may rise to
over seven. It is the view of these authors that, in addition to an
excessive and perverted mobilization of the carbohydrates,
adrenalin produces inhibition of the pancreatic function.
The glycosuria which follows the exhibition of adrenalin results
from the operation of both momenta. Zuelzer's experiment, in
which he effected the inhibition of adrenalin glycosuria by means
of pancreatic extract, is explained by the supposition that, in
this instance, the excess of sugar set free by the adrenalin was
metabolized by the action of the reinforced pancreatic hormone.

That adrenalin exercises an inhibitory influence upon the
activity of the pancreas, may be assumed from Bendicenti's obser-
vation that pancreatic secretion is inhibited by large doses of
adrenalin. By experimenting on dogs with pancreatic fistula,
Glassner and Pick proved that the pancreatic secretion completely
ceases after large closes of adrenalin, while, at the same time, a
marked glycosuria makes its appearance.

Acting upon the assumption that the internal secretion of the
pancreas is governed by the autonomous vagal nerve, and that

* According to Aronsohn, adrenalin glycosuria is inhibited both by fever
and by heat-puncture. According to Richter^ Ellinger and Selig, the heat
puncture does not affect the glycosuria, which seems to be reduced only
where there is simultaneous bacterial infection. After renal injury there is
no glycosuria. (Ellinger and Selig.)

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226 INTERNAL SECRETION

stimulation of the vagus produces hypersecretion of the pancreas,
Eppinger, Falta, and Rudinger tested the effect of pilocarpin —
which is a specific toxin to the autonomous stimulatory system —
in adrenalin glycosuria, and found that its action in this con-
dition was completely inhibitory.

The conclusions to which the results described above seem to
point are : that adrenalin exercises an inhibitory influence upon
the internal secretory activity of the pancreas ; and that the
internal secretion of the pancreas limits the action of adrenalin
in certain directions. The pancreas hormone regulates the
metabolism of sugar in the organism, and its influence may serve
to limit, or even to prevent, the hyperglyccemia and glycosuria
which result from the superfluity of the carbohydrates, brought
about by the agency of adrenalin. Lowi's reaction points further
to the conclusion that the pancreas hormone exercises an influence
upon the inhibition of certain organs possessing a sympathetic
innervation. Where the activity of the pancreas is normal, the
mydriatic action of adrenalin is not manifested, but appears only
after suppression of the pancreatic internal secretion.

The manner in which the action of adrenalin is modified by
the thyroid apparatus has already been discussed at length. It
will be remembered that, according to Eppinger, Falta, and
Rudinger, adrenalin fails not only to produce glycosuria, but also
to raise the blood-pressure in animals which have been deprived
of their thyroid. Ritzmann pointed out that, in animals with an
excess of glycogen, the glycosuric action of adrenalin is less
affected by thyroid suppression than the vaso-constrictor.
Removal of the parathyroids increases adrenalin glycosuria.
According to these authors, then, the thyroid promotes the action
of adrenalin while the parathyroids inhibit it. They ascribe the
increased metabolism of albumin and of fats, which follows the
exhibition of adrenalin, to promotion of the thyroid function ; so
that it appears that adrenalin, in its turn, promotes the activity
of the thyroid and inhibits that of the parathyroids.

There is yet another direction in which the animal organism
is affected by the action of adrenalin, namely, the temperature of
the body. The subcutaneous and intraperitoneal injection of
adrenalin sometimes produces a considerable rise in temperature ;
the effect of intravenous injection is less marked. Whether this
increase is due to an increased production of heat or to a
diminished radiation, is at present unknown. It may be that
both factors are in operation, the increase in combustion arising
out of the excess of carbohydrates, the decrease in radiation from
the extreme vaso-constriction. The analogy between the conditions
under which the metabolism of the carbohydrates takes place,
suggests a comparison between the effect which adrenalin has
upon temperature and the so-called " heat-puncture " ; for adren-
alin raises the heat-tone (Warmetonus) by acting upon the

THE SUPRARENAL SYSTEM 227

peripheral terminals of those nerves, the central stimulation of
which produces the effect of " heat-puncture."

The tables on pp. 222 to 225 show the effects of adrenalin in so
far as they are at present known. For purposes of comparison,
they also include all that is at present known concerning the
sympathetic and autonomous innervation of the vegetative organs.

THE SITE OF ACTION OF ADRENALIN.

In his rlrst work upon the effects of suprarenal extract (1901),
Langley emphasized the fact that the results produced by this
substance are never identical with those obtained by stimulation
of the cranial-autonomous or sacral-autonomous nerves. Phen-
omena exactly similar to those obtained in the eye, by stimulation
of the oculomotor; in the heart and intestinal canal by stimulation
of the vagus; in the rectum, urinary bladder, and internal genitals
by stimulation of the pelvic nerve, are never produced by supra-
lenal extract. The increased secretion of saliva cannot be
regarded as an exception to this rule, for it is not accompanied
by vaso-dilation such as that which accompanies stimulation of
the chorda tympani. On the other hand, it is noticeable that the
effects which suprarenal extract produces are, in nearly all cases,
similar to those obtained by stimulation of the sympathetic
autonomous nerves. In many instances, the effect of the extract
and that of electric stimulus of the sympathetic are identical. These
results seem to point directly to the view that suprarenal extract
exercises a specific stimulatory action upon the sympathetic nerve-
terminals. Vet, in view of the fact that, in the case of the eye,
the vessels, the submaxillary gland, and the muscles of the hair,
this action is constant after degeneration of the post-ganglionary
fibres, Langley was compelled to admit that suprarenal extract
may also have a direct influence upon the unstriated muscles.

Four years later, Elliott drew attention to the fact that, in
spite of the difference in the method of the sympathetic innervation
in different animal species, the effects of adrenalin upon the
involuntary muscles were everywhere the same as those produced
by stimulation of the nerves supplying them. The strength of the
effect varies only with the frequency of the normal physiological
impulse, which individual muscles receive during life by the
agency of the sympathetic. The physiological stimulatory action of
adrenalin is undoubtedly peripheral, but the question as to which
portion of the periphery is the site of its activity demands further
investigation. This site is most probably to be sought, either in
the peripheral sympathetic nerve-terminals, or in the unstriated
muscles themselves.

That adrenalin exercises a direct action upon the muscles, was
suggested by various phenomena and was, until recently, assumed
by the greater number of authors. Lewandowsky and even

228 INTERNAL SECRETION

Langley were inclined to adopt this view, chiefly on account of
the fact, so frequently illustrated, that the action of adrenalin is
unaffected by so-called degenerative resection of the sympathetic
nerves — that is to say, in cases where degeneration of the resected
nerve has already taken place. On the other hand, the experi-
ments of Brodie and Dixon show that, \vhere the sympathetic
nerve endings are paralysed by apocodein, adrenalin is inactive,
in spite of the fact that the muscles have retained their contract-
ility, as shown by the effect of agents, such as barium chloride,
which have a direct action upon the musculature. It is hardly
possible to imagine a chemical destruction of adrenalin by
apocodein, hence the only assumption open to us is, that apocodein
suppresses those portions of the tissue which, under normal con-
ditions, react to the influence of adrenalin.

Dixon and Brodie localized the seat of action of adrenalin in
the sympathetic nerve-terminals. These they defined as " con-
necting links between muscle and nerve, which do not, however,
form a component part of either the muscular or the nervous
fibres." They assume, moreover, that after resection of the
nerves, this " neuro-muscular junctional tissue " does not undergo
degeneration ; and that this explains the constancy of the effects
of adrenalin after degenerative resection of the nerves.

The histological evidence in favour of this theory is to be
found in a discovery described by Fletcher (1897). By intra vitam
staining with methylene blue, he discovered a nervous network
in the retractor muscle of the penis of the rat, which does not
undergo degeneration after resection of either the motor or
the inhibitory nerve supplying it, but which does disappear after
resection of both. If such a peripheral network were present in
all involuntary muscles with a double innervation, the constancy
of the action of adrenalin after degenerative resection of the
sympathetic would be explained by the fact of this network
remaining intact.

Elliott next investigated the manner in which different muscles
react to adrenalin after : first, denervation (degenerative resection
of the post-ganglionary sympathetic nerves) ; and second,
decentralization (degenerative resection of the preganglionary
sympathetic nerves). He found that he was unable to provoke
contraction by electric stimulus of a denervated portion of the
retractor of the penis of the dog, but that adrenalin was more
active upon such muscle than upon that portion in which the
innervation \vas normal. After decentralization and denervation,
stimulus of the hypogastric and pelvic nerves produced no effect
upon the urinary bladder of cats, though relaxation of the bladder
and constriction of the urethra were obtainable by means of
adrenalin. After removal of the superior cervical ganglion and
the ciliary ganglion, together with the ciliary nerves, the instilla-
tion or intravenous injection of adrenalin provoked dilation of the

THE SUPRARENAL SYSTEM 22Q

pupil of maximal duration, while physostygmin produced myosis
of the normal control eye only. All that these experiments prove
is, that the tissue which reacts to the influence of adrenalin
becomes increasedly sensitive to the action of this substance after
decentralization, and even more so after denervation. But in the
case of the retractor muscle of the penis, which undoubtedly
possesses a double innervation, this result can hardly be due to
the persistence of Fletcher's nervous network, seeing that the
integrity of the latter is dependent upon the nerve cells of the
peripheral ganglion. It is evident from this that the site of the
activity of adrenalin cannot be situated in the nerve endings in the
general sense of the term ; that is to say, in so far as they are
demonstrable, anatomically by methylene blue, and physiologic-
ally by degeneration after nervous resection.

Upon the other hand, it is very difficult to account for the
effects which adrenalin has upon the unstriated muscles, and
especially for the different effects (contraction and relaxation)
which it produces upon muscles of similar structure, by the theory
of a direct action upon the muscles themselves. Hence, the seat
of the elective influence of adrenalin can only lie in the junction
of the sympathetic nerve-fibres with the muscles. We must, then,
assume that the neuro-muscular system is composed of cell, fibre,
and terminal derived from the nerve, and of muscle-cell and
contractile fibrilla derived from the muscle, and that these two
portions are connected by means of a third, the myoneural
junction.

During the embryonal period, the muscle fibrilla possesses
a direct contractility only, and in certain parts of the unstriated
muscular structure, especially in the lower vertebrates, this
developmental stage persists throughout life. But in the course
of ontogenetic and philogenetic development, the greater number
of the unstriated muscles acquire a relationship to the sympathetic
nervous system. The myoneural junction, derived partly from
the muscular substance, and partly from the sympathetic nerves,
develops to form the mechanism \vhich controls the manner in
which the muscles react in response to nervous stimuli. Whether
the muscle is influenced in a positive or a negative sense, whether
in response to such influence it contracts or relaxes, depends upon
the myoneural junction. Adrenalin exercises a specific stimulatory
effect upon this portion of the neuromuscular system, and this is
proved by the following facts : first, it does not influence muscles
which have not a sympathetic innervation (as, for instance, the
muscles of the bronchi); and second, it does not affect all muscles
in the same way, but produces contraction or relaxation according
to the nature of the myoneural junction through which it acts.
This specific action of adrenalin has revealed the fact, that the
neuro-muscular junction tissue is characteristic of the sympathetic
system and distinguishes it from the cranial and sacral autonomous

230 INTERNAL SECRETION

systems. In the case of the latter systems, the relationship
between nerve and muscle is biochemical and similar to that
between nerve and muscle in striated muscles.

The sensibility of a muscular tissue to adrenalin is propor-
tional to the degree in which the myoneural junction is differenti-
ated, and this, in its turn, seems to depend upon the frequency
of the impulses which, under normal conditions, it receives
through the agency of the sympathetic. In other respects, its
irritability is independent of the nervous impulses.

Owing to the fact that its trophic centre is situated, not in the
nerve cell but in the muscular nucleoplasm, the irritability of the
myoneural junction is not destroyed by degenerative resection of
the nerve. On the contrary, we sometimes encounter the startling
phenomenon of a denerved and decentralized tissue having a
hypersensibility to chemical stimulation by adrenalin. The
" paradoxical dilation of the pupil ' which, after denervation
(extirpation of the superior cervical ganglion), follows the instil-
lation of adrenalin into the eye of rabbits and of cats, while the
normal eye of these animals does not react to adrenalin, has
already been described. As wre then pointed out, this phenomenon
is explained by the suppression of the inhibitory sympathetic
fibres. Elliott believes, however, that it is rather due to increased
irritability of the denerved peripheral tissue.

After denervation, the blood-vessels, the retractor muscle of
the penis, and the hair muscles all react to adrenalin. That, after
denervation, adrenalin also increases inhibitory activity, such, for
instance, as that of the urinary bladder, is highly probable, but
as yet without definite proof.

This hypothesis explains a number of peculiarities in con-
nection with the action of adrenalin, some of which have long
been recognized. It is wTell known that, in cats, while adrenalin
is active, stimulation of the vagi does not produce cardiac
inhibition, stimulation of the depressors is not followed by a fall
in blood-pressure, nor stimulation of the nervi erigentes by con-
traction of the urinary bladder. As soon as the effect of adrenalin
has passed off, the muscles respond to stimulus in the usual
manner. There was a general disposition to ascribe to adrenalin
a transitory paralysing action upon the terminals of the cranial
and sacral autonomous nerves. We now know that adrenalin
effects an almost maximal stimulation of the myoneural
sympathetic terminals, and that it produces results which are
dependent upon these. It is obvious, therefore, that, in each
organ, the response to electric stimulus can be changed by the
action of adrenalin only in a manner and to a degree such as
would result from a strong stimulation of the sympathetic nerve-
fibres. While adrenalin is active, stimulation of the sympathetic
does not produce more intense activity. When the adrenalin
action has passed off, the results of such stimulation are neither

THE SUPRARENAL SYSTEM 23!

increased nor diminished, but represent the normal response. In
those organs, however, in which, in addition to a sympathetic,
there is also an antagonistic autonomous innervation, the result of
the specific action of adrenalin will be so marked an increase in
the strength of the sympathetic effects, that the autonomous inner-
vation will appear to be paralysed. Similar results are observed
after the simultaneous stimulation of the sympathetic and
autonomous nerves of any organ, the sympathetic effects, in this
case also, far outweighing those of the autonomous innervation.
In cases where, while the sympathetic is under the influence of
adrenalin, stimulation of the antagonistic autonomous nerve (vagus,
pelvic nerve) is without effect, the result is due, not to paralysis cf
the latter, but to a preponderance of the chemical over the electric
influence upon the nerve-terminals. Hence, as soon as adrenalin
ceases to act upon the sympathetic, electric stimulus of the
autonomous nerve produces the customary result.

In the course of his investigations into the physiological
action of the ergot preparations, namely, cornutin (Kobert),
sphacelotoxin (Jacoby), chrysotoxin or ergotoxin (Dale), A. H.
Dale discovered certain remarkable departures from the known
method of action of adrenalin, to which a special interest attaches.

The first effect produced by small quantities of the ergot
preparations is a stimulation of all the organs possessing
unstriated muscle structure. Such doses bring about contraction
of the blood-vessels and consequent increase in blood-pressure,
together with contraction of the uterus and of the sphincter muscle
of the iris. We have as yet no certain knowledge as to the site
of origin of this stimulatory action. Larger doses produce
progressive inhibition of the motor elements which were previously
stimulated. At this stage, adrenalin fails to effect either a rise
in blood-pressure or uterine contraction. A still further increase
in the size of the doses of ergot produces the paradoxical result,
that adrenalin in quantities which, in the first instance, effected an
enormous rise in blood-pressure and were negatived where the
ergot dosage was moderately increased, now bring about a fall
in blood-pressure, the degree and duration of which is propor-
tionate to the amount of adrenalin exhibited. In the same way,
a quantity of nicotine which at first increased the tension of the
vessels now diminishes it. Stimulation of the splanchnic nerve or
of the spinal cord, instead of producing the customary rise in
arterial tension, is followed by a fall. Moreover, substances such
as barium chloride, which, under normal conditions, exercise a
direct stimulatory action upon the involuntary muscles, are now
followed by a rapid increase in arterial tension ; while pituitary ex-
tract, the action of which is to raise blood-pressure, increases the
tension of the vessels in animals at the third stage of ergot
poisoning.

It is, moreover, easy to prove that this effect of adrenalin in

232 INTERNAL SECRETION

lowering blood-pressure is not due to a decreased cardiac activity,
but is the expression of a peripheral vasodilation.

A similar gradual inversion of the characteristic action of
adrenalin is also seen in the case of other organs. The behaviour
of the uterus is entirely analogous. After moderately large doses
of ergot, the pregnant uterus will not contract in response either
to adrenalin or to stimulation of the hypogastric nerve ; on
the contrary, both methods produce considerable uterine relax-
ation. This applies to the rabbit and the ape. In the case of
the cat, stimulation of the sympathetic, whether direct or by
means of adrenalin, inhibits the movements of the virgin uterus,
while, in the pregnant uterus, it produces strong contraction.
Toxic doses of ergot do not alter the inhibitory action of adrenalin
upon the virgin uterus of the cat, but the pregnant uterus responds,
no longer by contraction, but by relaxation.

The spleen which, under normal conditions, responds to
adrenalin by contraction, after ergot poisoning responds by
relaxation. The internal sphincter muscle of the cat, in which
the action of adrenalin normally produces contraction, likewise
relaxes under the toxic influence of ergot. The stimulatory effect
observed in the urinary bladder of the ferret, as the result either
of adrenalin or of irritation of the hypogastric nerve, becomes
inhibitory under the toxic influence of ergot.

Acute ergot poisoning produces no change in the nature of
the results which follow stimulation of the cranial and sacral
autonomous nerves, or of the nerves supplying the skeletal
muscles. Stimulation of the vagus produces the customary effects
of inhibition of cardiac activity and contraction of the stomach,
intestine, and gall-bladder. Stimulation of the chorda tympani
provokes secretion of saliva ; and stimulation of the pelvic nerve
is followed by the customary contraction of the urinary bladder
and large intestine, and by dilation of the vessels of the penis.
After poisoning by ergot, the skeletal muscle contracts in
response to stimulation of its motor nerves in the same manner
as under normal conditions. It is evident, then, that the
inhibitory action of ergot is confined to the myoneural junctions
of the sympathetic system.

A closer investigation shows, however, that this conclusion is
subject to certain modifications. The following table shows the
effects which adrenal has in stimulating the sympathetic nerves,
both under normal conditions and after large doses of ergot.

The results which this table includes may be classified in
three groups :

(1) Where the sympathetic innervation is exclusively
inhibitory, as in the stomach, intestines, urinary bladder, and
virgin uterus, ergot poisoning produces no change in the effects
brought about by adrenalin and by stimulation of the sympathetic.

(2) Where the sympathetic innervation is exclusively stimu-

THE SUPRARENAL SYSTEM

233

latory (motor), as in the arteries of rabbits, in the heart, the
ileoco^cal sphincter, the urethra, the dilator muscle of the iris,
the pilomotor muscles and the retractor muscle of the penis, the
stimulatory action of adrenalin upon the sympathetic system is
more or less weakened by ergot poisoning, or may in some cases
even be abolished.

Organ

Vessels (cat, dog)

,, (rabbit)

Heart muscle

Spleen (cat) ...

Stomach (cat)

Small intestine (dog, cat, ape)
Large intestine (cat)
Ileocaecal sphincter (cat) ...
Internal anal sphincter (cat)

Gall-bladder

Fundus of the urinary bladder (cat)
„ ,, „ (ferret)

Urinary bladder and urethra (cat)
Pilomotor muscles
Dilator muscle of the iris

Uterus (virgin, of the cat)
Uterus (pregnant, of the cat)

,, (rabbit, ape)
Retractor of penis (dog) ...

Effects of sympathetic stimulation and
of intravenous adrenalin injection

Under normal conditions After ergot poisoning

s.
s.
s.
s.
I.
I.
I.
s.
s.
I.
I.
s.
s.
s.
s.

I.

N. or weak S.
N. or weak S.
I.
I.
I.
I.
N.
I
I.
I.
I.
N.
N".

N. with adrenalin,
weak S. after electric
sympathetic stimulation.
I. or S. and I. ... I.

S. ... I.

S. ... I.

S. N.

S = stimulation ; I = inhibition ; N = negative result.

(3) Where the sympathetic innervation is twofold, both
stimulatory and inhibitory in character, the stimulatory action
preponderating under normal conditions, as in the vessels of
the carnivore, in the spleen, the internal anal sphincter, the
urinary bladder of ferrets, the uterus of rabbits and apes, and
the pregnant uterus of cats, the action of adrenalin and the effect
of electric stimulation of the sympathetic are exclusively inhibitory
after ergot poisoning. It is evident from this that structures
having a sympathetic innervation do not all respond to the action
of ergot in the same manner. Those with inhibitory sympathetic
innervation are entirely uninfluenced; those with stimulatory in-
nervation become paralysed; where both stimulatory and inhibitory
fibres are present, the inhibitory function, which was previously
masked by the activity of the stimulatory fibres, becomes apparent
as soon as these are put out of action.

Dale's experiments show that the same structural elements
are influenced by the active principle of ergot as by adrenalin,
and that the site of this influence lies in the sympathetic myoneural
junction tissue. The inhibitory action of ergot is, however, con-
fined to the motor myoneural junction tissue. Whether or no
in organs with a double sympathetic innervation, the stimulatory
and inhibitory functions are associated with the* same substratum

234 INTERNAL SECRETION

or are morphologically differentiated, is a question to which these
observations of Dale's do not supply an answer. The results
included in Group 3 render the former supposition the more
probable; and these results are, moreover, evidence in favour of
Langley's theory of the existence of a " receptive substance."

The results described above, together with extensive investi-
gation into the action of nicotine and of curare, suggested to
Langley that the cells possess two component parts: (i) a sub-
stance which performs the specific function of the cell, contraction
and secretion ; (2) receptive substances, which react to chemical
influences and nervous stimuli and which are able, in their turn,
to affect the metabolism of the cells. According to this view,
toxins such as nicotine, curare, atropine, pilocarpine, adrenalin,
and strychnine, which were believed to exercise an influence upon
the nerve terminals, do not act upon the terminals but upon a
constituent of the reacting cell. This theory supplies a final
answer to the question as to whether adrenalin acts directly upon
the muscle itself, as Langley at first supposed, or whether it acts
upon the sympathetic nerve endings. The myoneural junction
forms a portion of the receptive substance, and is situated in
the neighbourhood of the nerve terminal. The cells may contain
either stimulatory or inhibitory receptive substances, or they may
contain both ; the effect of nervous stimulation will depend upon
the extent to which both receptive substances are influenced by
the nervous impulse.

According to Langley, not adrenalin only but other products
of secretion, such as thyroidin and the internal secretion of the
reproductive glands, react upon receptive substances in the cells-
which are not necessarily connected with nerve fibres.

THE BY-EFFECTS OF ADRENALIN.

In addition to the physiological effects already described,,
adrenalin exercises certain other influences, partly physiological
and partly toxic in character, which it is convenient to describe
as "by-effects."

Such a physiological by-effect is the stimulation by adrenalin
of the vasomotor and vagus centres in the medulla oblongata, to
which reference has already been made. From what we now
know of the action of adrenalin, those phenomena which appear
after intravenous injection as the outcome of the stimulation of
certain nervous centres, are due, not to the direct action of the
substance itself, but to changes which it brings about in the
circulatory conditions. In regard to its action upon the vagus
and the consequent slowing of the pulse, there is no doubt that
the result is due to stimulation of the vagal centre in consequence
of the increased blood-pressure (Biedl and Reiner). The fact
that the slowing of the pulse is immediately relieved by resection

THE SUPRARENAL SYSTEM 235

of the vagus or by atropine paralysis of the vagal terminals, is
almost certain evidence in favour of this theory. It is, however,
a more difficult matter to prove that the influence upon the
vasomotor centres is secondary, though from what we know of
the effects of high blood-pressure upon these centres, the assump-
tion seems highly probable. Moreover, the exhibition of adren-
alin is followed by other phenomena, due to the stimulation of
certain other centres, which are certainly not provoked by the
action of the substance itself, but are the result of the increased
arterial tension.

To this group of phenomena belong the changes which are
observed in the respiratory conditions after the injection of supra-
renal extract or of adrenalin. After the injection of therapeutic
doses, the respiration becomes shallow and diminishes in
frequency. The shallowness is due to diminution of the
inspiratory movements, the reduction in frequency to the pro-
longing of expiration. Sometimes there are isolated gasps and
sighs, or there may be several prolonged expiratory pauses. If
the injections are repeated, the shallowness remains, but the
prolonged expirations disappear, and the breathing becomes
slightly accelerated (Kahn). At the same time, the height of the
expirations remains at the former level. The inspirations
gradually become deeper, until, by the time the blood-pressure
has fallen to the normal, the depth and frequency of respiration
has also reached the normal.

Boruttau attributed this influence of adrenalin upon expir-
ation to a direct inhibitory action, or at least to a reduction in
the sensibility to stimuli of the respiratory centre in the medulla
oblongata. It would be more accurate, perhaps, to speak of ' ' an
increased sensibility to stimulus on the part of the inhibitory
centres," especially since Kahn has shown that the respiratory
reflexes produced by centripetal stimulation of certain nerves,
undergo a marked increase in intensity after the injection of
suprarenal extract. Such are, the improved inspiration which
follows weak stimulation of the central vagus stump ; the improved
expiration which follows stimulation of the superior laryngeal
nerve ; and the suspension of expiration (Kratschmer's reflex)
which follows stimulation of the nasal branches of the trigeminus.

We have no proof that these changes in respiratory activity
are the result of the direct action of adrenalin upon the respiratory
centres; hence we are compelled to regard them, like the changes
which take place in the bulbar and vagal vasomotor centres, as
the result of changes in the circulatory conditions.

Among the effects of adrenalin of which we at present know
very little, are those influences, perhaps physiological, but more
probably toxic, which it exercises upon the striated muscles.
According to Oliver and Schafer, suprarenal extract, like veratrin,
provokes an extension of the graphic curve of contraction of the

236 INTERNAL SECRETION

gastrocnemius of frogs, as well as of the forearm muscles of dogs.
According to Langlois, suprarenal extract produces a paralysis of
the motor nerve endings, similar to that provoked by curare.
Boruttau compared the action of adrenalin upon the striated
muscles to the changes which take place in the first stage of
fatigue. On the other hand, Dessy and Grandis believe that
fatigued nerve muscle preparation of the frog is stimulated to
renewed activity by the action of adrenalin. Panella, who con-
firmed this view, found that, in frogs, the action of the active
principle of suprarenal was antagonistic to that of curare; it
neutralizes the inhibitory effect which minimal doses of curare
have upon the muscles, and in cases where curare paralysis has
already made its appearance, it hastens the return to normal
conditions. The results of Joteyko's investigations into the
nature of adrenalin, seem to show that it produces neither stimu-
lation nor inhibition of muscular action, but that it affects the
muscular sarcoplasm in such a way as to render it more sensitive
to nervous stimulus. These changes in irritability are, however,
so slight as to be demonstrable only by special methods.

The experimental evidence which we at present possess is
not sufficient to decide the question, as to whether the influence
which adrenalin exercises upon the striated muscles is physio-
logical or toxic in character. Observation of the heart muscle
yields results which seem to point to the latter conclusion. For,
in addition to the changes which have been described, certain
phenomena are occasionally observed in connection with the
heart muscle, which it is impossible to regard as other than toxic.
In dogs, especially, both large doses of adrenalin and the injection
into the veins of extract of the chromaffine bodies (Biedl and
Wiesel), are frequently followed by arhythmia, and in some
instances by a sudden fluttering which terminates fatally.

TOXIC ACTION.

When given in moderate doses, the influence of adrenalin is
purely physiological, but when employed in large quantities its
action is violently toxic. It exercises a destructive influence upon
a number of tissues, and produces acute symptoms which may
end in death.

The amount of the toxic dose of adrenalin is, to a certain
extent, dependent upon the animal species and upon the method of
exhibition. The intravenous injection of .1 to .2 mg. per kilo
usually proves fatal to dogs, rabbits, and guinea-pigs. Amberg
gives the toxic dose of epinephrin — though this is probably not
identical with adrenalin — as i to 2 mg. per kilo in dogs. Cats,
as a general rule, tolerate somewhat larger doses of adrenalin, the
toxic ^ose being as high as .5 to .8 mg. per kilo (Lesage). The
size of the dose, the intravenous injection of which is immediately

THE SUPRARENAL SYSTEM 237

followed by death, is larger in proportion to the distance of the
site of injection from the heart.

When injected subcutaneously, ten to fifty times the amount
is borne. The lethal dose is about 8 to 10 mg. per kilo in guinea-
pigs and rabbits, 5 to 6 mg. in dogs. Frogs tolerate a dose ten
times larger in proportion to their weight than rabbits. About
.1 mg. injected subcutaneously is fatal to mice weighing 10 to 15
grms. Abderhalden and Slavu employed a similar dose of
1-suprarenin. These authors found that, in the case of mice, the.
lethal dose was followed, either by convulsive symptoms lasting a
few minutes, or by coma lasting several hours \vith a terminal
fall in temperature. They found the action of d-suprarenin much
less toxic, the fatal dose being .1 to .5 grm. The same authors
also discovered that, if the animals are previously treated with
increasingly large doses of d-suprarenin (.2 to 5 mg.), they
acquire a definite tolerance of the 1-component and will bear an,
amount two to ten times as large as under ordinary conditions.
According to Watermann, the immunizing action of d-suprarenin.
is observed not only in regard to the fatal dose of 1-suprarenin,,
but also in the case of the dose which provokes glycosuria. 2 mg.
1-suprarenin produced little or no sugar in the urine of rabbits,
which had been previously treated with increasing doses (10 to
50 mg.) of d-suprarenin, though under ordinary conditions, such
a dose of 1-suprarenin is invariably followed by glycosuria.

A. Frohlich found that the intravenous injection of d-supra-
renin (2 to 5 mg.) induced a condition in dogs and cats, in which
the blood-pressure \vas entirely unaffected by the injection of
natural adrenalin, by 1-suprarenin in doses of i mg., or
by stimulation of the splanchnic nerve. In this state, death by
asphyxia is not preceded by any rise in blood-pressure. Accord-
ing to Frohlich, the non-toxic d-suprarenin, when given in large
doses, combines with certain nervous or muscular portions of the
blood-vessel cells and renders them completely inaccessible to the
action of 1-suprarenin, to which these cells are, as a rule, very
susceptible. Abderhalden, Kautzsch and Miiller were unable to
confirm Frohlich's findings; they believe that the results of his
experiments wrere largely influenced by the presence, in his ani-
mals, of relative cardiac insufficiency.

There is no doubt that the organism acquires a certain
tolerance of the toxic action of adrenalin, for, by giving it at
intervals of twenty-four hours or longer in increasingly large
doses, rabbits, for instance, will take quantities up to .4 mg.
without signs of untoward effects. Moreover, it has been
definitely proved by Elliott and Durham, that, where animals are
under continuous adrenalin treatment, adrenalin antibodies are
not formed in the organism.

When injected into the peritoneum, the lethal dose of adren-
alin is about the same as when the injection is given subcutan-

238 INTERNAL SECRETION

eously. Falta and Ivcovic recently discovered that, if exhibited
by way of the stomach or intestines, or if given intravesicularly,
enormous quantities of adrenalin are tolerated without toxic
symptoms of any kind. No signs of poisoning followed the
introduction with the probang of 20 mg. of adrenalin into guinea-
pigs, 1 6 to 50 mg. into rabbits, and 150 mg. into dogs. The
amount of adrenalin in the urine, after both subcutaneous and
intraperitoneal injection, was insignificant. After exhibition by
the mouth, however, considerable quantities of adrenalin, or of a
substance possessing the chemical, physiological and toxic
properties of adrenalin, were found in the urine. The authors
believe that, when introduced into the stomach, adrenalin becomes
fixed, either in the mucosa of the gastro-intestinal canal, or by
the agency of the digestive secretions ; that in this manner it loses
its specific physiological and toxic properties ; and that, when
present in large quantities, it is again released in the kidneys.

Although adrenalin undoubtedly has a wide therapeutic
application, it must be remembered that it is by no means a
harmless substance. In its clinical employment, the subcutaneous
injection of i mg. is frequently sufficient to provoke toxic
symptoms, such as palpitation and headache, while in older
people whose vessels are sclerosed, there may be rigors (Falta).
Some time ago v. Fiirth pointed out the danger attaching to the
indiscriminate employment of suprarenin.

The symptoms shown by animals dying of adrenalin poison-
ing, as well as the cause of death, vary to a certain extent with
the method of employment of the drug. After the injection of
large quantities into the jugular vein, the animals usually collapse
at once and die after a few respiratory movements. In such
cases, death is due to momentary arrest of the heart's action or to
fluttering, consequent upon the cessation of circulation. The
injection of the simple lethal dose, more particularly into
the peripheral veins, frequently produces cedema of the lungs in
rabbits, the animals dying within a few minutes. Many of the
symptoms which appear in connection with the respiratory
apparatus, such as the shallowness and infrequency of the breath-
ing, the progressive dyspnoea, together with the fact that the
animals may be kept alive for a long time by means of artificial
respiration, point to inadequacy on the part of the respiratory
nervous apparatus. This nervous inadequacy may be primary
or, and this is more probable, it may be a secondary result of the
•changed circulatory conditions.

The subcutaneous or intraperitoneal injection of sufficiently
large doses is, at first, followed by a stage of intense excitement,
accompanied by repeated vomiting and sanguineous diarrhoea;
later on, there is increasing weakness and, finally, extreme
prostration with complete paralysis ; death follows after a few
hours — twenty-four at the most. The autopsy reveals a high

THE SUPRARENAL SYSTEM 239

degree of hyperaemia of all the internal organs; a serous, and
occasionally sanguineous, fluid is present in the pleural, peri-
toneal, and pericardial cavities; there are sub-pleural, sub-
pericardial, and epicardial ecchymoses, relaxed heart muscle,
pulmonary haemorrhages and, occasionally, pulmonary oedema.
The abdominal viscera, especially the intestine, are not only
markedly hyperaemic, but they are frequently covered with exten-
sive haemorrhagic patches.

There are, undoubtedly, good grounds for ascribing the fatal
termination which follows the intravenous injection of large
quantities of adrenalin, to profound circulatory disturbances; but
where the substance is introduced either subcutaneously or into
the peritoneum, there is no evidence as to the cause of death.
The destructive influence which adrenalin has upon the tissues,
which will be fully discussed later, suggests, however, that the
cause of death in these cases is to be sought in a destruction of
the vital tissues.

Of the toxic effects which adrenalin exercises upon individual
tissues, the most conspicuous is the necrosis which it sometimes
produces at the site of either subcutaneous or intraperitoneal
injection. As far as my observation goes, this process is of very
frequent occurrence; it affects the subcutaneous cellular tissue
and is more marked in proportion to the weakness of the adrenalin
solution employed. The subcutaneous injection of .1 mg. of the
usual solution of i : 1000 into rabbits, rarely produces necrosis;
but necrosis almost invariably appears if the same dose is diluted
with large quantities (50 to 100 c.cm.) of sterilized normal saline
solution. If this method is employed, marked oedema will appear
at the site of injection, and this will be distinctly visible the next
day, becoming haemorrhagic later. In the course of the next few
days, the skin becomes more or less extensively necrosed and
finally heals, after forming a scab.

The subcutaneous or intravenous injection of adrenalin is
followed by inflammatory and degenerative changes, not at the
site of application only, but also in organs distant from it. These
changes are observed after a single injection and are more marked
where the injections are repeated. The kidneys show signs of
inflammation and infiltration, together with haemorrhages and
necrosis; there are haemorrhages and necrotic and cirrhotic
changes in the liver; symptoms of inflammation appear in the
lungs ; and necrotic processes are seen in the mucosa and muscular
structure of the stomach, intestines and urinary bladder. Schlayer
found that the injection of adrenalin was followed by changes in
the renal tissue resembling those of contracted kidney. Both
Erb and Fischer found that the repeated injection of adrenalin
into the veins of rabbits, was followed by multiple cerebral haemor-
rhages, associated with pathological changes in the substance of
the brain. The cause of these haemorrhages probably lies in a
primary lesion of the cerebral vessels.

240 INTERNAL SECRETION

The most conspicuous of the toxic effects of adrenalin is that
which it exercises upon the circulatory organs. The repeated
injection of adrenalin produces serious changes in the heart ;
hypertrophy of the left ventricle, myositis fibrosa, ischa^mic in-
farction, foci which have undergone hyaline degeneration, and
necrosed patches, have all been observed.

Of the changes effected by suprarenal extract, or by adren-
alin, upon the circulatory apparatus, those which may be experi-
mentally induced in the arteries have received the most attention.
It is expedient to the present purpose to enter rather more fully
into this subject.

Josue was the first to show, in 1902, that the repeated injection
of adrenalin into the veins of rabbits produces atheroma of the
vessels. Jores had previously tried to produce changes in the
vessel walls by means of suprarenal tabloids given by the mouth,
but his experiments were quite unsuccessful.

Later, experiments were carried out upon animals of varying
species with the different suprarenal preparations; with adrenalin
obtained from the suprarenal and with synthetic preparations,
such as methylaminoacetopyrocatechin, by Sturli ; and with syn-
thetic suprarenin and its components, 1- and d-suprarenin, by
Biedl.

Experiments with dogs have produced somewhat variable
results. Fischer and Mori, as well as Pearce and Stanton,
obtained negative results ; while Tarantini and Braun found that
the intravenous injection of adrenalin was followed by vascular
changes similar to those seen in rabbits immediately after such
injection. According to Loeper, Lissauer, v. Hansemann and
Boveri, the symptoms are intensified by feeding the animals with
calcium ; moreover, animals, the normal diet of which is rich in
calcium, such as the hare, horse and cow, are more susceptible
to vascular changes than animals whose normal food contains
but little calcium (dog, cat).

The rabbit is a very reliable subject for such experiment,*
and has been employed in the great majority of cases. It is
evident that, in the first place, the appearance of changes in the
vessel walls is dependent upon the manner in which the drug is
exhibited. The results of subcutaneous injection have occasion-
ally been positive, but far more often negative, in character. After
intratracheal injection, Kiilbs observed typical changes in the
aorta; Fischer found that intraperitoneal injection was not fol-
lowed by such changes ; Erb noticed slight changes in the aorta ;
d'Amato observed similar changes after the introduction of
Vassale's preparation, ' paraganglin," into the stomach; and
Tarantini obtained only negative results by the latter method.

' Klotz and Bennecke think that the large calcium contents of rabbits'
blood is significant in this connection.

THE SUPRARENAL SYSTEM 241

The most reliable results have been obtained by means of
intravenous injection (Erb, B. Fischer, K. Ziegler, Lissauer,
Braun, Minorescu, Scheidemandel, v. Koranyi, Pearce and Stan-
ton, v. Rzentkowski, Kiilbs, Hedinger, Loeb, Loeper, v. Frey
and Meyer, Pic and Bonnamour, &c.). Kaiserling is the only
author who is not convinced that the changes in the aorta are
directly due to the action of adrenalin. The vast majority of
authors hold the opinion that the results of adrenalin experiments
are in no sense accidental, and that there is, as far as we know
at present, no reason to doubt that the changes observed in the
vessels of rabbits are the outcome of the action of this substance.

The vascular changes take place in response to quite small
quantities of adrenalin. Braun found that, after a single in-
jection of .1 mg., several calcareous foci were present in the
aorta; he found, also, that the repeated injection of .001 mg. of
Clin's adrenalin, or even of fractions of this quantity, offered the
best means of studying the preliminary stages of "adrenalin
sclerosis."

Speaking broadly, these changes take place more readily in
old animals than in young ones;* there are, moreover, certain
idiosyncrasies peculiar to individuals and to varieties,! but there
is no sex incidence (Bennecke) ; and it is certain that diet
exercises a modifying effect (v. Koranyi). J

Where small doses are employed, the changes are distributed
throughout the entire vascular system (Braun). Of the observers
who employed larger doses, the greater number describe changes
in the aorta only. The changes appear first and are most marked
in the upper portion of the thoracic aorta, though they are
occasionally met with in a slighter form in the abdominal aorta.
According to v. Rzentkowski, the most frequent site is at the
fork where the vessel branches. The macroscopic findings, as
described by different authors, agree in their main points with
those originally set forth by Josue.

At first, small, whitish, granulated patches, of about the size
of a pin's head, make their appearance upon the inner surface of
the aorta, and gradually combine to form round or band-like
plaques. They early undergo calcification, patches no larger
than a pin's head assuming an indented cup-like form. Later on,
cup-like, round or oval aneurysmal pouchings are formed, often
with rough chalky ridges between them. Diffuse calcification is
also observed, though its occurrence is somewhat rare.

The histological changes (Braun) consist, in the first instance,

* Josue thinks that young; rabbits are not susceptible to adrenalin.
This view is confirmed by O. Loeb and Githens, but is disputed by Ben-
necke.

t Albinos and the more finely-organized breeds are less resistant to
adrenalin.

+ According to v. Koranyi, rabbits fed on carrots have a greater power
of resistance than those fed on oats.

16

242 INTERNAL SECRETION

of serous infiltration of the media; proliferation of and hyper-
trophic changes in the muscles of the vessels, and injury of the
elastic elements in the vessel walls, especially of the lamina
elastica interna, together with consecutive, and probably com-
pensatory, proliferation of this tissue. In its earlier stages, it is
difficult to define the exact nature of the injury to the muscular
portion of the vessel walls. It is certain, however, that at a very
early stage there are softening of the tissue, nuclear changes, and
thickening of the fibres, the latter being probably compensatory.
In the case of vessels of the muscular type, the changes in the
intima — the " hyperplastic proliferation of the intima ' —are, as
a rule, apparent when the media are only slightly affected. At a
later stage, the proliferation of the intima in vessels of both kinds
becomes degenerative.

The final stage consists in necrosis of the muscle cells (Erb,
Torri, Fischer, Hedinger, Lissauer, Kiilbs, Ziegler, Saltykow,
&c.), together with calcification of circumscribed areas, and
various changes in the elastic fibres. The question as to whether
the muscular changes are preceded by fatty degeneration has been
differently solved by different authors. Klotz, Saltykow, Pearce
and Stanton, Lissauer and Bennecke believe that this is the case;
on the other hand, Fischer, d'Amato and Flagella, and Scheide-
mandel have never observed fat.

Where there are foci of calcification, the elastic lamella? fre-
quently appear to be stretched; their normal undulations dis-
appear; and "granulated, elastic' fibres are observed. Later
on, where the lesion is very pronounced, the elastic lamella? may
tear, or rather break, afterwards splitting and crumbling until
they finally disappear. Fatty degeneration of the elastic fibres
has also been described (Klotz).

Calcification is frequently present at a very early stage.
According to Trachtenberg and Miesowicz, formation of cartilage
also takes place. At the beginning, the calcified foci are, as a
rule, sharply defined from the sound tissue. Where the media
is completely destroyed, a deep and progressive pouching of the
wall gradually takes place and an aneurysm is formed. The foci
and the chalky scales upon the media become surrounded later
by cellular proliferations, which consist of leucocytose and lym-
phocytose infiltration, granulation tissue and proliferation of
muscle cells. It is my own experience (Biedl and Braun) that
all these changes take place. The descriptions which have been
given of giant cells are doubtless well founded. The hyper-
trophic muscle fibres, especially in section, closely resemble
cartilage cells. In the later stages, there is connective tissue
formation (Ziegler), diffuse sclerosis, fibrous degeneration of the
media (Scheidemandel, Torri), reactive inflammation, mesarter-
itis, and endarteritis (B. Fischer).

The changes in the intima consist, at first, of endothelial pro-

THE SUPRARENAL SYSTEM 243

liferation (Erb, Kiilbs, Saltykow) ; fatty degeneration of the
proliferated endothelium (Saltykow, Klotz) ; and connective tissue
thickening of the intima (Papadia, Watermann). According to
K. Ziegler, the proliferation of the intima is wholly compensatory,
its purpose being to rill up the inequalities of the inner surface
of the vessel. This can apply, however, to a small proportion of
cases only. F. Falk has frequently observed proliferation of the
intima and of its component parts in portions of the small vessels
\\hich had become pouched as a result of the process. Fissure
of the lamina elastica interna is frequently observed, as well as
the occurrence of nuclei (unstriated muscles) in the intima of the
small vessels. It is probable that changes (softening) do not take
place in the media of the small vessels, or if they do, they can
only be of the slightest description. Here and there, pronounced
connective tissue traits appear in the portions of the media border-
ing upon the adventitia (Falk).

K. Ziegler explains the sporadic appearance of the diseased
condition by the implication of the vasa vasorum. With regard
to the primary localization of the disease, all authors, with the
exception of Loeper, Papadia and Boveri, are agreed that the
changes in the media are essential, the changes in the intima
secondary, in character. Whether, however, this rule applies
equally to the small vessels, is a point upon which no certain
pronouncement can at present be given. The tissue which is
first affected is the muscular structure of the vessels (B. Fischer,
Falk, &c.), although v. Rzentkowski, Marchand, Scheidemandel
and Trachtenberg localize the site of earliest affection in the
elastic portions of the vessel walls.

The pathogenetic factors in the changes brought about by
adrenalin in the arteries are : its effect in raising blood-pressure ;
its toxic action upon the vessel walls ; and perhaps, also, a
direct influence upon the vasa vasorum.

Changes similar to those in the aorta are also observed in
the pulmonary artery, in the veins (d'Amato), and in the
lymphatics (Donzello and Vito Tardo), in all of which the con-
ditions governing pressure could hardly be altered, to any appre-
ciable extent, by the action of adrenalin. These facts militate
against the view that the increased blood-pressure is the sole
pathogenetic factor. Moreover, L. Braun, and later Waterman,
both observed identical changes in the arteries in cases where,
by injecting adrenalin in combination with amyl nitrite, they had
excluded every possibility of increased blood-pressure. Similar
results were obtained where adrenalin was administered simul-
taneously with other substances which lower blood-pressure;
Boveri, for instance, employed adrenalin with opothyroidin ;
Mironescu adrenalin plus euphthalmin, which is a substance of
the atropine group.

B. Fischer proved that changes in the vessels may be also

244 INTERNAL SECRETION

brought about by the agency of many substances which do not
raise pressure, if these are administered in a suitable manner.
Such substances are: normal saline solution in large quantities;
hydrochloric, phosphoric, and lactic acids ; calcium phosphate,
potassium bichromate, uranium nitrate, chloral amide, phlorizin,
trypsin, pepsin, thyroidin, and dried mammary gland. It
must be conceded, however, that these substances never produce
changes as marked as those which result from the action of
adrenalin.

The toxo-chemical action of adrenalin is still further proved
by the results of Falk's experiments. While ignoring the rise in
blood-pressure produced by adrenalin, he succeeded in intensify-
ing or reducing the arterial changes which followed it by
injecting, together with adrenalin, substances which have no
influence upon blood-pressure, their action being purely
chemical.* According to Falk, a repeated, transitory rise in
pressure and functional hyper-stimulation of the muscles of the
vessels, are essentially the predisposing causes of necrosis of the
vessels. " High blood-pressure alone never gives rise to serious
injury of the media, that is to say, to regressive changes; for
hyperactivity is, in itself, far more likely to lead to a gradual
hypertrophy of the various layers forming the walls of the vessels.
It is in this way that Falk explains the results of experiments in
which changes in the vessels, in every way resembling those
provoked by adrenalin, were brought about by repeated mechanical
hypertension induced by the injection of gamboge or croton oil,
with simultaneous compression of the abdominal aorta.

In company w*ith L. Braun, I investigated the effect which
purely mechanical hypertension exercises upon the vessels. We
found that, in the rabbit, sheep, and ape, repeated compression of
the aorta above the point of departure of the renal artery gives
rise to lesions of the vessels, which upon the whole, are analogous
to those produced by adrenalin. From the results of experiments
carried out under special conditions, we concluded that the
vascular lesions depend, not only upon the hypertension, but also
upon the extreme pressure fluctuations which take place in the
arterial system, and which make special demands upon the
elasticity of the vessel walls. f

* The arteriosclerosis was either prevented or arrested by the simul-
taneous injection of chemotaxic substances, such as : dead staphylpcocci,
pyocyaneusprotein, oil of turpentine, aleuronate, and sesame oil ; it was
enormously increased by the subcutaneous injection of croton oil, gamboge,
and bacterial toxins. Falk thinks that the absence of arteriosclerosis is due
to the increase in the amount of lymph. After Biedl and Offer had proved
that the glocosuric action of adrenalin is inhibited by lymphagogue sub-
stances, Falk found that the injection of extract of leeches, which increases
the circulation of lymph, was likewise unattended by changes in the
vessels.

t A detailed account of " compression sclerosis " as observed by Braun
and myself appeared in the Sitzungsberichten der k. Akad. d. Wissensch.
in .Wien. Vol. 119. IQII.

THE SUPRARENAL SYSTEM 245

Serious changes in the aorta of rabbits after compression of
the abdominal aorta are described by W. Henwood Henry; and
Klotz observed similar changes in rabbits after they had been
repeatedly suspended with the head downwards.

These experiments illustrate the important part played by
changed haemodynamic conditions in the etiology of lesions of
the vessel walls. They serve, moreover, to establish the prob-
ability of this agent as a factor in the causation of adrenalin
sclerosis. The discovery that similar changes are produced in the
vessel walls by other substances, whose property it is to increase
blood-pressure, such as digalen, digitoxin, strophantin, barium
chloride, ergotin, nicotine, and formaldehyde, may be regarded
as confirmatory evidence, although it is not possible in these
instances to exclude the operation of chemico-toxic factors.

In spite of much searching investigation, it has not been
possible, up to the present, to arrive at any conclusive decision
concerning the pathogenesis of adrenalin arteriosclerosis. But
the increase and the fluctuation in pressure, on the one hand, and
the toxic injury to the vessel walls, on the other, are undoubted
factors in the causation of the condition.

These findings are confirmed by the results of certain experi-
ments which I recently undertook, with the object of discovering
the changes brought about in the vessel walls by means of 1- and
d-suprarenin. I found that, when given in quantities too small to
provoke a rise in blood-pressure, serious sclerotic changes
followed the employment, not only of the 1-component whose
property it is to raise blood-pressure, but also of the d-component
which, owing to its slight toxicity, may be given in larger doses.
In no case did I find that treatment by subcutaneous injection of
d-suprarenin created a tolerance of subsequent intravenous injec-
tion of 1-suprarenin. The changes in the vessels to which
d-suprarenin gives rise are undoubtedly in the nature of toxic
injury, brought about by the agency of a substance, the affinity of
which to certain components of the vessel walls is suggested' by
certain experiments of A. Frohlich's, which have already been
described.

The following facts are known concerning the part played
by certain physical conditions in the causation of a sclerosed
condition of the vessel walls.

Pregnant animals appear to be less susceptible than others
to the influence of adrenalin (Loeb and Githens, Loeper, Boveri,
v. Koranyi). It is certain that the conditions of pregnancy,
castration (Thevenot), cachexia (L. Loeb and Githens, Pic and
Bonnamour), and fatigue (Thevenot), are not favourable to the
development of adrenalin lesions. During the period of lacta-
tion, the resistance to the action of adrenalin is lowered (Pic and
Bonnamour, Thevenot). As far as the effect upon thyroid-
ectomized animals is concerned, opinions are divided. It must

246 INTERNAL SECRETION

be conceded that, upon the whole, the effect which different
physical conditions have upon the enlargement of the vessels as
induced by adrenalin, is at present insufficiently investigated.

The influence which certain drugs have upon the changes in
the vessels produced by adrenalin, has formed the subject of
extensive investigation. Of these, iodine has received the most
attention.

v. Koranyi found that the simultaneous exhibition of adren-
alin and iodine inhibits the changes which adrenalin provokes in
the vessels. Boveri arrived at the same conclusion, but Biland
obtained quite opposite results. He found that the simultaneous
exhibition of iodide of potassium and suprarenin favoured the
appearance of changes in the aorta. Hedinger, Loeb, and
Fleisher, as well as Kalamkarow, bring forward a large amount
of evidence in confirmation of Biland's findings; Klienenberger,
on the other hand, is unable to show that the effects of adrenalin
are inhibited by the action of iodine. The inhibitory influence of
iodipin upon the development of adrenalin sclerosis, depends
upon the amount of sesame oil which it contains (Schrank).
According to Mansfield, the simultaneous employment of cholin
with adrenalin does not arrest the changes in the vessel walls.

The vast majority of authors who have occupied themselves
with the question of the changes which adrenalin produces in
the vessels, have discussed this condition in its relation to the
clinical form of arteriosclerosis. The views which different
authors hold upon this subject are, however, very diverse. Josue,
Loeper, Gouget, Gilbert and Lion, Boveri, Braun, etc., believe
that the two conditions are more or less identical ; while Fischer,
v. Rzentkowski, Scheidemandel, Hedinger, d'Amato, Lissauer,
Loeb, Klotz, Saltykow, etc., lay stress upon the differences which
subsist between the two conditions. Certain signs, such as the
calcification of the media as seen in the clinical condition, are
believed by many authors (v. Erb, Biland, Bennecke, Klotz,
Marchand, Saltykow, etc.) to be common to both pathological
forms.

ADRENALIN AS A SECRETORY PRODUCE OF THE

ADRENAL SYSTEM.

It has been shown that adrenalin is a well defined chemical
substance, minimal quantities of which produce definite physio-
logical results. The next step is to discover whether this sub-
stance is formed and passes into the circulation during life, or
whether it comes into existence post mortem.

The first question to be decided, however, is — in which of the
two suprarenal systems is adrenalin formed? As stated in an
earlier chapter, Vulpian and Virchow were able to obtain the
colour-reactions characteristic of adrenalin with the medullary
substance of the suprarenal only; with that tissue, in fact, which,.

THE SUPRARENAL SYSTEM 247

as Henle proved, stains brown in watery solutions of chromic acid
and the chromates. Oliver and Schafer next discovered that the
specific action of suprarenal extract is obtained exclusively with
the extract of the medulla, extract of the cortical substance being
negative. It was shown by both Langlois and S. Vincent, that
blood-pressure is raised by those extracts only which are obtained
from animals, the suprarenals of which are composed of medullary
and cortical portions. Vincent found that extracts of the so-
called suprarenal bodies (Balfour) of Selachii, were physiologically
active and, in combination with Moore, he succeeded in obtaining
with these substances the chemical reactions characteristic of the
chromogen of the suprarenal medulla. Extracts of the interrenal
bodies were partially active owing, Vincent believes, to the
inclusion of a proportion of medullary substance; extracts of the
bodies of Stannius of Teleosteii were completely inactive. These
tests were only employed to prove toxicity.

I next found that extracts obtained from the adrenal organs
of Selachii possess all the physiological properties of adrenalin.
It is a noteworthy fact that, if adrenal organic extract is injected
into the branchial arteries of rays or torpedoes, a rise in blood-
pressure takes place similar to that which follows the injection
of adrenalin. Finally, it was shown by Biedl and Wiesel,
that extracts of the extracapsular chromaffine tissue, more par-
ticularly extract of the accessory sympathetic organs in the
neighbourhood of the abdominal aorta of children (Zuckerkandl),
produce contraction of the peripheral vessels and increased cardiac
activity, by which a rise in arterial tension is effected. These
authors also discovered that the substances exercise a transitory
injurious effect, first upon the right heart, and afterwards upon
the left, which is manifested by the occurrence of arhythmic beats.
They emphasize the fact, and in this they are supported by A.
Kohn, that the physiological reaction which is regarded as the
specific effect of suprarenal extract, is a property of the extract
of the chromaffine cell-group. In view^ of these results, it is
hardly possible to doubt that adrenalin is a chemical component
of that tissue which is distinguished, histologically, by the chrom-
affinity of its cells, and which has received the name of adrenal
tissue.

A certain amount of information as to the quantity of adren-
alin present in the suprarenal and in the free portions of the
adrenal system, is supplied by histological investigation. The
chromaffinity of the adrenal cells, that is to say, the property which
their cytoplasm has of staining brown or yellow-brown with
chromium salts after suitable fixation, is the measure of their
adrenalin contents.

The most suitable fixing fluids are mixtures of potassium
bichromate and formalin (Kohn, Wiesel). The objects must be
as fresh as possible when put into the fixing fluid, for the chrome
reaction disappears with remarkable rapidity after death, the cells

248 INTERNAL SECRETION

refusing to stain after twelve or, at the outside, thirty hours. It
should be further borne in mind that all cells do not stain equally
intensely, and that their chromaffinity is by no means always
parallel to their adrenalin contents, as revealed by other methods.
In the experiments of Schur and Wiesel, in which prolonged
narcosis in rabbits was followed by reduction and total disappear-
ance of the chromaffinity of the suprarenal medulla, I found a dis-
crepancy between the chromaffinity of the suprarenal extract em-
ployed and its effect in raising blood-pressure. For instance, the
hypertensive action of one extract was of about normal intensity, but
the chromaffinity of the suprarenal from which it was derived was
very much reduced. Whether, in these cases, the slight chrome
reaction is due to insufficiency of the adrenalin contents, or to the
presence of non-chromophile pre-stages of adrenalin, is at present
undecided. Whatever the cause, however, findings such as these
show very clearly that Henle's chrome reaction can be employed
at best as a provisional quantitative test only for adrenalin.

Battelli was the first to attempt to record in actual figures the
amount of adrenalin contained in the suprarenals. For this
purpose, he employed a colorimetric method of his own with
ferric chloride, but was able to obtain only approximate results.
Battelli and his pupil, S. Ornstein, measured the amount of
adrenalin in the suprarenals of man, rabbits, and guinea-pigs, by
estimating the increase in blood-pressure produced by the extracts
of those organs. The results of their experiments showed that
the adrenalin contents of both suprarenals are approximately the
same in the dog and the rabbit, but that in the guinea-pig the
amounts differ, the excess being in the right or left organ indiffer-
ently. They also proved that, in the case of the dog and the
rabbit, extirpation of one capsule did not lead, at any rate within
the next few days, to a change in the adrenalin contents of the
other. In the case of the dog, however, a reduction was occasion-
ally observed in the adrenalin contents of the capsule left in situ.

Battelli's tables show that i grm. of suprarenal substance
contains, upon an average, i mg., or slightly more, of adrenalin.
It was estimated that 18 grm. of suprarenal substance of cattle
contained a mean quantity of 4.3 grm. of medullary substance,
and .031 grm. of adrenalin ; that is to say, .75 per cent, of adrenalin
was present in the medullary substance.

According to Battelli, the adrenalin contents of the suprarenals
of different animals, to every 1,000 kg. of body weight, are as
follows :

Man 0603 grm. adrenalin per 1000 kilo.

Ox .074--077

Horse ... .0816-. 12 ,, ,, ,,

Sheep U5-.I2I ,, „ ,,

Pig .o;S-.oS4 ,, ,, ,,

Do£ ... .o666-.ii6 ,, ,, ,,
Rabbit ... .083

Guinea-pig ... .229 ,,

THE SUPRARENAL SYSTEM 249

Although these figures possess an approximate value only,
they show that the adrenalin contents in proportion to body weight
are very much the same in different animals. The guinea-pig
forms the only exception, the adrenalin contents in this instance
being twice, or nearly three times, as large as in other animals.

Quantitative chemical tests for adrenalin have not as yet been
carried out by means of the more improved modern methods. The
following facts have been ascertained concerning the adrenalin
contents of the suprarenals under both physiological and patho-
logical conditions.

Langlois and Rehns found that the suprarenals of foetuses
yielded, at the end of the first half of pregnancy, extracts which
produced a rise in blood-pressure, and also gave a positive reaction
with ferric chloride. Judging by the chromium reaction, the
portions of the adrenal system which are external of the supra-
renals contain adrenalin earlier in the life of the embryo than the
cells of the medulla (Wiesel).

That the adrenalin contents of the suprarenals are affected
by changes in the physiological conditions, was first shown by
Battelli and Roatta. These authors found that the amount of
adrenalin in the suprarenals of dogs, which had been allowed to
run in a treadmill until completely exhausted, was reduced to a
third of the minimal normal amount. Where the muscular
exertion was followed by muscular repose of several hours dura-
tion, the adrenalin contents became increased until far in excess
of the normal.

Schur and Wiesel confirmed these results also with dogs.
They found that, after running at the treadmill for six to seven
hours, there was a distinct reduction in the cells of the medulla
and total disappearance of their chromaffinity ; there was no
reaction to ferric chloride; and extract of these suprarenals failed
to produce mydriasis. By means of the last-named test, they
proved that, at the same time, the blood contained a large amount
of adrenalin. Schur and Wiesel also discovered that prolonged
anaesthesia, as the result of ether, chloroform, or A.C.E. mixture,
produced in rabbits a reduction, or even complete disappearance,
of the adrenalin in the medulla as well as of the chromaffinity of
the latter, while at the same time adrenalin was found to be
present in the blood. Kahn, however, was unable to confirm the
results of Schur and Wiesel, either after muscular fatigue or after
prolonged narcosis.

Considerable interest is attaching to the manner in which the
adrenalin contents of the suprarenals are modified by pathological
conditions. It has long been known that, in certain infective
diseases, changes take place in the suprarenals, and these have
been studied by means of experiment. Roux and Yersin
described a high degree of hypera?mia in the suprarenals of
guinea-pigs, after experimental diphtheritic infection or poisoning

250 INTERNAL SECRETION

by toxins. Charrin and Langlois found that the injection of
pyocyaneus toxin was followed by pronounced hypenemia and
increase in the volume of the suprarenals, and Pettit observed
histological degenerative changes. Bogomolez discovered serious
changes in the suprarenals, namely, necrosed and hemorrhagic
areas, after infection with diphtheria bacilli ; and Tscherwenzow
observed similar signs after infection with plague bacilli, Labzine
after streptococcus infection.

According to Langlois, the amount of the active substance
which raises blood-pressure is apparently unchanged in the hyper-
aemic suprarenal ; while, after chronic infective conditions, the
capsule, though increased to three or even four times its original
volume, yields extracts which are totally inactive. According to
Luksch, the suprarenals of rabbits poisoned with diphtheria toxin
or by the injection of other bacterial toxins (tuberculosis, typhus),
do not contain a substance which either raises blood-pressure or
produces enlargement of the pupil. This author also found that
suprarenal extract obtained from ura^mic animals or those poisoned
with phosphorus, is inactive, but that positive results were yielded
by extracts obtained after hunger, fever, poisoning with hydro-
chloric acicl, and resection of the spinal cord.

Schur and Wiesel found adrenalin in the blood after double
nephrectomy, and after the excision of wedge-shaped pieces from
the kidneys ; there was, moreover, a change in the chromaffinity
of the suprarenals, the medullary substance containing cell-
groups which were strongly chromophile, together with other
groups which were achromophile. After prolonged renal injury,
both the suprarenal medulla and the free chromaffine bodies
present appearances which suggest hypertrophy of the chromaffine
tissue.

Molnar and Goldzieher found adrenalin in the blood of rabbits
after the subcutaneous injection of pounded and rubbed-down
kidney. They also found histological signs of hypertrophy in
the suprarenals in thirty clinical cases of chronic nephritis.

There has been, up to now, no systematic investigation of the
adrenalin contents of the suprarenals in different clinical condi-
tions ; and exact information as to the amount of adrenalin present
in the suprarenals in Addison's disease is particularly scanty. In
two cases of Addison's disease, I found that the extract obtained
from the suprarenals, which had undergone serious pathological
changes, when injected intravenously, produced no effect upon the
blood-pressure. In a clinical case described by Neusser, which
he believed to be one of suprarenal hypertrophy, I found that the
extract obtained from the suprarenal, which had undergone pro-
nounced carcinomatous degeneration, was exceptionally active. A
portion of a suprarenal, obtained from a case of extreme cardiac
hypertrophy, which was handed over to me by my colleague Stork,
yielded an extract with strong hypertensive properties. On the

THE SUPRARENAL SYSTEM 251

other hand, I have always found that extracts of hypernephroma
are negative in their results.

The above data concerning the variation in the adrenalin
contents of the suprarenals, point with some degree of certainty Lo
the suprarenal tissue as the site of origin of adrenalin.

The question as to whether adrenalin is formed during life,
and is continuously supplied to the blood-stream by way of the
veins of the suprarenal capsule, has already been answered in the
affirmative in a communication of Vulpian's. Vulpian found
that the blood in the suprarenal veins contains the substance
which gives a green reaction with ferric chloride. By means of
the vaso-contractor action of blood from the suprarenal veins,
Cybulski showed that the active substance is formed continuously
in the suprarenals and continuously discharged from them into the
blood-stream. His results have been confirmed in several direc-
tions (Langlois, Biedl, Dreyer), and it has, moreover, been shown
that the production of the active substance of the suprarenals is
subject to the influence of the nervous system (Biedl). Ehrmann
next proved, by means of his more sensitive test with enucleated
frogs' eyes, that there is a continuous supply of adrenalin from
the suprarenal to the blood-stream. Fie was able to show, more-
over, that the amount of the substance supplied varies in different
animal species, while in individuals of the same species it is
substantially the same. The adrenalin contents in cats is low,
in rabbits it is high. Ehrmann concludes that, upon the whole,
those animals are most sensitive to adrenalin which have the larger
amount of it circulating in their blood. The amount of adrenalin
present in the blood in the suprarenal veins of rabbits, is equal
to an adrenalin solution of between one in one million and one
in ten million, that is to say, .0000005 £rm- 'n l c.cm. of blood
serum.

Watermann and Smit found that blood serum from the vena
cava produced mydriasis when undiluted only, and they estimated
the adrenalin contents of the caval blood at .000001 grm. per
cubic centimetre. They found that electric stimulation of the
suprarenal, by which all the sympathetic nerve fibres e'ntering the
organ are stimulated, produced an increase in the adrenalin con-
tents of the blood in the vena cava, for the serum of such blood
caused enlargement of the pupil, even in a i : 10 or i : 12 solution.

The suprarenal secretory process has long proved a subject
of interest and investigation to the morphologist. The first point
to be considered in this connection is the activity of the chrome-
brown adrenal tissue, which was investigated by Stoerk and
v. Haberer under exceptionally favourable conditions. They
were able to study the secretory process during excessive muscular
exertion, and also to study the hypersecretion which accompanies
compensatory suprarenal hypertrophy. As the result of their
efforts, considerable light has been shed upon the nature of the
secretory process of the suprarenal medulla.

252 INTERNAL SECRETION

Seeing that the morphology of the adrenal system is every-
where the same, what is known of the secretory processes of the
suprarenal medulla may be taken as typical of the entire suprarenal
system. Whether forming the medullary portion of the supra-
renal capsules, or present in the form of isolated bodies, either
unattached or associated with the sympathetic nervous system,
adrenal tissue is invariably composed of rows and spheroid
agglomerations of cells, held together by a delicate structure of
connective tissue, and forming a large-meshed net. The
parenchymatous cells are always placed close against the blood-
vessels, and are, as a rule, separated by the endothelium only,
though occasionally also by a delicate connective-tissue sheath,
from the lumen of the capillaries and the enlarged sinus-like veins.
The cytoplasm of the living chrome-brown cell contains extremely
minute granules, which are, however, coarser in certain animal
species. Some of these granules cluster closely together, while
others are arranged more loosely ; they are not so highly refractive
as fat-granules; they dissolve in water and in alcohol, but are not
soluble in ether, acetic acid, the etherial oils, or in xylol. In
fresh unhardened and unstained preparations, these granules are
scarcely visible; they do not stain satisfactorily by any known
method, the best, however, being iron-haematoxylin with which
they colour a pale grey. When unstained, they are most easily
recognizable by means of a mixture consisting of Miiller's fluid
and formaline or by the various osmium solutions. By using
Zenker's fixing fluid, it is sometimes possible to obtain a good
eosin coloration. According to Poll, these granules have a cer-
tain relationship to the nuclear colouring substances. They colour
pale pink with Ziehl's solution, lake by van Gieson's method,
mauve with methylene-blue eosin, and greenish with Unna-
Pappenheim's methylene-green pyronin mixture.

It is principally these fine granules which respond to the
ferric chloride and chromium tests, and give the reaction which
is characteristic of adrenalin. It is true that microscopic prepar-
ations with ferric chloride are not entirely free from objection.
But with fixing fluids containing chromium (chrome formol),
these granules take on a characteristic coloration varying from
yellow to brown, which does not, however, equally affect either
all the cells or all the granules in the cells.

Ciaccio suggests that the granules are of two kinds; that
they at first stain brown with chromium and afterwards pass into
the iron-green stage, which represents the end product of secretion.
The evidence in favour of this theory is, however, wholly
insufficient, and particularly so in face of the fact that adrenalin
itself reacts to both tests.

In addition to the fine granules, other cell-contents, such as
pigment granules, lipoid granules, etc., have been described.
Stoerk and.v. Haberer have described the occurrence of large rods

THE SUPRARENAL SYSTEM 253,

and wedge-shaped granules which are arranged in a peculiar
manner in the protoplasm, and which stain black with iron
heematoxylin. But the biological significance of these bodies,
that is to say, their relationship to the secretory process, is by no
means clear.

According to Stoerk and v. Haberer, the process of the secre-
tion of adrenalin takes place in the following manner : the chrome-
brown secretion is formed by the fine granules, which become
gradually more heavily charged until a certain secretory climax
is reached, when the chrome-brown secretion is discharged into
the intragranular cytoplasm. The cytoplasm, which is character-
ized by its pronounced affinity for basic aniline dyes, becomes
saturated with the chrome-brown secretion and, at this stage,
yields the diffuse ferric chloride reaction. The nuclei of the
adrenalin-forming cells are distinguished by their small provision
of chromatin, and by their peculiar situation at that cell-surface
which is farthest removed from the vein against which the cell
is situated. They sometimes react to chromium, which suggests
that they also are saturated with the secretion.

When the cell contents have, up to a certain point, become
saturated with the secretion, the latter gradually becomes diffused
through the cell membrane and the capillary wall into the blood.
At the same time, the cytoplasm and the granules gradually cease
to react to chromium, and the process starts afresh. It appears
from this that, if classified according to the nature of its secretory
processes, the adrenal system belongs to the group of meroendo-
krinal glands (Poll).

After its transference from the cells to the blood-stream, the
substance is easily recognizable in the capillaries by its yellow-
brown coloration. Its tardy solubility in serum, and certain
microscopic appearances, give it a certain resemblance to the
mucous type of secretion. This adrenal substance is characteristic
of the vessels of the suprarenal medulla, and is found neither in
the vessels of the cortex nor in other vessels. It is distinguishable
by its peculiar refractivity in native preparations, and was formerly
observed in the venous blood of the suprarenals as a plastic mass
(Gottschau, Biedl). It was at that time erroneously believed that
the granules in this amorphous mass were the actual secretion. As
Stoerk and v. Haberer showed, these shining granules are not
identical with the chrome-brown granules, though their functional
significance is, up to the present, not clear.

It may be regarded as proved that the product of the adrenalin-
producing cells reaches the blood-stream in fluid form. Stilling
supposes that the transference of the viscid secretion is effected
by means of the numerous and important lymphatics ; but in this
he is wrong, for this function is performed by the veins. The
suprarenal vein plays the part of excretory duct to the medullary
substance of the suprarenal.

254 INTERNAL SECRETION

PHYSIOLOGICAL ADRENALIN.EMIA.

The secretion from the intracapsular portion of the adrenal
system is continuously supplied to the general circulation by way
of the suprarenal vein ; thus the blood always contains a certain
amount of adrenalin, and a physiological adrenalinsemia is
maintained.

Battelli was the first to prove the presence of adrenalin in the
peripheral blood. After suitable concentration, he tested the vaso-
constrictor action of normal serum from dogs, and found that its
action was equal to that of an adrenalin solution of i :io to i : 20
millions.

Ehrmann was unable to obtain mydriasis of frogs' eyes with
serum from the peripheral blood of rabbits. According to Schur
and Wiesel, both Ehrmann's reaction and the ferric chloride test
are invariably negative. O. B. Meyer, however, proved the
presence of adrenalin in normal blood serum by means of portions
of blood-vessels from the living body, this test being more
sensitive than the above-named reactions. By the same method,
Schlayer proved the presence in human blood-serum of a sub-
stance which produces vaso-contraction.

Fraenkel advanced conclusive proof of the presence of
.adrenalin in the serum of blood in the peripheral vessels. He
found that serum from rabbits and cats, when diluted to twice its
volume, was invariably active in the uterus of rabbits after
removal from the living body. Human sera from healthy subjects,
either undiluted or in solutions of 1:5 and i : 10, produce
phenomena similar to those resulting from adrenalin. Similar
results have been occasionally obtained with solutions of i :2 and
i =40 and, in three instances, with i 150. Judging by the results
of Fraenkel's experiments, the minimal adrenalin contents of
i c.cm. of peripheral blood may be estimated at .0000001 mg.,
the maximal adrenalin contents at about .0000025 mg.

Using these figures as a basis, the total adrenalin contents of
a dog weighing 15 kg. is as follows : The whole of the blood
provision is 1200 c.cm. and contains a minimum of .00012 mg.,
.a maximum of .003 mg. adrenalin. Now compare with these
figures the amount which passes from the suprarenals into the
vena cava. Before this can be done, however, we must know^ the
velocity of the blood circulating in the suprarenals. There is no
direct information as to the volume of the blood in the suprarenal
veins. In certain older experiments of mine, I estimated the
amount of venous outflow by counting the drops as they left the
veins, and I reckoned that, in a dog weighing 15 kilo, the maximal
velocity of the stream was roughly .1 c.cm per second. These
figures are the same, though this is by the way, as those more
exact results which Burton-Opitz obtained with Hurthle's velocity
register (Stromuhr) in the case of the blood flowing through the

THE SUPRARENAL SYSTEM 255

submaxillary gland. According to my figures, then, 6 c.cm. blood
pass per minute from the suprarenals into the general circulation.
If Ehrmann's calculation, that i c.cm. suprarenal venous blood
contains .0000005 mg. adrenalin, is correct and, judging from
the comparatively slight sensitiveness of his method, this figure
is probably too low — certainly not too high — .000003 mg- adrena-
lin passes into the circulation per minute. The total produc-
tion of adrenalin would be .00432 mg. in twenty-four hours,
but the quantity demonstrable in the blood is only .00012 mg.—
about the fortieth part of the daily supply from the suprarenals.
Even by Fraenkel's quantitative test for adrenalin, which is much
more accurate, the maximal total of .003 mg. in the blood is far
less than the amount produced, as revealed by Ehrmann's not
very sensitive reaction.

These figures represent approximate data only, but they show
that a considerable portion of the adrenalin supplied to the blood
very rapidly disappears from it.

The transience of the physiological effects of adrenalin
injection points in the same direction. The increase in blood-
pressure passes off at the end of a few minutes, and this happens
equally after an amount which, when given refracta dost, would
serve to produce vaso-contraction 100 times or more.

What ultimately becomes of the adrenalin in the blood is a
question which early came under discussion. Oliver and Schafer
held the view that, when injected intravenously, the active sub-
stance of the suprarenal accumulates and is, for a time, stored up
in the tissues in which it eventually becomes active. They were,
however, thinking chiefly of the muscles. They believe that the
disappearance of the substance from the blood results, neither from
its destruction in the blood, nor from its accumulation in the supra-
renals, nor yet from its excretion in the urine, but from the fixation
of the substance and its secondary oxidation within the reacting
tissues. This theory is confirmed by Cybulski and Szymonowicz,
with this reservation : that, seeing that after the exhibition of
large quantities of suprarenal extract, the active substance is
demonstrable in the urine, it is to be 'assumed that a certain
proportion of the active substance is excreted by way of the
kidneys.

It seems hardly probable, however, that an appreciable pro-
portion of the adrenalin present in the blood is excreted in the
urine. Urine drawn off from the bladder shortly after the
intravenous injection of large quantities of adrenalin does not
contain a substance which increases blood-pressure (Embden and
v. Fiirth). That a minimal proportion of the adrenalin in the
blood may pass into the urine is undoubtedly possible. Abelous
and Bardier account for the vaso-contractor effect which normal
human urine has, after suitable concentration, by the presence of
a substance identical with or closely related to adrenalin, namely,

256 INTERNAL SECRETION

urohypertensin. But it must be remembered that the accounts both
of " urohypertensin " and of " urohypotensin," which is described
by the same authors, are in need of further confirmation. As
Comessatti showed, Ehrmann's reaction is useless as a test for
adrenalin in the urine. Whether or not the substance, which
Schur found by his chemical test to be present in normal human
urine, is identical with adrenalin, is a question which must for
the present remain unanswered.

As previously stated, according to Falta and Ivcovic,
adrenalin, when introduced in large doses into the stomach, does
not attain to specific activity within the organism, but is excreted
in the urine.

More important than its excretion by \vay of the kidneys, is
the manner in which adrenalin becomes destroyed within the
organism itself. Such destruction takes place, in the first instance,
in the blood and depends principally upon the alkalinity of the
latter. According to Embden and v. Fiirth, .1 grm. of hydro-
chloric suprarenin, if added to 200 c.cm. of defibrinated ox-blood
and continuously aerated at incubation temperature, disappears,
almost entirely in two hours. In " laked " blood, the disappear-
ance is even more rapid. A .1 per cent, soda solution has a more
energetic action than either blood or blood-serum. The relatively
lower activity of the blood is probably due to the fact that a
proportion of the alkaline contents of the blood is fixed.

That the degree of the alkalinity of the blood plays an im-
portant part in the disappearance of adrenalin, is shown by
Kretschmer's experiments. By means of the intravenous injec-
tion of acids, he succeeded in prolonging to five or six times the
normal, the hypertension produced by adrenalin in rabbits. The
addition of acid-ions, inhibits the destructive action of the
hydroxyl-ions in the blood and the tissues, upon the adrenalin.

Another factor in the destruction of adrenalin is the liability
of the adrenalin molecule to oxidation, more especially in alkaline
solutions.

Langlois believed that the destruction of adrenalin was princi-
pally oxidative. He and Athanasiu found that the vaso-contractor
constituent of suprarenal extract may be rendered negative by
means of ozonized air (aeration) and by the oxidase of crabs'
blood. The fact that, in cold-blooded animals, the vaso-constrictor
effect may be shortened by warming and lengthened by cooling, is
accounted for, in Langlois's view, by the dependence of processes
of oxidation upon temperature. He believes that all the tissues,
and especially those of the liver, intestine and, to a certain small
extent, the lungs, take part in the oxidative destruction of
adrenalin. He bases his conclusion chiefly upon the results of
experiments in which solutions of suprarenal extract were rapidly
rendered inactive by the addition of the fresh pounded liver and
intestine of rabbits; while, on the other hand, the artificial circu-

THE SUPRARENAL SYSTEM 257

lation through the lungs of saline solution containing suprarenal
extract, produced only a slight lowering of the activity of the
suprarenal extract.

Battelli found that the artificial circulation of blood containing
adrenalin through the liver destroyed the activity of that substance,
the alkali and the influence of oxygen converting it, as in vitro,
into oxyadrenalin. Livon found that, when added to the pounded
liver and striated muscles of guinea-pigs, adrenalin became
rapidly reduced in quantity.

According to Embden and v. Fiirth, however, the addition of
pounded liver, lung or muscle to adrenalin solution and the artifi-
cial circulation of blood containing adrenalin through the liver
or lungs, is followed by only slight reduction, if any, in the
amount of the adrenalin. They suggest that this persistence of
adrenalin has a connection with the formation of acids in the
organs. They do not think that the transience of the effect upon
the vessels is due to a rapid oxidation of the adrenalin, but explain
this phenomenon by the fact that the contraction of the vessel
muscles ceases as soon as, owing to diffusion or dilution with
blood or tissue lymph, the concentration of die suprarenin falls
below a certain point.

According to Elliott, however, the excessive quantities of
adrenalin employed in these experiments render them unreliable
as evidence regarding the disappearance of adrenalin from the
tissues. He himself found that artificial circulation through the
lungs did not reduce the adrenalin contents to any appreciable
extent, but that artificial circulation through the intestine was
followed by a marked diminution in the amount of the substance.

From the results of certain experiments, Langlois concluded
that the liver played an important part in the destruction of
adrenalin. These experiments showed that the amount of supra-
renal extract which, when injected into the jugular vein, produced
marked hypertension, produced no effect whatever when injected
into a mesenteric vein.

Carnot and Josserand found, howrever, that the pharmaco-
dynamic effect upon blood-pressure of a given adrenalin solution,
was very much reduced where such a solution was injected into
the carotid or femoral artery and allowed to flow with the stream
in a peripheral direction, the adrenalin thus traversing the vessels
supplied by these arteries before entering the general circulation.
Passage through the liver also affected the action of adrenalin,
but to a less degree. The loss wras greatest after circulation
through the intestine, the injection into a mesenteric artery of
.064 mg. adrenalin to every kilo of body wreight producing no
effect upon blood-pressure.

The absence of hypertensive effect on the part of adrenalin
in localities where it normally produces intense vaso-
constriction, may further be explained by the fact that the

17

258 INTERNAL SECRETION

substance, to a certain extent, blocks its own passage into the
general circulation. It is able to overcome, to a very small extent
only, the resistance produced by the extreme contraction of the
vessel walls ; thus the major portion of the substance passes
gradually, by a process of diffusion, into the surrounding tissue.

Elliott, whose experiments confirmed those of Carnot and
Josserand, holds the view that the disappearance of adrenalin from
the blood is in direct ratio to the development of its effects in the
tissues. That a comparatively small amount of adrenalin dis-
appears in the liver, in spite of the large amount of tissue which
that organ contains, is probably explained by the fact that the
vaso-constrictor effect produced by adrenalin in the liver is also
comparatively small.

Although these observations seem to point to the fact that
adrenalin is used up and destroyed by the tissue elements which
it excites, they do not supply a sufficient explanation of the
transience of the 'effect of large doses of adrenalin.

It has been shown by experiments of the most varied descrip-
tion that, after the specific action of adrenalin has passed off, the
substance has not by any means disappeared from the blood.
Weiss and Harris injected adrenalin into the general circulation
of frogs after ligature of one iliac artery and observed the results
in the webs of both feet. After the vaso-constriction had entirely
passed off in the wreb of one foot, they removed the ligature from
the artery and found that intense vaso-constriction appeared in
the web of the other. These authors, similarly to Ehrmann and
Miller, also found that blood taken from an animal after the
effects of adrenalin had passed off, could be used to produce
hypertension in a second animal.

These observations show beyond all doubt that, after its
introduction into the blood-stream, adrenalin neither disappears
nor does it undergo any depreciation of its pharmacodynamic
value.

In face of this fact, the question as to the mechanism by
which adrenalin achieves its effect requires further consideration.
The experiments of Straub and Kretschmer, which supply evi-
dence of the most valuable description concerning the part played
by adrenalin in the physiology of the organism, also throw im-
portant light upon this matter.

These experiments are based upon facts supplied by Straub
concerning the mechanism by which the effects of muscarin are
brought about. These facts are as follows :-

(1) A toxin which has already penetrated the cell which has a
specific sensibility to it, is inactive.

(2) A toxin which has not as yet penetrated such a specific
sensitive cell, is also inactive.

(3) It is only in the course of, and by means of, the penetration
of the toxin into the cell, that the specific toxic action takes place.

The observations, to which reference has been already made,

THE SUPRARENAL SYSTEM 259

of Weiss and Harris and others, seem to show that the action of
adrenalin is similar in type to that of muscarin ; that when, at
the site of activity, a certain degree of saturation has been reached,
no further effect is possible ; and certainly that no permanent effec,
is obtainable by repeated exhibition of tlie substance. Kretsch
mer's experiments consisted in the repetition, at regular intervals,
of the intravenous injection of a certain fixed quantity of adrenalin.
They showed that, although the same hypertensive effects could
be produced successively and as frequently as desired, a permanent
rise in blood-pressure was not obtainable by the non-continuous
exhibition of adrenalin, however large the doses. It is evident
from this that, in the case of adrenalin, unlike that of muscarin,
there is no cessation of absorption on the part of the specific cells,
and that a condition of chemical balance does not obtain.

A permanent increase in blood-pressure, lasting for three
hours, was, however, obtained by the continuous transfusion of
adrenalin, the velocity being maintained at .00001 to .00002 grm.
per minute.* The hypertensive action increases the velocity of
the transfusion up to a certain maximal point, beyond which the
increase in velocity does not produce a further rise in blood-
pressure. Interruption in the flow of the adrenalin is followed
by a return of the blood-pressure to the normal, while the duration
of the after-affects will be in proportion to the amount of adrenalin
present in the blood at the moment of interruption. In view of
the fact that the action of adrenalin lasts only as long as the
substance is present in the blood, Kretschmer believes thai
adrenalin acts as an irritant poison, and that the method of action
is, up to a certain point, similar to that of muscarin, trie action
in both cases depending upon the difference between the con-
centration in the blood and the concentration in the cytoplasm.
Adrenalin differs from muscarin, however, in that the balance
between the two concentrations, which takes place in the case of
muscarin, is absent in the case of adrenalin. The disturbance of
balance is probably due to the continued rapid destruction of
adrenalin which goes on in the interior of the cell.

What is known concerning the action of adrenalin upon the
vessels applies equally, as Ritzmann pointed out, to its glycosuric
action. Observation of the method by which adrenalin produces
glycosuria supplies certain data concerning the physiological
significance of this substance. These suggest that the continuous
flow of adrenalin, producing a condition of physiological adrena-
lina^mia, may exercise an immense influence upon the permanent
tone of organs with a sympathetic innervation, more particularly
upon the vascular tone and upon the sugar tone (Zuckertonus).

* By continuous transfusion of very dilute suprarenal extract I suc-
ceeded in obtaining and demonstrating (1805) a protracted vaso-contraction,
so that the blood-pressure which, after destruction of the entire spinal cord,
had fallen almost to zero, rose to 160 mm. Hg. and remained at this level
for several hours.

260 INTERNAL SECRETION

The regulation and the maintenance of tone in every depart-
ment of the sympathetic system, is a function of the internal
secretion of the adrenal system.

EXPERIMENTAL SUPRARENAL STIMULATION,
EXPERIMENTAL HYPERSECRETION.

Although the symptoms of suppression which follow extirpa-
tion of the suprarenals have formed the subject of exhaustive study,
experiments in stimulation, by which the organs are impelled to
hyperactivity, are becoming increasingly rare. In the course of
his observations of the innervation of the intestinal movements,
Jacobj (1892) found that extirpation of the suprarenals was fol-
lowed, in fasting animals, by spontaneous intestinal movements;
and that epinephrectomy, similarly to resection of the splanchnic
nerve, negatives inhibition of intestinal movement without, how-
ever, producing paralysis of the vessels. These results induced
him to attempt experimental stimulation of the suprarenals. He
found that electric stimulation of these organs, as well as of the
nerves which connect the suprarenals with the ganglion coeliacum,
has the effect of arresting intestinal movements which are already
in progress. The secretion of urine is at the same time very much
diminished, and in two instances he found that suprarenal stimu-
lation was followed by an increase in arterial pressure. According
to Jacobj, the suprarenal nerves contain fibres which inhibit in-
testinal movement. These observations were not confirmed by
later authors (Pal, Apolant), but in the light of our present know-
ledge concerning the action of adrenalin upon blood-pressure,
peristalsis, and urinary secretion, they have a certain interest.

In 1897, I investigated the physiology of the innervation of
the suprarenals, a subject which, up to then, had received no
attention. I found that the splanchnic nerve contains fibres which
cause vaso-dilation writhin the suprarenal area, and that stimula-
tion of these fibres produces suprarenal hypera?mia, the direct
result of the active vaso-dilation. That the suprarenals possess
also a vaso-constrictor innervation is to be inferred from the
effect which suprarenal extract has upon these organs, although
I was unable to trace the anatomical course of the vaso-constrictor
nerves. I also investigated the secretory process of the supra-
renals, together with the manner in which it might be modified
by the presence of secretory nerves. I made use of the vasotensor
action of the venous blood to determine the amount of active sub-
stance produced, but I was unable to obtain definite proof by this
method of the presence of suprarenal secretory nerves. The results
of my experiments, however, make it appear highly probable that
both the production of the secretion by, and its transference from,
the gland — or, more correctly, the medullary portion of the gland-
are subject to the control of the nervous system ; and that, more-
over, the splanchnic nerves contain suprarenal secretory, in addi-

THE SUPRARENAL SYSTEM 261

tion to suprarenal vasodilator, fibres. My results have since been
confirmed by Dreyer, and completed by the successful demonstra-
tion of an increased vaso-constrictor action of the suprarenal blood
during stimulation of the splanchnic nerve.

Erhmann was unable to discover, by means of the high'ly
sensitive frog's-eye test, that the adrenalin contents of the blood
in the suprarenal veins was changed by the addition of pilocarpin
or atropine. As we have already pointed out, Waterman and
Smit found an increase in the adrenalin contents of the blood in
the vena cava after faradic stimulation. These authors showed
at the same time that puncture of the floor of the fourth ventricle
produces, in addition to glycosuria, an increase in the adrenalin
production, the peripheral blood which is normally inactive
acquiring a mydriatic action after this operation. This finding
completes A. Mayer's discovery, already described, namely, that
after total epinephrectomy puncture of the fourth ventricle
ceases to produce glycosuria.

These experiments prove beyond a doubt that the secretory
process of the adrenal system is under the control of the sym-
pathetic nervous system ; that the peripheral vasomotor and
secretory fibres are contained in the splanchnic nerve ; while
their centre is probably situated in the medulla oblongata.

There have been, of course, numerous attempts to produce,
by experimental measures, alteration in the function of the supra-
renals and variation of their adrenalin contents. The results of
such experiments have already been described and, as we have
seen, a reduction in the adrenalin contents may be brought about
by the most varied methods, more particularly by the experimental
production of toxic and infective states. These findings are the
expression of hypof unction on the part of the organ.

It is probable that hypersecretion on the part of the adrenal
system is illustrated by the results of an experiment made by
Battelli and Roatta. They found that, in the interval of repose
which followed exhaustive muscular exertion, there was an increase
in the adrenalin contents of the suprarenals of dogs. It is
probable that the changes in the suprarenal medulla and in the
extracapsular chromaffine substance observed by Schur and
Wiesel after renal injury, and regarded by them as- hypertrophic,
also belong in this category.

An experimental hyperadrenalism is produced in animals
after each exhibition of adrenalin ; owing, however, to the
transient action of the substance the effect is very fleeting. By
means of Kretschmer's method of continuous transfusion of
minute quantities of adrenalin, a condition of hyperadrenalinaemin
may be maintained for several hours. The method seems likely
to throw still further light upon the results of this condition.

The prolonged exhibition of adrenalin by subcutaneous, in-
traperitoneal, or intravenous injection does not, apparently, lead
to hyperadrenalinism. These methods serve, however, to illus-

262 INTERNAL SECRETION

trate the effects, either physiological or toxic, according to the
size of the dose, which result from the action of adrenalin. In
addition to the changes in the vessels, chronic glycosuria is
observed, together with progressive emaciation. The autopsy
shows that, in addition to the changes in the vessels and the
organs, there is sometimes a marked increase in the volume of
the suprarenals and hypertrophy of the suprarenal cortex.

PATHOLOGICAL ADRENALIN^EMIA AS SEEN IN

MAN.

Neusser was the first to assume a pathological hyperfunction
on the part of the suprarenals. He based his conclusion upon a
clinical case, in which the symptoms pointed to chronic Bright's
disease, while the autopsy revealed carcinomatous degeneration
of one suprarenal capsule, together with numerous cerebral
haemorrhages. Neusser was inclined to regard the arteriosclerotic
changes and the thickening of the vessels, which Kolisko observed
in young persons with suprarenal affections, as results of the
continued high blood-pressure, brought about by suprarenal
hypersecretion.

A large number of French authors (Darre, Pilliet, Vaquez,
Aubertin and Ambart, Josue, Widal and Boidin, Menetrier,
Monod and Loumeau) emphasize the fact that the hypertension
in chronic nephritis and in arteriosclerosis may be traced back
to hypersecretion on the part of the suprarenals, the latter con-
dition finding its anatomical expression in hyperplastic and
adenomatous changes in those organs. The anatomical changes
which they describe affect the suprarenal cortex only.

Wiesel, wrho was the first to inquire into the condition of
the adrenal system in renal diseases, found that, in all the cases
associated with cardiac hypertrophy of long standing, there was
marked hyperplasia of the chromaffine tissue in the suprarenal
medulla, in the solar plexus, and in the neighbourhood of the
left coronary artery. He assumed from this that the cardiac
hypertrophy present in renal affections, as well as certain cases
of idiopathic cardiac hypertrophy, are of suprarenal origin. This
discovery of WiesePs paved the way for the experiments of
Schur and Wiesel, undertaken with the object of demonstrating
the presence of adrenalin in the blood-serum of persons with
chronic renal disease; they found that such sera produced
mydriasis of frogs' eyes and gave a positive ferric chloride re-
action. The fact that the blood serum of persons with chronic
nephrosis produces mydriasis is confirmed by a large number of
authors (Kaufmann and Mannaberg, Goldzieher and Molnar,
Eichler, Comessati, Reicher, Makaroff, Miesowicz and Macziag).
Pal describes the frequent presence of mydriatic substances in
the urine of pregnant women and persons with nephritis. Accord-

to Diem, however, the urine of persons, both with and with-

THE SUPRARENAL SYSTEM 263

out nephritis, gives a positive Ehrmann reaction in about the
same percentage of cases ; though Comessati believes that the
Ehrmann test for adrenalin has a very limited scope when applied
to urine.

As we have already pointed out, the mydriasis produced by
blood serum is not a conclusive test, that is to say, the reaction
is not confined to adrenalin. Bittorf, for instance, obtained
mydriasis with the serum of healthy persons after the exhibition
of salicylic preparations. That adrenalin is present in the serum
in chronic nephritis, is not confirmed by other biological tests.
Schlayer found that normal human serum produced marked con-
traction of portions of arteries removed from living oxen, while
the contractions produced in such portions of arteries by the
serum of nephritic persons were, in the greater number of cases,
much weaker. The significance of these negative findings is,
however, very much modified by a later discovery of Schlayer's;
to the effect, namely, that O. B. Meyer's test for adrenalin by
means of portions of arteries, is practicable with blood obtained
from animals of the same species only. In the case of blood from
animals of a different species, an increase in the adrenalin con-
tents has the effect of reducing the contractions. That chronic
nephritis is not associated with pathological adrenalinasmia, is
well shown by the results which A. Fraenkel obtained, by the
most reliable of modern biological methods, with the uterus re-
moved from living rabbits. He found that, in chronic interstitial
nephritis with pathognomic hypertonicity, the variation in the
adrenalin contents was the same as in the blood of subjects with
sound kidneys.

It must be borne in mind that, although a pathologically
increased adrenalina^mia, producing abnormal tonicity of the
vessels, would supply a satisfactory explanation of the hyper-
tonicity and cardiac hypertrophy in chronic renal disease, certain
proof of the existence of such a condition is, up to the present,
by no means forthcoming. Schur and Wiesel, who based their
experiments upon the assumption of a direct connection between
hypertension and adrenalinaemia, were compelled to abandon this
theory. They were unable invariably to produce mydriasis with
serum from nephritic patients, and they were unable to establish a
parallel between this reaction and a hypertonic condition.*

The possibility was recently suggested by v. Neusser and Wiesel that
a primary hyperplasia of the chromaffme system might lead to true
renal processes. Conditions which demand an increased consumption of
adrenalin, and of these the most important is forced muscular exertion,
may produce hypertrophic processes of the adrenal system. In such a
case the increased amount of adrenalin would cause a permanent vaso-
contraction, which might give rise to anatomical changes in the renal
vessels, which would prepare the way for the development of a nephrosis.
The authors lay stress upon the fact that, in cases of true contracted kidney,
the etiology of which is still obscure, hyperplasia of the chromaffine tissue
is invariably present.

264 INTERNAL SECRETION

An abnormal activity on the part of the adrenal system
would, in my opinion, not only produce a heightened vascular
tone, but would also manifest itself in other signs of irritation on
the part of the sympathetic nervous system. A manifestation of
such a condition, in the form of a well-defined clinical entity, is,
ho\vever, at present unknown. As far as we can judge, Graves's
disease is invariably associated with an increase in the adrenalin
contents of the blood, which is proved both by the mydriatic
property of the serum and by the tonic action of preparations of
the uterus. Fraenkel found that the adrenalin contents of the
blood in Graves's disease were increased to from four to eight
times the normal, the total amount in these patients being 50 to
100 mg., as against the 12^ mg. present in the blood of normal per-
sons. It is remarkable in this connection that an increased blood-
pressure is not, as a rule, associated writh Graves's disease.

THE FUNCTION OF THE ADRENAL SYSTEM.

From the facts which have been presented in the foregoing
pages, the nature and functions of the adrenal system may be
defined as follows : —

The adrenal system is an essential portion of the body of all
vertebrate and some invertebrate animals. It has a specific struc-
ture, characterized morphologically and genetically by peculiar
features ; the nature of its function is distinctive and is probably
dependent upon origin.

The structure of the adrenal system is characterized by the
peculiar nature of the elements of which it is built up, namely, the
chromaffine cells.

The adrenal system is distinguished anatomically by its wide
distribution over the wThole of the body,^as well as by the lack
of independence of its parts. These conditions are explained by
the history of the development of the system.

The chromaffine cells are derived from the same primordial
beginning as the sympathetic ganglia and they develop, up to a
certain point, as part of the sympathetic nervous system. A con-
siderable portion of the adrenal system permanently retains its
genetic relationship with the sympathetic, becoming associated
only in part with the blood-vessels. The so-called free portions
of the system are, however, found distributed all over the body in
connection with the sympathetic nerves and ganglia. They
occur partly in the form of more or less extensive agglomera-
tions of chrome-brown cells, called paraganglia (Kohn) ; and
partly as isolated structures attached to the great vessels — such
as the suprarenal bodies of the Selachians, the carotid gland, and
the accessory organs of the sympathetic (Zuckerkandl) — though
the relationship of these bodies to the adrenal system has been
recognized only in comparatively recent times. The lack of in-

THE SUPRARENAL SYSTEM 265

dependence is shown by the fact that, at a very early develop-
mental stage, a portion of the adrenal system attaches itself to
the embryonal interrenal and, in the higher vertebrates, combines
with it to form an apparently homogeneous organ, the suprarenal.
The medullary substance of the suprarenal is merely a somewhat
considerable, intracapsular portion of the adrenal system and, as
Kohn aptly remarks, is to be regarded as a large ganglion, the
suprarenal paraganglion, formed by the fusion of several smaller
ganglia.

In order to understand the functional significance of the
adrenal system, an accurate knowledge of the quantitative value of
the suprarenal medulla is essential. The fact that the medullary
substance of the suprarenal was earlier recognized and has become
altogether better known than the extracapsular portions of the
adrenal system, produced this result, that morphological and
physiological investigation has been almost exclusively con-
fined to the intracapsular adrenal tissue. Investigation re-
vealed the existence of an important internal secretory
process, and this was at first regarded as a function of the
suprarenal as a whole. But even later, after the peculiar
position of the chromaffine tissue had been recognized, the
physiological importance of the suprarenal medulla was very
much over-estimated. There w*as an inclination to ascribe to the
suprarenal medulla all the functions which are the property of
the chromaffine system in general, for the sole reason that these
functions had been proved to be attributes of the medullary por-
tion of the system. For this reason it is very important to re-
member that the free portions of the adrenal system are not only
genetically and structurally identical with the medullary substance
of the suprarenal, but that they possess the same functional signifi-
cance and that there is definite proof of this (the survival of animals
without suprarenal medulla, compensatory hypertrophy of the
extra-capsular chromaffine tissue, the similar effects of para-
ganglion extract). Not only is the suprarenal medulla not the
sole active portion of the adrenal system, but it is not even the
most important part of it. When we remember the wide distribu-
tion of the nervous system in the body, and consider that large
and small groups of chrome-brown cells are attached to every one
of its ganglia, that they lie in many plexuses and are found almost
everywhere where sympathetic fibres and cells occur ; and that, in
addition to these, the adrenal system includes a number of in-
dependent structures — we can hardly doubt that the free portions
collectively present a far larger mass of active, functional tissue
than that section of the system which is enclosed in the supra-
renals. These are facts which must not be lost sight of in any
attempt to estimate the physiological significance of the activity
of the adrenal system.

Functionally, the adrenal system belongs to the group of the

266 INTERNAL SECRETION

internal secretory organs. The morphology of the secretory pro-
cess is well known. The product of secretion is formed in the
granules in the cells and is transferred to the blood-stream in fluid
form. Not only have we morphological proof of the secretion, but
its presence in the venous blood has been demonstrated chemically ;
in the face of these facts, it is not possible to doubt the
secretory function of the adrenal tissue. The objections which
Kohn advanced upon morphological and genetic grounds against
the inclusion of the adrenal system among the internal secretory
organs, is, however, justified to this extent ; the chromamne cells
do not conform to the type of the epithelial cells ; and agglomera-
tions of chromafBne cells do not conform to the type of the true
glands. But from the physiological standpoint, the specific pro-
ductive activity of the adrenal tissue fully justified its inclusion
among the internal secretory organs.

There is a continuous formation by the adrenal system of a
substance of known chemical constitution, named adrenalin, which
may also be obtained synthetically. This substance passes into
the circulation and is carried by the blood-stream into all the
tissues of the body. The passage of adrenalin by way of the
nerves, which Lichtwitz assumed, has no physiological signifi-
cance.

Adrenalin is a typical dissimilatory hormone, which acts
upon certain tissue elements and reinforces their katabolic activity.
The activity of this hormone is exclusively confined to organs with
a sympathetic innervation, and it invariably coincides with the
results produced by electric stimulation of the sympathetic nerves
supplying those organs. Adrenalin produces its effect, not upon
the specific functional portion of the reacting cell nor upon the
nerve-ending itself, but upon a portion of the cell body situated
in the neighbourhood of the nerve-ending, the so-called receptive
substance which, in the involuntary muscles, is termed the myo-
neural junction. The activity of the hormone elaborated by the
adrenal system, is the permanent expression, during the life of the
individual, of the genetic relationship between the adrenal and the
sympathetic nervous systems.

It must not be imagined that adrenalin is merely a sympathetic
stimulant and therefore of use only in promoting the functions of
the organism ; on the contrary, its activity is fundamentally and un-
ceasingly necessarv to the normal function of the entire sym-
pathetic system. The parallel between the developmental pro-
cesses and the dependence, shown in many directions, of the
activity of the sympathetic upon the presence of adrenalin, as
well as the continuous formation of this hormone — expressed by
its presence as a physiological constituent of the blood — point to
the fact that adrenalin is essential to the maintenance of sym-
pathetic tone and to the normal function of the sympathetic system.
These factors show, moreover, that changes in the condition of

THE SUPRARENAL SYSTEM 267

excitability of the sympathetic system, especially in so far as they
make themselves felt in the periphery, are associated with varia-
tions in the activity of the adrenal system.

That the maintenance of tone by the sympathetic system in
the cardiac and vascular muscles is an important factor in the
normal circulation of the blood, has long been known and has
been duly appreciated. A far-reaching significance is also attach-
ing to the tonic innervation of all vegetative organs, this tone
being maintained, partly by stimulation, and partly by inhibition,
on the part of the sympathetic system. The sympathetic also
regulates the sugar contents of the blood, and in this way exer-
cises a determining influence upon the metabolism of the carbo-
hydrates, which plays so important a part in normal muscular
exertion. It seems probable from recent observations that the
metabolism of albumin and of salt, as well as the composition of
the blood, undergo a certain degree of modification by the. agency
of the sympathetic. Seeing that adrenalin is the hormone by
which the irritability of the sympathetic system is regulated, it
is evident from the foregoing, that the functional significance of
the adrenal system is enormous.

It will be readily understood that the peculiar anatomical
arrangement of the adrenal system renders its total suppression,
wrhether experimentally or by pathological processes, impossible.
Once again it must be pointed out that extirpation of the supra-
renals is followed, not by suppression but, at the most, by in-
adequacy of the adrenal system, and that signs of a lowering of
the sympathetic nervous tone would hardly be the outcome of such
a condition. The most important of the symptoms of a lowered
vascular tone, namely, the fall in blood-pressure, is, as a matter
of fact, absent. It is true that accounts have been given of
changes in the metabolism of the carbohydrates. Moreover, the
symptomatology of Addison's disease does not permit the in-
ference that the condition is exclusively the outcome of the cessa-
tion of activity on the part of the adrenal system. For it is
highly probable that the symptom-complex of Addison's disease
includes the signs of disturbance of the suprarenal cortex, a dis-
turbance of which anatomical proof has frequently been forth-
coming.

The effects which an abnormally increased adrenalina?mia has
upon the organism may be exactly estimated by means of experi-
ment. A condition of acute hyperadrenalinism is invariably
accompanied by symptoms of increased irritability on the part of
the sympathetic system.

THE TNTERRENAL SYSTEM.

The interrenal system is present in all vertebrates ; it takes
the form of paired or unpaired bodies of various sizes. It is

268 INTERNAL SECRETION

distinguished structurally by its lipoid cell contents and genetically
by its mesodermic origin in what is known as the interrenal zone.
During embryonal life, the interrenal system is extended over
large portions of the body, but as development progresses the
space which it occupies becomes more restricted. Principal bodies
are formed by the amalgamation of several suprarenal buds, by
regressive processes, and by the fission of single accessory bodies.
In the cyclostoma and in fish, the interrenal system remains at
this developmental stage. From the amphibia upwards, a large
portion of the interrenal system combines, at the next develop-
mental stage, with certain portions of the adrenal system to form
either a row of small bodies, as in the amphibia, or an isolated
organ such as the suprarenal of the amniota. In mammals and
more particularly in man, the principal mass of the interrenal
tissue is represented by the suprarenal cortex, while the structures
which were formerly regarded as buds split off from the principal
organs, or as accessory suprarenals, are now known to be in-
dependent portions of the interrenal system, or accessory inter-
renals.

Such accessory interrenal structures (see table, p. 1,37) are fre-
quently, though -not constantly, found attached to the suprarenals
and forming part of them ; in the neighbourhood of the kidneys
and suprarenals; in the genital region — the ligamentum latum in
the female (Marchand, Rossa), and the spermatic cord, epididymis,
and testicles of the male (Dagonet, Wiesel, Chiari) ; and occasion-
ally in other parts of the abdominal cavity.

The accessory interrenals of the higher vertebrates have a
considerable structural similarity with the cortical substance of
the suprarenals. Occasionally these bodies possess all three
layers, though, as a rule, the two outer layers only are present.
In the earlier accounts of these organs, they are described as
having a medullary portion ; it is probable, however, that the
error arose from mistakes as to the identity of the innermost zona
reticularis.

That the free portions of the interrenal system have a func-
tional significance is proved by the progressive development of the
split-off portions; by the compensatory hypertrophy of the so-
called accessory suprarenals in mammals, after removal of the
suprarenals (Stilling, Velich, Wiesel) ; by the compensatory hyper-
trophy of portions of interrenal bodies left in sitii in Selachians
(Biedl) ; and by the survival of Teleostians after the removal of
all except their anterior cranial interrenal system (Giacomini).

Experiments with the object of determining the function of
the interrenal tissue are, at the present moment, chiefly concerned
with that portion of the interrenal system which is represented
by the cortical substance of the suprarenal. There is no lack of
hypothesis, but the only fact supported by experiment which sheds
light upon the functional significance of the suprarenal cortex is

THE SUPRARENAL SYSTEM 269

the following : The removal of the cortical substance — providing
a 1 \\ays that it is not replaced by the vicarious intervention of
highly developed accessory interrenals, as in some animal species,
notably rats — is not consistent with the continuance of life.

j

Some interesting anatomical data are to hand. Elliott and
Tuckett compared the weight of the suprarenals in different
animals and found that, as a general rule, the size of the supra-
renal increases with the weight of the body and with the develop-
ment of the muscles. They found, moreover, that the increase
in the size of the organ is principally due to an increase in the
cortical portion. The lower the status of the species in the order
of vertebrates, the larger in proportion is the adrenal system and
the part which it plays in the formation of the suprarenal ; while,
at the same time, the amount of interrenal tissue, and especially
the suprarenal cortex, is proportionally reduced. There is, more-
over, an increase in the volume of the suprarenal cortex in the
course of the development of the individual. The medullary sub-
stance increases only slightly with the growth of the individual,
but the volume of the cortical substance becomes very much
augmented. In the guinea-pig, for instance, a five-fold increase
in the weight of the body is accompanied by a twelve-fold increase
in the weight of the suprarenal cortex, the medullary portion re-
maining practically unchanged. The exceptional size of the
suprarenals is characteristic of guinea-pigs and is almost entirely
the result of extreme development of the cortical part, this portion
being in the guinea-pig nearly ten times as large as in the dog.
The increase in the size of the cortex during extra-uterine growth
is also observed in the cat, dog and rabbit.

A still further growth of this portion of the suprarenal takes
place during pregnancy. Suprarenal hypertrophy in pregnancy
was first observed by Guieysse in guinea-pigs and has since been
observed in animals of different species (Stoerk and v. Haberer)
and in man. This hypertrophy is not entirely the result of an
increase in the cortical substance, although the cortex is the part
chiefly affected. There is at the same time an increase in the
chromaffine cells, in which numerous karyokineses are observed.

The similarity between the cells of the suprarenal cortex and
those of the corpus luteum verum is specially commented upon
by Mulon, Wallart and others. Mulon even regards the corpus
luteum verum as a temporary suprarenal cortex.

That there is a connection between the suprarenals and the
activity of the sexual glands, is shown by the observations of
Marassini, Cecca, and Teodossieff. These authors found that,
after castration, there was an increase in the weight of the supra-
renal, principally due to hypertrophy of the cortical substance.
Marchand describes suprarenal hypertrophy in pseudoherma-
phroditism. On the other hand, the observations of Bullock and
Sequeira, Adams, Shattock, Linser, Thumin, Brotz, and others>

270 INTERNAL SECRETION

have shown that tumours and hypertrophy of the suprarenals are
associated with pubertas praecox ; and it is believed by many that
the suprarenals, and the cortex more especially, exercise an in-
fluence upon the genital glands and upon the somatic and psychic
development of the individual during puberty. In Addison's
disease (Kyrle) and in congenital hypoplasia of the suprarenals
(Tandler), there are extensive changes in both the generative por-
tion and the interstitial cells of the testicles. According to Elliott
and Tuckett, there is no relationship between the suprarenals and
the reproductive glands.

The occurrence of hypertrophy of the suprarenal cortex and
of tumours of different kinds is by no means rare. Epithelial new-
formations may proceed from the cortical substance of the supra-
renal and also ifrom the accessory interrenal tissue. Of these, the
most important are the renal hypernephroma, described by Grawitz
under the name of struma suprarenalis ; tumours of the female
genitals, proceeding from Marchand's accessory suprarenals ; and
epithelial tumours of similar structure in other parts of the body.
All these pathological findings have as yet, ho\vever, supplied
no explanation of the function of the suprarenal cortex.

The physiology of the interrenal system is at present confined
to the investigation of its chemical composition and the more
minute study of its structure and of the structural changes which,
under special conditions, are observed in the suprarenal cortex.
The physiology of the interrenal system as it stands to-day is
chiefly the histo-physiology of the suprarenal cortex.

HISTOLOGY OF THE SUPRARENAL CORTEX.

The connective tissue sheath of the suprarenal is connected
with the centre of the organ by means, partly of thickish strands
conveying the nerves and blood-vessels, and partly by delicate
connective tissue lamellae which radiate from the periphery to the
centre. A short distance from the capsule, these strands and
lamellae become connected by cross and oblique anastomoses, and
by this means the outer cortical zone is defined. Since Arnold's
time this layer has been called the zona glomerulosa. These con-
nective tissue processes, some of which are vertical, while others
are joined together by means of a portion which curves outwards,
enclose long fan-shaped portions, 20, 40 and 60 microns in
breadth, which are again divided into smaller roundish spaces by
means of transverse processes. It is in these rounded spaces thai
the parenchyma cells are situated. In the median portion of the
cortex, the radial arrangement of the connective tissue strands
become more open, enclosing parallel spaces in which isolated
connective tissue septa conveying capillaries are arranged trans-
versely and diagonally (zona fasciculata, Arnold). In the internal
portion of the cortex, the connective tissue processes become still

THE SUPRARENAL SYSTEM 271

more delicate and, in the neighbourhood of the medulla, they
break up into a line net, composed of the finest connective tissue
threads (zona reticularis, Arnold), in the meshes of which single
parenchyma cells are situated. At the boundary between medulla
and cortex there are again a certain number of thicker connective
tissue threads running tangentially.

The fans formed by the lamellae of connective tissue are
divided into meshes of different sizes by delicate septa running
transversely and diagonally. These meshes contain the cortical
cells, not as Ecker described them, in the form of bladders or
tubules, but, both in man and in animals, in typical, solid cell-
columns without cavity — the cortical cylinders of Kollicker. These
cell-columns are usually composed of a single row7 of cells, though
occasionally of two or three; they traverse the external layer either
directly or in a winding fashion, and end in the transverse con-
nective tissue processes, or they may curve back like an arch and
terminate in one another. In the median layer, these cell-cylinders
are arranged in drawn-out radiating columns, in accordance with
the shape of the meshes formed by the longitudinal connective
tissue threads. In the interior, the columns break up into a net-
work formed by single rows of cells, in the meshes of which the
tine capillaries are situated. The meshes of the network, which
at first are rounded, become flattened radially as they approach
the medulla.

The form and size of the cells in the individual layers, varies
with the changes in the arrangement of the connective tissue struc-
ture and of the cell columns. The cells in the external zone are,
upon the whole, small in size and are of various shapes. In the
human suprarenal these cells are mostly polygonal ; in tangential
sections they appear in the form of rounded balls and cell nests
enclosed in connective tissue. The cells in the median layer are
larger in size ; in form, they are rounded polygons which are
occasionally elongated in the direction of the column ; and they
are arranged several together, side by side, transversely of the
column. As they approach the internal layer, the cells become
smaller in size and either cubic or polyhedral in form; while the
cells in the innermost cylinders are frequently oblong.

The connective tissue which runs between the cortical cell
cylinders carries numerous capillaries and veins. These vessels
pass between the cell columns and are somewhat dilated in the
outer layer; they are especially numerous in the internal zone.
Actual main arteries are not present in the cortex. The cortical
cells are placed directly against the thin vessel walls, which are
composed of endothelium and are sometimes enclosed in a delicate
connective tissue membrane.

The arrangement of the cortical parenchyma is, in the main
points, the same in all mammals, though the form, size and
arrangement of the cells varies. In many species the zona

272 INTERNAL SECRETION

glomerulosa is absent altogether. The form of the cortical cells
is polygonal in man only; in the greater number of mammals the
cells of the outer zone are long, narrow and cylindrical in shape.
The most perfect cortical cylinders are observed in the horse and
the dog. In microscopic sections taken from these animals the
cell strands appear as perfect rings which closely resemble tubular
glands. Whether or no the cortical cell groups enclose a lumen
is a question of the utmost importance to both pathological and
physiological histology, and one which has recently been sub-
jected to searching investigation by Stoerk. He showed that,
under normal conditions, there is no free space within the loop-
like arrangement of cell cylinders, although the appearance of
these sometimes closely simulates a lumen formation. Where,
for instance, owing to the over-tilling of the suprarenal vessels,
there is extravasation of blood into the external cortical layer, the
cell columns become detached from the connective tissue by which
the vessels are conveyed; thus, appearances are produced which,
where the extravascular blood is not demonstrable as such, bear
a misleading resemblance to transverse and oblique sections from
glands. This effect is heightened by the fact that compression
of the cell contents produces an apparently basal position of the
nuclei. From the nature of his findings, Stoerk is convinced that
the suprarenal cortex does not assume the formation of a true
gland under either normal or pathological conditions (hyper-
trophy, adenoma).

The most important structural characteristic of the cortical
cells is supplied by the lipoid granules which they contain ; these
resemble fat granules and are usually known as the cortical
granules. The chemical nature of these granules will be described
later; their histological characteristics are, briefly, as follows :-

If the cortex of a fresh mammalian suprarenal is teased out
in physiological saline solution, the result will be a granular mass
containing, in addition to single perfect polygonal cells filled with
granules, an enormous number of free spheroids. These are pale
yellowish in colour, very bright, double refractive, and i to 4
microns in size. Occasionally, these spheroids run together to
form, in some cases, largish drops, in others, what are known
as myelin forms. The large drop formation is very well seen after
the addition of glacial acetic acid, concentrated mineral acids, or
33 per cent, liquor potassa? solution ; though, when diluted, the
same acids and potash solution produce no change. The cortical
granules are soluble in fat solvents (ether, chloroform, xylol,
alcohol, though more slowly by the latter), and the addition of
water to these solutions produces the same globular formations.
The cortical granules do not stain with either fuchsin, methylene
blue, or other similar colouring agents ; but they stain vividly with
the specific stains for fat (alkanna, sudan III, scarlet R) ; and in
perosmic acid they colour a profound black. If, after colouring

THE SUPRARENAL SYSTEM 273

with osmium, the preparations are treated with alcohol, chloro-
form, or xylol, or cleared and mounted in Canada balsam or
bergamot oil, it will be seen that the granules have become dis-
solved, leaving a diffuse brown coloration in the cells. Mounted
in oil of cloves, however, they remain black for weeks, and in
glycerine for even longer.

The cortical granules are best seen by means of the specific
dyes for fat, provided that, after fixing the portions of suprarenal,
no powerful fat solvents such as ether, chloroform, or alcohol, are
employed in the further treatment. The best method of preparing
the specimens is to fix in formalin, cut frozen, and stain with
sudan III or scarlet R, when the granules will take on a red
colour. If subsequently treated with osmium (twenty-four hours
in Altmann's mixture), however, the granules in these frozen sec-
tions— unlike fat, which usually stains black immediately — take on
a brown colour and become black only when further treated with
alcohol. If, however, after treatment with osmium, the frozen
sections are treated with bergamot oil, the brown granules will
immediately dissolve ; if ether or xylol are used, solution follows
very rapidly ; chloroform and benzine are slower in their effects,
but solution follows within a quarter of an hour. If, after treat-
ment with osmium, the granules are treated with alcohol until
they become black (twenty-four hours), they will still dissolve
rapidly and entirely in bergamot oil, though to a less extent in
the other fat solvents ; they will still dissolve, though very
slowly, in ether and xylol, but they cease to be soluble in benzine
and chloroform.

For the study of the cytological structure of the suprarenal
cortex, the best results are obtained by fixing in formalin, formalin-
Mtiller, Zenker's fluid, and particularly in the different osmium
solutions. By these methods the cortical granules are at first
browned and become black only after treatment with alcohol.

On account of the solubility of the granules in ether and
xylol, these reagents cannot be used to prepare sections for paraffin
imbedding; the granules are, however, insoluble in chloroform
or benzine, and these may be employed.

Sections should not be cleared in xylol or mounted in Canada
balsam, as the cortical granules are to a large extent dissolved
by these, so that, after a few days, only a few blackened or brown,
osmium-stained cortical cells remain. When mounted in oil of
cloves, the granules last for some weeks. The most satisfactory
results are obtained by clearing and mounting sections which
have been stained with osmium in glycerine or a saturated solution
of potassium acetate.

In addition to the lipoid granules of the cortex, Alt-
mann's fuchsinophile granules stain readily, even in embryonic
suprarenals (Plecnik). These are round bodies of the same size
as the lipoid granules; they are composed of several layers
18

274 INTERNAL SECRETION

arranged in such a way that the smallest is nearest to the nucleus.
At the cell periphery they are surrounded by the layer containing
the lipoid granules. Where, however, as the result of the group-
ing of the cortical cells, the juxtaposing cell surfaces are free from
lipoid granules, in fuchsin preparations these areas are seen to be
crowded with fuchsinophile granules. There is no evidence to
show that these granules are changed into lipoid granules. The
effect of ether upon sections is to dissolve, not only all the lipoid
granules stained with osmium, but also a large proportion of
the fuchsinophile granules, the remaining portion of the latter
remaining unchanged (Plecnik).

The cells of the suprarenal cortex also contain pigment. This
is seen in the inner layer, the zona reticularis, where it takes the
form of yellowish granules, even in sections coloured by the
ordinary nucleus and cytoplasm stains. These granules colour
black with Heidenhain's iron haematoxyjin, and a deep grass-
green with Unna's polychrome methylene blue and differentiation
with glycerine ether. In these preparations, even small quanti-
ties of pigment are clearly visible against the blue nuclei and the
unstained cytoplasm. The sections should not have been pre-
viously fixed in osmium solutions. When fixed in Altmann's
mixture the pigment loses its yellow colour, becomes a dirty green,
and is readily distinguished from the intensely black lipoid
granules. The embryonal suprarenal contains no pigment ;
Plecnik found that it was present in very small quantities in the
suprarenal of an infant 6 days old.

The pigment is found both in free cells and in those which
contain cortical granules. If sections which have been stained
with osmium are treated with ether and then coloured with iron
hasmatoxylin, large clear spaces will be observed in the zona
reticularis in place of the black lipoid granules; while the pigment
granules, also coloured an intense black, will still be visible in the
alveolated body of the cell. According to Dostojewsky, this
alveolate network represents, not the filamentous portion only,
but the entire cell-plasm. Thus it appears that the lipoid granules
occupy the plasmic spaces, while the pigment granules are situated
in the cytoplasm itself (Plecnik).

CHEMISTRY OF THE SUPRARENAL, EXCLUSIVE OF

ADRENALIN.

In spite of the immense interest which has been aroused in
the physiologically active substance of the suprarenals, or perhaps
because attention in general, including that of chemists, has been
focused upon the physiological side, the advanced methods of
modern chemistry have, up to now, supplied only the first begin-
nings of a knowledge of the chemical constitution of the supra-
renal.

THE SUPRARENAL SYSTEM 275

Nabarro's experiments have acquainted us with the albu-
minoids of the suprarenal. These experiments show that the
suprarenal contains an albumin which coagulates at 70°, certain
globulines which coagulate at between 56° and 75° ; and one or
more nucleoproteids. Thus far, then, the suprarenals do not
differ from the other organs, seeing that the globulins and the
nucleoproteids are present in all tissues. According to the older
accounts, the suprarenal contains also the following : of the pro-
ducts of regressive metamorphosis it contains hippuric and tauro-
cholic acid (Vulpian and Cloez), benzoic acid and taurin (accord-
ing to Seligsohn, but not confirmed by Stadelmann), leucin,
tyrosin, xanthin bases (xanthin, methylxanthin, hypoxanthin,
epiguanin, according to Okerbloom), inosit (Kiilz) ; of the carbo-
hydrates it contains glycogen (Lubarsch), a substance resembling
jekorin (Manasse), and salts, of which potassium phosphate is
present in exceptionally large quantities (Halliburton).

A. C. Croftan discovered a diastatic ferment, and M. Jacoby
an oxidative ferment, an aldehydase, in the suprarenal cortex.
The suprarenal further contains a nuclease which splits up nucleo-
proteids, xanthin bases being formed (Jones).

The proof of the presence of cholin in the suprarenal was a
discovery of the highest importance. As early as 1888, it was
stated by Guarnieri and F. Marino-Zucco that w^atery extracts of
suprarenal contain neurin (in the terminology of to-day, cholin)
and they assumed that the neutralization of the neurin in the
body was a function of the suprarenals. Exact proof of the pre-
sence of cholin was, however, first offered by Lohmann (1907).

It wTas Lohmann Ts object to isolate from the suprarenal the
substance present in suprarenal extract which produces an effect
first observed by Giirber, namely, the lowering of blood-pressure.
The suprarenal was first freed from fat and cut into small pieces,
and, by means of hot water with the addition of a small amount
of acetic acid, a triple extract was obtained. The concentrated
extract was purified by Kutscher and Steudel's method with
tannin, baryta and oxide of lead, and afterwards precipitated with
phosphorotungstic acid. The precipitate was split up with baryta
and the alloxur, or purin, bases were first extracted by means of
nitric acid, and a further group of bases, " the arginin fraction,"
was afterwards extracted with baryta. The filtrate was again
precipitated with phosphorotungstic acid, the precipitate again
split up with baryta, and, after removal of the superfluous baryta
with carbonic acid, the bases were reduced to a thick syrup. A
concentrated extract of this syrup was obtained by repeated treat-
ment with boiling absolute alcohol. The bases obtained from
the alcohol extract possessed marked hypotensive properties. The
concentrated alcoholic extract was precipitated with alcoholic
solution of platinic chloride. The platinates, which were in-
soluble in alcohol, wrere converted into chlorides with sulphuretted
hydrogen, and then, by the addition of a watery solution of auric

276 INTERNAL SECRETION

chloride, the aurate of cholin is obtained. By crystallization twice
repeated, and by ascertaining the melting-point and the amount
of gold present, the insoluble aurate was found to be homogeneous
and was analysed. The result yielded by analysis was cholin
auric chloride. The aurate was converted into the chloride with
sulphuretted hydrogen, and this was employed in experiments
upon animals. It appeared that, when injected into the veins of
a cat in a quantity of .036 grm. in .5 c.cm. of Ringer's solution,
this cholin chloride produced a sudden fall in blood-pressure and
violent lachrymal and salivary secretion, followed by the death
of the animal. That the influence of cholin was antagonistic to
that of adrenalin was shown, not only by the effect upon the
blood-pressure, but also by the effect upon portions of intestine
removed from the living cat. The action of adrenalin in produc-
ing relaxation of the intestine was arrested by the addition of
cholin, and violent muscular contractions followed. In further
experiments, Lohmann tested the effects of adrenalin and cholin
upon the heart when taken from the living rabbit ; he found that
the increased and accelerated cardiac activity produced by
adrenalin was negatived by the weakening and slowing of the
contractions which followed cholin. The antagonism between
adrenalin and cholin was found to be mutual ; it was especially
noticeable that the profuse salivary flow produced by the sub-
cutaneous injection of cholin, was absolutely controlled by the
simultaneous injection of adrenalin. Lohmann was no more able
than Frank and Isaac later, to prevent the occurrence of adrenalin
glycosuria by means of cholin. According to Mansfeld, the sub-
cutaneous injection of cholin will arrest the development of the
changes in the vessels brought about by adrenalin.

Lohmann next investigated the distribution of cholin in the
suprarenal and he discovered that it is possible to obtain nearly
nine times as much from the cortex as from the medulla. He
ascribes the cholin contents of the medulla to the presence of
cortical substance and arrives at the conclusion that, in the same
way that adrenalin is formed only in the medulla, so cholin is
formed solely in the cortex.

Lohmann also described the manner in which he obtained
a further auric salt, by the slow concentration of the mother-lye
of the cholin auric chloride obtained from suprarenal extract. This
auric salt was crystallized and found to be neurin gold.* This

* The constitutior.al formula of neurin (trimethylvinylammonium
hydroxyd) is as follows : —

CH3— N

This base is obtained from cholin by the splitting off of a molecule of
water out of the ethylalcohol, by which the latter is converted into the
vinyl residue.

THE SUPRARENAL SYSTEM 277

gold combination was converted, by means of sulphuretted hydro-
gen, into the chloride and was employed in experiments upon
animals. The intravenous injection of .01 grm. of neurin chloride
into rabbits produced a fall in blood-pressure immediately fol-
lowed by a considerable rise. There were at first several strong
expiratory movements, followed by a reduction in the respirations.

That cholin was present in the animal economy had long been
knowrn, and the nature of its pharmacological activity had re-
peatedly been investigated (Gaehtgens, Bohm, Brieger, Cervello,
Asher and Wood, Formanek).

Cholin (trimethyloxethylammonium hydroxyd) : —

CH2 OH

CH3-N

formerly called neurin, was first discovered in the bile by Strecker,
and afterwards found, as a product of the decomposition of lecithin
or of protagon, in watery extracts of the brain, and by Mott and
Halliburton, in the cerebro-spinal fluid. The latter authors were
inclined to regard the fall in blood-pressure observed by Schafer
and Moore after the injection of extract of the brain, and by
Schafer and Vincent after the injection of that constituent of
pituitary extract which is soluble in alcohol, as an effect of cholin.
Osborn and Vincent found that the injection of extracts of any
portion of the nervous system produced a distinct temporary fall
in blood-pressure. They concede that these extracts contain cholin
in small quantities, but they do not ascribe the result to the action
of this substance ; for the lowered tension persisted after full doses
of atropine, whereas, according to their experiments, the effect of
atropine upon cholin is invariably to convert the vaso-dilator action
into a vaso-contractor one. Vincent and Sheen next discovered
that a substance which reduces blood-pressure is obtainable from
muscular tissue of all kinds, as well as from the kidney, liver,
spleen, testicles, pancreas, ovaries, lungs, thyroid, thymus, supra-
renals and the hypophysis cerebri. Vincent and Cramer showed
that watery extracts of nervous tissue contain two groups of sub-
stances, both of which, when injected intravenously, reduce blood-
pressure. One group dissolves readily, the other is scarcely
soluble, in absolute alcohol. The alcoholic solution contains two
depressant substances. The action of the one is neutralized by
atropine, that of the other is unaffected by it. The alcoholic
solution yields a slight precipitate with platinic chloride, and this
precipitate, when purified, yields prismatic crystals, the platinum
contents of which are 32.8 per cent., which corresponds to the
platinic double salt of dicholinanhydride. These observers found
no cholin in extracts of the brain, and they are of the opinion

278 INTERNAL SECRETION

that the hypotensive action of these extracts is independent of
cholin.

The wide distribution of cholin in the organism was em-
phasized by Claude and Blanchetiere (1907), who also pointed
out that cholin is present in the greater number of tissues and
secretions of the body, though not in a free state but in combina-
tion with lecithin, v. Fiirth and Schwarz showed that cholin is
present in intestinal extract and in secretin (so-called), and that
it stimulates the secretory activity of the pancreas and of the
salivary glands. The effect of cholin upon secretion is com-
pletely neutralized by atropine. They also found that the con-
stituent of the thyroid which lowers blood-pressure, is identical
with cholin. Schwarz and Lederer found depressant substances,
which they identified with cholin, in extracts of thymus, spleen and
lymph glands.

Finally, Gautrelet found cholin in the pancreas, spleen, ovary,
thyroid, kidney, testicle, pituitary and salivary glands, bone
marrow, and gastric and intestinal mucous membranes of animals
of various species. He came to the conclusion that the common
active principle of the extracts of those organs which were included
by Livon in the description " hypotensive glands," is cholin, the
activity of which is antagonistic to that of adrenalin. He divides
the internal secretory organs into those which are cholinogenic
and those which are adrenalinogenic (chromaffine), and he believes
that the regulation of arterial pressure is brought about by the
interactivity of these two antagonistic systems.

The evidence which these observations supply of the almost
ubiquitous occurrence of cholin in the animal economy, has largely
diminished the importance of Lohmann's discovery. The
presence of comparatively large quantities of cholin in the supra-
renal cortex can hardly be regarded as proof of the production of
cholin as a specific function of that tissue. It is far more probable
that cholin represents a product of the decomposition of the
phosphatides which all organs contain, and that the comparatively
large quantities of cholin which are present in certain tissues,
merely show that such tissues are very rich in those lipoids. These
phosphatides are very liable to hydrolytic decomposition, in the
process of which they give off cholin. The presence of cholin is
not a proof of its pre-existence under physiological conditions.

But the physiological activity of cholin, and especially its
antagonism to adrenalin, requires more careful investigation.
Modrakowski showed that the cholin (Merck) of commerce brings
about a fall in blood-pressure and a slowing of the pulse, which
may be arrested by means of atropine ; that it also produces
increased salivary and pancreatic secretion as well as increased
secretion of urine; but that these results are wholly attributable to
products, resembling muscarin, of the decomposition of cholin,
and more particularly to trimethylamin. Pure cholin is a com-

THE SUPRARENAL SYSTEM 279

paratively non-toxic substance and, as Blum pointed out, in doses
of .6 to 2 mg. per kilo of body weight, produces only a transitory
increase in blood-pressure, and has no effect whatever upon
the secretions. I was able to convince myself that Modrakowski
was right in his findings, and they have since been confirmed by
Busquet and Pachon. A pure cholin which was prepared by my
colleague, S. Fraenkel, when injected into the veins of dogs in
quantities of 4 mg. to every kilo, produced a distinct, though very
transitory, increase in blood-pressure. After being kept for a few
days, the preparation acquired a distinct odour of trimethylamin,
and in doses of even 2 mg. produced marked hypotension and
slowing of the pulse. After atropine, a fresh injection of the
substance produced slight hypertension. This substance proved,
after keeping, to be actively toxic, for animals into which it was
injected in doses of i mg. per kilo died within a few hours.

According to these findings, then, cholin is neither specific to
the suprarenal cortex, nor is its action antagonistic to that of
adrenalin.

The suprarenal contains yet other substances, the importance
of which to the vital processes has only recently been discovered.
These are the lipoids. The presence of fat and substances similar
to fat is mentioned in some of the older writings upon the supra-
renals, but at that time our knowledge of the chemistry of these
substances was very scanty. It is only recently, and indeed very
recently, that we have arrived at any definite knowledge of the
nature of the lipoids. The interest which has been aroused in
both physiologists and pathologists by the lipoid substances in
general, has drawn a certain amount of attention to those of the
suprarenal in particular.

I have occupied myself with researches — in which I made use
of the most recently discovered chemical methods — into the nature
of the lipoid substances; and, in so far as my results concern the
lipoids present in the suprarenals, they may be given here. In
order fully to understand these results, it is necessary briefly to
explain the older views, based almost entirely upon histological
and biochemical material, and to show the manner in which recent
chemical science has modified our views concerning the nature of
the suprarenal lipoids.

It has long been known to morphologists that the suprarenal
cortex, or rather the entire interrenal system, occurring in verte-
brates of whatever species, possesses a remarkable cytological
peculiarity, namely, the presence in the cells of fat-like
lipoid granules, from which the name ' lipoid tissue," used
to describe the interrenal tissue, is derived. However much the
structure and arrangement of the interrenal system may vary—
and according to H. Poll these variations are constant in mam-
mals of the same species — the lipoid granules, or cortical granules
as they are called, are a constant and characteristic feature both

2 So INTERNAL SECRETION

of the cortical cells and those of all interrenal tissue. What was
known of the morphological relationships and the microchemical
properties of these granules supplied the material for the investi-
gation of their chemical composition.

This occurrence of peculiar granules in the suprarenal cortex
was first described by Simon and Ecker (1846), and has been
confirmed by all subsequent investigators. The older authors
regarded them solely as fat-granules, and were content to describe
their distribution in animals of different species and the quantities
in which they were to be found in the different parts of the cortex.
According to Kolliker, there are animals, such as carnivora and
rodents, in which the amount of fat in the suprarenals is so large
that it lends a yellow-whitish colour to the entire cortex. There
is also a large amount of fat in the external portion of the cortex
in the horse; while in the swine and in ruminants, on the other
hand, the cortex is grey in colour, the cells being pale and having
apparently little fat. The suprarenal of man occupies a middle
place between the two, there being in youth but little fat, though
this increases by degrees until finally the entire cortex, with the
exception of the inner zone, acquires a yellow-white appearance.
The greater number of authors find that the granules, which they
believe to be fat globules, are most numerous in the median portion
of the cortex; that they diminish considerably in number towards
both the inner and outer cortical boundaries; and that the cells
of the inner layer contain, in addition to the cortical granules,
certain other cell-contents, more particularly pigment.

Moers and Arnold described the resistance which the more
shining of these granules offer to alkalies and acetic acid; "but
A. von. Brunn was the first to inquire into the actual nature of
these bodies. He found that the numerous shining granules in
the cells of the external zone did not dissolve in acetic acid and
ether, and that they did not stain black with osmic acid ; he con-
cluded from these findings that they could not be composed of
fat. For the same reasons, Braun believes that the more strongly
refractive bodies in the suprarenal cortex of reptiles are only
partially composed of fat. Gottschau also describes the highly
refractive granules, present in the inner layer of the cortex in
mammals, as insoluble in acetic acid and liquor potassa?.

A detailed account of the microchemical relationships of the
cortical granules was first given by H. Rabl. He found that
cortical granules from the suprarenal of the hen were soluble in
alcohol, ether and chloroform ; that they stained black with osmic
acid and red with alkanna. While, however, fat treated with
osmium was insoluble in choloroform and bergamot oil, the
blackened cortical granules proved to be soluble in these reagents
and in xylol. For these reasons, Rabl held that the cortical
granules, though not fat, were allied to it. These findings were
confirmed by M. Pfaundler in the case of the dog and the

THE SUPRARENAL SYSTEM 281

horse. Alexander, however, lays special emphasis upon the
fact that cortical granules did not stain black with osmium, but
that they acquired a brownish tone, and for this reason must be
composed of a chemical substance other than fat.

In 1895, Kaiser! ing discovered that by far the greater number
of the cortical granules are double refractive to polarized light.
They had long been known to have a high refractivity, and Orgler,
who carried Kaiserling's experiments still further, gives the
following account of their microchemical nature. The granules
measure .4 to 18 microns, and have an average dimension
of 4 to 5 microns. They are soluble in water, readily
soluble in ether and chloroform, and dissolve slowly in
alcohol. They are unaffected by caustic soda solution, acetic
acid, and concentrated sulphuric acid. They stain red with
sudan III., at the same time losing their double refractivity.
When treated with osmic acid they take on a grey-black tone,
and if allowed to remain for a longer period in osmic acid-
fixing by Altmann's method, for instance — they stain black.
Treatment with osmium, as well as fixing and hardening by other
methods, destroys their anisotrophy, thus their optic differenti-
ation from the fat-granules disappears. They are soluble in xylol,
chloroform, and bergamot oil, and at this stage this is the only
distinction between them and fat-granules treated with osmium,
the latter being insoluble in these reagents. Orgler concludes
that the cortical granules are not identical with fat ; from their
double refractivity, the manner in \vhich they are influenced by
osmium, and their resistance to acetic acid and caustic soda solu-
tion, he thinks it highly probable that they are related to the
myelin of the medullary nerve-fibres.

The chemistry of the cortical granules was minutely investi-
gated by Hultgren and Andersson. These authors found that the
microchemical reactions of the cortical granules were in every case
the same as those of fat. Their greater solubility after treatment
with osmium is their only point of difference. Alexander showed
that lecithin is present in the suprarenals in large quantities, and
Hultgren and Andersson incline to a relationship between this
substance and the cortical granules, taking further into consider-
ation the large quantity of so-called myelin forms which appear
in the etheric solution after the addition of water. They W7ere
unable to demonstrate phosphorus in the cortical granules, and
were thus compelled to leave the question of their lecithin contents
unsolved. All that they could say was that the cortical granules
are composed of fat, but that they probably differ in certain
respects from the other known fats. In 1902, P. Ewald discov-
ered that the suprarenal cortex coloured a diffuse pale pink with
scarlet R., and he believed that this was due, not to fatty degener-
ation, but to infiltration of fat.

Plecnik's observations (1902) are of exceptional interest. He

282 INTERNAL SECRETION

found that, in the suprarenal cortex of a human embryo 5 cm.
long, all the cells contained granules, though these were smaller
in size and in number than in the adult. In an embryo 12 to 15
cm. long, the granules had increased considerably in size, and
were much more numerous, especially in the peripheral cells.
These conditions are maintained through the later developmental
stages, and change very little during the post-embryonal period.
The comparative maximal number of cortical granules is reached
during the second six months after birth ; from then onwards the
number is subject to variation which is largely unexplained. But
an increase in the number of granules in the cortex is by no
means to be regarded as the result of fatty degeneration. Plecnik's
experiments shed important light upon the nature of the cortical
granules, because he applied to the suprarenals the test which
Lewinson gives for fats, namely, a modification of Weigert's
chrome-ha?matoxylin stain for the medullary sheath of the nerves.
He found that, after the suprarenals had been hardened for some
time in Miiller's mixture, the granules in the cortex were stained
blue in exactly the same manner as the fat in the interstitial cells
of the testicles, while subepicardial fat and the fat of phosphorus
kidney did not stain by this method. The granules in suprarenals
treated by this method frequently colour black after treatment
with Altmann's mixture and rinsing in water. This is not the
case, however, with subepicardial fat and phosphorus kidney fat.
By means of i per cent, osmic acid, Bernard and Bigart (1902)
were able to differentiate between two cell types, or more properly,
two cell conditions, in the external layer of the zona fasciculata, the
so-called zona spongiosa. Of these two cell types, one contained
larger or smaller globules of common fat which stained in the
usual manner with osmium, \vhile the other contained granules
which, in response to osmium, took on a shade varying from light
to dark grey. Mulon next showed that the grey granules are
soluble in turpentine, xylol, bergamot oil, and cedar-wood oil.
The cells known as spongiocytes are, according to Mulon, cells
the protoplasm of which is filled with granules resembling fat.
Their spongy appearance is merely the result of the secondary
solution of the globules during mounting. Bernard and Bigart
call this substance " labile fat," and consider that it is a product
of normal cell-function, while ordinary fat may, under conditions,
be a pathological product. Bernard, Bigart and Labbe believe
that labile fat is lecithin or a mixture of lecithins. By extraction
with ether and alcohol, they estimated both the total amount of
fat and the total amount of phosphorus in the suprarenal, and
found that the proportion of the phosphorus fat to the whole
amount of fat was as follows : — 45-3 : 100 in the horse, 48.8 : 100 in
the sheep, 52.7 :ioo in the rabbit. In the horse, the phosphorus
fat forms 6.77 per cent, of the organ ; in man the proportion of
lecithin fat to the whole amount of fat is 13.1 : 100, the lecithin fat

THE SUPRARENAL SYSTEM 283

amounting to 2.08 per cent, of the total weight. According to
these authors, lecithin is actively produced by the suprarenals.
They found that, during muscular exertion, there was a consider-
able increase in the number and size of the labile fat granules in
the spongiocytes, but that the ordinary fat remained unchanged.

Mulon (1903) points out the double refractivity of the cortical
granules in the suprarenals of guinea-pigs, though this, as we
know, had already been discovered by Kaiserling. Mulon also
comments upon the fact that, as early as 1866, Darest described
double refractive granules in the ovum, in the suprarenals, and in
other tissues ; and that Dastre, in 1877, showed that these granules
are composed of lecithin. According to Mulon, oleate of soda and
lecithin are the only double refractive granules which are soluble
in ether and alcohol. He calls the zona spongiosa the zone
lecithinogene. He found that the cortical granules, like those of
the medullary sheaths, stain blue by Regaud's modification of
Weigert's ha^matoxylin copper method. Bonnamour and
Policard proved that the cortical granules of the suprarenals of
frogs possess the following characteristics : they stain grey-black
with osmium ; they are afterwards soluble in Canada balsam and
in xylol ; and they colour blue with Weigert's hasmatoxylin.
These authors consider that the cortical granules are composed of
a phosphorus fat belonging to the lecithin group.

These double refractive granules, which were believed to be a
specific product of the suprarenal cortex, were also found by
Kaiserling in an amyloid kidney with pronounced fatty changes;
and Kaiserling and Orgler discovered similar granules in organs
which had undergone regressive and fatty degenerative changes,
for instance, in regressive changes in the thymus, fatty degener-
ation of the intima cells of the vessels, in large white kidney, &c.
They believed these double refractive granules to be identical with
the myelin globules found by Schmidt and F. Mu'ller in the
bronchial mucus, and they described the granules which they had
discovered as " myelin " without, however, attaching a chemical
significance to the term. Albrecht also described as myelin the
globular formations and the figures which appear in the cell-body
as the result of nuclear decomposition — as seen for instance post
mortem in the kidney if kept at the temperature of the body — and
which, unlike the nucleus, stain red with neutral red. Dietrich and
Hegler also described the occurrence of myelin figures which
were formed by autolysis in organs kept under aseptic conditions.
By rapidly bringing crushed suprarenal cortex to a moderate
degree of heat under the microscope, Albrecht produced every
possible change in the appearance of the double refractive
granules, from slight increase in size to enlargement equal to that
of the globules seen in fatty infiltration of the liver, together with
pronounced double refraction, and, in many instances, distinct
formation of myelin forms. Certain other authors (Orgler,
Loehlein, Rosenfeld) believed that the double-refractive substance

284 INTERNAL SECRETION

seen in fatty degeneration and cloudy swelling is protagon, and
this is in accordance with the theory of Kaiserling and Orgler.

O. Herrmann (1905) minutely investigated the double refrac-
tive substances resembling myelin present in the suprarenal
cortex. The double refractive substances are present in varying
quantities as physiological constituents of the human suprarenal
from the embryonal state until old age. They are present in the
form of round globules of varying size, and they are characterized
by the following reactions : they resist alkalies and acetic acid ;
they stain slightly yellow with Lugol's solution ; when warmed,
pink with Millon's reagent; they are readily soluble in chloroform
and ether ; in alcohol they dissolve slowly ; they stain brown with
osmium, at the same time losing their double ref ractivity ; when
fixed in Flemming's solution they stain black.

The most important thing about these double refractive sub-
stances, however, is their attitude towards neutral red ; they do not
stain w7ith this reagent. On the other hand, in addition to the
globules, myelin masses are found, and these stain with neutral
red. In badly fixed sections where the nuclei do not stain, the
neutral red staining of myelin bodies is more easily recognized.
It is evident then that the double refractive granules are not
identical with the myelin substances, which colour with neutral
red (Albrecht).

After hardening in formalin, needle-shaped crystals stained
with fat-ponceaux are observed in addition to the globules;
these crystals take up dyes, and are in many instances still refrac-
tive. Double refractive globules similar to those in man are found
in large numbers in rats, but they are not present in guinea-pigs,
nor, as a general rule, in rabbits. The cells of the suprarenal in
rabbits are filled with small, polyhedral granules, which frequently
combine to form largish scales, are not double refractive, and in
fresh preparations do not stain with neutral red.

These granules stain with neutral red in preparations in which
autolytic processes have occurred, either when kept in an
incubator, or in the abdominal cavity, free or enclosed in india-
rubber bags. Their double refractivity is not, however, increased,
and there was no actual proof of the transformation of the poly-
gonal granules into larger myelin forms or into globules. Colour
reactions show that fatty acids are present in the external layer
of disconnected suprarenal grafts. This is most readily explained
by the assumption that the leucocytes in combination with the
fluids of the body which penetrate into the external layer, -bring
about a process of resorption, which is attended with a splitting
up of myelin.

Herrmann was unable to obtain from the results of his
experiments any further information concerning the nature of the
amorphous masses in the suprarenal of rabbits, as well as of the
double-refractive globules which occur in profusion in the supra-
renal of man, and in small quantities in the suprarenal of rabbits.

THE SUPRARENAL SYSTEM 285

Napp (1905) published the results of his investigations into
the fat-contents of the suprarenals in different pathological con-
ditions. He takes no account, however, of the manner in which
the double refract! vity is affected, and he describes as fat only that
portion of the cell contents which stains with sudan red. Babes
and Jonesco have also published communications respecting the
distribution of fat in the suprarenals. These authors assert that
the distribution of fat in the suprarenal cortex differs with the
age and species of the individual, and that its amount is very
much diminished by different pathological conditions, such as
inanition and acute and chronic infective diseases. They found,
further, that there is a reduction in the number of the fat-granules
in the suprarenal cortex of rabbits, if hypertrophy of the organ is
induced by the intravenous injection of adrenalin. Babes finds
that, in suprarenals containing a large amount of fat and in
suprarenal adenoma, the cortical cells are filled with crystalline
double refractive granules, the reactions of which are similar to
those of protagon. These double refractive granules may entirely
crowd out the ordinary fat.

Elliott and Tuckett (1906) undertook minute investigations
into the histology of the cortical granules. They found that the
cortex contains four different substances, all of which may be
regarded as the products of secretion ; these are the fat granules,
the double-refractive substance, the pigment granules of the
cortex, and the chromaffine substance of the medulla. The fat in
the suprarenal cortex differs from other fats in its ready solubility
in etheric oils; it colours red with scarlet R. The double refrac-
tive substance which is soluble in ether occurs in the suprarenal
cortex in association with true fat, though the distribution of the
two substances is not identical, and they may occur in different
parts of the cortex. In the guinea-pig, true fat is found in the
external third of the cortex only, \vhile the double refractive sub-
stance occurs throughout the whole cortex. In the cat, the double
refractive substance is generally situated in the external cortical
layer, though it is sometimes met with in the internal layer, com-
pletely separated from the fat. In the rabbit, the distribution of
faj, is regular and, when viewed with a polarization microscope,
glittering crystals appear to be also regularly distributed through
the cortex. In the human suprarenal the conditions are the same.
In certain species, though fat is present, the double refractive
substance is absent, as for instance, in the case of the cortex of
the sheep and the whale. In others, on the other hand, as for
instance in the hen, the double refractive substance is present in
such large quantities that the entire cortex appears to be filled with
large needle-shaped crystals, irrespective of the cell boundaries.
According to Elliott and Tuckett, the fat and the double refractive
substance are two different secretory products of the suprarenal
cortex, but are, however, intimately related to one another. When
the body is in the resting state, the amount of the double refractive-

286 INTERNAL SECRETION

substance increases, while the fat is reduced in proportion. Where
muscular exertion is prolonged to fatigue, the double refractive
substance disappears, and the fat spreads through the whole of
the cortex. The authors point out, however, that these substances
may neither of them represent the most important general product
of the secretory activity of the cortex, for they may be absent in
certain species, as in the case of the sheep. The brown pigment-
granules are specific to the suprarenal cortex of guinea-pigs.
These accumulate during repose and disappear very rapidly
during exhausting muscular exertion, fat being formed in the
cytoplasm in their place.

These authors give no account of the chemical nature of the
double-refractive substance; but they point out that it cannot be
identical with fat, and they think that its refractive power probably
points to myelin in combination with lecithin.

As we have seen, this double-refractive lipoid substance was
almost invariably believed to be lecithin. The assumption was
justified by Virchow's discovery, as early as 1857, of the presence
of a substance which he described as myelin (medullary) in the
suprarenal, and which, from its chemical nature, he identified
with the substance which Gobley described as lecithin. A little
later, Bennecke pointed out that cholesterin, in combination with
a peculiar substance of fatty nature, plays the chief part in the
formation of myelin substances. But the peculiar richness in
lecithin of the suprarenals was again emphasized by Alexander.
He obtained his exceptionally high figures by multiplying by 8.8,
the phosphorus contents of the etheric extract of suprarenal. The
brothers Marino-Zucco, as well as Guarneri and Marino-Zucco,
obtained neurin and glycerite of phosphoric acid from etheric
extract of suprarenal. Manasse obtained a body from the supra-
renals, the phosphorus contents of which were 4.44 per cent., and
which, after decomposition by means of acids, yielded a carbo-
hydrate. Manasse concludes that this lecithin-carbohydrate com-
bination is jecorin.

Orgler (1904) analysed the suprarenals with the object of
ascertaining if they contained a body resembling protagon.
Liebreich gave the name of protagon to a homogeneous substance
which he regarded as the matrix of the lipoids found in the
brain.* By means of alcoholic and etheric extraction, Orgler

'7 Later on, protagon was erroneously regarded as a body chiefly com-
posed of cerebrin and lecithin, because it yielded, as the products of
decomposition, cerebrosides, which are free from phosphorus, and phospha-
tides. Cerebrin is a body containing CON, as yet not exactly defined;
while, from the results of Strecker and Diakonow's investigations, lecithin
was commonly regarded as di-stearyl-glycerinite of phosphoric-acid-cholin.
But Thudichum had already suggested, and it was afterwards proved by
Fraenkel, that saturated lecithins of this description do not exist; that all
lecithins are unsaturated phosphatides ; and that Diakonow himself had
isolated the unsaturated oleic acids from his own lecithin. Thus the finding
of a saturated di-stearyl lecithin must be attributed to erroneous description
of the experiments on the part of the text-books.

THE SUPRARENAL SYSTEM 287

obtained a yellow-white body from the suprarenals, which was
found under the miscroscope to consist of fine, slightly bent
needles arranged in rosette form. After repeated crystallization
he obtained a snow-white body which, as it did not stain with
osmium, he believed to be free from lecithin. The phosphorus
contents were 1.6 per cent.; higher, therefore, than the figure
given for protagon by the majority of authors. Owing to the
small amount of substance at his disposal, he was able to test for
the carbohydrates by colour-reactions only, and the results of
these were positive. From the results of his investigations,
Orgler held the double refractive granules to be protagon.

After, however, Panzer had shown that the double refractive
substances in the kidney are not protagons — that is to say, they
are not combinations with phosphorus — but are cholesterinesters,
Adami and Aschoff continued the investigations made by
Lehmann and Schenk into the nature of the fluid crystals. They
endeavoured to obtain by synthesis, combinations corresponding
to those of the double refractive globules found in the body, corres-
ponding therefore to the fluid crystals. They found that the
most important ingredients are cholesterinesters, whether pure or
in combination with oleic acids, fats, or cholesterin. These experi-
ments pointed to the probability of the double refractive substance
of the suprarenal being of a cholesterinester-like nature. On the
other hand, Wright pointed out that mixtures of cholesterin with
oleic acids may also yield double-refractive globules, and he lays
stress upon the fact that the suprarenal cortex contains a mixture
of cholesterin with lecithin and oleic acids, and that these are to
be regarded as products of secretion.

Rosenheim and Tebb isolated a white crystalline substance
from the suprarenal cortex of the ox, which contained 3.4 per cent,
phosphorus, and the physical properties of which corresponded to
Thudichum's diamidomonophosphatide, sphingomyelin, the most
important constituent of the so-called cerebral protagon. This
substance possessed a characteristic, which they describe, namely,
that of sphere-rotation, and it crystallized into anisotropic sphere-
crystals.

In 1909 the same authors published their further investigations
into the nature of the suprarenal lipoids.

In the first extract of dried suprarenal obtained with acetone,
they found a large quantity of a crystalline substance which con-
sisted principally of stearic acid, mixed with the cholesterinesters
in small quantities. The latter were not identified, but their
nature wras assumed from analogy with the cholesterinesters which
Panzer isolated from large white kidney. From the matrix of
the cold acetone extract, they isolated free palmitic acid, an
unsaturated oleic acid, and fat.

From the hot acetone extract they obtained a smaller quantity
of a crystalline substance from which they isolated cholesterin

288 INTERNAL SECRETION

stearate and cholesterin palmitate in a state of chemical purity.
They obtained, further, the phosphatide, sphingomyelin, and the
non-phosphoric galactocide, phrenosin. The phrenosin was
identified by polarimetric estimation of the galactose obtained
after hydrolysis. Free cholesterin was carefully \vatched
for, but was not found to be present. Even with Windau's
extremely sensitive digitonin reaction, free cholesterin could not
be detected in either the hot or cold acetone extract of suprarenal.
These authors lay stress upon the fact that their results do not
support Powell White's assumption, that the double refractive
substances of the suprarenal consist of a mixture of free cholesterin
and fatty acids. On the contrary, the results of these experiments
confirm another view held by Powell White, to the effect, namely,
that the pure cholesterinesters do not yield double refractive
granules, but that when in combination with fatty acids, the
granules which they yield are double refractive. Seeing that the
presence under physiological conditions of true cholesterinesters
in the organism is denied by Biinz, Tebb, and by Moore, this
account of cholesterin palmitate and cholesterin stearate in the
suprarenal is very remarkable.

According to Rosenheim and Tebb, the double refractive sub-
stances of the suprarenal consist of a mixture of free stearic and
other fatty acids, together with a small proportion of sphingo-
myelin.

In his review of the morphology of the lipoicl substances (1909),
Aschoff affirms, upon the ground of results yielded by his own
experiments, that the following bodies may show double refractive
myelin forms, and, occasionally, globules :

(1) The phosphatides, including lecithin, though the latter is
difficult to obtain in a state of chemical purity.

(2) The soaps of the oleic acids.

(3) The cholesterinesters.

(4) Solutions of cholesterin in the phosphatides, in the oleic
acids, and the fats.

(5) Solutions of the cholesterinesters in the fats (perhaps also
in the phosphatides, though, up to now, this has not been tested).

Of the double refractive substances included in these five
classes, the cholesterinesters alone constantly and readily yield
permanent emulsions of double refractive globules. The sub-
stances in classes i and 2 frequently yield transient accidental
globule formations with double refractivity, but the results cannot
be relied upon. The substances in classes 4 and 5, on the other
hand, invariably yield emulsions containing globules, but these
are either not double refractive, or there is coarse crystalline pre-
cipitation of the globules without typical crystalline formation.
In all essentials, then, the double refractive substance is repre-
sented by the cholesterinesters.

In regard to the colour reactions of the cholesterinesters,

THE SUPRARENAL SYSTEM 289

Aschoff affirms that they colour a yellowish red with sudan, a
weak reddish colour with Nile blue sulphate, and grey with osmic
acid ; that they do not stain with neutral red or by Golodetz's
method ; and that, after fixing with chrome, they are converted into
insoluble lipoids with a positive colour reaction to sudan red.

The colour reactions of the double-refractive globules are
identical with those of the cholesterinesters. They stain with
sudan, Nile blue sulphate, and ponceau red in the same manner
as the neutral fats, and they are unaffected by the Golodetz
process which, by means of a mixture of formaldehyde and
sulphuric acid, stains the smallest traces of cholesterin a brown
to violet colour. Aschoff adopts the view that the presence of
the double refractive globules may represent only a modification
of the ordinary fatty degeneration, a special sort of storing-up of
fat, and that the occurrence of the double refractivity does not
point to a degenerative, endogenous formation of the globules.
The processes are invariably pure infiltration processes. This is
shown by the occurrence of isotropic and anisotropic globules
side by side in the same cell, and especially by the physiological
occurrence of such granules in the cells of the suprarenal cortex.

Nothing definite can be said concerning the physiological
significance of anisotropic substances. The view which prevails
at present is that, of the lipoids, lecithin plays the part of stimu-
lant of the ferments which serve as protective agents to the
cholesterins. It has been definitely proved by experiment that
with substances of a saponin nature (saponin, digitonin), choles-
terins give additive combinations which are insoluble and which
do not decompose readily. Of the functions of the globular
formations which are described as " myelin," we know practically
nothing.

In most cases where the double refractive substance is of
pathological origin, the process appears to be one of resorption
or of accumulation, characterized by marked profusion of the
cholesterin combinations.

Up to the present, no explanation has been found for the
physiological occurrence of the double refractive substance in the
suprarenal cortex. The assumption of Bernard and White, that
the suprarenal cortex secretes lecithin and cholesterin in combin-
ation with fat, is pure hypothesis.

Aschoff also mentions Ciaccio's finding, that treatment with
chromates renders the so-called myelin-forms of the suprarenal
cortex difficult of solution, and that at this stage, in spite of
treatment with alcohol and xylol and embedding in paraffin, they
show a very distinct sudan coloration. Ciaccio carried out certain
experiments with what he believed to be pure lecithin and
protagon, and he considers, from the results which he obtained,
that this sudan reaction is specific to lecithin, and he believes
lecithin to be a product of cell-metabolism.
19

2QO INTERNAL SECRETION

the other hand, as Aschoff justly points out, Ciaccio's
chemical tests cannot be regarded as of any very great value,
seeing that protagon does not exist as a chemical entity and that
pure lecithin is scarcely obtainable. The term lecithin is not
applicable to the lipoids of the suprarenal ; all that can be posi-
tively stated is, that they are lipoids, that like the medullary
substance of the nerves, treatment with chromates renders them
insoluble, and that they give a sudan reaction. From what has
been observed up to the present, it seems far more probable that
they are cholesterinesters and sphingomyelin.

In my own researches into the nature of the so-called lipoid
substances, the material was provided by the suprarenals of
swine, while the method which I employed was an adaptation of
S. Fraenkel's method for fractional distillation of the lipoids of
the brain.* It must be explained, first of all, that the process
consists in extracting the different groups of lipoid substances
in such a manner as to separate the groups in the process of
extraction. The tissues are first dehydrated with cold acetone,
and are then successively subjected to the action of a number of
suitable organic solvents. By this means, the cholesterin group
is separated from that of the unsaturated phosphatides, and this
again from that of the saturated phosphatides and the sphingo-
galactosides. By weighing the extracts it is possible to ascertain,
not exactly, but approximately, the amount of the total lipoids
as well as that of the single lipoid groups, together with the
relationship which these bear to the total amount of lipoids.

It has been shown by Fraenkel and his co-workers that every
organ contains lipoids which are, as a rule, characteristic of it ;
and that the same organ, in different classes of animals, contains
phosphatides and lipoids which are also chemically differentiated.
The differentiation which exists between the lipoids of different
organs in different species on the other hand, is both qualitative
and quantitative. Finally, it must be borne in mind that, in spite of
their ready crystallinity, the lipoids which are normally present
in the tissues may not be demonstrable by histological tests, for
they may be present in a state of solution in one another. Under
pathological conditions, the breaking-up of such a state of in-
solution may cause the one or the other substance to appear.

My experiments were conducted in the following manner :
Fresh pig's suprarenals were freed from the surrounding fat, cut
up in the mincing machine, dehydrated with plenty of cold
acetone, and then exhaustively distilled by means of boiling
acetone. The acetone extract contains the entire group of the
cholesterins, free cholesterin, cholesterinester, possibly also the

* These experiments were carried out under S. Fraenkel's direction
in the laboratories of the L. Spiegler Institute in Vienna. A detailed
account, together with chemico-analytical results, will be published in the
" Biochemischen Zeitschrift."

THE SUPRARENAL SYSTEM 2C)I

neutral fats and fatty acids, together with single phosphatides
soluble in acetone. Distillation with benzine follows, and this
process carries off the whole of the unsaturated phosphatides,
together with minute quantities of the sphingogalactocides. Sub-
sequent distillation with benzol, absolute alcohol, diluted alcohol
and ether yields the saturated substances.

The results of my analysis of the suprarenals of pigs were
as follows : The organs contained 74.61 per cent, of water to
25.39 per cent, of dry substance. Of this dry substance, 61.12
per cent, was albuminoids, &c., and 38.88 per cent, was lipoid
substances, together with extractive substances not as yet
chemically defined. These figures show the richness of the
suprarenals in lipoid material. But it must be remembered that,
by employing the whole suprarenal for these experiments, no
distinction between medulla and cortex is possible, and that the
scantiness of the medullary lipoid contents considerably lowers
the relative lipoid figure. By itself, the cortex would show a far
higher lipoid proportion.*

In any case, however, the suprarenals are among the organs
which are richest in lipoids, for more than a third of the total
dried substance consists of lipoids.

TABLE OF RESULTS OBTAINED BY DISTILLATION OF THE SUPRARENALS

OF PIGS.

25.39 Per cent, dry substance to 74.61 per cent, water. Percentage of

Dry substance 61.12 per cent, proteins, &c., 38.88 per cent, lipoids, &c. lipoid substances

Cold acetone extract (undefined extractive substances, cho-j -M 8 )

-jlesterin, cholesterinesters, unsaturated r ^Q' \6o.l

" " I phosphatides, possibly fats j

Benzine extract (unsaturated phosphatides) ... ... ... ... 24.68

Benzol extract . I I . 1.^4^ 15.2

Alcoholic and etheric extracts f saturated grouP j .. ... 13.86j

The figures which K. Linnert obtained by the same process
writh the brain of pigs are given for the sake of comparison.

23.09 per cent, dry substance to 76.91 per cent, water.

Dry substance 37.38 per cent, proteins, &c., Percentage of

and 62.62 per cent, lipoids lipoid substances

Acetone extract ... ... ... ... ... ... 22.48

Benzine extract ... ... ... ... .. 41.16

Benzol extract ... ... ... ... ... ... 25.02

Alcoholic extract ... ... ... ... ... n-35

From the hot acetone extract a cholesterinester was obtained
in crystalline form which, from the shape of its crystals, its

To obtain a clear idea of the lipoid contents of the interrenal tissue,
experiments should be carried out with Selachians, and these I propose to
undertake within the near future. Our knowledge in this direction is at
present confined to Grynfellt's statement, that Ville found fat in the inter-
renal bodies of Selachians, and that, upon saponification, this fat yielded
oleic acid, palmitinic acid, and stearic acid. Only the microscope test was
employed.

292 INTERNAL SECRETION

melting point, and its elementary analysis, was identified with
cholesterinpalmitate C27H45O (C10H31O). This substance was
present in a comparatively large quantity. .8 grm. was obtained
in a state of chemical purity from 2,320 grm. of suprarenal.

Special interest is further attaching to the discovery of a
cholesterinester which crystallized into very fine needles, which
became illuminated under crossed Nicol's prism; molecular
weight, 740. Elementary analysis showed figures corresponding
to the formula C51H92O2 ; thus the substance may be described as
carnauba-acid-cholesterinester.

These findings supplied material for a further investigation
of the question as to whether or no the suprarenal is the source
of the cholesterinester present in the blood. It is well known
that Hiirthle found cholesterinoleate, cholesterinpalmitate, and
cholesterinstearate in blood serum. The examination of pigs*
blood for cholesterinester shows that cholesterincarnaubate is not
present in the blood in demonstrable quantities.

Of the further results of my experiments, I propose to mention
here only that the benzine extract contains the monoamidomono-
phosphatide cephalin. The diamidomonophosphatide discovered
by Rosenheim, namely, sphingomyelin, must be present in the
alcoholic fraction, but, up to now, I have failed to isolate it.

My investigations into the nature of the suprarenal lipoids
cannot be regarded as complete, and it is proposed to pursue them
further at a future date. They show, however, that Aschoff's
view, that the double-refractive substance present in the lipoid
granules is represented by the cholesterinesters, receives con-
siderable support from the results of chemical analysis. They
suggest, moreover, that the cholesterinesters are substances
specific to certain organs, and perhaps also to certain species,
which are produced in the suprarenal, but which cannot be re-
garded as products of secretion, destined to be carried off by the
blood-stream.

THEORY OF THE FUNCTION OF THE INTERRENAL

SYSTEM.

At a first glance, the remarkable profusion of the lipoid
substances in the suprarenal cortex suggests that this tissue is
the locality in which the lipoid substances required by the entire
organism are formed. Hence the hypothesis arose that the lipoid
substances, the presence of which in each cell was believed to be
essential to the acquirement by that cell of its nutritive material,
were formed by a process of secretion in the suprarenal cortex,
or rather in the suprarenal tissue. The evidence in favour of a
secretory process on the part of the cortex was supplied by the
different nature of the lipoid contents in different cells ; by the dif-
ference between cells in different parts of thecortex, containing little

THE SUPRARENAL SYSTEM 293

fat, but much of the double refractive substance; by the finding of
fatty spheroids furnished with a double refractive cap ; and by other
phenomena indicative of a developmental cycle on the part of
the lipoid substances. Bardier and Bonne, who investigated the
structure of the suprarenal cortex after tetanizing the muscles,
found that there was an increase in the number of the cell
vacuoles, together with an increase in the volume of the cortical
granules; they interpreted these changes as the signs of an in-
creased secretory activity. Not only the lipoid granules, but the
pigment granules and other cell contents, were at that time re-
garded as products of cortical secretion.

A further consideration of the arguments in favour of secre-
tion led, however, to the conclusion that they were insufficient
to establish the existence of a secretory process occupied with the
elaboration of certain definite substances. The evidence merely
shows that the cortical cells are the locality in which certain
substances, more particularly the lipoids, are formed, and that
these lipoid granules form cell-contents of a kind subject to con-
siderable variation in the matter of number and size ; but it does
not show that these cell contents are destined to pass into the
blood-stream. Comparative chemical examination of the supra-
renals and of the blood lends no support to this theory in so
far as the lipoids are concerned. Bonnamour's own experiments,
together with a critical survey of the literature of the subject,
led him to the conclusion that the findings which, up to now, are
forthcoming, do not justify the assumption of a secretory activity
on the part of the interrenal tissue.

Bonnamour regarded the suprarenal cortex as an organ
which, owing to its high lipoid contents, is peculiarly suited to
the absorption and neutralization of the toxic products of meta-
bolism.

The earlier investigators ascribed an antitoxic activity to the
suprarenal as a whole. According to the brothers Marino-Zucco,
the suprarenals neutralized neurin ; Abelous and Langlois believed
that they rendered harmless those products of muscular activity
which produce the symptoms of fatigue. The antitoxic activity
of the suprarenals was believed to extend also to exogenous toxins,
and there are a number of communications (Oppenheim and
Loeper, Bernard and Bigart) which describe the effects of supra-
renal and of suprarenal extract in reducing the activity of various
toxins. In so far as these results are concerned with toxins-
such as phosphorus, strychnine, cyanide of potassium, &c. — the
effect of which is antagonistic to that of adrenalin; the apparently
antitoxic action is sufficiently explained by the slowing of re-
sorption which, as A. Exner showed, is a property of adrenalin.
It may be mentioned here that the neutralization of strychnine
by adrenalin which Falta and Ivcovic described, is, in
Jaunschke's opinion, partly accounted for by this property of
adrenalin and is in part the result of adrenalin stimulation.

2Q4 INTERNAL SECRETION

Matters are quite otherwise, however, in regard to the anti-
toxic activity of the suprarenal cortex. The anatomical and histo-
logical changes which take place in the suprarenal in infective
diseases, and in experimental poisoning with bacterial toxins, have
been described in an earlier chapter. Later experiments (Oppen-
heim and Loeper, Bernard and Bigart, Moschini, Nicolas and
Bonnamour) have shown beyond all doubt that poisoning with
metals is accompanied by structural changes in the cortical cells,
changes in the nature of the lipoid granules, as well as signs of
hyperplastic processes in the suprarenal cortex; and that these
changes are even more marked in experimental infective and toxic
states induced by bacterial agents.

The suprarenal lipoids are able te fix and neutralize toxins
in vitro. Myers showed that cobra toxin loses its toxicity if
mixed with an emulsion of suprarenal cortex, but that its toxicity
is unchanged by emulsion of the suprarenal medulla. According
to Elliott, diphtheria toxin is not neutralized by suprarenal ex-
tract. Takati's experiments show that both phrenosin and
the oleic acid obtainable from it (Thudichum's neurostearic acid),
neutralize large quantities of tetanus toxin. Rosenheim and
Tebb drew attention to the large amount of oleic acids which the
suprarenal cortex contains.

Further experiment is required, however, before the anti-
toxic activity of the interrenal system and the part played therein
by the lipoids can be established. It is the business of future
investigators to decide whether the antitoxic process extends to
the products of normal metabolism, and whether the neutralization
of endogenous toxins is a physiological function of the interrenal
tissue. An antitoxic activity on the part of the suprarenal cortex,
and a relationship between this activity and the elaboration of
adrenalin in the suprarenal medulla, have long been assumed, but
the hypothesis is without sufficient foundation. A closer investi-
gation of the arguments in its favour shows that there are no
grounds for the assumption of a combined antitoxic and internal
secretory activity on the part of the suprarenals.

If, however, we consider the possibility of the interrenal
system being a true internal secretory organ, which supplies a
specific hormone, different from adrenalin, to the blood-stream,
the assumption is supported by observations which point to the
suprarenal as an influential factor in the growth of the body, the
development of the sexual glands, and the changes which take
place during puberty in the normal human organism. There is
sufficient evidence in this direction to justify the inclusion of the
interrenal system among that group of organs which, like the
thyroid, thvmus, hypophysis cerebri, and the sexual glands,
exercise either a direct or indirect influence, by means of their
assimilatory hormones, upon the somatic and psychic develop-
ment of the individual.

THE SUPRARENAL SYSTEM 295

THE SUPRARENAL CONSIDERED AS AN ENTITY.

In the absence of any certain knowledge regarding the
physiological activity of the interrenal system, it is difficult to
arrive at a conclusion concerning the functional relationship be-
tween the portions of the interrenal and adrenal systems which
are united to form the suprarenals. The two systems are morpho-
logically so different and, in a large number of animal species,
are topographically so entirely separate, that an independence
and an autonomous functional activity on the part of both must
be assumed. Even the anatomical union of portions of the two
systems into a single organ cannot be regarded as proof of a
functional interdependence. For the topographical association
of morphologically and physiologically differentiated tissues is
not without analogy — on the contrary, it is of frequent occurrence
in the organism. But it cannot be denied that the inclination
on the part of the interrenal and adrenal systems to unite to form
a morphologically homogeneous organ — an inclination which in-
creases and becomes more intimate with phylogenetic develop-
ment— suggests that this specific association is not without sig-
nificance. There may also be a functional connection, a co-
ordinate or subordinate relationship between the two systems,
which thus unite in the suprarenal for the performance of a
higher organic function.

The absence of definite facts has not, however, militated
against the formulation of hypotheses concerning the function
of the homogeneous suprarenal. Even before it was known that
the suprarenal system was biologically made up of two parts,
Langlois attempted to combine into one the two theories at that
time current concerning the function of the suprarenals. He
believed that the internal secretory and the antitoxic activities
were interdependent. This view, which was adopted by Neusser,
Boruttau and partly also by Battelli, may be formulated as fol-
lows : That certain toxic products of metabolism, chiefly the
result of muscular exertion, are neutralized by the suprarenal
cortex, and that from the material thus supplied the adrenalin
necessary to the working of the economy is elaborated by the
medulla.

The experiments of Abelous and Langlois, already described,
constitute the evidence in favour of the accumulation and neutra-
lization, within the suprarenal, of the products of muscular
fatigue. Boruttau then concluded that, after the transformation
process, portions of the original products of fatigue remained un-
changed in the suprarenal. His view is based upon experiments
in which a change in the contractions, similar to the first stages
of fatigue, was produced in frog's muscle after treatment with
curarin by the application of suprarenal extract. Battelli and
Roatta found a decrease in the adrenalin contents of the supra-

296 INTERNAL SECRETION

renal of dogs exhausted by muscular exertion, and a progressive
increase during recovery from such exhaustion. Battelli explains
these findings by, in the first instance, an abnormal expenditure
of the finished adrenalin ; and in the second, by the deposition
and accumulation of fresh precursors. He supposed that these
precursors, which he terms proto-adrenalin, represented the
material for the progressive increased production of adrenalin
during repose. Schur and Wiesel demonstrated the increased
adrenalin contents of the blood during muscular exertion by
means of Ehrmann's pupil reaction, and the diminution in active
substance present in the suprarenal by the weak chromium re-
action. These findings of Schur and Wiesel's were, however,
not confirmed by Kahn's very exact experiments.

Abelous, Soulie and Toujan investigated the formation of
adrenalin in the suprarenal by means of a series of experiments,
and the results at which they arrived are very remarkable. It
must be assumed that these authors employed, as a quantitative
adrenalin test, the colorimetric method with iodine which they
themselves formulated. They first showed that there was an
increase in the adrenalin contents of pounded suprarenal, if the
latter was kept for twenty-four hours at a temperature of 40°.
In their view, however, this post-mortem formation of adrenalin
takes place principally in the cortical substance. For they found
that, after twenty-four hours in an incubator, the adrenalin con-
tents of the pounded cortex were 33 to 60 per cent, higher than
those of the control specimen kept at o°. These results led them
to the conclusion, that adrenalin is formed in the cortex and is only
stored up in the medulla. In a further series of experiments, they
next showed that the addition to pounded suprarenal of a small
quantity of tryptophan, obtained by auto-digestion of the pan-
creas, was followed by a considerable increase in the adrenalin
contents ; and they think it probable that tryptophan is one of
the matrices of adrenalin. They found, however, that the addi-
tion of pure tryptophan did not produce anything like the same
effect as the fluid product of pancreatic auto-digestion. They
tried, therefore, the effect of autolysates or extracts of putrefying
organs, and found that here also there was an increase in the
adrenalin contents of the pounded suprarenal ; from this they
conclude that adrenalin is formed post mortem in the cells of
the suprarenal. The fact that putrid substances from the muscles
produce a very large increase (the double and over) in the
adrenalin contents, appears to them a proof of the relationship
between the formation of adrenalin and the chemical processes of
the muscles.

Toujan next carried out experiments supplementary to these;
he summed up the results in a definite statement, that the supra-
renal cortex contains a precursor of adrenalin, and that adrenalin
is formed from it.

THE SUPRARENAL SYSTEM 297

Toujan found that cortical extract, which had been so com-
pletely freed from medullary substance that it ceased to give a
chromium reaction, contained a vasotensor substance which did
not react to ferric chloride. He regards this cortical product as
a crude precursor of adrenalin and gives to it the name of pro-
adrenalin ; he identifies it with the granules which are histo-
logically demonstrable in the cortical cells, and which are com-
bined with a body of fatty nature. He found that, after twenty-
four hours in a thermostat, the specific action of cortical extract
is very much more intense than that of fresh extract, and he
considers this sufficient proof of the formation of adrenalin from
the crude substance which he discovered in the cortex.

The results communicated by Toujan are in need of further
confirmation. H. Poll, who expected to be able to confirm " these
remarkable findings," reports as follows : " Proadrenalin and
adrenalin, cortical extract and medullary extract, all react to most
tests; they respond in the same way to oxidizing substances
(Battelli's iodine method), they produce glycosuria, contraction of
the unstriated muscle fibres, and mydriasis of frogs' eyes." In
regard to the latter, Poll mentions that the reaction was effected
by Ehrmann ; in the other instances he does not make it clear
whether the experiments were his own or not.

In regard to the glycosuria test, it must be mentioned that
Landau also believed that glycosuria originated with a substance
present in the suprarenal cortex. In opposition to the well-
founded view that adrenalin is present in the medullary substance
and in extracts of other portions of the adrenal system, Landau
suggests the possibility that adrenalin obtained by Takamine's
method is derived from the suprarenal cortex. He states that,
after the intravenous injection of cortical extract, death followed
rapidly, the same symptoms and post-mortem signs being ob-
served as after the injection of medullary substance and of
adrenalin. Landau's statements do not, however, bear analysis.

The only exact proof, up to the present, of the formation of
adrenalin after death is supplied by G. Bayer's experiments, and
these do not confirm the hypothesis advanced by Toujan.

Bayer found that, when pounded suprarenal was diluted with
putrid material, a stronger and more rapid mydriasis was pro-
duced than when the suprarenal was diluted with water. But
when employed alone, the putrid fluids also produced mydriasis,
probably due to the presence of phenylalanin, and this was fol-
lowed by myosis. An increase in the adrenalin contents was not
demonstrable by Ehrmann's reaction. The iodine test produced
a stronger reaction in suprarenal cells to which putrid fluids
were added than in the control cells which were treated with
water. Further experiment showed, however, that this result
was not due to the post-mortem formation of adrenalin, but to
an intensification of the chemical test. According to Bayer, the

298 INTERNAL SECRETION

putrid liquids contain alanin, phenylalanin, and probably other
products of the decomposition of albumin, and by these the
colorimetric iodine test for adrenalin is intensified. Bayer be-
lieves that the increase in the amount of adrenalin which Abelous,
Soulie and Toujan describe, is apparent only.

Thus the only experimental evidence which has been ad-
vanced up to the present, in favour of a functional inter-
dependence between cortex and medulla, is proved to be un-
reliable.

Poll writes as follows concerning the hypothesis of a unity
of function on the part of the suprarenals : "Whether right or
wrong, it is undoubtedly true that this hypothesis brings into
line in what is, at first sight, a most remarkable manner, a
number of anatomical and physiological facts which are other-
wise obscure." The morphology of the homogeneous suprarenal,
and its vascularization — especially the intimate vascular association
between cortex and medulla in mammals — undoubtedly suggest
an important functional relationship between the two parts.

The remarkably rich vascularization of the suprarenal, and
the peculiar relationship which subsists between the parenchyma
cells and those of the surrounding capillaries — and there is no
doubt that the capillaries act as ducts for the conveyance of the
medullary secretion — have already been described. The circu-
lation throughout the entire organ is remarkable and unique, and
demands a short description.

The older scientists, of whom Ecker (1844) was the first,
noticed that, in certain classes of animals, the suprarenal possesses
a portal system of its own.

Ecker's descriptions and drawings of the suprarenals and
their vessels in the adder (Coluber natrix) show7 that these organs
lie close to the ven^e renales revehentes, on the inner surface of
the ovary in the female, and on the inner surface of the testicle
and vas deferens in the male; that they are furnished with venous
vessels (vena? suprarenals advehentes) formed by the combina-
tion of two or three intercosto-spinal veins, which extend to the
external surface of the organs where they form arcade-like anas-
tomoses. From these proceed the minute branches which, to-
gether with the hair-like arterial vessels, form the capillary system
of the suprarenals. Numerous fine venous branches are given
off by the capillary network, and these combine to form larger
veins leading away from the organ (vena? suprarenales revehentes)
and opening either into the vena renalis revehens sinistra, or
directly into the vena cava posterior. According to Ecker, then,
Ophidians possess, in addition to hepatic and renal portal veins,
a third or suprarenal portal system, the roots of which are situated
in the wall of the body and the spinal cord, while its branches are
distributed through the suprarenals. Ecker also states that the
vascular conditions in Chelonians and tailed Batrachians to some
extent resemble those in Ophidians.

THE SUPRARENAL SYSTEM 2Q9

The small portal system of the suprarenals was minutely in-
vestigated in different animal classes by S. Jourdain (1859). He
found that it was present, not only in Ophidians, but in Chelo-
nians, crocodiles and Saurians (Corti, 1847), thus in all the
reptilian orders.

In this " Beitrage zur Entwickelungsgeschichte des Venen-
systems der Amnioten " (1892) F. Hochstetter gives a detailed
description of the suprarenal portal system in reptiles, together
with an excellent drawing showing the conditions in Lacerta
viridis. In a later work he describes the suprarenal portal system
in Crocodilns niloticus.

In Batrachians (anura), according to Jourdain, the branches
of the vena renalis efferens, before uniting in the median line to
form the vena cava posterior, form long anastomoses and a series
of long arcades, which surround the yellowish bodies of the
suprarenal, and to some extent pass into the suprarenal tissue.
Jourdain does not, however, venture upon a decision as to whether
this arrangement constitutes a suprarenal portal system. Jourdain
found that, in Selachians, a small number of fine venous branches
led into the external layer of the suprarenal cortex, while the
median layer contained numerous veins leading into the venas
cardinales ; he believes that this represents a small portal system.
In Jourdain 's drawings, the " suprarenals " are invariably asso-
ciated with arterial branches, but it is not possible to say whether
these suprarenals are interrenal bodies or whether they are adrenal
organs. The intimate association, in fish, between the suprarenal
system and the arterial and venous vessels, has been commented
upon by all the more recent investigators, but a suprarenal system
as such has not been described.

A special interest is attaching to the conditions which obtain
in birds. The suprarenals are here furnished with two separate
veins upon both sides. Upon the median side of the suprarenal
—that which is nearest to the vena cava — is a comparatively short
and broad vein (vena suprarenalis interna), which opens into the
vena cava. Upon the lateral side of the organ is a second vein
(vena suprarenalis externa), the course of which is complicated.
In the majority of birds, the vena externa is formed by the union
of one or two dorsal intervertebral and intercostal veins, together
with a perforating dorsal cuticular vein. More rarely, a sacral
intervertebral vein and a vein from the upper suprarenal surface
empty themselves into the vena externa. As early as 1844,
Neugebauer foresaw the real significance of this vena externa.
The comparatively large size of the lumen at the place where the
vein enters the organ, together with the absence of a direct com-
munication with the vena interna, suggested to him the idea that
this vein might convey blood to the organ.

A few years later, the existence of a vena afferens upon the
external surface of the suprarenal of birds was proved by Gratiolet.

300 INTERNAL SECRETION

Jourdain found that it was present in more than thirty species,
and he discovered that fluid injected into the vena externa passed
readily into the vena interna, and vice versa. He believes, how-
ever, that the communication between the two vessels is not direct
but that it is effected by means of a network of capillaries, the
vena externa representing the afferent, and the vena interna the
efferent, portion of the portal system of the suprarenal. He was
unable, however, to bring direct proof in support of his theory.

Since Jourdain, there has been, as far as my knowledge goes,
no further investigation into the relationship between the two
suprarenal veins in birds. It seemed to me advisable that the
matter should be elucidated, and Professor F. Hochstetter was
kind enough to lend me his help in the matter. Up to the present
it has not been found possible to obtain the venous capillary
network of hens by means of corrosion preparations. But I was
able to follow the course of the vessels very exactly in a series
of sections obtained from the embryo of a sparrow immediately
before hatching. I found that the vein which approaches the
suprarenal from the lateral side, enters the organ, forms large
sinuous spaces within it, and probably afterwards breaks up into
capillary vessels. In sections taken more towards the cranium,
large veins filled with blood are seen at the median surface of the
suprarenal; these are the ven^e suprarenales ; they run in an
oblique direction towards the vena cava and open into it. The
arterial vessels also approach the organ upon the median side.

It is evident from this that a suprarenal portal system is
present, not only in reptiles, but in birds, and that blood is con-
veyed to the suprarenals by veins as well as by arteries.

In mammals, however, blood is supplied to the suprarenals
by way of the arteries only. According to Pettit, conditions
resembling the portal system of birds are encountered in certain
mammalian species. The last intercostal vein proceeds directly
to the suprarenal, and opens into the vena cava at the place where
the kidneys form an angle with it, in which angle the suprarenal
lies, close against the walls of both vessels. If one or more
branches from the suprarenal veins empty themselves into the
intercostal vein, the appearance produced will suggest that the
latter is not an efferent, but an afferent, vein. Pettit draws atten-
tion to a peculiar venous distribution which he has observed in
monkeys and in certain rodents (kangaroo, sheep), and which has
been observed in man by some French anatomists (Ouenu and
Lejars). Single branches proceed from the venous arches of the
adipose capsule of the kidney to the suprarenal, which they cover,
finally penetrating into the interior of the organ. Pettit is
inclined to regard these venous branches as indications of a
suprarenal portal system.

It is, however, very doubtful whether these rudimentary venas
afferentes suprarenales have a functional significance in mammals.

THE SUPRARENAL SYSTEM 30!

However this may be, the vascular distribution in the suprarenal
— that is to say, the arrangement of the arteries leading to it and
the manner in which they communicate with the great central
vein leading from it — is very remarkable. Flint's excellent work
and the experiments of Srdinko have supplied very exact infor-
mation concerning the suprarenal in mammals, and this is supple-
mented by Landau's corrosion preparations. Based upon the
representations of these authors, the suprarenal circulation appears
to be as follows.

A large number of the arteries which enter the suprarenal
break up in the cortex into a network of capillaries, which traverse
the connective tissue septa in a manner which accords with the
structure of the latter, being straight in the zona fasciculata, and
forming a network in the zona reticularis. After traversing the entire
cortex, the blood reaches the medulla in wide sinus-like vessels ;
in the medullary capillaries it flows round the chromaffine cells,
and afterwards collects in small veins which increase in size, and
all of which open into the great central vein. The arteries, and
probably the afferent veins which supply the suprarenal capsule
and the portions of the zona glomulerosa abutting on to it, also-
break up into capillaries, which again combine to form the vena?
revehentes.

A certain number of the arterial vessels, the arterias per-
forantes (Srdinko) penetrate the cortex and reach the medulla
directly ; there they break up into capillaries, which also follow
the course of the cell columns, and finally discharge their blood
into the great efferent vein. This separate blood supply of the
medulla is the outcome of the secondary invasion, during fcetal
life, of the interrenal organ by adrenal tissue.

This peculiar vascular distribution has been interpreted in
the following manner (Poll). It is suggested that, in the first
place, the blood from the body which has become deprived of its
adrenalin contents, is carried by the vessels which exclusively
serve the medulla directly to the adrenalin-forming cells, that these
part with the secretion with which they are charged, and that the
blood, with its reinforced adrenalin contents, is again returned to
the general circulation. In the second place, the venous blood dis-
charged from the cortex contains the products of the metabolism of
this tissue, which constitute the raw material for the elaboration of
adrenalin, and this raw material is immediately conveyed to the
medulla. It would seem from this that, in certain species in which
the adrenalin demand is very high, as in mammals and birds,
there is a combination on the part of the two apparatuses which
contribute to the elaboration of adrenalin, thus establishing a
perfected method of production. In species in which the two
suprarenal systems are independent, the semi-product supplied by
the interrenal bodies is carried through the entire circulation
before it reaches the site of its ultimate completion, namely, the
adrenal tissue.

302 INTERNAL SECRETION

This assumption of a function on the part of the interrenal
tissue by which the raw material of adrenalin is provided, would
explain the importance of the interrenal tissue to the life of the
organism ; and would account for those instances where animals
survive double epinephrectomy, by the presence of accessory inter-
renals which thereafter become hypertrophied. In such cases as
these, Poll believes that the organism returns, to a certain extent,
to a previous developmental stage, that at which the two supra-
renal systems are topographically independent, as in fish.

Fascinating though this hypothesis of an interdependent
function on the part of the two suprarenal systems may be, it
must be remembered that its sole foundation at present is upon
morphological grounds ; that it rests entirely upon the ontogenetic
and phylogenetic association of portions of the interrenal and
adrenal systems, together with the peculiar conditions which
govern the vascular communication between the two systems. It
must not be forgotten that, up to now, all attempts to prove a
homogeneity of function on the part of the suprarenals, whether
by experimental biology or from the results of human pathology,
have signally failed.

It must be frankly confessed that, as things are at present, we
have as little certain knowledge concerning the functions of the
homogeneous suprarenal as we have of the function of the inter-
renal tissue; and it is only by means of investigation of the latter
that we can hope to arrive at any definite information concerning
the former.

CAROTID GLAND AND COCCYGEAL BODIES.

The carotid gland, wrhich we have learnt to regard as a por-
tion of the adrenal system, may be briefly described as follows.
In man, this organ measures 5 to 7 mm. in length, 2^ to 4 mm.
in breadth, and ij mm. in thickness. It is situated at or within
the bifurcation of the common carotid artery and, on account of
its situation and its considerable nervous provision, was, by the
older anatomists, called the intercarotid ganglion.

Luschka (1862) was the first to undertake an exact micro-
scopic examination of this body ; his findings led him to the
conclusion that it was a glandular organ auxiliary to the cervical
sympathetic. He believed it to be a nerve gland, and named it
glandula carotica. Arnold (1865) next declared that the glandular
structure described by Luschka was, in reality, an arrangement
of blood-vessels, the walls of these vessels being formed of several
layers of epithelium ; he recommended that the organ should be
called glomeruli arteriosi intercarotici. According to Eberth (1870),
however, the cell-agglomerations resembling epithelium by which
the vessels are surrounded, do not form a true epithelium, but a
vascular perithelium. Waldeyer (1872) compared the epithelial

THE SUPRARENAL SYSTEM 303

cells which he found in the vessels of the testicles with Eberth's
perithelial cells from the glandula carotica, and with other peri-
vascular formations also composed of large cells from the
coccygeal bodies. Waldeyer classed these three structures
together under the name of " perithelial organs."

The supposed glandular character of the carotid organ
appeared at hrst to be borne out by the history of its development.
Stieda (1881) came to the conclusion that the glandula carotica was
a glandular organ developed from the epithelium of one of the
branchial clefts. Jakoby (1895) lnen proved that the epithelial
derivative of the third branchial cleft, which was supposed by many
authors to be the primordial beginning of the carotid organ, is, in
reality, the beginning not of that organ but of the external para-
thyroids (glandula parathyroidea III). This was confirmed
by later authors (Prenant, Simon, Groschuf, Verdun, Fusari). At
the present day, the branchial origin of the carotid organ is main-
tained by Alaurer, but only in this sense, that he believes that it
splits off from one of the parathyroids which take their rise in the
second branchial cleft. These embryological discoveries have, to
a large extent, undermined the theory of the carotid organ as an
epithelial gland.

The examination of certain tumours of the glandula carotis
led Marchand (1891) to the conclusion that this organ repre-
sents neither the development of a vascular network, nor is it a
gland or a ganglion ; he regards it as a rudimentary organ for
which he proposes the name of nodulus caroticus.

R. Paltauf (1891) studied the development of the carotid
organ and its tumours, and he classed this structure with the
glandular organs, in the sense in which we are accustomed to
describe the lymph-glands and the thymus as " glands." This
definition involves neither a definite physiological function, nor a
histological or histogenetic uniformity.

Schaper (1892) particularly emphasizes the fact that the
typical cell agglomerations in the carotid organ are neither vessel-
wall cells nor gland cells; that, moreover, the organ is in no sense
rudimentary, but, like the coccygeal gland and other large or
small agglomerations of similar cells (perithelial cells and plasma
cells), it may possess a definite physiological function.

Stilling (1892) was the first to describe cells in what, like the
other authors, he terms the ganglion intercaroticum, which, like
the medullary cells of the suprarenals, stain brown with potassium
bichromate. He compared these cells with those which he found
in the smaller bodies attached to the abdominal sympathetic.
Stilling says : The intercarotid ganglion is neither a simple
vascular network, nor a rudimentary organ : it is a vascular
gland, or blood-gland, with a structure analogous to that of the
suprarenal capsules."

The absence of any certain knowledge concerning the

304 INTERNAL SECRETION

character of this organ is expressed by the fact that, in the new
anatomical terminology, its designation was glomus caroticum.

A. Kohn's (1910) minute histological investigations have com-
pletely elucidated the systematic position occupied by the carotid
organ. It is essentially composed of a largish agglomeration of
groups of chromaffine cells, and is traversed by a considerable
number of nerve fibres, the majority of which are without medulla,
and in which the cell balls and single ganglion cells are situated.
The organ is extremely vascular and the structure and arrange-
ment of the vessels are not in any way characteristic. Its pri-
mordial beginning is in embryonal ganglion cells of the inter-
carotid sympathetic nerve plexus. According to Kohn, the most
fitting name for the organ would be " paraganglion inter-
caroticum," and it should be included in the group of the
paraganglia, which he regards as members of the sympathetic
nervous system. But, as we have previously shown, the para-
ganglia form part of the adrenal system, and the paraganglion
intercaroticum cannot be classed separately from these.

The coccygeal body (glomus coccygeum) was termed by
Luschka (1859) glandula coccygea, and was described by him as
a reddish yellow body of about the size of a small pea, situated
at the tip of the os coccyx and depending from the terminal
branches of the medial sacral artery. Luschka himself held that
this organ " might prove to be an integral portion of the sym-
pathetic nervous system, but that in the meantime, owing to
certain external characteristics, it w7as expedient to include it in
the mixed company of the ductless glands." And there the so-
called coccygeal gland has remained. The structural analogy
between this organ and others of the same group (hypophysis
cerebri, glandula carotis, suprarenal) has frequently been pointed
out. Waldeyer compared the round cells of the interstitial con-
nective tissue of the testis with the coccygeal and carotid glands,
and classed them together under the name of perithelial organs.

Not only is there a similarity of structure between the carotid
and the coccygeal glands, but, according to Jacobsson, they also
resemble one another in their histogenetic relationship to the
sympathetic. According to Kohn, the carotid and coccygeal
glands are only the terminals of the continuous paraganglion
chain by which the sympathetic is accompanied. Schapper ex-
pressed the same view.

And yet O. Stoerk (1907) showed that the cells of the
coccygeal gland do not react to chromium during either fcetal
or post-fcetal life ; and further, that they probably have a genetic
connection with the media of the vessels. According to Stoerk,
moreover, the coccygeal gland has no developmental relationship
to the sympathetic; the structures which Jacobsson identified with
the primordial beginnings of this body have no connection with
it whatever, but are in reality young chromaffine bodies.

HYPOPHYSIS CEREBRI 305

In his book on comparative anatomy and embryology (1907)
S. v. Schuhmacher shows that the coccygeal gland of man
corresponds to the glomuleri caudales of lower mammalian species,
and that both are to be regarded as arterio-venous anastomoses.
The primal origin of the coccygeal gland in man is to be found
in a local thickening of the medial sacral artery and its branches.
The muscular fibres of the vessels assume an epithelioid appearance
even in the embryo. In adults the cells of the muscular structure
of the artery are shortened and broadened, the nuclei are spheroid
and react weakly to dyes. Thus it appears that the layers which,
in the anastomotic vessels, are the continuation of the arterial
muscles, have been taken for everything except what they are,
namely, modified vessel muscles. According to v. Schuhmacher,
this organ in man should rightly be termed glomus coccygeum ;
like the glomeruli caudales of animals, it consists of a network
of branched and convoluted vessels, which cannot in any sense
be credited with an internal secretory function.

HYPOPHYSIS CEREBRI (CEREBRAL APPEND-
AGE,* PITUITARY GLAND).

From the earliest times the pituitary body has been regarded
as an organ possessing a secretory function. Galen and Vesalius
believed that the mucus (pituita) formed in the brain was excreted
by the agency of the pituitary body. Later authors, however,
(Willis, Vieussens, Sylvius, Boerhave, Monroe) inclined to the
view that the cerebro-spinal fluid was secreted by that organ.
Magendie (1847), who investigated the genesis of the cerebro-
spinal fluid, regarded the hypophysis as an organ resembling the
lymph glands, and he believed that it collected the lymph from
the brain and conveyed this lymph into the circulation.

Liegeois (1860) was the first to include the hypophysis among
what were at that time known as the vascular or blood glands ;
he described histological findings which he believed pointed to
the formation of blood in this organ. It is interesting to note
that the brothers Wenzel (1810) believed that epilepsy was due
to an accumulation of colloid in the hypophysis.

After the formulation of the doctrine of internal secretion by
Brown-Sequard, a large number of observations were published
which sufficiently justified the inclusion of the hypophysis among
the internal secretory organs. The fundamental argument was
supplied by Rogowitsch, who found that extirpation of the
thyroid was followed by hypertrophy of the hypophysis. The

* Before the introduction by Soemmering of the term Hypophysis
cerebri, the following names were also used : Glans pituitam excipiens
Vesalius, caput rosse, colatorium, labrum, lacuna, infusorium, concha pelvis,
cmbotum, pelvis colatoria, sentina encephuli.

20

306 INTERNAL SECRETION

decisive evidence was, however, brought forward by Marie (1886)
who, under the name of acromegaly (abnormal growth of the
" acral " portions of the body), described a clinical condition, not
sharply separated from gigantism, which had previously attracted
the attention of a certain number of authors (Friedreich, hyper-
ostosis of the entire skeleton ; Lombroso, general hypertrophy or
macrosomia ; Fritsche and Klebs, gigantism). In combination
with Marinesco (1891), Marie showed that changes of the hypo-
physis, generally tumours, are invariable in this condition, and
it seemed from this that the cause of the peculiar anomalies of
growth must lie with the pathological condition of the hypophysis.

This momentous discovery of Marie's excited an immense
amount of interest in the clinical and pathologico-anatomical
aspects of anomalous development, while at the same time it
pointed to the hypophysis as the centre of interest. These re-
searches extended to the morphology of the organ and its patho-
logical changes, with the result that a considerable number of facts
have been brought to light which largely explain its functional
significance.

Physiological research was first conducted by means of
experimental extirpation. An important advance was made by
Oliver and Schafer (1894), who discovered that the watery extract
of hypophysis possesses distinct physiological properties.

The most instructive 'results have been obtained, however, by
means of hypophysis surgery in man, and these results have been
confirmed and completed by recent experiments with animals.

ANATOMY.

The hypophysis is situated within the cranium at the base of
the brain ; it is connected with the latter by the infundibulum ;
and it more or less completely fills the sella turcica. The sella
turcica is lined with dura mater, which, in the form of a fibrous
lamella (diaphragma sellas turcica?), covers the surface of the
hypophysis, leaving a circular opening through which the in-
fundibulum passes. The lateral boundaries of the hypophysis
are formed by the walls of the cavernous sinus. The infundi-
bulum is surrounded by the circular sinus of Ridley, formed from
small anterior and posterior venous branches. The hypophysis is
separated from the internal carotid artery by the sinuses of the
dura mater. It lies in the anterior angle of the optic commissure,
the posterior portion of the organ being occasionally covered by
the anterior edge of the commissure.

The hypophysis is flattened from back to front and upon the
surface. Its average size in an adult man is given by Erdheim
as follows: breadth, 14.4 mm.; thickness, 21.5 mm.; height,
5.5 mm. The average weight at the average age of 33 J years is
given by Comte as 59 eg. Caselli found that in fifty men

HYPOPHYSIS CEREBRI 307

the average weight was 66.7 eg., in fifty women, 73.1 eg.
His figures are high owing to the fact that his subjects
were mentally alienated; it is said that, in this class of case,
the weight of the hypophysis is in inverse ratio to that of
the brain. According to Erdheim and Stumme, the average
weight of the hypophysis in the male is, in the second decade of
life, 56.3 eg. ; in the third decade, 59.3 eg. ; in the fourth decade,
64.3 eg. From then onwards the weight gradually declines ; in
the fifth decade it is, on an average, 61.4 eg. ; in the sixth, 60 eg. ;
and in the seventh, just a shade higher, 61.2 eg. The average
weight of the hypophysis in women who have never borne a
child is, decade for decade, almost identical with that of men ; in
women in whose pregnancy anamnesis is unknown, the average
weight is generally higher — 71.6 eg. as against 60. i in nullipara
and 61 in men. During pregnancy the hypophysis undergoes
a remarkable increase in weight. The minimum weight of 65 eg.
in a primapara is larger than the minimum weight in a nullipara;
even the maximum known weight of 75 eg. in a nullipara does
not equal the average figure of 84.7 eg. in the primipara. The
increase in the size of the hypophysis takes place almost ex-
clusively in the length and breadth ; in the anterio-posterior
diameter it is barely noticeable. At the termination of pregnancy
the weight is again reduced, but should pregnancy again occur
it rises to a figure even higher than before. The average weight
of the hypophysis in the multipara at the termination of normal
pregnancy is 106 eg., a figure considerably in advance of the
weights which have been ascertained in the case of the primipara.
The difference in the maximal weights is even greater, that of the
multipara being 165 eg. and that of the primipara no eg. The
increase in weight is accompanied by structural changes which
will be described later.

The hypophysis is supplied with blood by means of minute
branches from the internal carotid artery; the blood is carried
away into the circular sinus by small veins.

Section of the hypophysis shows, even to the naked eye, that
the organ consists of two parts ; the anterior portion is a hard,
kidney-shaped lobe, concave posteriorly, pale yellow to grey-red
in colour, and represents the epithelial or glandular portion of
the hypophysis (the true pituitary gland). The posterior portion
is a smaller, rounded, white, soft lobe, situated in the concavity
of the anterior lobe; it represents the nervous or infundibular
portion of the organ (the true hypophysis or neurohypophysis).
The two lobes are joined together and enclosed in a common
fibrous capsule. The hypophysis is attached to the brain, as
previously mentioned, by means of the funnel-shaped infundi-
bulum. The latter is a prolongation of the floor of the third
ventricle, the tuber cinereum ; it first forms a hollow sphere which
represents a prolongation of the third ventricle, it then penetrates

308 INTERNAL SECRETION

the diaphragma sellas turcicas and the dura mater, and finally
enters the hypophysis, where it terminates in a slightly thickened
end. The infunclibulum usually enters the hypophysis at the
centre of the hilus of the anterior lobe, though occasionally it
enters the lobe itself. The tissue connection is always with the
infundibular portion only.

HISTOLOGY.

The anterior lobe of the hypophysis consists of a connective
tissue framework, with longish oval interstices at the periphery and
larger rounded ones in the interior. These spaces contain groups
of cell columns, which sometimes form glandular tubules provided
with a lumen. Flesch divided the glandular cells of the anterior
lobe into two classes in accordance with their size, form, and
specific colour reactions ; namely, the chromophile cells, and the
chromophobe or adelomorphous cells.

Of the chromophile cells, some are spheroid or polyhedral ;
with a nearly homogeneous protoplasm, which is full of fine
granules and stains strongly with eosin ; while the nuclei are small
and round, frequently in the centre of the cell, and stain well with
ha^matoxylin. These are known as the eosinophile cells. A
second group is composed of somewhat large cells, of regular
shape, which stain a very good dark blue with hasmatoxylin ; they
are filled with coarse granules, the nuclei are placed eccentrically,
and the plasm contains rounded vacuoles. These are known as
the cyanophile or basophile cells.

The chromophobe principal cells (Hauptzellen) are undefined
in outline; the plasm is sometimes brittle and does not fix well
by the ordinary methods; while the nucleus is large, either round
or irregular in shape, and possesses a chromatin network which
stains readily.

The topographical distribution of these three groups of cells
is by no means constant. As a general rule, the principal mass
of the eosinophile cells is found in the hinder portion of the
anterior lobe, while the basophile cells usually lie towards the
front. The principal cells are not peculiar to any precise locality,
but are characterized by their topographical relationship to the
chromophile cells ; they frequently occupy the centre of alveoli or
cell cylinders, thus becoming surrounded by chromophile cells.

The changes which Erdheim and Stumme observed in the
enlarged hypophysis of pregnant women, chiefly take place in
the tissue of the anterior lobe of the organ. The cut surface,
which is normally grey-red in colour, becomes remarkably light
and reddish-grey to grey-white ; it becomes softer and yields a
milky juice. These changes in colour and consistency are due
to the appearance, in enormous numbers, of a new kind of cell,
namely, the pregnancy cells; and these outnumber the eosinophile

HYPOPHYSIS CEREBRI 3CKJ

cells which, under normal conditions, largely predominate. The
actual number of the eosinophile cells remains unchanged, but
they are noticeably reduced in size. The basophile cells are
entirely unaffected, the whole of the pregnancy changes taking
place within the principal cells. These practically cease to exist
as such, being almost entirely transformed into pregnancy cells.
The pregnancy cells have large, light, irregular nuclei, with
abundant plasm which is distinctly granular and stains red with
eosin. They accumulate in large numbers in the two lateral por-
tions of the hypophysis; in the posterior portion, where the
eosinophile cells are ranged in compact masses, they are scanty
but not entirely absent. The pregnancy cells are grouped in
broad columns and in alveoli, generally occupying the centre of
the alveolus. Occasionally, when pregnancy is at its height,
these cells form agglomerations which suggest adenomatous
hyperplasia. After parturition, involution of the pregnancy cells
takes place and they largely reassume their former appearance
of principal cells. There is, however, an increase in the number
of the principal cells now present, and at the next pregnancy
these undergo changes similar to the last, so that the result,
though qualitatively the same as at the first pregnancy, is quanti-
tatively very much more intense.

In the hinder boundary layer of the anterior lobe (Pere-
meschko's medullary layer, Thaon's region inter globulaire), a
fissure is frequently, though not invariably, observed in the
neighbourhood of the hilus ; it is lined with a single layer of
cubical cells or, more rarely, ciliated columnar cells, and its
hollow- is either empty, or contains a substance which stains pale
blue with haimatoxylin. This fissure represents the embryonal
hypophysal cavity. Two kinds of vesicles or follicles are also
observed in this region. By the side of the fissure, and sometimes
in place of it, rounded vesicles are occasionally seen, which are
lined with columnar epithelium and filled with an amorphous
mass ; they are probably formed from depressions in the posterior
wall of the embryonal hypophysal cavity. A second variety of
vesicles, found in the same neighbourhood, is considerably larger ;
both in appearance and in their colloid reactions, these vesicles
are reminiscent of the follicles of the thyroid. The vesicle wall
is composed of cubical cells, which do not stain readily and con-
tain large nuclei ; the lumen of the vesicle is sometimes filled with
an amorphous homogeneous mass. In addition to a finely granu-
lar basophile substance, an eosinophile substance resembling the
colloid of the thyroid is sometimes seen. Vesicles of this descrip-
tion are usually encountered in the posterior medullary layer, and
occasionally also in the interior of the anterior lobe.

By means of Golgi's method, Gentes and Pirrone discovered
nervous elements in the walls of these vesicles, similar to those in
the sensory cells of the olfactory region of the nasal mucous
membrane.

310 INTERNAL SECRETION

Pisenti and Viola, as well as Caselli, found cells with large
nuclei in this layer of the hypophysis, which might be regarded
as residues of the endodermal portion of the embryonal hypo-
physis (v. Kupffer). According to Launois and Mulon and to
Thaon, changes also take place during pregnancy in the posterior
portion of the anterior lobe, which these authors interpret as signs
of glandular hyperplasia and hypersecretion.

The communication between the posterior lobe of the hypo-
physis and the brain, represented by the infundibulum, varies in
man both in length and thickness; it is composed of glia fibres
with few nuclei and the upper portion encloses a canal, the re-
cessus infundibuli, which is lined with ependyma cells and repre-
sents the continuation of the third ventricle. This hollow is
occasionally prolonged into the hypophysis and in some species,
notably cats, it constantly extends as far as the posterior lobe.

The posterior lobe of the hypophysis, the pars nervosa, is
considerably smaller than the anterior lobe; "it lies posteriorly, in
the hollow formed by the glandular portion, the opening of which
is downwards. This lobe extends into the sella turcica, in the
posterior wall of which a groove for its reception is sometimes
observed. Histologically, the posterior portion consists of a loose
stroma, which is a mixture of connective tissue elements and
neuroglia, the latter predominating. In preparations coloured by
Weigert's glia method, Thaon observed a small proportion of
fine collagenic fibres, together with a manifold but not close
network of glia fibres, in which isolated light, round nuclei were
distributed. The tissue had few blood-vessels, and frequently
appeared to be infiltrated with an amorphous substance, which re-
sembled the substantia gelatinosa Rolandi of the spinal cord.

The question as to whether the nervous portion of the hypo-
physis contains nerve cells has formed the subject of repeated
investigation. Both Krause and Berkley describe true nerve cells
and nerve fibres; Ramon y Cajal found cells of an undefined
kind in young rats, together with delicate fibres which were cer-
tainly nervous and which proceeded from nerve cells situated at
the base of the brain behind the chiasma ; these nerve fibres
descended through the infundibulum, formed a plexus in the
posterior lobe and terminated in free branches. Kolliker, as well
as Caselli, did not believe that true nerve cells were present in
the posterior lobe; they considered the cell elements present in
it to be glia cells and ependyma cells. Gentes discovered a
considerable network of nerve fibres by Golgi's method, and this
finding was confirmed by Thaon.

According to A. Kohn, the foundation tissue of the neuro-
hypophysis is to be regarded as primitive glia in this sense, that
its elements are invariably associated with the ependyma, the
matrix of all glia elements. He points to the occurrence of a
peculiar pigment, which is found chiefly in the glia fibres and

HYPOPHYSIS CEREBRI 31 1

to a small extent only in the glia cells. This pigment is neither
a fat nor a lipochrome, but is probably a product of decomposition
quantitatively increasing with age. In consequence of the in-
timate relationship between the anterior and posterior lobes of
the hypophysis, together with the penetration of epithelial cells
into the neuro-hypophysis, the latter contains a considerable pro-
portion of epithelial, glandular elements and products, all of which
are derived from the anterior lobe and, in a histological sense,
belong to it. Kohn is unable to confirm, from the morphological
standpoint, Joris's view that the posterior lobe of the hypophysis
is a secretory gland.

The structural indifference of the posterior lobe of the hypo-
physis forms a remarkable contrast to the proved physiological
activity of the extract obtained from this portion of' the organ.

Secretion. — Owing to its histological characteristics, and
especially those presented by the anterior lobe, the hypophysis
has been accredited a secretory function, though the views adopted
concerning the nature of its secretory product are somewhat diver-
gent. The fat granules which it contains are, however, unani-
mously regarded as a physiological product of cellular secretion.
According to Erdheim, fine fat granules make their appearance at
the beginning of post-fcetal life, and these become progressively
larger until old age, when they are larger than nuclei. They are
found in all the cells, in the shape of rings and spheres as well
as in different vacuole forms. The granules in the chromophile
cells are large in size, but few in number; those in the adelo-
morphous cells are small and very numerous. They colour with
sudan, scarlet R. and osmium; they are soluble in ether and
alcohol ; and they are not double refractive. According to Thaon,
the treatment of sections stained with osmium reveals different
degrees of solubility, and he concludes from this that the granules
are composed of fats of different kinds. He finds that the fat
granules of the hypophysis contain little oleic acid, and believes
that they are combined with an albuminoid molecule.

The cell granules represent another product of hypophysal
secretion. Saint Remy and Benda, more particularly, do not
regard the chromophile and chromophobe cells as different cell
varieties, but they believe them to represent different stages of
secretion on the part of a single cell variety. According to Benda,
the adelomorphous cells which contain no granules and only
isolated basophile fragments, are the young forms, the secretory
starting point; the cells filled with acidophile granules represent
the secretory climax ; while the pale nuclear groups filled with
dust-like amphophile granules are the product of the final secretory
stage. Benda believes that the acidophile granules represent the
measure of the secretory activity of the hypophysis cells; that
they are produced during functional activity, and that at the
resting stage their formation ceases.

312 INTERNAL SECRETION

Quite recently, however, Gemelli expressed the view that the
chromophile and chromophobe cells represent two different cell
varieties. Pirrone, Guerini, Launois, Thaon and Joris adopt
Benda's view, with this modification that they regard colloid as
the end product of the secretory process.

The amorphous substance resembling the colloid of the
thyroid is regarded by Benda, Gemelli and others as the product
of degeneration. Erdheim regards it as rudimentary and re-
miniscent of a time when the organ possessed an external secretory
function. By many authors, particularly those of the French
school, the colloid substance is regarded as the product of normal
secretion.

Of the chemical nature of this colloid, all that is known is
that it is insoluble in water, alcohol and ether; that it does not
yield gelatine after boiling; and that, unlike mucin, it swells in
acetic "acid and afterwards dissolves. It has been identified with
the colloid substance of the thyroid and this is confirmed by the
discovery of iodine in the hypophysis.

The colloid substance is present in the hypophysis of the
human embryo at three and a half months; in adults, it is found
in the cell columns and is particularly abundant in the vesicles in
the neighbourhood of the hilus, and in the blood-vessels. In
addition to a strongly coloured, eosinophile, homogeneous colloid,
the hypophysis, like the thyroid, also contains a less homo-
geneous, granulated, basophile substance resembling coagulated
albumin. The colour differentiation of the colloid substance
depends upon the different granulation of the acido- and baso-
phile cells.

The presence of the colloid substance between the cells, in
the vesicles, and in the lumen of the capillaries is regarded as
proof of its excretion by way of the blood-stream. Thaon showed
the manner in which the secretion is excreted in series of sections
from hypophyses which showed signs of hypertrophy. In addi-
tion to colloid, he found fat granules between the cells and in the
capillaries; he was unable to demonstrate the presence of lym-
phatics in the hypophysis. According to Thaon, the secretion is
eliminated from the hypophysis in two ways; one, through the
cell base into the blood-vessel with which it is in contact; the
other, through the opposite cell wall into the lumen of a vesicle,
where present.

The presence of colloid in the vesicles may be considered to
be evidence of the deposition of this substance ; thus it is possible
to regard the hypophysis as a storage gland, similar in character
to the thyroid apparatus. Thaon believes that the physiologically
active substance of the posterior lobe, is merely the secretory
substance elaborated by the anterior lobe, which accumulates in
the vesicles in the neighbourhood of the hilus. The method of
preparing pituitary extract does not permit of any separation of

HYPOPHYSIS CEREBRI 313

this medullary layer from the posterior lobe. Silvestrini also
locates the active substance in the medullary layer ; Salvioli and
Carraro, on the contrary, believe that it is contained in the pars
nervosa.

It should be mentioned that Livon held the view that the
internal secretion of the hypophysis passes into the brain by way
of the nerve fibres in the peduncle.

HISTORY OF DEVELOPMENT.

Since the. earliest investigations by Rathke in 1838, the
development of the hypophysis has formed one of the most
widely discussed problems in the department of embryology.
Even to-day, the views held concerning it are very divergent.

The subject of the earliest discussion, in which, in addition
to Rathke, Reichert, Luschka, Kolliker, Fr. Miiller, His, Maclay,
and Duvry were concerned, was the supposed relationship between
the hypophysis and the epithelium of the buccal cavity, Rathke's
pouch more particularly. Mikalkovics's experiments with mam-
mals, Goette's experiments with amphibia, and Dohrn's experi-
ments with ammoccetes, appear to show that the hypophysis is
exclusively ectodermal in origin. This view was shared by the
vast majority of embryologists and finds expression in the text-
books of the subject.

The development of the hypophysis is described by Hert\vig
as follows : In the embryo of a rabbit, 6 mm. in length, at a
developmental stage when the cephalic flexure and the stomadseum
have already made their appearance, the site of the future hypo-
physis is situated anteriorly and dorsally of the spot where the
anterior end of the chorda dorsalis immediately approaches the
insertion of the pharyngeal membrane. After the perforation of
the pharyngeal membrane (in the chick on the fourth day, in
the human embryo in the fourth month), a groove is formed,
shallow at first, but gradually becoming deeper, which is known
as Rathke's pouch or the hypophysis pouch. This groove, which
develops in the direction of the funnel-shaped, depending base
of the thalamencephalon, becomes clothed with several layers of
cylindrical cells, and eventually forms a longish pouch (embryo
rabbit, 12 mm.).

At a later stage, this pouch is almost completely divided from
the primitive mouth cavity by the development of the carti-
laginous base of the skull, a narrow opening only being left.
At the same time, the posterior wall of the pouch has reached the
infundibulum and has been pushed backwards by it into the
cavity of the pouch (embryo rabbit, 20 mm.). A little later, the
lumen becomes obliterated and the pouch forms a solid cell
column. In Selachians, the pouch persists throughout life as a
hollow canal, one end of which penetrates the cartilaginous base

314 INTERNAL SECRETION

o

of the skull, while the other communicates with the epithelium of
the oral mucosa. The hypophysis is now a closed structure, but
in the human embryo, in the second half of the second month,
hollow tubes' are formed in the anterior and ventral wall of the
cavity ; these penetrate into the surrounding connective tissue,
which is very vascular (embryo rabbit, 30 mm.), and become cut
off from the cavity of the hypophysis to form isolated structures.
The whole of the pouch now breaks up into tubes in the same
way, thereby forming the anterior lobe, in the posterior portion
of which traces of the original cavity still remain. The anterior
lobe is now joined by means of connective tissue to the posterior
lobe, which has in the meantime developed from the infundi-
bulum.

Traces of embryonal development are observed in the human
hypophysis during the entire course of post-fcetal life. The
fissure lined with epithelium which is present in the anterior
lobe, is the post-fcetal representative of the original pouch ; while
the cavities filled with colloid, by which this fissure is frequently
replaced, are the outcome of the division of the pouch. Erdheim
discovered that, from uninvolved remnants of that portion of the
hypophysis cavity which is inserted in the anterior lobe,
agglomerations of pavement epithelium are formed; these are
encountered within a circumscribed area of the anterior lobe,
either in isolated groups or associated with adelomorphous cells
or vesicles. According to Erdheim, these agglomerations of
pavement epithelium may develop into pituitary tumours of the
kind known as pavement epithelium sarcoma.

The road traversed by the hypophysis in the course of its
development is represented', in all except a few isolated instances,
by a bony channel which passes through the sphenoid bone and is
called the canalis cranio-pharyngeus. In and under the mucosa
of the pharyngeal roof of new-born infants, Erdheim discovered
a cord composed of hypophysis tissue which he named the
' pharyngeal roof hypophysis " (Rachendachhypophyse). Haber-
feld, who carried Erdheim's investigations still further, found
that this cord, which he termed " hypophysis pharyngea," was
constant in man at all ages; he did not regard this structure
as an embryonal remnant, but believed it to be a fully developed
accessory hypophysis, with a function identical with that of
the true hypophysis. Haberfeld showed that, in isolated cases,
remnants of hypophysis tissue visible to the naked eye are
situated along the entire length of this cord, and that they may
form the site of origin of hypophysal tumours. As a matter of
fact, Erdheim observed such a tumour in an unusual situation,
the course of its development extending below the sella turcica,
while the hypophysis, which was normal in size and shape,
retained its position undisturbed.

These findings point to a purely ectodermal origin of the

HYPOPHYSIS CEREBRI 315

hypophysis, but the view has been contested upon many sides.
First Hoffmann, and later Orr, assumed a relationship between
the hypophysis and the ectoderm of reptiles. As the result of
his later investigations (1894), v. Kupffer, who had previously
accepted the ectodermal origin of the hypophysis in all verte-
brates, arrived at the conclusion that, in addition to the ectoderm,
the entoderm — the epithelium of the archenteron in particular-
is concerned in the formation of this organ. According to him,
the hypophysis has three primitive sources of origin ; the first is
ectodermal and is a remnant of a phylogenetically old oral cavity
(palasostoma), situated above the spot where the mouth afterwards
develops, and which, later, becomes Rathke's pouch ; the second,
which is entodermal, is situated behind the pharyngeal membrane
and is formed by an outgrowth, sometimes hollow and sometimes
solid, of the cephalic intestine (preoral intestine), the blind end
of which forms the pouch described by Seessel ; the third or
cerebral portion is provided by the infundibulum and infundi-
bular gland. In the monorhines and myxinoids, the infundi-
bular gland only is present, the palasostoma forming the perma-
nent nasopharyngeal passage. In Petromyzons, Elasmobranchii,
and Teleosteii, the infundibular gland and the dorsal gland-com-
plex of the naso-pharyngeal passage are both present.

v. Kupffer's view is shared by Valenti and partly also by
Nussbaum ; but the inclusion of the entoderm in the formation of
the hypophysis is denied by St. Remy in the case of birds and
mammals, by Hoffmann in the case of Selachians, and by B.
Haller in the case of all vertebrates. Valenti, who has carried
out a fresh series of investigations with embryo chicks and rab-
bits, maintains the view, however, that the hypophysis contains
an ecto-entodermal portion, derived from the preoral intestine.
Corming and Rossi, on the other hand, insist upon a purely
ectodermal origin.

PHYSIOLOGY OF THE HYPOPHYSIS.

Experimental Extirpation. — It was Horsley (1885) who, in
order to compare the results of the removal of the hypophysis
with those which follow thyroiclectomy, first undertook the extir-
pation of that organ. His experiments, like those of Dastre
(1889) and Gley (1891) were completely negative, the animals
dying immediately after operation. Following the theory pro-
pounded by Marie and Marinesco concerning the pathogenesis
of acromegaly, Marinesco (1892) next carried out extirpation
experiments with cats. Since that date, hypophysectomy has
been performed on animals of different species, and according
to various methods. But these attempts, if we except quite the
most recent, supplied no satisfactory information concerning the
importance of this organ to the life of the organism and the nature

316 INTERNAL SECRETION

of its functional significance. The animals most frequently em-
ployed were the cat and the dog, though a certain amount of
material has been provided by other animals (frog, tortoise, hen,
rabbit).

Experimental extirpation from the oral cavity of the hypo-
physis of frogs, as carried out by Caselli (1900), did not yield
results of any value. Gaglio (1902) operated upon frogs and tor-
toises by the same method, however, and found that, though some
of his animals died very shortly after, apparently as the result
of infective conditions, others lived one and a half to three months
without pathological symptoms. Bofeano, a pupil of Paulesco's,
describes (1906) extirpation of the hypophysis of frogs by the
supra- and latero-cranial methods ; he found that, two to three
days after total extirpation, his animals invariably died, with sym-
ptoms of neuro-muscular asthenia; while control animals operated
upon by the same method, the hypophysis being only partially
removed or left intact, remained perfectly normal, with the
exception of slight symptoms of central nervous stimulation.

G. Fischera (1905) operated upon hens. He obtained access
to the organ from the base of the skull, by means of an incision
at the edge of the lower jaw ; with the aid of the thermocautery,
he divided the basal sphenoid bone in the middle line, thus laying
bare the hypophysis. Of forty hens, eleven died shortly after
operation, twenty-nine survived and were destroyed after four
months. The autopsy showed that, in eight cases, the hypophysis
Was undamaged; in seventeen, it was partially injured; and in
four, completely destroyed. Operation was followed in the first
few days by symptoms of fatigue and depression, which soon
passed off. Two of the hens in which the hypophysis had been
entirely destroyed showed signs of arrested development. The
results of Fischera's experiments led him to conclude that, in
young hens, the hypophysis is not essential to life, and that the
symptoms which follow its removal are in no way characteristic.
Even the arrestation of development cannot be regarded as a
constant symptom.

The extirpation experiments which Gley carried out with
rabbits are, on account of their faulty technique, of very little
value. Experiments with cats and dogs are the only ones which
have supplied reliable information concerning the function of the
hypophysis ; this is attributable, not only to the frequency with
which these animals have been employed, but to the better
operative technique by means of which such experiments have
been accomplished. Cats and dogs have been employed as sub-
jects for hypophysectomy by a large number of authors
(Marinesco, Vassale and Sacchi, v. Cyon, Caselli, Gatta, Kreidl,
Biedl, Friedmann and Maass, Delia Vedova, Lo Monaco and
van Rynberk, Pirrone, Gemelli). The method which was first
employed and was later in most frequent use, was that of opening

HYPOPHYSIS CEREBRI 317

up the hypophysis from the base of the cranium by way of the
oral cavity. The organ was usually destroyed either with a
thermocautery or by the injection of chromic acid ; removal was
effected with spoon-forceps, generally of the operator's own
design.

Lo Monaco and van Rynberk followed up Gley's experiments
with rabbits, the method they chose being from the vertex of the
skull. After opening the dura mater, these authors penetrated
between the hemispheres at a spot previously determined upon,
and after passing through the corpus callosum they reached the
infundibulum and from there they were able to reach the hypo-
physis. In twenty-eight cases out of forty-four they succeeded in
removing the hypophysis by this method.

This method was very justly condemned by Paulesco ; he
pointed out that it is faulty in all essentials, for it inevitably pro-
vokes secondary lesions of more or less grave a character, that it
is accompanied by serious risk of infection, and that it does not
properly accomplish what is, after all, the chief object of operation,
namely, the exposure of the organ. Paulesco (1906) introduced
a new method of hypophysectomy ; he employed the lateral
approach, beneath the temporal lobe.

I have employed this method myself in a large number of
experiments. In my earlier experiments with cats, I used the
buccal method of reaching the hypophysis, but in the later experi-
ments with dogs which I carried out with Dr. M. Silbermark, wre
invariably employed the intercranial operation. This method,
which was also adopted by Gushing, fulfils all requirements.
After practising upon the cadaver, we \vere able to perform the
operation with a considerable degree of certainty, and out of a
series of fifty animals we did not lose one from post-operative
haemorrhage, meningitis or sepsis. It may be remarked in pass-
ing that this method may be employed with equal success for
the purpose of exposing any structure at the base of the brain
in the median cranial fossa, and is especially suited to the inter-
cranial resection of the second to sixth cranial nerves. What is
fundamentally new about the method is that it permits of a con-
siderable dislocation of the brain without damage to it. An
opening of suitable size is made in the squamous portion of both
temporal bones, and the dura mater is opened upon both sides.
With a flat bent spatula the temporal lobe may now be lifted and
pressed to one side, without in any way crushing the substance
of the brain. In a good light, after mopping out the cerebro-
spinal fluid, the hypophysis will be seen hanging like a berry on
a stalk in front of the optic nerve, by the side of the internal
carotid artery, and behind the oculomotor nerve. The organ is
now clearly visible under conditions eminently suited to operative
intervention. It may be severed from its peduncle and left free
in the cavity of the brain; or it may be entirely removed; or

318 INTERNAL SECRETION

single lobes or portions may be removed. This operation is very
rarely followed by haemorrhage. After operation, the elevator is
removed, the brain returns to its position, the dura mater is put
into place and kept there by the temporal muscles, and the incision
in the temporal cuticle is sewn up.- We found, in our experiments,
that Paulesco's resection of the zygomatic arch was unnecessary
and, provided that the openings in the squamous portions of the
temporal bones are sufficiently large, the structures in the sella
turcica may also be easily reached without such resection.

What, then, are the results of experimental extirpation of the
hypophysis ? In order to arrive at a clear answer to this question,
it is necessary to consider separately the results yielded by the
older experiments, before the introduction of Paulesco's method.
In a large number of instances the animals operated upon by the
older investigators died either immediately or very shortly after
operation. Under these circumstances it was not possible to
decide whether death was due to the removal of the hypophysis,
or whether it resulted from the serious surgical intervention with
its attendant danger of infection. A small proportion of animals
survived for a brief period, one for three weeks, and some lived
even longer. It will be remembered that Lo Monaco and van
Rynberk destroyed their animals after thirty-five to eighty-six
days.

The relative short span of life after extirpation was regarded
by many as a proof of the vital character of the hypophysis,
though other investigators, whose animals lived for longer periods,
ascribed the fatal termination to momenta other than suppression
of the organ. Lo Monaco and van Rynberk, especially, laid
great stress upon the fact that, after their transcerebral operation-
which was undoubtedly very drastic, seeing that it necessitated a
serious lesion of the infundibulum and the opening of the ven-
tricle— their animals survived and showed no pathological sym-
ptoms. Single animals, with what the autopsy showed to be an
uninjured hypophysis, yet showed all the symptoms of hypo-
physis suppression ; while others again, in which the hypophysis
was found to be absent, remained normal.

These contradictory views concerning the results of hypo-
physectomy are explained by the ill-defined and obscure nature
of the symptoms by which the operation was accompanied. In a
large number of cases, on the one hand, symptoms of depression
are described, ranging from dulncss and apathy to paralysis and
even coma; while in others, symptoms of motor stimulation,
fibrillary tremors and tonic cramps are reported; and in yet other
instances, no symptoms, either of stimulation or of depression,
were observed. The effects upon the vegetative nervous system
were also very differently described. Many authors found
polyuria, unaccompanied by abnormal constituents ; others describe
albuminuria; others again, glycosuria; while many were unable
to report changes in either the circulation, secretion, or respiration.

HYPOPHYSIS CEREBRI 319

The only decisive observations are those obtained from later
experiments carried out by Paulesco's method. Paulesco and
Gushing have described the results of such hypophysectomies. I
employed the method myself in combination with Silbermark, as
well as with Leishner and Denk.

Paulesco performed total hypophysectomy with twenty-two
dogs and two cats. His animals lived for ten to forty-eight hours
at most. The autopsy revealed neither haemorrhage nor suppura-
tion at the site of operation, and the other findings were also
negative. The autopsy showed that, in fourteen dogs, extirpation
was not complete, portions of hypophysis tissue of varying size
having been left in situ. These animals lived three to seven to
ten days; where the amount of tissue left behind was large, they
lived longer (seventeen, twenty-three, sixty-seven, 151, 158, 196,
and 395 days). The almost complete suppression of hypophysal
activity was not revealed by any marked symptoms, and Paulesco
found that even those animals which survived for a considerable
time did not show any signs of trophic disturbance.

In three dogs, a portion of the anterior lobe only was removed.
These animals lived without special symptoms for twenty-three,
sixty-six, and 932 days respectively. The complete destruction of
the cortical substance of the anterior lobe with the thermocautery
proved fatal to seven dogs, death following as rapidly as after
total hypophysectomy. Five animals survived the removal of
the posterior lobe for thirteen and sixty-nine days, eight months,
and two years respectively ; there were no pathological signs, and
the animals eventually died from accidental affections.

The loosening of the hypophysis from the sella turcica was
found to be quite negative. According to Paulesco, death follows'
separation of the hypophysis from the base of the brain by resec-
tion of the peduncle, as rapidly as after complete, or almost
complete, extirpation. That this result is not due to the opening
of the third ventricle, is proved by the fact that the opening of
the third ventricle alone is not followed by death. Neither can
the fatal result be ascribed to the lesions at the base of the brain,
for in the control animals such lesions produced only symptoms
of motor stimulation, and these were invariably absent after
removal of the hypophysis.

Paulesco concluded that the hypophysis is an organ which is
essential to life, and that the suppression of its function is rapidly
followed by death. In his opinion, the vital portion is the cortical
substance of the epithelial anterior lobe.

Gushing confirms Paulesco's view of the vital character of
the hypophysis. Nevertheless, his experiments seem to show
that the results of total extirpation are less rapid in young dogs
than in old. He was able to prolong the lives of his animals by
the previous or simultaneous transplantation of the anterior lobe,
as well as by the injection of extract of the anterior lobe. Accord-
ing to Gushing, total extirpation of the hypophysis is followed

320 INTERNAL SECRETION

within a few days, or at latest a few weeks, by symptoms character-
istic of cachexia hypophysopriva, terminating in death.

After extirpation of the posterior nervous lobe, the inter-
mediate portion being generally removed with it, animals usually
survive and show no pathological signs. Partial extirpation of
the anterior lobe is consistent with the continuance of life. In
isolated cases, however, it leads to remarkable symptoms, such as
increased deposition of fat, polyuria, transitory glycosuria, and
falling of the hair. The most striking result, however, was the
reduction in sexual activity, shown anatomically by atrophy of
the testicles and ovaries. Acute thyroid hypertrophy was also an
occasional sequel to hypophysectomy.

Judging by Cushing's experiments, the anterior hypophysal
lobe represents the vital portion of the organ, the complete extirpa-
tion of which is followed by death, its partial extirpation by dis-
turbances of growth and of metabolism and by derangement of
the activity of the sexual organs.

From the results of my own experiments I am able emphatic-
ally to confirm Cushing's views. We found that complete
extirpation of the hypophysis was rapidly followed in both adult
and young growing animals by death; the post-mortem findings
were negative. Where the posterior lobe only was removed, the
animals lived without symptoms for months, ultimately dying of
intercurrent disease. Where extirpation was performed only on
the anterior lobe, a portion of the tissue being left in situ, the
animals lived for weeks and months, the autopsy showing, how-
ever, a remarkable deposition of fat in the omentum and retro-
peritoneal space, together with pronounced atrophy of the entire
sexual apparatus. The ovaries and uterus of a 3-year-old bitch
presented appearances similar to those of an animal of a few
weeks old.

Quite recently (December 3, 1909), B. Aschner described extir-
pation experiments with dogs, in which he employed' the older
method of reaching the organ, namely, by way of the oral cavity.
He succeeded in removing the complete hypophysis by this means.
A proportion of his animals died within the first eight days, and
he ascribes this to the removal, with the hypophysis, of too large a
portion of the infundibulum. Other animals survived operation
for several months. In full grown animals the results wrere
practically nil ; there was a certain change in the metabolism of
the carbohydrates, similar to that seen in thyroidless dogs. The
effects of adrenalin in producing glycosuria and symptoms of
stimulation of the sympathetic were much less marked in these
dogs than in normal dogs, and the different phases of alimentary
glycosuria were much reduced.

The suppression of the hypophysis was followed, in young
animals, by profound disturbances. These animals were very
backward in growth and weight as compared with control

HYPOPHYSIS CEREBRI $21

animals ; there was a shortening of the skull and especially of
the muzzle, hypoplasia of the genitals, anomaly in the growth of
the hair, considerable deposition of fat, even fatty degeneration
of the internal organs (liver), and temperamental changes. The
dogs ceased to bark, they breathed heavily, they became somewhat
apathetic, the sensibility to electric stimulus and to pain became
very much less, while their movements were indolent, and they
seemed to have become less intelligent. In male animals, sperma-
togenesis ceased, in female animals there was involution of the
ovarian follicles.

A glance at the material provided by experimental extirpation
of the hypophysis shows that a good deal of light has been shed
upon the functional and physiological significance of that organ.
It is evident, in the first place, that the hypophysis is an organ of
vital importance to the organism, the removal of which is
followed by death. This is conclusively proved by the results of
Paulesco's method of complete hypophysectomy, the contradictory
results obtained by certain investigators being probably attribut-
able to the faulty nature of their technique. " Total hypo-
physectomy " can only be described as such where, in addition
to the removal of both lobes, the hypophysal peduncle is also
severed. The peculiar significance of this peduncle is shown by
the fact that, even where the hypophysis is allowed to remain
in situ, death follows resection of the peduncle as promptly as after
complete hypophysectomy. This remarkable phenomenon was
first observed by Paulesco, and has since been confirmed by me ;
all that we can do is to record the facts, for no explanation of
them is at present forthcoming.

The results of experimental extirpation also show the differ-
ence in the physiological value of the two lobes of the hypophysis.
The removal of the posterior lobe is unattended, over a period of
months, by pathological signs. Total extirpation of the anterior
lobe, on the contrary, is immediately fatal. It appears, however,
that this applies only to older animals, young dogs having a
longer duration of life.

The results of total or partial destruction of the anterior lobe
are also best seen in young animals. The suppression of function
is manifested in a considerable increase in the fat body, which
may amount to adiposis universalis, with pronounced hypoplasia
of the sexual glands, together with arrested development and
infantile habit. The influence which the hypophysis has upon
the sexual glands is seen also in the case of older animals, partial
destruction of the anterior lobe being followed by marked atrophy
of the genitals.

PITUITARY EXTRACT.

Since the discovery by Oliver and Schafer of the vaso-con-
tractor action of pituitary extract, the symptoms which follow the
21

322 INTERNAL SECRETION

exhibition of this substance have formed the subject of manifold
investigation ; further evidence, moreover,, has been furnished of
the internal secretory activity of the organ.

The chemistry of the hypophysis has, up to now, been hardly
sufficiently investigated. We know that it contains a relatively
large proportion of phosphorus and calcium ; iodine (Ewald and
Schwitzler), bromine (Paderi), and traces of arsenic (Gautier) have
all been discovered. According to Gautrelet, the hypophysis,
like many other organs, contains cholin.

Of the active pharmacodynamic substance of the hypophysis
we know only that it is dialyzable ; that it is not destroyed by
reducing agents, such as boiling; and that it is insoluble in
alcohol and ether. For experimental purposes, as well as in
clinical medicine, the dried organ obtained from cattle, sheep,
horses, cats, and dogs is employed, or extracts prepared from
the dried or fresh organ in normal saline solution are used. As
may be imagined, the dosage of such pituitary preparations is
not very exact. An extract obtained with chloretone from the
posterior lobe of the hypophysis has recently been put upon the
market by Messrs. Parke, Davis and Co., under the name of
hypophysin or pituitrin ; the manufacturers state that i c.cm. of
this extract is equal to o.i grm. of the fresh, and .01 grm. of the
dried, substance.

Pituitrin does not react either to ferric chloride or to the
sublimate test given by Comessatti for adrenalin, or to the
Frankel-Allers test. It does, however, produce mydriasis of
frogs' eyes. According to Allers, when boiled with caustic soda
solution it gives off a distinct odour of alkylamin, while the liquid
becomes brown ; this author considers it probable that the hypo-
physis contains a substance which, similarly to adrenalin,
possesses an alkaline amino-nitrogen constituent.

The general toxicity of pituitary extract is inconsiderable and
not to be compared with that of adrenalin or suprarenal extract.
Numerous accounts are given of extracts equal to ij to 3 fresh
hypophyses (Mairet and Bosc, Conti and Curti, Gamier and
Thaon, Salvioli and Carraro, Etienne and Parisot, Renon and
Delille, Hallion and Carrion) being exhibited as a single dose,
while Urechia reports a case in which the extract of ten ox-hypo-
physes was tolerated in a single dose. The direct effects of
intravenous or subcutaneous injection of pituitary extract are
transient apathy, somnolence, occasionally accelerated respiration
and increased secretion of urine. After the intraperitoneal injec-
tion of large quantities of pituitrin (10 to 15 c.cm.), I observed
transient excitement, followed by marked depression and muscular
weakness, which afterwards developed into complete paralysis of
the hinder extremities and terminated, at the end of twenty-four
hours, in death. The intravenous injection of large quantities of
pituitrin is sometimes followed by a sudden arrest of cardiac

HYPOPHYSIS CEREBRI 323

activity or by pulmonary oedema. After repeated exhibition of
small quantities of the substance there was a marked loss in
weight. The phenomena which Urechia observed after the rein-
jection of pituitary extract after an interval of ten days, were
probably anaphylactic in character.

According to Delille, there is an essential difference between
the toxic action of the anterior and the posterior lobes, the toxicity
of pituitary extract being principally or even exclusively the
property of the posterior lobe.

THE PHYSIOLOGICAL ACTIVITY OF PITUITARY

EXTRACT.

It was first ascertained by Oliver and Schafer that the injec-
tion of extract of the hypophysis into the veins produces a prompt
and very marked increase in arterial pressure ; this differs from
that produced by suprarenal extract in its duration, which is
longer by several minutes. This hypertension results, partly from
contraction of the vessels, and partly from increased cardiac
activity, and it is not disturbed by resection of the cord or of
the medulla. The peripheral effect of this hypertension is illus-
trated by the fact that, if a fluid containing pituitary extract is
circulated through the hinder extremities of frogs, there is a
marked reduction in the venous outflow. The increased cardiac
activity was shown in the myographic curve which Oliver and
Schafer obtained with the heart after its removal from the living
body.

The effect of pituitary extract upon the circulatory apparatus
is, in many respects, analogous to that of suprarenal extract,
though it differs in certain important particulars. The vaso-con-
strictor action is much slighter, and the marked slowing of the
pulse, together with inhibition of auricular contraction, produced
by suprarenal extract where the vagi are intact, is absent in the
case of pituitary extract. On the other hand, after resection of
the vagi, pituitary extract produces, not an acceleration, but rather
a retardation of the cardiac beats.

The findings of Oliver and Schafer were confirmed in all
important particulars by later investigators. Howell next dis-
covered that the substance which produces vaso-constriction and
slowing of the pulse is principally contained in the extract of the
posterior lobe, the pars nervosa. He also discovered the remark-
able fact that a second injection, given half to one hour after
the first, has practically no effect upon the circulation. Howell's
findings were confirmed by Schafer and Vincent, who discovered,
further, that the second injection is followed by a fall, instead of
a rise, in blood-pressure. According to these authors, the fall in
pressure is brought about by the action of a second substance with
depressant properties, which is obtainable by extraction with

324 INTERNAL SECRETION

absolute alcohol, treatment of the alcoholic residuum with ether,
and solution in sodium chloride. If the substance obtained by
this method is injected into the veins, a transient primary hypo-
tension is observed, which is probably due to peripheral vasodila-
tion and is not preceded by a rise in blood-pressure. This hypo-
tension is similar to that obtained by the injection of cholin, but
unlike the latter, it is unaffected by atropine.

Osborne and Vincent next showed that extracts of nervous
tissue (brain, spinal cord, peripheral nerves) give rise to a con-
siderable transient fall in blood-pressure, which is also unaffected
by resection of the vagus and by atropine, and which is brought
about by peripheral vasodilation. Contrary to the view expressed
by Halliburton, it is certain that this result is in no way due to
the action of cholin.

According to v. Cyon, pituitary extract contains two sub-
stances which possess entirely different properties. The one,
hypophysin, which is obtained by boiling pituitary extract, has
an influence upon the heart; its intravenous injection is followed
by groups of slow, strong beats, and this effect persists after
resection of the vagi. Extracts obtained at a temperature of
38 to 40° C. usually possess a vaso-constrictor effect which v. Cyon
believes to be brought about by inhibition of the nervous
depressor.

The effects of pituitary extract in raising pressure and slowing
the pulse — the latter only where the vagi are intact, however — are
confirmed by Livon, who includes the hypophysis in the group
of the hypertensive glands ; while Silvestri, on the contrary,
obtained only a fall in blood-pressure with extract of the posterior
lobe. After the injection of a quantity of infundibular extract
equal to about one-fifth of the posterior lobe, Gamier and Thaon
observed a rapid rise in pressure with slowing of the pulse,
followed after ten to twelve seconds by a rapid transient fall in
pressure, which was again followed by a marked rise. The
slowing of the pulse was not observed after the resection of the
vagi. Similar phenomena are described by Salvioli and Carraro,
Pal, Lockhart-Mummery, and Legge.

By means of plethysmographs of different organs, Hallion
and Carrion showed that the rise in pressure brought about by
pituitary extract is associated with a vasoconstriction in
different organs, in the nasal mucosa and thyroid gland more
particularly. In the kidney there was, after an initial vaso-con-
traction, a continued vaso-dilation. These authors point out the
antagonistic effects of pituitary to those of ovarian extract, the
latter, as far as their experiments showed, producing a fall in
blood-pressure together with a characteristic vaso-dilation in the
thyroid gland.

Quite recently (December 17, 1909), Falta and Ivcovic stated
that they injected 2\ c.cm. of an extract obtained from the glandu-

HYPOPHYSIS CEREBRI 325

lar portion of the hypophysis into dogs and rabbits, and produced
a profound fall in blood-pressure which, in atrophied animals, lasts
for a comparatively long time. The lowered pressure, which, at the
end of forty seconds, spontaneously returns to the normal figure,
may be relieved by means of adrenalin. In two instances, after
injection of the extract, the blood-pressure fell to zero, and
respiratory and cardiac activity ceased. In one case the animal
was saved by the injection of 2 c.cm. pituitrinum infundibulare ;
the heart-beats recommenced, the blood-pressure rose rapidly to
normal, and the animal completely recovered.

Finally, L. Etienne and Parisot found that the repeated injec-
tion of pituitary extract into rabbits produced permanent hyper-
tension and cardiac hypertrophy, which were apparent fifteen days
after the last injection ; there were, however, no sclerotic changes
in the vessels.

The results which have been described comprise the whole of
the material at present available concerning the influence of
pituitary extract upon the circulation. It may then be taken as
proven that pituitary extract, or rather the extract of the posterior
hypophyseal lobe, produces a high degree of blood-pressure, which
differs from that provoked by adrenalin in its slighter intensity
and longer duration. The diminished, or negative, action of a
second injection may be regarded as specific.

The hypotensive action of pituitary extract described by cer-
tain authors demands further investigation. It is very necessary
that we should know whether the fall in pressure is a by-effect of
pituitary extract, or whether it is due to a specific activity on the
part of the glandular portion of the organ.

There is no doubt that the rise in arterial tension is mainly
the result of peripheral vaso-contraction. But further investiga-
tion is necessary both to locate the seat of this vaso-contraction
and to decide whether the vaso-contraction which takes place in
the thyroid gland and the nasal mucous membranes, and the
vaso-dilation which takes place in the kidney, are specific effects
of pituitary extract.

Pituitary extract also influences the action of the heart, by
slowing and strengthening its beats. This effect is in part
attributable to stimulation of the cardiac inhibitory nervous
centres. The experiments of Hedboom and Allen, Cleghorn,
and, later, Herring, \vith the living heart from frogs and mammals,
have proved, however, that the slowing of the pulse is unaffected
by resection of the vagi, and it seems probable from this that
pituitary extract also exercises a direct action upon the muscular
substance of the heart. This conclusion is further justified by
the fact that the constriction of the vessels is produced not, as in
the case of adrenalin, by stimulation of the peripheral nerve-
terminals, but by a direct action upon the involuntary muscles;
moreover, the effect which pituitary extract has upon the muscles
is also demonstrable in the case of other organs.

326 INTERNAL SECRETION

That pituitary extract exercises a direct contractor influence
upon the vessel walls is proved by Salvioli and Carraro's experi-
ments with artificial circulation. Dale's experiments, to which
reference has been made in a previous chapter, show that pitui-
tary extract resembles barium chloride, which is known to stimu-
late the involuntary muscles, in that it produces a rise in blood-
pressure at that stage of ergotoxin intoxication at which a fall in
blood-pressure is produced by adrenalin. Pal, de Bonis, and
Susanna tested the action of pituitary extract by O. B. Meyer's
method upon portions of arteries obtained from the living ox.
According to Pal, pituitary extract produces a contraction of the
carotid, mesenteric, and femoral arteries in the same manner as
adrenalin, while its action upon the cardiac and renal vessels is
the opposite to that of adrenalin. The coronary arteries, which
enlarge in response to adrenalin, contract under the influence of
pituitary extract. The peripheral portion of the renal artery
which is situated in the pelvis dilates in response to pituitary
extract, while the proximal portion contracts.

The direct muscular action of pituitary extract was proved by
Cramer and Borchardt, as well as by Pal, by the enlargement of
the pupil of enucleated frogs' eyes.

Special interest is attaching to the discoveries of v. Frankl-
Hochwart and Frohlich concerning the effect of pituitrin upon
the urinary bladder and the uterine muscles. In cats and dogs,
pituitrin stimulates the muscles of the urinary bladder to a mode-
rate degree, but it also increases the sensibility to electric stimulus
of the autonomous motor nerve to the bladder, namely, the pelvic
nerve. The sensibility of the inhibitory sympathetic, the hypo-
gastric nerve, is unaltered. Maximal contraction of the uterus
muscles of the rabbit is sometimes produced by pituitrin, and at
the same time the uterus becomes considerably more sensitive to
the influence of the uterine nerves which are supplied by the
hypogastrics. Both these results occur independently of the
blood-pressure and, like the effects upon the heart and vessels,
they are observed after the first injection only. On account of its
effect in increasing the sensibility of the muscles of the urinary
bladder and the uterus, these authors suggest the employment of
pituitrin as a therapeutic agent.

The effect which the extract of the posterior lobe has upon
the muscles of the uterus and intestine is also described by Blair
Bell.

According to v. Frankl-Hochwart and Frohlich, hypophysin
does not affect the sensibility of either the nerves of the salivary
glands or the chorda tympani, nor does it influence erection, in
so far as the latter is produced by peripheral stimulation of the
autonomous erection nerve. In opposition to v. Cyon, these
authors state that the sensibility of the autonomous vagus
supplying the heart is unaffected by the influence of hypophysin.

HYPOPHYSIS CEREBRI 327

An ordered relationship, such as that which exists between the
action of adrenalin and certain nerve terminals, has not been
proved in the case of hypophysin.

Very characteristic of the action of pituitary extract is the
increased diuresis which, according to Magnus and Schiifer, fol-
lows intravenous injection, and, if the injections are repeated,
continues for some time. This is in accordance with the increase
in the volume of the kidney, as shown by oncometric methods.
Schiifer and Herring next proved that the substance which pro-
duces diuresis is contained in the posterior lobe of the hypophysis ;
that it is dialyzable, is insoluble in ether and alcohol, and is not
destroyed by boiling ; the extract of the anterior lobe they found
to be non-diuretic. Moreover, they found that diuresis is also
produced by pituitary extract when injected intravenously or into
the peritoneum.

Borchardt found that the subcutaneous injection of pituitary
extract into rabbits produced hyperglycasmia and glycosuria.

With regard to the manner in which metabolism is influenced
by pituitary extract, Schiff found that, in one clinical case of
acromegaly and one of paralysis agitans, there was an increase
in the excretion of phosphorus, which he ascribed to the decom-
position of organs containing much phosphorus, such as the
nervous system and the bones. In one case of acromegaly
Moraczewski found retention of Ca and P2O5 ; the administration
of pituitary tabloids reduced the excretion of Ca, Mg, and P2O5.

The exhibition per os of pituitary tabloids in man is followed
in the normal subject by increased metabolism of gases ; in per-
sons with acromegaly, metabolism is only very slightly increased
(Magnus-Levy, Salomon).

Experiments intended to show the effect of pituitary extract
upon metabolism in animals have produced conflicting results.
Osward found that pituitary substance, when given by the mouth
to dogs, produced no effect upon the excretion of phosphorus and
nitrogen. Thompson and Johnson, on the other hand, found an
increased excretion of nitrogen, urea, and phosphorus in the
urine, together with a reduction in the weight of the body.
Malcolm exhibited the glandular and nervous portions of the
hypophysis separately; he found that, when given by the mouth,
the anterior lobe produced retention of phosphorus, the posterior
lobe excretion of phosphorus. The excretion of Ca, Mg, and
N was increased by the exhibition of the fresh gland, but rather
diminished than otherwise by the exhibition of the dried gland.

According to Falta, Bolaffio and Tedesko, the effect of
pituitrin upon the metabolism of salt is similar to that of the
thyroid substances. They found that, in fasting dogs, there was
an increase of the quotient N:P2OS in the urine, together with
an increased excretion of phosphorus in the faeces. The excess
of the calcium excreted carries a proportion of phosphorus with

328 INTERNAL SECRETION

it into the intestine. The proportion of the alkalies to nitrogen
in the urine also increases after the exhibition of pituitrin in
the same way as after thyroid. Thus both thyroid and pituitary
increase the general metabolism of salt, the larger part of the
excess being carried off by the intestines.

After the injection of pituitrinum infundibulare into dogs
with normal nitrogen metabolism, Falta and his co-workers found
that, whether the animals were fed on flesh or on milk and white
bread, there was invariably an increase in the metabolism of
albumin.

As far as the metabolism of purins was concerned, there was
a rise in the excretion of uric acid with simultaneous reduction in
the allantoin nitrogen. This is probably clue to the increased
diuresis, owing to which a larger proportion of uric acid is with-
drawn from oxidation to form allantoin.

A definite influence of pituitary substance upon the metabol-
ism of the carbohydrates has not been observed. The sugar-
contents of the blood are not augmented; but the exhibition of
adrenalin in dogs which have previously been treated with
pituitrin is followed by a remarkable increase in the excretion of
sugar.

It is interesting to note that four rabbits, which Delille treated
with injections of pituitary extract over a period of fourteen
months, became very fat.

What is at present known concerning the effect of injections
of pituitary extract upon the growth of the bones, is insufficient
to justify a definitive pronouncement. Caselli was unable to
influence the processes of growth in young dogs and rabbits by
means of glycerine extract of pituitary. Cerletti found that the
subcutaneous or intraperitoneal injection of such extract pro-
duced backwardness in weight and in the development of the
bones; the long bones, especially, were short in comparison with
those of the control animal. Taking into consideration the fact
that large quantities of the, by no means indifferent, extract were
employed in these experiments, the results cannot be regarded as
conclusive.

EXPERIMENTAL STIMULATION OF THE
HYPOPHYSIS.

The changes produced in the general circulation by the
mechanical and electric stimulation of the hypophysis were investi-
gated by E. v. Cyon. Upon the results of these investigations,
together with the known properties of pituitary extract, he based
his theory concerning the function of the hypophysis, v. Cyon
regarded the hypophysis and the thyroid as protective organs to
the brain, whose function it is to prevent a dangerous flush of
blood to that part. These organs, acting in concert, regulate the

HYPOPHYSIS CEREBRI 329

intercranial circulation and the conditions governing blood-
pressure within the cranium. The regulation of pressure is to a
certain extent automatic, for every rise in pressure within the
cranium mechanically stimulates the hypophysis; this stimulation
is conveyed reflexly to the vagus centre and a slowing and
strengthening of the cardiac contractions results ; while, at the
same time, the vaso-dilator fibres contained in the vagus nerve
produce an enlargement of the vessels in the thyroid, and by
this means the superfluous blood is carried away from the brain.
The intracranial rise in pressure also causes the hypophysis to
part with a larger amount of its active substance, which produces
a chemical stimulation of the vagus and simultaneous rise in
blood-pressure. Thus, the auto-regulation by the hypophysis of
intracranial blood-pressure is effected by stimulation of the vagi
upon the one hand, and by increased arterial tension resulting
from contraction of the peripheral vessels upon the other.

With regard to the latter point, v. Cyon believed that the
contraction of the peripheral vessels resulted in a reduction in
the amount of blood circulating within the cranium. But it must
be remembered against this that, as all evidence up to the present
goes to show, processes which give rise to a contraction of the
vessels of the systemic circulation, thus producing an increase
in arterial tension, also augment the blood contents of the cranial
cavity. The higher the arterial blood-pressure, the larger the
quantity of blood circulating through the brain, which, under
these conditions, may amount to several times the normal. Thus
it is evident that a temporary anosmia of the brain cannot be
effected by this means, and that the effect produced upon the
cranial circulation bv the active vaso-tensor constituent of the

J

hypophysis wrould be, not the result anticipated by v. Cyon, but
one diametrically opposed to it (Biedl and Reiner).

As far as the stimulation of the vagus centre is concerned,
the conditions are as follows : The dilation of the thyroid vessels
as the result of stimulation of the vagus, which v. Cyon described
and which forms the groundwork of his theory, is not confirmed
by Lusenna, who found that the vaso-dilators of the thyroid are
contained, not in the vagus, but in the sympathetic. It is un-
deniable, however, that increased pressure within the cranial
cavity produces stimulation of the vagus centres, and that by
this means a slowing and strengthening of the cardiac beats is
effected. But the question arises as to whether this so-called
vagus phenomenon occurs as the result of high blood-pressure,
brought about by the agency of the hypophysis. In support of
this assumption v. Cyon states : (i) That mechanical or electric
stimulation of the hypophysis produces changes in the blood-
pressure curve, such as would follow a sudden compression of
the aorta, namely, hypertension, slowing and strengthening of
the heart-beats, and the so-called vagus pulse ; (2) that the vagus

330 INTERNAL SECRETION

phenomenon does not accompany compression of the aorta in
cases where the hypophysis has iirst been destroyed. After the
destruction of the hypophysis, it is not possible to produce the
vagus pulse by either aortic compression or reflex stimulation of
the aorta (by way of the nasal mucosa or trigeminus), the result
in every instance being to accelerate the pulse. According to
v. Cyon, there is no doubt that stimulation of the vagi, in con-
sequence of hypertension within the cranial cavity, is effected by
the agency of the hypophysis ; in other words, that the increased
pressure acts directly upon that organ and the stimulation of the
vagi is re flex ly produced by the stimulation of the hypophysis.

These statements of v. Cyon's do not, however, stand the
test of minute investigation and they are entirely unconfirmed
by later authors (Biedl and Reiner, Caselli, Pirrone, Lo Monaco,
and van Rynberk, Livon, Gaglio). It is true that stimulation of
the hypophysis, and electric stimulation more particularly, occa-
sionally produces increased pressure and changes in the frequency
of the pulse, together with respiratory changes, but similar
phenomena may be produced in the same way by stimulation of
the greater portion of the cerebral cortex and of the cerebral
ganglia. Livon even states that the hypophysis itself is incapable
of stimulation, and that the changes are due to the leakage of
the faradic stream into the surrounding portions of the brain.

The destruction of the hypophysis does not bring about
changes in either the pressure of the blood or the frequency of
the pulse. Moreover, the vagus phenomenon in company with
high blood-pressure is observed after, as before, this operation
(Biedl and Reiner).

The theory of a mechanical hypophysal function must be
regarded as demolished. The only author who confirmed the
phenomena observed by v. Cyon after stimulation of the hypo-
physis is F. Masay, and he believes that stimulation of the hypo-
physis promotes the flow of secretion from the organ into the
blood, and that by its action upon the muscles of the vessels a
rise in blood-pressure is produced.

In the present state of our knowledge, the only assumption
possible is that, if the hypophysis does influence the circulation,
this result is effected by the agency of a chemical hormone, and
is to be regarded as the outcome of the internal secretory function
of the organ.

DISEASES OF THE HYPOPHYSIS IN MAN.

Of the clinical conditions which are associated with patho-
logical changes in the hypophysis and the pathogenesis of which
is undoubtedly in some way dependent upon that organ, the
most important is the condition first described by P. Marie under
the name of acromegaly. This disease usually attacks individuals

HYPOPHYSIS CEREBRI 331

who have reached the adult stage; the predisposing cause is
unknown. The first symptoms are manifested through the nervous
system ; they are lassitude and muscular pain, progressive apathy
and somnolence, and eventually headache. Derangement of
sexual activity occurs very early in the course of the disease,
shown in women by the cessation of menstruation and in men
by impotence. The first pathognomic symptoms consist in
changes in the external appearance of the patient; the face be-
comes distorted, due partly to unequal growth of the soft portions
and partly to enlargement of the facial bones. In advanced cases,
the entire face is enlarged, the eyebrows are prominent, the eye-
lids thickened, the nose enormously increased, the lips swollen
and the zygomatic arches and lower jaw extremely salient. The
peculiar appearance of persons with acromegaly is enhanced by
the over-development of the soft parts of the mouth, the tongue
in particular being so large as almost to prevent the closing of the
mouth.

Simultaneously with these appearances or somewhat later,
gradual progressive deformity of the extremities takes place. The
hands and feet become clumsy — larger and broader than the
normal — the long bones, however, remain almost unaltered. The
enlargement of the ends of the extremities is due in part to a
thickening of the skin, especially of the subcutaneous tissue, and
in part to a characteristic growth of the bones of the terminal
phalanges of the ringers and toes.

The clinical appearances of acromegaly are generally, though
not invariably, accompanied by symptoms which point to the
presence of a cerebral tumour. These are : headache, giddiness,
vomiting, failing intelligence, and somnolence. Other symptoms
permit of the localization of the tumour and point to the hypo-
physis as the site of the lesion. Of these, the most important are
disturbances of vision, which consist, in the first instance, of
bitemporal hemianopsia, followed by progressive amblyopia and
amaurosis. At first the fundus is normal, later on there is pri-
mary atrophy of the optic nerve and, occasionally, choked disc.
Exophthalmos is by no means rare, but it is noticeable that the
projection of the eyeballs, like the derangement of vision, is
periodic in character and is obviously dependent upon changes
in the volume of the tumour. Paralytic symptoms are sometimes
observed in other cerebral nerve areas. A valuable aid to the
diagnosis of hypophysal tumours has recently been furnished by
radiological methods. Skiagrams show a deepening of the sella
turcica, the floor of which appears to be thinner; the dorsum
sellas shows usure and appears elongated. Where the tumour is
outside the sella turcica and is developed from the cranio-pharyn-
geal canal, the sella is flattened and the entrance to it is enlarged ;
the further growth of the tumour may completely destroy the
floor of the sella turcica (Schliller).

33 2 INTERNAL SECRETION

Of the other clinical symptoms, glycosuria is the most im-
portant and is of comparatively frequent occurrence. The fre-
quency of acromegalic diabetes, as reported up to now, is 10 to
35.5 per cent, and over. The intensity and the course of the
glycosuria are subject to considerable variation.

The other metabolic changes observed in acromegaly are not
typical. In some instances the total metabolism has been found
to be increased (Magnus-Levy), in others it has been found
to be unaltered (Salomon). Several authors found retention of
nitrogen, and they associated this with the abnormal growth of
the tissues. With regard to the metabolism of salt, several
authors (Moraczewski, Edsal and Miiller, Parhon) found reten-
tion of P, Ca, and Cl. Franchini found retention of N, CaO
and MgO, accompanied by excretion of P and Cl. It is very
difficult to estimate the metabolic changes in acromegaly, owing
to the fact that the condition is frequently associated with myx-
oedematous symptoms (Pineles). On the other hand, Magnus-
Levy points out that the metabolic changes of acromegaly possess
certain analogies with those of Graves's disease; such, for in-
stance, are the excessive perspiration, so frequently observed; the
increased combustion, proved in a certain number of cases; and
slight or severe glycosuria.

The course of the disease is usually chronic and extends over
a period of years. Cases are occasionally met with, however,
where, owing to the rapid growth of the hypophysal tumour, the
fatal termination takes place sooner and is accompanied by the
general symptoms of intercranial pressure. In many instances
the patients die as the result of intercurrent affections. In the
typical course of the disease, progressive emaciation and cachexia
make their appearance at the end of a term of years and lead,
ultimately, to death.

Of the pathologico-anatomical findings in acromegaly, the
most important are the changes in the hypophysis itself, first
described by Marie and Marinesco. Before considering the
pathogenetic significance of these changes, it is expedient first
to describe the post-mortem findings in the other organs and
tissues. The increased volume of the soft parts is brought about
by thickening of the epidermis, hypertrophy and enlargement of
the papilla? of the skin, and pronounced infiltration of the sub-
cutis, with proliferation of the subcutical connective tissue. The
connective tissue proliferation extends also to the deep-lying soft
parts and to the interstices of the muscle fibres ; the latter show
enlargement and proliferation of the nuclei and, later on, de-
generative changes. The hypertrophy of the mucosa, especially
noticeable in the case of the tongue, is caused by hyperplasia of
the mucous membranes, proliferation of the papilla?, and multi-
plication of the connective tissue. Occasionally the visceral
organs are also enlarged. A hyperplastic thymus is by no means

HYPOPHYSIS CEREBRI 333

a rare rinding, and the thyroid may have undergone strumous
degeneration or be markedly atrophied.

The changes in the bones are not as pronounced as the
clinical symptoms would seem to show. The ends of the bones
and the terminal phalanges are undoubtedly broadened and en-
larged, but this is chiefly due to exostoses and irregular absorption
of the cortical layers, and to bony outgrowths at the joints-
changes which must be regarded as secondary results of the
hyperplasia of the soft parts. The clavicle is usually very much
enlarged. In addition to the changes in the sphenoid bone, the
bony skull shows premature obliteration of the sutures ; exostoses,
especially at the muscle attachments ; enlargement of the antrum
and of the frontal sinus; increase in the volume of the superciliary
arch, the zygomatic arch, and the inferior maxilla. Investigation
of the histology of the bones shows that these results are due,
not to specific pathological processes, but to the deposition and
resorption of bony substance, in a manner identical with that of
the normal growth of the bones. In addition to these changes,
hypoplasia or degeneration of the sexual glands is a frequent
accompaniment of the condition.

The most important point in regard to the pathogenesis of
acromegaly is undoubtedly the behaviour of the hypophysis.
Marie and Marinesco found that changes in the hypophysis were
a constant feature of the condition ; these consisted in increased
volume, with hyperplastic proliferation and secondary sclerosis
of the connective tissue, together with various neoplasms. The
frequent, indeed almost constant, association of changes in the
hypophysis with acromegaly is commented upon by the majority
of the later authors. Enlargement of the hypophysis was found
in forty-four out of forty-eight cases by Hutchinson, and in
sixty-five out of seventy cases by Modena. In a large number
of cases the hypophysal tumour is the expression of hypertrophic
and hyperplastic processes writhin the organ. According to
Benda, the process consists in an increase of the glandular epithe-
lium of the anterior lobe, especially of the chromophile and
eosinophile cells. The hyperplasia may even extend to the forma-
tion of adenomatous strumas. In the majority of cases, the
tumours of acromegaly are true hypophysal tumours — adenoma,
adenocarcinoma, sarcoma and, more rarely, teratoma and tera-
toid growths. Those cases of acromegaly in which no tumour
was found (according to Cagnetto they are six in number) are
probably explained by the fact that the new formation was
situated externally of the sella turcica in the hypophysis
pharyngea, and thus escaped observation. Pathological changes
in the hypophysis in acromegaly may be regarded as constant
post-mortem findings.

It is no longer possible to consider the hypophysal tumour
in the light of an unimportant by-symptom, or as a co-ordinated

334 INTERNAL SECRETION

splanchnomegalic symptom, of no etiological importance ; on the
contrary, it is essential that we should recognize its fundamental
pathogenetic significance. Now that we know that pathological
conditions of the hypophysis may produce widely different clinical
conditions, the occurrence of hypophysal tumour without sym-
ptoms of acromegaly, can no longer be adduced as evidence
against the hypophysal origin of acromegaly. So long as our
knowledge of the nature of the changes in the hypophysis which
lead to acromegaly is incomplete, these negative cases must be
regarded with special interest ; in so far as the pathogenesis of
acromegaly is concerned, however, they are irrelevant.

The relationship between hypophysal tumour and acromegaly
has been variously interpreted. The original view of Pierre
Marie, which was adopted by a large number of authors, was
that acromegaly was the expression of insufficiency or suppression
of the hypophysal function, in the same way that myxcedema
expresses insufficiency on the part of the thyroid gland. This
theory is supported by the frequent occurrence of destructive
changes in the hypophysis. A further very strong piece of evi-
dence in favour of this view is afforded by the acute form of
acromegaly described by Stern berg, in which the condition, in
its most clearly defined clinical form, develops practically under
the eyes of the observer. In all these cases the post-mortem re-
vealed an acute progressive tumour, frequently sarcoma, of the
hypophysis. It wras already known to Marie that the hypophysal
changes frequently consisted only in hyperplastic processes,
though this seems hardly consistent with the theory of a reduced
activity on the part of the organ. It has been pointed out upon
many sides, that simple glandular hyperplasia and adenoma are
of far more frequent occurrence than destructive tumours asso-
ciated with connective tissue proliferation. With regard to the
malignant form, Hanau and Benda found that tumours, which
at first sight appeared to be sarcomatous, contained cells derived
from the hypophysal epithelium and they described these tumours
as hyperplastic, malignant adenoma. Hanau suggests that the
same adenomatous form may have been present in other cases
which have been described as sarcoma.

Certain animal experiments which seem to show that the
extirpation of the hypophysis does not produce pathological
changes in animals, were at one time regarded as important
evidence against the assumption of a suppression of hypophysal
activity in acromegaly. But to-day this argument has little
weight, for we know that the suppression of the hypophysis in
animals, as in man, is not by any means an indifferent occur-
rence; on the contrary, it is followed by a number of pathological
symptoms. The backwardness in development so clearly seen in
young animals after hypophysectomy may be taken as proof of
an influence exercised by the hypophysis upon the growth of

HYPOPHYSIS CEREBRI 335

the bones. Judging by this, the increased development of the
fl acral " portions is to be interpreted, not as a sign of reduced,
but rather as the manifestation of an intensified, functional
activity. But it is a remarkable fact, that the extirpation of the
hypophysis of animals produces results in one direction, which
are similar to those brought about by acromegaly in man ; both
lead to arrest of development, and particularly to defective function
on the part of the sexual glands.

A second hypothesis, first propounded by Tamburini, regards
acromegaly as the result of two pathological processes in the
hypophysis. There is at first hypertrophy, leading to hyper-
function of the organ, and this explains the signs of increased
growth in different parts of the body. The second phase consists
in degeneration and reduction of functional activity, which pro-
duces the cachexic symptoms observed in the later stages of the
condition. The assumption of a hyperpituitarism, of an increased
internal secretory activity on the part of the hypophysis, was
supported by a discovery of Benda's, since confirmed by others,
that, in certain cases of acromegaly, the diffuse hyperplasia and
hyperplastic adenoma, commonly known as struma, show not only
regular increase in the number of the cells, but also a remarkable
multiplication of those eosinophile cells, which Benda regards as
the active functional elements of the hypophysis. A case of
acromegaly described by Lewis is particularly interesting in this
connection, for here, though the macroscopic appearance of the
hypophysis was normal, the microscope showed that the number
of the eosinophile cells was increased.

Benda, who regarded the hyperplastic proliferation of the
chromophile cells as the cause of increased hypophysal secretion,
was at first inclined to support Tamburini's theory. In a later
publication, however, he modified his view. He pointed out that
it is not possible to regard the clinical course of acromegaly as
assuming two distinct phases, for in the classical form of the
disease, malignant acromegaly, the development of the tumour in
the hypophysis is intimately associated with the derangement of
growth and the general deterioration of the organism. Benda
regards the developmental disturbances as constant, but purely
symptomatic, accompaniments, and defines the true primary
disease as a tumour-like, connective tissue new formation, having
an undeniable resemblance to myxcedema and elephantiasis; he
ascribes the pathological symptoms to the excessive supply of a
secretion of specific toxic action, the function of which, under
normal conditions, is unknown, but the over-production of which
produces serious lesions of the tissues of the body. Benda believes
that the granules resembling zymogen in the chromophile cells
represent the secretory product of the hypophysis.

The absence of any foundation for this last assumption, to-
gether with a critical appreciation of the known facts, led Cagnetto

336 INTERNAL SECRETION

to deny the theory of hypersecretion in the causation of acrome-
galy. He pointed out that cases occur in which the hyperplasia
and adenomatous struma of the hypophysis are associated with
multiplication of the chromophile cells, but in which the symptoms
of acromegaly are not present. Moreover, cases of acromegaly
with adenoma of the hypophysis are observed, in which the
adenoma do not contain chromophile cells. It must be borne in
mind, however, that the chromophile cells are, almost certainly,
not the only secreting element, and that, as Erdheim and Stumme
showed, in the hypophysal hypertrophy of pregnancy, it is the
chromophobe cells which play the leading part. That acromega-
lous thickening of the nose, lips and hands frequently takes
place during pregnancy is another piece of evidence in favour
of the hyperpituitary origin of acromegaly, although it contradicts
Benda's assumption of the primal importance of the chromophile
cells.

The whole of the anatomical material which we at present
possess points to the hypophysal tumour, and consequent
increased hypophysal internal secretion, as the causative factors
in the production of the symptom-complex of acromegaly. The
weightiest argument in support of this theory is the fact that, in
all cases where hypophysal tumour is associated with acromegaly,
the tumour is composed of true hypophysal tissue.

It remained for operative surgery to prove, in so far as
experimental measures permit, the dependence of acromegaly
upon hypophysal affection, and by this means to provide decisive
evidence in favour of the theory of hypersecretion.

Sir Victor Horsley was the first to recommend the extirpation
of the hypophysal tumour in acromegaly. The operation was
first performed by Caton and Paul in 1893, but without success.
In 1906, Horsley described the results of thirteen operations,
without, however, supplying information as to the indications and
symptomatic features of these cases. He obtained access to the
hypophysis by opening up the dura mater from the central cranial
fossa. Schloffer next considered the question as to whether or
not the hypophysal tumour is operable, and by what methods; he
concluded that the extracranial nasal method was the most prac-
ticable. In one instance,- he operated for hypophysal tumour with
what at first appeared to be favourable results, but after two and
a half months the patient died. v. Eiselsberg next performed
hypophysis operations upon three patients, one of whom presented
the clinical signs of acromegaly and died as the result of acute
sepsis. The other two cases will be described later. Borchardt
also describes the result of extirpation of a hypophysal tumour
in an anacromegalous case, the operation, in this instance, lead-
ing to an improvement of the headache.

Hochenegg (1908) was the first to succeed in removing, by
way of the nose, a hypophysal tumour from a woman of 30

HYPOPHYSIS CEREBRI 337

with typical acromegaly ; the promptness and the success of his
results were literally startling. Five days after operation, the acute
headache and periodic disturbances of vision had disappeared,
and the teeth in the upper jaw had closed up ; from the eighth
day, the hands and feet became noticeably smaller ; at the end of
three months, with the exception of insignificant traces of thicken-
ing of the soft parts, the involution of the acra was complete.
Menstruation reappeared and became regular. At the end of
six months, the acromegalous symptoms had entirely disappeared,
but the patient had an enlargement of the thyroid gland. Histo-
logical examination of the extirpated tumour showed it to be a
malignant adenoma and quite free from typical chromophile cells.

Another case, that of partial recovery from acromegaly, is
described by Gushing (1909). He performed partial hypo-
physectomy of the hypertrophied anterior lobe. The symptoms
of intercranial pressure did not entirely disappear, but there was
an appreciable reduction of the acral parts.

A second case of acromegaly was successfully treated in
Hochenegg's clinic and is described by A. Exner. The patient
was a woman, aged 37 ; seven years previously the menses ceased
and the power of vision became progressively reduced ; increased
growth of the acral parts had been noticed for four years,
and abnormal growth of hair for three. At the time of operation,
the symptoms of typical acromegaly were well developed, and a
tumour the size of a walnut was removed from the hypophysis.
After operation, the headache, which had previously been very
violent, ceased ; the skin of the hands and feet became thinner ;
the circumference of the ringers became smaller ; the bristly
moustache hairs fell out ; the teeth closed up ; and the tongue
became reduced in size. In this case also, the thyroid developed
a middle lobe which could be distinctly felt upon palpation. In
this case, as in the first, the tumour was a malignant adenoma
(Wurmbrand).

The therapeutic results of hypophysis extirpation in acrome-
galy supply the last conclusive link in the chain of evidence in
favour of the theory, that the causative factor in acromegaly is
to be sought in hypersecretion of the hypophysis. Such being
the state of things, it is not surprising that, in those cases where
hyposecretion was assumed and the condition was treated by
organo-therapeutic methods with pituitary substance, the specific
acromegalic symptoms remained unchanged. In those rare in-
stances where benefit has been derived from the use of pituitary
substance, the subjective symptoms, especially the headache, were
affected, while the developmental changes were entirely unaltered.

If we regard acromegaly as a manifestation of hyperpituitar-
ism, the question arises as to why spontaneous recovery does not
take place in cases where there is malignant degeneration of the
hypophysal tumour and where, from the nature of the histological

22

338 INTERNAL SECRETION

conditions, a reduction of the secretory elements is to be assumed.
This, however, is readily understood, if we remember the enormous
difficulty of estimating the functional activity of the different
structural elements; moreover, judging by experience in other
directions, it is by no means improbable that the specific function
of the tissue of a malignant tumour is similar to, and may be
even stronger than, the specific function of the normal tissue. It
is a by no means rare thing in acromegaly for the anomalies of
growth, after progressing to a certain point, to arrive at a stand-
still ; there may even be regression, followed later by cachexia
with regressive nutritional disturbance. It was upon these facts
that Tambtirini founded his hypothesis. Finally, it must not be
forgotten that hyperfunction of the hypophysis is associated with
changes in the activity of other internal secretory organs, the
influence of which upon the general economy may continue,
though in'a perverted sense, after the primary factor, the hypo-
physal hyperplasia, has either ceased to exist or has undergone
regressive changes.

This latter possibility leads us to the question : What is the
primiim m ovens in acromegaly? From the nature of the evidence,
it appears unquestionable that the hypophysis is the site of origin
of acromegaly, and that the nature of the illness is dictated by
hypersecretion on the part of that organ. But the question as to
whether we are to regard the pathological condition of the hypo-
physis as primary, or merely as the secondary result of organic
affection in other parts of the body, remains unanswered. The
latter assumption is permissible, for numerous experiments have
shown that there is a physiological interrelationship between the
hypophysis and other internal secretory organs, namely, the
thyroid, thymus, suprarenals, and especially the sexual glands.
Moreover, pathological conditions of these organs are associated
with profound changes in the hypophysis.

The interrelationship between the thyroid gland and the
hypophysis has already been described. Rogowitsch first showed
that thyroidectomy is followed by hypertrophy of the hypophysis,
and his finding is confirmed by all later observers. In the depart-
ment of human pathology, it has also been shown that, in myx-
(Kdema and other related subthyroidic conditions, there is
frequently enlargement and pathological change of the hypo-
physis. Of the manner in which hypophysectomy in animals affects
the thyroid gland, we know only that Caselli found hypertrophy
of the entire thyroid apparatus. In the two cases which recovered
after hypophysectomy at Hochenegg's clinic, there was distinct
increase in the volume of the thyroid. Pineles emphasized the
clinical relationship between acromegaly and myxcedema, which
he believes to be shown, not only in the comparatively frequent
co-existence of the two conditions, but also in the similarity of
many of the symptoms and in the occurrence in acromegaly of

HYPOPHYSIS CEREBRI 339

pathological changes in the thyroid gland. It is an undoubted
fact that, in many of its aspects, acromegaly resembles Graves's
disease. Enlargement of the thyroid apparatus is frequently
observed in acromegaly, and Lancereaux believed that this condi-
tion results from a stimulation of the processes of growth, brought
about by the enlarged thyroid gland, and modified and controlled
by the hypophysis. As things stand at present, it is difficult to
estimate the significance of the part played by the thyroid appa-
ratus in acromegaly. That hypothyrosis produces an enlarge-
ment of the hypophysis is undoubtedly true, but it can hardly be
regarded as the primary cause of such enlargement. There is
an equal probability that the hyperpituitarism brings about a
reduction of function, and consequent atrophy, on the part of the
thyroid. The assumption of an interrelationship between the
activities of the two organs is justified by clinical experience, and
it remains for experimental pathology to crystallize this assump-
tion into a certainty.

Persistence of the thymus in acromegaly is by no means rare.
The inconstancy of the finding, however, deprives this pheno-
menon of the causative significance attributed to it by Klebs.

The relationship between the suprarenals and the hypophysis,
especially in acromegaly, has not as yet been sufficiently investi-
gated. After extirpation of the suprarenals, Alquier observed
signs of moderate hyperplasia of the hypophysis in a dog; Boinet
found that hypertrophy was exceptional in rats; while Marenghi
found marked hypertrophy in guinea-pigs, rabbits and cats.
Hyperplastic changes in the hypophysis have been described in
suprarenal disease in man (Thaon, Delille) ; while, on the other
hand, adenoma and cystic degeneration of the suprarenals have
been observed in acromegaly. Delille points to the frequent
occurrence of suprarenal hypertrophy; together with Renon, he
discovered that hyperplasia of the suprarenals may be produced
by the repeated intraperitoneal injection of pituitary extract.

Best known is the interrelationship between the hypophysis
and the sexual glands; the part played by the latter in the causa-
tion of acromegaly is as yet, however, undecided. The changes
in the sexual organs observed in acromegaly, and especially the
cessation of the menses in women, are among the earliest sym-
ptoms of the disease. Later on, there is cessation of sexual desire
and sterility, accompanied by atrophy of the genital glands. The
changes in the sexual glands in acromegaly have been minutely
described by Tandler and Gross. Not infrequently, the secondary
sexual characteristics disappear and there may be even a partial
return to the heterosexual type. Many authors (Freund, Ver-
straeten, Campbell, Breton and Michaud) believe that the changes
in the sexual glands are a causative factor in the production of
acromegaly. There is a certain amount of foundation for this
assumption, for it has long been known that the sexual glands

34O INTERNAL SECRETION

exercise a considerable influence upon the general processes of
growth.

In the meantime, a large number of physiological, patho-
logical and experimental facts have come to light which show the
influence of the sexual glands upon the hypophysis. Comte and
a number of later authors (Launois and Mulon, Guerrini, Morandi
Cagnetto, Thaon) found that the hypophysis regularly enlarges
during pregnancy, and that during lactation it returns to the
normal. These changes were from the first regarded as signs of
hyperfunction, and the discoveries of Erdheim and Stumme after-
wards supplied incontrovertible evidence of hypophysal hyper-
trophy during pregnancy and of the changes which take place
in the structure of the organ. Fichera's valuable work next
showed that the changes in the hypophysis during pregnancy are
due to a reduction of activity on the part of the ovary. After
the castration of male and female animals, he found hyperplasia
and hypertrophy of the hypophysis which exactly resembled the
hypertrophy of pregnancy. The weight of the hypophysis in
capons and oxen, as well as in castrated female animals, was twice
as large as in normal animals, and this hypertrophy was reduced
by the exhibition of extract of the sexual glands. By examina-
tion of the skulls of skeletons, and by means of skiagrams of
living castrated animals, Tandler and Gross next showed that
there was anatomical enlargement of the sella turcica. In three
animals from which the testicles or ovaries had been removed
several years previous to death, Rossle found considerable en-
largement of the hypophysis; as also in one animal, the uterus of
which had been extirpated four days previously. The association
of hypophysal hypertrophy with aplasia of the genitals and with
the results of castration, was conclusively proved by Jutaka-Kon's
investigations.

If the excessive growth of the hypophysis in acromegaly is
considered in the light of these facts, it is readily conceivable that,
as certain authors believe, the derangement of the internal secre-
tory function of the sexual glands may be the primary cause of
the condition ; that it gives rise to secondary proliferation of the
hypophysis ; and that the latter, in its turn, brings about the
typical changes of acromegaly. Stumme regards the anomaly of
the internal secretory function of the sexual glands as a primary
metabolic disturbance leading, where there is congenital pre-
disposition, to tumour formation in the hypophysis. It cannot
be denied that, in many of its aspects, the clinical complex of
acromegaly suggests a primary affection of the sexual glands.
It is suggestive in this connection, that the development of
hypophysal tumour and of acromegaly are frequently preceded
by symptoms of chlorosis, a condition which has been regarded
as connected with the genital tract. On the other hand, there
are reliable observers who affirm that, in many cases, the changes

HYPOPHYSIS CEREBRI 341

in the genital organs in acromegaly do not appear until the con-
dition is far advanced.

In the present incomplete state of our knowledge, it is not
possible to define with certainty the primary origin of the hypo-
physal changes which give rise to the symptoms of acromegaly.
It may be that the condition is not the outcome of a single,
definitive cause. Hypertrophy of the hypophysis may take place
primarily as the result of adenoma formation, which is extremely
frequent in that organ; or it may be a secondary condition, the
result of the primary affection of other internal secretory organs
and of the sexual glands more particularly. From the known
interrelationship between the hypophysis and the sexual glands,
as well as from the fact that atrophy of the sexual glands is
invariable at some stage of acromegaly, it seems highly probable
that suppression of the function of the sexual glands plays a part,
first in the causation of the clinical complex of acromegaly, and,
afterwards, in the furtherance of the processes of growth by which
the disease is characterized. Knowing, as we do, the manifold
interactivities which subsist between the various internal secretory
organs, it is not difficult to see that other internal secretory organs
besides the hypophysis may be concerned in the production of
acromegaly, in the same way that Graves's disease is attributable
to the influence of organs other than the thyroid. Regarded from
this point of view, acromegaly belongs to the group of the poly-
glandular diseases.

A second pathological condition which is associated with the
hypophysis is gigantism (gigantismus, macrosomia). The classi-
fication of gigantism as a pathological condition is justified by
the facts : first, that abnormal longitudinal development of the
bones and increase in the volume of the organs must be regarded
as a perversion of the processes of growth ; and second, that
abnormality of growth rarely occurs singly, but is almost invari-
ably associated with derangements of the function, and of the
anatomical constitution, of different organs. It is only the giants
of fairy tales who, in addition to their size, are favoured with
exceptional physical and mental advantages. A closer acquaint-
ance with the giants of our day, as well as a careful analysis of
the descriptions which have come down to us of the giants of old,
shows that normal giants — that is to say, persons of exceptional
size and free from deformity or other pathological signs, such as
were assumed by Langer, and later by Sternberg — are very rarely
encountered. The vast majority of giants are undoubtedly abnor-
mal and belong to the class of pathological individuals.

Launois and Roy, who have made a special study of this
phase of abnormality, define the condition as follows : Gigantism
is an anomaly of skeletal growth which leads to a height of the
body in excess of the average dimension of the race, and is
associated with characteristic morphological and functional de-
rangement.

342 INTERNAL SECRETION

Gigantism attacks men more frequently than women, and
usually takes its rise at the period of puberty. Thus at the age
of 1 8 to 20, the height of the subject may be 190 to 200 cm., or
more ; and at 25 to 30, when the normal individual has long ceased
to grow, it may be still increasing.

The parts principally affected are the extremities, especially
the lower ones, while the trunk is only slightly influenced, and
the skull appears small in comparison with the rest of the body.
The excessive length of the lower part of the body, as compared
with that of the upper part, is characteristic of typical gigantism.
Separation of the epiphysal synarthroses, and hypertrophy of the
osseous substance of the long bones, may be seen in vivo by means
of skiagrams. Subsequent anatomical investigation confirms
these findings, and shows the persistence of the cartilage at the
junction between the epiphysis and diaphysis, as well as the
imperfect ossification of the sutures and various signs of hyper-
ostosis. The vertebral column frequently shows postero-lateral
curvature (kyphoskoliosis). The most remarkable point about
gigantism, however, is that, in the majority of cases, the skeleton
of the face and of the acral portions shows changes which are
distinctly characteristic of acromegaly. Exaggeration of the
zygomatic arches, marked projection of the supraciliary arches,
prognathism of the lower jaw, thickening of the bones of the skull,
enlargement of the antrum and sinuses, and deepening of the
sella turcica, are the usual facial characteristics of the gigantic
subject. With these, changes of the hands and feet, entirely
analogous to those of acromegaly, are frequently associated.

Of the internal findings, the most interesting is undoubtedly
the condition of the hypophysis. The deepening of the sella
turcica points to an enlargement of the organ, and this was
established by Launois and Roy, who found that, in ten cases of
gigantism which they examined post mortem, there was more or
less marked increase in the size of the hypophysis. In the
majority of cases there was hyperplasia of the glandular tissue and
adenoma formation ; more rarely there was vascular struma ; and
in a few cases there was sarcoma and epithelioma.

In the majority of cases of gigantism, the weight of the brain
is remarkably small in proportion to that of the body. The
reports of the condition of the thyroid glands are not unanimous.
In the greater number of cases, the thyroid was much
enlarged, the weight varying from two to six times the normal.
In one case, Wells showed that the iodine contents, though rela-
tively normal, were absolutely very much increased. On the
other hand, there are descriptions of cases of gigantism in which
the thyroid was normal or even comparatively small. Persistence
of the thymus has not been described.

The most remarkable changes in gigantism are those pre-
sented by the sexual glands. Reduction of sexual activity,

HYPOPHYSIS CEREBR1 343

absence of menstruation in women, and sterility in both the male
and the female, are among the clinical symptoms of gigantism.
In rare cases, a preceding stage of sexual hyperactivity has been
observed (Buday and Jancso). In contrast to the other internal
organs, which show hyperplasia, the sexual glands are usually
atrophied with signs of degenerative lesion. The secondary
genital organs and genital excretory ducts (prostate and penis,
uterus and vagina) are also, as a rule, remarkably defective in
development, and signs of infantilism are by no means infrequent.
Lack of intelligence; mental apathy and indolence; lack of mus-
cular tone and power ; poorness of hair all over the body,
especially that of the pubes, axillae, and in the male, of the beard;
and, in many cases, excessive development of the panniculus
adiposus — these are all signs that the organism has remained at
an infantile stage of its development. The slight powers of
resistance of the subjects of gigantism is shown by the fact that
they usually die at an early age as the result of accidental illness.
Those cases of gigantism which pass on into definite acromegaly
are the only ones which offer a better prognosis concerning the
duration of life. The anomalies of metabolism are, as yet, unin-
vestigated. The comparatively frequent occurrence of glycosuria
or even of serious diabetes, is worthy of remark.

The pathogenesis of gigantism was first discussed by Pierre
Marie in the course of his investigations into the nature of
acromegaly. Marie believes that true gigantism is characterized
by an excessive increase of all the processes of normal bony
growth ; and that it is to be distinguished from those cases of
symptomatic gigantism in which there is abnormal growth of
certain portions only, as, for instance, in acromegaly, elephanti-
asis, and certain forms of congenital syphilis.

The similarity between certain of the symptoms in gigantism
and in acromegaly — especially the enlargement of the sella turcica
as seen in museum specimens — together with the fact that the
subjects of gigantism frequently develop the typical signs of
acromegaly, led many authors to dispute this theory of Marie's.
Brissaud and Meige adopted the view, based upon the relation-
ship between acromegaly and gigantism, that the conditions both
originate in the same pathological processes, and that they differ
from one another only in the moment at which the pathological
process takes place. According to Brissaud, gigantism is the
acromegaly of the period of growth, acromegaly the gigantism
of the adult stage; and acromegalic gigantism is the result of a
pathological process, which commences during the period of
growth and continues on into the period in which growth has
ceased.

This theory received valuable support from the exhaustive
investigations of Launois and Roy. These authors also dis-
tinguished between two forms of gigantism, the acromegalic and

344 INTERNAL SECRETION

the infantile ; but they lay stress upon the fact that the number of
cases included in the former class increases as the two forms are
more carefully studied, and that it would be hardly possible to
bring forward a case of infantile gigantism which did not present
some of the signs of acromegaly. The subject of infantile gigan-
tism, if he lives until his epiphyses are ossified, becomes acrome-
galic. After that, he ceases to increase in height and the
endochondral is replaced by periosteal hyperossification. Launois
and Roy showed that the skeleton of the giant Constantin, whose
skeleton they very minutely investigated, presented the infantile
type of gigantism in the extremities and the acromegalic type in
the skull. Gigantism is the acromegaly of those individuals,
irrespective of age, whose epiphysal cartilage has not undergone
ossification. If all the subjects of gigantism are not acromegalic,
they may at least become so. The fact that disturbances of
growth are invariably associated with pathological changes in the
hypophysis, led these authors to regard that organ as the source
of origin of gigantism.

That the hypophysis plays a leading part in the pathogenesis
of gigantism is undoubted. This applies to those cases particu-
larly in which gigantism has, from the first, been associated with
acromegaly. In infantile gigantism, on the other hand, primary
disgenitalism must be included as a probable causative factor.
This is suggested by the similarity of the symptoms in this con-
dition with those observed after castration before the onset of
puberty, as well as by the relatively slight changes in the hypo-
physis and the lateness of the stage at which these take place.
According to Fichera, these changes are also only secondary
results of the suppression of the activity of the sexual glands. The
peculiar disposition of the hypophysis to pathological change, to
which reference has already been made, may be the reason why,
in these cases, the processes of growth are more prolonged, and
the dimensions of the individual thus greater than is commonly
the case after castration.

A further factor in favour of gigantism is supplied by the
thyroid gland. After early castration the thyroid generaliy
atrophies and the suppression of its function brings about an
inhibition of the processes of growth. But in the majority of the
subjects of gigantism the thyroid has been found to be normal or
even hypertrophied ; it seems possible that the condition may, in
part, arise from the fact that the abnormal stimulation of the
processes of growth, which results from the suppression of the
sexual glands and the hypertrophy of the hypophysis, receives no
inhibitory check from the thyroid gland.

A few attempts have been made to treat gigantism by organo-
therapeutic methods with ovarian and testicular extracts, but
success has been very rare (Maisonave, Dor, Hudovernig). The
results seem to show, however, that the primary genetic factor in

HYPOPHYSIS CEREBRI 345

infantile gigantism is supplied by the defective internal secretory
activity of the sexual glands. Fischera succeeded in modifying
the changes in the hypophysis after castration by the exhibition
of extract of the sexual glands, and this seems to suggest the
employment of the method in the treatment of secondary hypo-
physal disease.

All researches into the pathogenesis of gigantism suggest
that the condition is the outcome of hyperpituitarism ; that, in the
acromegalic form, this hyperpituitarism is the primary cause of the
abnormal development of the body; while, in the infantile form, it
is probably the secondary result of primary disgenitalism, and
acts in concert with the latter.

Another pathological condition associated \vith changes in the
hypophysis is hypophysal obesity, or dystrophia adiposogenitalis
(Bartels). This condition was first described by A. Frohlich
(1901). He found that, in a case which showed' symptoms of
hypophysal tumour, there was a very rapid increase in corpu-
lence, together with infantile character of the sexual glands, and
he assumed that this peculiar clinical complex was produced by a
specific action on the part of the hypophysis. Since that time
Frohlich 's type has been described by a large number of observers.

The most striking symptom is the obesity, which may attain
enormous dimensions. It consists, partly in the deposition of fat
in certain localities — particularly the breast and the abdomen — and
partly in a general increase of the entire fat-body. At the same time
the skin is remarkably dry and low in temperature, the secretion
of the sweat glands is reduced, and there are trophic disturbances
of the hair and nails. The second important symptom is the
hypoplasia of the genitals, which is associated with imperfect
development of the secondary genital organs, together with
infantile habit. Symptoms of cerebral tumour, with suggested
localization in the hypophysis, complete the clinical picture.

The etiological significance of the hypophysis in this con-
dition receives remarkable confirmation from a case described by
Madelung, that of a Q-year-old girl, who developed signs of
general obesity after a bullet wound in the head, the bullet remain-
ing lodged in the sella turcica. But Erdheim disputed the
hypophvsnl origin of this form of obesity, and showed that, in
isolated cases, the hypophysis is found under the microscope to
be entirely normal. He believes that the cause of the condition
lies in an influence exerted by a tumour in some area at the base
of the brain, and inclines to the infunclibulum, in which a trophic
centre may be assumed. According to Marburg, however,
Erdheim's observations do not supply proof of his theory; but
even if we allow it to stand and assume that the infundibulum only
is affected by the lesion, the condition might yet be due to indirect
disturbance of the hypophysis, owing to the destruction of the
glandular nerves which enter the hypophysis by way of the
infundibulum.

346 INTERNAL SECRETION

Dystrophia adiposogenitalis is regarded by some authors
(Schiiller, Tandler, and Gross) as the result of primary genital
atrophy. The influence of the internal secretory activity of the
sexual glands upon metabolism, and especially the obesity which
has long been known to follow the suppression of these organs,
will be "described in a later chapter. If we consider, however,
that the hypoplastic constitution shows, in addition to the signs
of infantile habit, hypoplasia of the genitals, together with a
remarkable development of the fat-body, we cannot be far
out in assuming adiposis cerebralis to be the result of defective
genital function together with secondary changes in other internal
secretory organs. It is, however, worth noticing that, out of
thirty-two cases of hypophysal obesity, twelve only showed
genital atrophy; and that genital involution was not always
observed in the earlier stages of the disease.

It is hardly possible, in view of the results of experimental
extirpation, to doubt the primary significance of the hypophysis in
the causation of dystrophia adiposogenitalis. The extirpation of
certain portions of the hypophysis, as well as of the entire organ,
is followed by symptoms in animals which have a profound
resemblance to the clinical type of hypophysal disease which
Frohlich described. Experimental investigation by Gushing and
by Aschner, as well as the results of my own experiments, all
show that partial hypophysectomy is invariably followed by a
considerable increase in the fat body, and by hypoplasia of the
sexual glands and of the entire genital tract. In the young-
animals which Aschmer operated upon there was also persistence
of the infantile habit. These experimental results show, more-
over, the nature of the derangement which takes place in the
hypophysal function. If the symptoms described are induced in
animals by experimental apituitarism, it is safe to conclude that
the clinical type described by Frohlich results from reduced hypo-
physal activity or hypopituitarism.

This assumption does not appear to be confirmed, however,
by the results of the operative treatment of dystrophia adiposo-
genitalis. One of the first operations for hypophysal tumour
successfully performed by v. Eiselsberg was upon the patient
described by Frohlich. The operation was followed by the dis-
appearance of the local symptoms due to the presence of the
tumour, while at the same time there was an improvement in all
the general symptoms which were attributable to the hypophysis.
The weight fell, the obesity was reduced, hair grew at the pubes
and in the axillae, and sexual activity manifested itself by erec-
tions. The disappearance of the dystrophic symptoms after the
removal of the hypophysal tumour appeared to be a weighty
argument against the theory of hypopituitarism. There is, how-
ever, another side to the question. If we assume that the tumour
only was removed, and that the hypophysal tissue was otherwise

HYPOPHYSIS CEREBRI 347

left intact, it is obvious that, with the removal of the tumour the
obstruction of function was abolished, the latter being allowed to
resume its normal course. This supposition is rendered more
probable by the subsequent history of the case. The improve-
ment lasted for nearly three years, the symptoms principally
affected being those which had been caused by the tumour, while,
after the first amelioration, the general symptoms ceased to make
further progress. At the present time the patient is still of
infantile habit, and there is no appreciable reduction of the corpu-
lence. In three other cases of the same kind upon which v.
Eiselsberg operated successfully, the tumour symptoms and the
general condition were improved, but the state of the genital
organs and the corpulence underwent no progressive improvement.
The indication for surgical measures lies, not in the trophic dis-
turbances, but almost exclusively in the progressive signs of cere-
bral tumour, such as violent headache and threatening blindness;
hence, if these symptoms show improvement, it is perfectly justifi-
able to describe the result as " satisfactory." In certain cases,
the operative removal of the tumour is undoubtedly the most
rational method of procedure. The results which have just been
described do not, however, disprove the significance of hypo-
pituitarism as a factor in the etiology of dystrophia adiposo-
genitalis.

The results of organo-therapy in this condition are not
unfavourable to the hypothesis of hyposecretion. Several
accounts (Levy and Rothschild, Axenfeld, Delille) have been given
of the beneficial effect of pituitary extract upon the obesity and
the reduced sexual activity. On the other hand, there is a general
consensus of opinion that the exhibition of pituitary extract in
acromegaly is not only useless, but that in many instances it
aggravates the symptoms.

In considering the diseases which originate in the hypophysis,
the fact is brought home to us — perhaps more nearly than in the
case of the other internal secretory organs — that disturbance of
the function of one organ is so intimately associated with dis-
turbance of the function of others, that it is sometimes difficult to
decide with certainty in which organ the primary pathological
affection is to be sought. As long as ten years ago, Pineles
pointed out the fact that there appears to be an intimate anatomical
and physiological interrelationship between the different blood
glands, which is manifested clinically by the fact that the patho-
logical disturbance of one gland is accompanied by symptoms
pointing to the functional derangement of one or more of the
others. Knowing, as we do, the many sided interactivity which
subsists between the different internal secretory organs, it is readily
conceivable that isolated diseases of single organs of this group
are very much rarer than, at a first glance, they would appear to
be. In the present state of our knowledge, the only course of

348 INTERNAL SECRETION

investigation which is open to us, is to start with the known
results of the functional derangement of any organ, and, by
following these up, to seek the primary link in the pathological
chain.

The scantiness of our knowledge concerning the function of
the hypophysis and the experiments which have been undertaken,
largely without success, with the object of determining the scope
of the hypophysal function in animals, probably account for the
fact that, in clinical conditions associated with changes in the
hypophysis, other internal secretory organs (thyroid, thymus,
sexual glands, pancreas, suprarenal) have always been accredited
with an equal and simultaneous participation. This was the
origin of the polyglandular syndrome of the French authors.
Under the designation insuffisance pluriglandulaire, Claude and
Gougerot (1907) described a symptom complex which they
assumed to result from the general atrophy and functional insuffi-
ciency of a number of internal secretory organs. Since then, a
number of similar cases have been described. That we have not
to do here with a well defined clinical entity is shown by the fact
that the functional derangement, in either the positive or negative
sense, of one organ is not by any means always followed by
•corresponding changes in the activity of other organs of the
group; for it more often happens that the hyperfunction of certain
internal secretory organs is associated with hypofunction on the
part of others, and vice versa. As a matter of fact, cases have
been described in which polyglandular insufficiency was associated
with either hyperpituitarism or with hypopituitarism (Delille).

The formulation of a separate clinical entity of polyglandular
origin, appears upon the whole to be premature. There is no
doubt that clinical observation and experimental research will
shed a good deal of light upon the interrelationships between the
different internal secretory organs ; but until experimental investi-
gation is put upon a sound physiological basis, we cannot hope
for any certain illumination of the pathogenesis of the newer
clinical types.

THEORY OF THE FUNCTION OF THE HYPOPHYSIS.

The study of the morphology, physiology and pathology of
the hypophysis has supplied a good deal of information concerning
the functional significance of that organ, but up to the present it
has not sufficed to create a definite and finished picture of its
physiological activity. The best that we can do is to draw from
the facts at our disposal an approximate conclusion concerning
the nature of the hypophysal function.

Morphologically, the hypophysis appears to be an organ com-
posed, both genetically and structurally, of two entirely different
portions. The anterior lobe may justly be regarded as a secretory

HYPOPHYSIS CEREBRI 349

gland; while the posterior lobe, which belongs genetically to the
nervous system, is found to consist later of indifferent glia
tissue. The intimate anatomical connection between these
heterogeneous tissue formations is very remarkable.

The importance of the anterior glandular portion is shown by
the results of physiological investigation and of clinical obser-
vation ; for we know7 that the removal of this part of the organ is
inconsistent with the continuance of life, and that its pathological
disturbance is followed by marked clinical symptoms. On the
other hand, it is not apparent from either post-mortem findings
or the results of experimental extirpation, that the suppression of
the posterior portion is attended by any consequences whatsoever.

If, however, the functional significance of the two portions is
tested by the activity of the extracts which they supply, the results
arrived at are very different. It must be remembered, however,
that we possess no proof of any kind that the active substance
present in pituitary extract, is formed in the organ during life
and by it passed on into the blood-stream. The assumption of
such a performance on the part of the hypophysis is founded upon
analogy, and receives considerable support from the fact that the
activity of pituitary extract is well defined and quite specific. It
is, moreover, a very remarkable thing that the true glandula
pituitaria yields an extract possessing no definite physiological
properties ; while the extract obtained from the neurohypophysis
produces definite and characteristic effects upon the animal
organism. Such are the vaso-constriction and immense rise in
blood-pressure produced in a number of organs; the stimulatory
action upon certain muscular structures, such as the heart, and
especially the uterus; and finally the increased diuresis. But
neither the operative removal of the neurohypophysis nor the
clinical symptoms which accompany hypophysal disease, supply
any proof that the suppression or perversion of the activity of
this part is accompanied by appearances pointing to the absence or
superfluity of the specific active substance. In face of these
facts, it is only with the greatest reserve that the substances in
the infundibular portion of the hypophysis can be described as
physiologically active hormones. The internal secretory activity
of the neurohypophysis and its functional significance are in need
of further investigation.

We are more favourably placed in regard to the anterior lobe.
In spite of the fact that the product of secretion has not as yet
been obtained in the organic extract, there is no doubt that this
portion of the hypophysis stands in intimate correlation with a
number of other organs, and that their interactivity is effected by
chemical means. That the £rlandula pituitaria belongs to thp
group of the internal secretory organs is proved by two sets of
facts.

In the first place, anatomical changes — that is to sayr

350 INTERNAL SECRETION

increased volume as the result of hyperplasia of the glandular
cells — are produced in the anterior lobe of the hypophysis by
alteration of function on the part of certain other internal secretory
organs. Suppression or modification of the thyroid function and
that of the sexual glands is followed by such hypertrophy.

In the second place, functional and anatomical changes in
the hypophysis are associated with changes in the thyroid gland,
the genital glands, and perhaps also in the suprarenals. The
exact manner in which these consecutive changes take place is
not, as yet, exactly known. It is probable that hyperf unction of
the hypophysis is associated with hypertrophy of the cortical
portion of the suprarenals, together with a diminution both of
function and of volume in the thyroid. The correlationship
between the hypophysis and the genital glands appears to be even
more complicated. Experiments with animals and observation of
Frohlich's dystrophia adiposogenitalis show that hypoplasia of
the genitals is combined with reduced hypophysal function ; while
acromegaly and gigantism, which are regarded as manifestations
of hyperpituitarism, are also characterized by defective sexual
activity.

The internal secretory activity of the hypophysis is mani-
fested, moreover, in the influence which this organ has upon the
metabolic processes which take place in the body. The most
important is undoubtedly the effect which it has upon develop-
ment. Even the hyperactivity of the hypophysis which is
observed during pregnancy as the result of inhibition of the
ovarian function, is associated with developmental changes which
affect not the soft parts only, but also the bones. A greater degree
of hyperpituitarism leads to abnormal growth in height and to
remarkable increase in the volume of the acral portions. On the
other hand, the removal of the anterior lobe of the hypophysis is
followed in young individuals by a marked arrest of development.
That form of hypopituitarism which leads, both in animals and
man, to a conspicuous increase in the deposition of fat shows how
important is the part which this organ plays in the metabolism
of fat.

THE PINEAL BODY.

(GLANDULE PINEALIS, EPIPHYSIS, CONARIUM).

The structure which Descartes believed to be the seat of the
soul must, upon clinical grounds, be included among those organs
which, by the agency of their internal secretion, exercise a
demonstrable influence upon the somatic and psychic develop-
ment of the individual, as well as upon the nutritional condition
•of the body and of certain tissues. In a work published last year,
O. Marburg gives a very complete account of the normal and

THE PINEAL BODY 351

pathological histology of the pineal gland, together with a
description and critical survey of the available clinical and patho-
logico-anatomical material concerning the affections of that organ.

Anatomy. — The pineal gland of man is, in the adult, a small
flattened body, nearly trilateral in shape, which is suspended free
between the anterior pair of corpora quadrigemina, with its base
directed forwards over the roof of the third ventricle; it is con-
nected with the posterior commissure of the third ventricle by
means of a medullary lamina issuing from its ventral portion. A
second medullary lamina, called the commissura habenularum,
issues from the dorsal part of the pineal body; it tails off into a
thin band, the pineal peduncle or habenula, and this is attached to
a thickening, the trigonum habenula;, situated at the posterior end
of the optic thalami. Between the two lamina; is the narrow
passage, blind at its caudal end, of the recessus pinealis. The
tela choroidea lies against the posterior portion of the dorsal
surface of the pineal gland ; with the anterior portion it forms a
pouch, the recessus suprapinealis, which opens into the third
ventricle.

Embryology. — From the roof of the thalamencephalon
(diencephalon) of the lower vertebrates, according to Edinger, two
buds are developed, which, proceeding dorsally, represent : (i)
the paraphysis; and (2) the pineal tubercle or dorsal pouch. The
paraphysis is not present in mammals, but the dorsal pouch is
represented by the recessus suprapinealis. At the boundary of
the thalamencephalon and the mesencephalon, are two other buds :
(3) the parietal vesicle ; and (4) the epiphysis. From the parietal
vesicle, in the lower vertebrates (fish, reptiles), the parietal organ
is formed (though many authors believe it to be formed from a
vesicular portion of the epiphysis), which breaks through the
•cranial capsule at the parietal foramen and persists as the so-
called " frontal patch " ; or, in saurians, as the parietal eye, which
has a formation similar to that of the eye of invertebrates. The
changes which take place in the position of the organ during the
embryonal stage are shown by the course of the parietal nerve, by
which communication with the ganglion habenula? is effected.
In the loose connective tissue between the recessus suprapinealis
and the pineal gland of new-born infants, Marburg found a
structure resembling the parietal nerve and ganglion of reptiles.
The pineal body is developed from the epiphysal protuberance,
which throws out lateral buds, becomes vascular, and gradually
changes into a glandular structure composed of solid cell masses.
This gland is not furnished with ducts; it communicates with
the brain by means of the pineal peduncle and the posterior
commissure.

Histology. — In new-born infants the pineal gland consists of
irregular lobes held together by a small quantity of connective
tissue; the lobes are composed of cells of almost the same type,

352 INTERNAL SECRETION

but arranged irregularly, being crowded together in the interior
of the organ. The pineal cells have a pale tinted protoplasm and
very characteristic nuclei, these being large and oval, and
crowded, over their entire circumference, with granules. Dimi-
trowa distinguishes four different nucleus forms. Other im-
portant histological details are : (i) The peculiar nature of the
ependyma of the recessus pinealis, in which cubical epithelium
and epithelium composed of goblet-like cylindrical cells alternate ;
and (2) the cysts which are observed at the base and in the
interior of the pineal gland of new-born infants, and which
probably represent obliterated blood-vessels. The pineal gland
shows signs of involution before the age of puberty, the first
symptoms being observed in the seventh year. The concretions
known as pineal sand or acervulus, which consist of calcium
phosphate and calcium carbonate, are found in the glia layer
which covers the commissura habenularum. As age increases, a
distinct increase of the connective substance at the expense of the
glandular tissue takes place. The glandular lobes are replaced
by plaques composed of connective tissue and a very fibrous glia
tissue, and these plaques contain isolated glandular cells. The
connective tissue septa further undergo hyaline degeneration, and
may completely calcify. Occasionally, homogeneous masses are
observed in the septa or in the interior of the glandular lobes and,
after the deposition of calcium salts, corpora arenacea are evolved
from them. The glandular cells also present signs of involution,
but, even in extreme old age, glandular cells are encountered
which are intact and, apparently, still functionally active. Cysts
formed, in the majority of cases, from the glia plaques as the
result of obliteration of the blood-vessels, are a very common,
finding in the pineal gland of adults.

Physiological experiments with the pineal gland are described
by E. v. Cyon. This author investigated the activity of extract
of the pineal gland of oxen and sheep. He found that, when
injected intravenously, they produced no effect upon blood-
pressure, but that small doses accelerated the heart's action, while
large doses retarded and strengthened it. Irregularity of the
cardiac beats, bigeminal and trigeminal pulses were also fre-
quently observed. According to v. Cyon, extract of pineal gland,
when given in small doses, excites the nervi accelerantes only;
in large doses it simultaneously stimulates the inhibitory cardiac
nerves, but in so irregular a fashion that the harmonious counter-
activity of the two sets of nerves is unbalanced. The cardiac
beats become irregular, but these irregularities disappear after
resection of both vagi. Further experiments showed that glycero-
sodium phosphate acts in the same manner as weak doses of
pineal extract, while glycero-calcium phosphate produces action
beats, as they are called, in the same way as' large doses of pineal
extract; but unlike those produced by pineal extract, these action

THE PINEAL BODY 353

beats continue after resection of the vagi. The results of these
experiments led v. Cyon to assume that it was the function of
the pineal gland to store up certain salts in organic combination ;
and that the physiological action of pineal extract is explained
by the presence of these salts, in comparatively large quantities,
both in the concretions in the spaces and distributed throughout
the tissue of the pineal gland. Calcium phosphate forms the
larger proportion of these salts.

v. Cyon also describes the results of direct experimental
stimulation of the exposed pineal gland of rabbits. He found
that electric stimulation produced contraction, together with a
change in the length and the shape of the organ. He supposes
this contraction to be produced by the striated muscles, the
presence of which in the pineal gland of oxen and calves has
been proved histologically by Nicolas and Dimitrowa. According
to v. Cyon, a contraction combined with a shifting of the pineal
gland would regulate the in- and out-flow of the cerebro-spinal
fluid in the third ventricle. Thus the pineal gland would fulfil
the mechanical function of automatically controlling the flow of
the fluid in the aqueduct of Silvius, enlarging or reducing the
channel in accordance with the pressure in the third ventricle,
v. Cyon thinks that, like the thyroid gland and the hypophysis,
the pineal gland belongs to that group of organs which, acting
partly alone and partly in physiological concert, control inter-
cranial pressure.

v. Cyon's experiments have not, as yet, been confirmed. As
far as the effect of pineal extract is concerned, Dixon and Halli-
burton (IQOQ) state that its intravenous injection is without
definite effect either upon blood-pressure or the cardiac contrac-
tions. The effect of pineal extract upon respiration, the intestines,
and the urinary secretion, is negative.

Pathological Anatomy. — Virchow was the first to draw atten-
tion to the pathological formation of cysts in the pineal gland.
Cysts have been recently described, the presence of which was
attended by no clinical signs whatever. In a number of in-
stances, serious pathological symptoms were present.

Teratoid formations are of frequent occurrence in the pineal
gland. Since Weigert's classical description (1875), several
accounts of pineal teratoma have been given. Askanazy (1906)
regarded these formations as developments from a germ which
gained access to the pineal gland at the earliest stage of embryonal
life. Marburg believes the starting point of pineal teratoma to
be the primordial beginning of the parietal eye. In so far as the
clinical results are concerned, Askanazy supposes that these
tumours act like a foetus and produce certain anomalies of growth
to be described later. According to Marburg, these anomalies of
growth are the result of premature destruction of the active func-
tional pineal tissue.

23

354 INTERNAL SECRETION

Tumour forms of the most varied description — glioma, sar-
coma, carcinoma, and tumours composed of different kinds of
tissue — have all been observed in the pineal gland.

Clinical Signs of Pineal Affection. — Disease of the pineal
gland is accompanied by certain very characteristic clinical signs,
which are to an extent analogous with those which accompany
pituitary disease.

Total destruction of the pineal gland, such as may be brought
about by malignant tumours, was in six cases accompanied by
profound cachexia with trophic derangement (decubitus). In a
case of pineal carcinoma described by Hempel, there was obesity
during the early stages which later developed into serious fat-
atrophy. In a case observed by Marburg, that of a 9-year-old girl
with symptoms of cerebral tumour, there was extreme obesity. The
autopsy showed a compound tumour of the pineal gland. The
literature of the subject provides other instances in which pineal
tumour is accompanied by remarkably good nutritional conditions
and exceptional development of the fat-body. Genital atrophy,
which invariably accompanies hypophysal obesity, is absent in
pineal disease, and Marburg is inclined to regard pineal obesity
as the result of increase in the amount of the active functional
pineal tissue, in other words, as a manifestation of hyperpinealism.
This deduction is by no means conclusive, for, in the first place,
as Marburg himself points out, it is extremely difficult to form
an opinion concerning the condition of the gland ; and in the
second, an exceptional development of the fat-body is also
observed in forms of pineal disease, which both the clinical sym-
ptoms and the anatomical findings show to be the outcome, not
of an increase, but of a reduction of the active functional pineal
tissue.

Of paramount interest are the observations published by
Ogle, Gutzeit, Oestreich-Slawyk, and more recently by v. Frankl-
Hochwart. In boys of under 7 years, in addition to symptoms
of cerebral tumour and disease of the corpora quadrigemina, these
authors observed abnormal growth in height, abnormal growth
of hair, premature development of the genital organs and of
sexual instinct, and mental precocity. The autopsy revealed
pineal tumour, generally teratoma. In these cases, the abnormal
growth, the premature mental and physical development, and the
remarkable genital hypertrophy were associated with a diminution
of the pineal tissue, or with what Marburg defined as dispinealism.

These data point inevitably to the conclusion that the pineal
gland is an internal secretory organ which influences metabolism,
though the details of its functional activity are at present not
ascertained. Still more important is the fact that, during the
period of its complete development, that is to say, until the seventh
year, this organ exercises a definite and apparently inhibitory
influence upon the development of the sexual glands, and it is

THE GENERATIVE GLANDS 355

probable that it has a secondary effect upon mental develop-
ment. The destruction of the pineal gland at this stage of exist-
ence leads to mental and physical precocity. That there is an
antagonism between the activity of the pineal gland and that of
the hypophysis is certain, for we know that pituitary insufficiency
produces hypogenitalism.

I have occupied myself for some time with experiments, the
main object of which has been to determine the clinical results of
pineal suppression. I have succeeded, so far, in extirpating the
pineal gland by a method similar to that which I employed in
hypophysectomy. As far as my observations go, the pineal gland
in the adult animal is a negligible quantity ; my experiments with
young animals are not as yet complete.

THE GENERATIVE GLANDS.

The generative glands possess chemical interrelationships
with a large number of other organs and tissues. The importance
of the part which these glands play in the general economy of
the organism is shown by a wealth of evidence such as is forth-
coming in the case of no other organ. It will be shown in the
following pages that, not only are physiological and pathological
processes modified by the function of the sexual glands, but that
the activity of these organs is associated with the profoundest
problems of general biology and embryology.

The first problem is concerned with the sexual characteristics.
In almost every class of animal, the type is represented and
maintained by two different groups of individuals, which differ
more or less widely from one another in habit, anatomical struc-
ture, functional activity, and certain other attributes. These
groups are defined as the male and female sexes. The question
arises as to whether this difference in the organization of the
sexes, this dimorphism, as it is called, is the outcome of the differ-
ence in the nature of the organs of reproduction. That these
organs are described as ' sexual ' organs is an illustration of
the prevailing inclination to regard the stigmata of sex as de-
pendent upon the organs of generation. Before the days of
anatomy, and the view prevails to-day among primitive peoples
(the Russian scopts, according to Pelikan, and the natives of
India, according to Roberts), the external genital organs and, in
women, the breasts, were regarded as the factors responsible for
the characteristics of sex. The Russian scopts believe that women
are rendered sterile by the removal of the breasts and the external
genitals. Helmont said: " Propter solum uterum mulier est
quod est," and this dictum was modified by the French physician
Cherau into : ' Propter ovarium solum mulier est quod est."
Virchow expressed the same view in these words : " Woman is

356 INTERNAL SECRETION

woman by reason of her generative glands. All the peculiarities
of her body and mind . . . everything, in fact, which in the true
woman we admire and revere as womanly, is dependent upon the
ovary." There are others (Geoffrey St. Hilaire, Klebs, Puech,
Hegar), however, who adopt a different view. Quite recently,
weighty arguments have been advanced by several authors
(Hegar, Halban, Pfluger) against the dependence of somatic and
psychic sexual characteristics upon the genital glands.

In order to grasp the precise significance of the problem, we
must first ask ourselves the question : What is the decisive factor
in the determination of sex? What is it which decides whether
from the fertilized egg, which contains both maternal and paternal
chromosomes in equal number, a male or a female individual shall
proceed ?

It is possible that sexual distinction exists in the unfertilized
egg; that, in fact, there are male and female ova which, after
fertilization, develop in accordance with an already determined
sex. In certain of the lower forms of life this is actually the
case. Under certain favourable external conditions, the aphis
produces only females ; at a low temperature with slight atmo-
spheric humidity, both males and females are produced, and
these pair. The pregnant female does not produce young, but
lays eggs, and from these, females are again hatched out. It is
evident that the sex of the individual is here determined in the
unfertilized egg.

Korschelt showed that Dinophilus apatris, a small worm,
lays eggs of two different sizes and that, from the larger of these,
females develop, while from the smaller, males proceed. Both
Nussbaum and Maupas found that, in the case of wheel-
animalcule (Hydatina senta}, the larger eggs of which develop
into females and the smaller into males, the results were affected
by external factors acting on the mother, such as surrounding
temperature and nutritional conditions.

A second method of sex differentiation, and one which recent
discoveries have shown in process of action, is by two distinct
varieties of spermatozoa. In certain insects, hemiptera and ortho-
ptera, two kinds of sperma cells are present, which differ from
one another in their chromosome contents. According to Wilson,
females proceed from eggs fertilized by cells with accessory
chromosome, males from eggs fertilized by the other cells.*

In bees, ants and wasps the conditions are different, there
being only one kind of egg and one kind of spermatozoon. Males
are produced by parthenogenesis, females proceed from fertilized
ova. The queen bee is impregnated once only, the semen being

* According to Omelczenko, Selenew and others, two kinds of sperma-
tozoon are also present in mammals and in man. Gram stains the body
of the one violet, of the second red. The two kinds of spermatozoon-bodies
are supposed to represent the two sexes.

THE GENERATIVE GLANDS 357

retained in the receptaculum seminis. From the eggs into which
the sperm cells penetrate, females — that is queens and workers-
are hatched, while from the unfertilized eggs, males — that is
drones — proceed. Lenhossek thinks it possible that the sperm
cells find access only to those eggs which possess female charac-
teristics and that they do not penetrate the male eggs.

These observations show that, in the lowrer forms of life,
sex differentiation may already exist in the unfertilized egg, or
it may be determined in the course of, or immediately after,
fertilization. But it must not be imagined that these observations
apply indiscriminately to animals of the higher orders. On the
contrary, where these are concerned, we know neither the factor
which determines sex nor the moment at which sex is decided.
The fact that twins from one ovum — which are probably the out-
come of division of the germ at a very early stage of segmenta-
tion— are almost invariably of the same sex, suggests that the
determination of sex in man also takes place at a very early
developmental stage.

This assumption is contradicted, however, by a large number
of facts. In the first place, the primordial beginning of the
body is, in all vertebrates, sexually indifferent. It is not until the
embryo has made considerable advancement — at the fifth week in
man — that a differentiation of the primitive genital trace into a
unisexual genital gland takes place. It may be that in vertebrates,
as well as in invertebrates, both male and female glands develop
simultaneously from the same primitive genital trace. As Pfliiger
showed in the case of Bufo cinereus, there is a developmental stage
of true hermaphroditism, which later passes off. Cases of herma-
phroditismus biglandularis are sometimes, though rarely, met
with in man ; these are individuals in which the generative glands
of both sexes are present either on one or both sides, or a female
gland on one side and a male gland on the other side. These
findings show that the sex of the individual is not determined
until a late stage of development, and that the differentiation of
the unisexual glands does not take place until after the develop-
ment of the undifferentiated sexual cells.

If the specific generative gland is regarded as the charac-
teristic of sex, the body of the embryo must be regarded as
sexless as long as the primitive genital trace remains undif-
ferentiated. Such being the case we should be compelled lo
admit that the determining factor in the differentiation of sex is,
as far as our present knowledge goes, unknown. We simply do
not know why it is that, at a certain moment in the life of the
embryo, the primitive genital trace develops, in one instance into
a testis, in another into an ovary, and in certain very rare cases,
into both.

But sexual dimorphism is not confined to dimorphism of the
cells of generation ; it extends to other bodily characteristics.

358 INTERNAL SECRETION

There is a striking difference, in the two sexes, in the structure
of the excretory ducts from the genital glands and in the external
genitals, as well as in those organs which are called the secondary
genital organs.

The study of embryology shows that the primitive beginning
of these apparatuses is, in both sexes, common and indifferent.
In addition to the primitive genital trace, it comprises the Wolffian
body or primordial kidney, the Wolffian duct or primordial
ureter, and Muller's duct. The latter runs along the lateral side
of the Wolffian duct and has a common opening with the latter
into the sinus urogenitalis. At the end of the third month of
embryonal life, this primitive beginning becomes differentiated in
accordance with the characteristics of one or the other sex, and
develops to form either the male or the female sexual apparatus.
But whichever the sex of the individual, portions of the charac-
teristics of the other sex remain as rudimentary organs.

If a testis develops from the primitive genital trace, an
epididymis is formed from the head portion of the Wolffian body ;
the caudal portion forms blind ducts which eventually become
the paradidymis and aberrant ducts ; and the Wolffian duct be-
comes the vas deferens. Muller's duct disappears, but the caudal
and cranial portions remain to form the hydatid of Morgagni and
the sinus pocularis (uterus masculinus).

Where the primitive genital trace develops to form an ovary,
Muller's ducts form the Fallopian tubes, uterus and vagina. That
portion of the Wolffian body which is in communication with the
ovarian tract shrivels up to form the parovarium (epoophoron),
which corresponds to the male epididymis. Vestiges of the caudal
portion of the Wolffian body persist as the paroophoron, situated
in the ligamentum latum, and occasionally also as structures cor-
responding to the ductuli aberrantes. The cranial portion of the
Wolffian duct forms a portion of the epoophoron with the appen-
dix vesicularis, while the remnants of the caudal portion form
the so-called ducts of Gaertner.

This brief sketch of the developmental history of the sexual
apparatuses shows that the primordial beginning of the secondary
genital organs is independent of that of the generative glands.
The secondary genital organs have a bisexual origin and, in
the adult animal, these show a certain degree of hermaphroditism.
This bisexual origin leads occasionally to the development of
both sets of genital ducts and external genitals, thus producing
instances of pseudo-hermaphroditism. Pseudo-hermaphrodites
are individuals in whom the genital glands are unisexual, while
the rest of the genital apparatus is, either wholly or in part,
bisexual.

As a general rule, the development of the excretory ducts
proceeds in accordance with the sexual character of the genital
glands, though malformations have been observed which seem

THE GENERATIVE GLANDS 359

to disprove such dependence. Such are the cases of double con-
genital agenesis of the genital glands, with complete development
of the external and internal sexual organs.

Interesting cases of hermaphroditic malformation have been
observed in animals. Kolliker describes a pig 15 months old,
which had well-developed testes, shrivelled seminal vesicles and
Cowper's glands, and a large uterus with two cornua. v. la
Valette St. George describes the findings in a striped water-newt
(Triton tccniatus) as follows : Testicles and male secondary sexual
stigmata, large ovaries but no oviduct. Gerhartz observed a
Rana esculenta with proponderating male characteristics, which
also possessed a well-formed oviduct, but had no ovaries nor
were eggs present in the testes. These observations show that
the secondary genital organs are not only not derived from the
same primitive beginning as the genital glands, but that their
further development also is sometimes independent of the latter.
There are certain exceptions to the rule that the sexual character
of the secondary organs is in accordance with that of the genital
glands.

In addition to the differentiated genital organs, which form
the primary stigmata of sex, there are other phenomena by which
the sexes are characterized. J. Hunter described these as
" secondary sexual characteristics " and includes under this head-
ing all the specific appearances which are not directly concerned
with the processes of reproduction. It is true, as Darwin pointed
out, that this definition is a loose one, for it is extremely difficult
to decide in individual cases whether a detail of structure or of
function is concerned with reproduction or not.

The term " secondary sexual characteristics ' is inexact for
another reason, namely, that it suggests a dependence of these
characteristics upon the genital glands, and of this we have at
present no proof. As we have shown in dealing with the
secondary genital organs, such proof is difficult to obtain.

The only justifiable grounds for distinction is the differentia-
tion between the cells of generation and the other somatic cells,
which is manifested in their biological behaviour. The somatic
cells are independent and capable of fission, but they are transitory
structures. The cells of generation, on the other hand, are not
autonomous, but they possess the capacity of forming another
individual after their nuclear portion has combined with that of
cells of the opposite sex.

Thus in all organisms with a sexual digenetic method of re-
production, there are two types of biologically incomplete cells
of generation, the male and the female, and these only attain
completion by means of the process of fertilization.

The somatic cells are completely autonomous, and a bio-
logical differentiation, such as that which characterizes the cells of
generation, is superfluous to their development; sexual dimor-

360 INTERNAL SECRETION

phism is absolutely excluded. But experience shows that there are
recognizable differences between the greater number of the cells
and tissues in the two sexes. Apart from the genital apparatus
and the organs associated with its functions, such as the mam-
mary glands, male and female individuals differ widely from
one another physically, as in the details of the skeleton, the dis-
tribution and the amount both of the adipose tissue and the hair,
the development of the larynx, &c. ; and these physical differences
are accompanied by equally marked psychic divergence. These
facts suggest the question : Are the somatic cells sexual in
character ? That is to say, are they formed from a male or female
primitive origin ? There is a second possibility, namely, that
the sexual differentiation of the somatic cells is secondary and
dependent upon the unisexual cells of generation, that is, upon
the reproductive glands. Both these hypotheses have their sup-
porters.

A large number of authors, Tandler and Gross more par-
ticularly, have laid stress upon the fact that what are called the
secondary sexual characteristics are, in reality, only characteristics
of the species, that is to say, properties peculiar to a species or
an order of vertebrates and having no primary relationship with
the organs of generation. Thus the mammary glands are the out-
come of an agglomeration of sweat glands which, later, became
the engine of a different function and was included within the
sphere of influence of the organs of reproduction. The beard of
the anthropoid apes and of man was also originally a charac-
teristic of species, for the upper lip of the human fcetus is clothed
with a hirsute growth which attains equal development in both
sexes. The antlers of the cervida?, again, were originally specific
characteristics of unknown function, which afterwards acquired
a secondary relationship to sex. Tandler and Gross were able
to prove that in the fcetus of the roe-deer there is a primitive
antler trace, the appearance of which is exactly similar in both
sexes, the only difference being that in the case of the male
development is progressive, while in the female further develop-
ment takes place in very rare instances only. The formation of
the antlers of reindeer is identical in both sexes, and the develop-
ment of the antlers in the female is unaffected by castration.

But this translation of the characteristics of sex into charac-
teristics of species merely postpones the solution of the problem ;
it does not supply any evidence in favour of either of the current
hypotheses. The characteristic signs of species are undoubtedly
foreshadowed in the embryo, but the direction of their subsequent
development must depend on one of two determining causes :
either thev already possess a tendency to develop in a certain
manner, that is to sav, thev have sex ; or their development is
modified and differentiated by the internal secretory activity of
a genital gland. Both are possible. If the secondary sex

THE GENERATIVE GLANDS 361

characteristics are regarded as characteristics of species, then the
assumption of a primitive trace, which is equally developed in
individuals of both sexes and which undergoes secondary dif-
ferentiation through the agency of the genital gland, supplies a
more probable hypothesis than that of Tandler, who held that
the sexual nature of the secondary characteristics, like that of
the genital glands, is determined in the ovum. But even if we
accept the first hypothesis, we are compelled to concede that the
normal development of the modified characteristics of species is
dependent upon the existence of an active genital gland; and
that the sexual differentiation of new-born infants is the outcome
of the activity of the genital gland during foetal life.

We will now proceed to a closer examination of the two
conflicting hypotheses concerning the origin of the sexual dimor-
phism of the somatic cells.

The one theory assumes that all the primordial embryonal
cells are sexually differentiated, and that the differentiation of
the somatic cells takes place before that of the cells of the primi-
tive genital trace. The assumption is that the unknown factor,
which decides whether the indifferent genital beginning shall
develop into a testis or an ovary, also acts upon the somatic cells,
thus laying the foundation for those differences of body in the
case of the two sexes, which make their appearance at a later
developmental stage.

The evidence in support of this view is supplied by the follow-
ing facts :-

In foetuses and new-born infants, a large number of tissues
are already sexually differentiated. That female babies have
smaller hands and feet and a lower average weight when born
than males, is well known. There is also a difference in the
brain of the two sexes and there is a very marked differentiation
of the bony framework of the pelvis. It is also known that certain
anatomical variations occur only in the male, certain others only
in the female. According to Rabl and Fischel, supernumerary
ribs and vertebra? are more frequently observed in males, while a
deficiency in the number of lumbar vertebrae is most frequent in
females.

These observations cannot, however, be regarded as con-
clusive ; for differences between the tissues of male and female
fcetuses do not make their appearance until after differentiation
of the genital glands, and the possible influence of the latter can-
not be excluded. Fehling was unable to observe female charac-
teristics in the pelvis before the fifth month of fcctal life, while
the primitive genital trace undergoes differentiation in the fifth
week.

The condition of pseudo-hermaphroditism has supplied a
large number of facts which point to the independence of the
sexual differentiation of the somatic cells from that of the ceils

362 INTERNAL SECRETION

of generation. Not only does the genital apparatus in pseudo-
hermaphrodites show abnormal development, though in a vary-
ing degree, but these individuals possess secondary somatic and
psychic sex characteristics which are not in accordance with the
type of their sexual glands.

There are, further, those numerous and undoubtedly bona
fide instances in which individuals, with normal unisexual genital
glands and normal internal and external genitals, possess more
or less clearly marked heterologous sexual characteristics. Such
are the large-boned muscular women with flat chests, narrow hips,
deep voices, and more or less beard; and the beardless men with
rounded outlines and soft flesh, with well-developed mammary
glands and high-pitched feminine voices. Halban suggests the
name hermaphroditismus secundarius for this class of abnormality,
thus enlarging the definition of hermaphroditism to include the
secondary stigmata of sex. Moreover, Halban considers that the
psychic properties and peculiarities of character, which are
described by the terms "masculinity" and "femininity," are
congenital characteristics of sex, and' the perversion of these he
also includes under the heading of secondary pseudo-hermaphro-
ditism.

To consider the more detailed aspect of hermaphroditism and
to describe the abnormal combinations of sexual stigmata which
have been observed would take us too far afield. The literature
of the subject is considerable. Neugebauer, in his recent report,
describes 1,300 cases of pseudo-hermaphroditism; but these
observations do not furnish certain evidence either for or against
the dependence of somatic sexual distinctions upon the cells of
generation. It is affirmed upon all sides that anomalies of the
sexual system are very frequently accompanied by structural de-
fects in other parts of the body, and that these defects are of a
kind which arise, in part, at a very early stage of development
(Hegar). So experienced a scientist as Neugebauer regards
pseudo-hermaphroditism as actually one of the symptoms of
general malformation. And Pick has recently shown that the
genital glands of pseudo-hermaphrodites are primarily malformed
from the time of the primitive genital trace; he points to the
remarkable preponderance of teratoma and tumours developed
from a teratomatoid primordial origin among the new formations
of pseudo-hermaphrodites. Pick regards these tumours as tissue
proliferations from a previous embryonal malformation, in a
malformed embryonal organ. It is interesting in this connection
that Bertkau, who has brought together all the known instances
of hermaphroditism among arthropoda, arrived at the conclusion
that all conditions leading 'to abnormality of any kind are
favourable to the development of hermaphroditism.

These observations seem very clearly to suggest that the
cause of the absence of the somatic stigmata of sex is to be found
in the imperfect differentiation of the cells of generation.

THE GENERATIVE GLANDS 363

The presence of heterologous sex characteristics has been
explained in various ways. Benda adopted the view that in the
higher vertebrates the primitive trace of the entire sexual apparatus
is female, and that the male type is a modified form of the female,
the outcome of specific influences at present unknown. Herbst, on
the contrary, assumes a primary male primitive trace, together
with stimulatory and inhibitory activities on the part of the
genital glands, by which the development of the sex characteristics
is affected.

These hypotheses are superfluous, however, in view of the
now certain fact, that the primitive genital trace is originally in-
different, therefore bi-sexual and, in the true sense of the term,
hermaphroditic. Moreover, true hermaphrodites are not so rare
as was formerly believed to be the case.

We now know that true hermaphroditism, in the morpho-
logical sense of the term, is observed in man, and that it occurs
in the form which formerly appeared most doubtful, namely,
hermaphroditism of the glands (ovotestis).

It has been asserted that physiological hermaphroditism, by
which is meant the presence of both sets of glands in a state of
physiological activity, is never encountered among the higher
vertebrates; that certain species of fish (myxina, serranus, and
some carp) are the only representatives of physiological herma-
phroditic vertebrates.

If, by the function of the genital glands, we understand the
production of semen and the release of ova, this pronouncement
is undoubtedly right. But in view of the internal secretory func-
tion of these glands, we are justified in describing as physiological
hermaphroditism those cases where tissue of the genital glands
of both sexes is morphologically demonstrable ; or rather, those
tissue elements to which a specific internal secretory activity is
ascribed. From the accounts of zoologists and veterinary sur-
geons, it appears that hermaphroditic glands, that is to say,
genital glands composed of both testicular and ovarian paren-
chyma, are of very frequent occurrence. A communication made
by Tourneux is particularly interesting; he states that in the
female mole there is, in addition to a functionally active ovary,
a rudimentary testicle, that is, rudimentary seminiferous tubules
with interstitial cells.

It is highly probable that the cells of Leydig in the testicle
and analogous cells in the stroma ovarii, represent the internal
secretory tissue of the genital glands. If this is the case, the
findings described in the previous paragraph must be regarded
as proofs of the existence of physiological hermaphroditism in
mammals.

Whether glandular hermaphroditism, either partial or com-
plete, occurs in man is a question which can be settled only bv
exact anatomical and histological investigation. But, owing

364 INTERNAL SECRETION

partly to the indefinite localization of hermaphroditic glands, and
partly to the undefined nature of their histological characteristics,
such observation is very difficult to carry out. If definite proof
of glandular hermaphroditism were forthcoming, it would be easy
to account for the presence of heterologous sex characteristics.
The assumption would necessarily be that male and female forma-
tive influences are mutually exclusive, and that the sex charac-
teristics of the body are in accordance with the nature of the
genital gland which is best developed and functionally most active.
But the important point in this connection would be, not the
conditions governing the functions of external secretion (sperma-
togenesis, ovulation), but the degree of development and func-
tional activity of that tissue of the genital gland by which the
internal secretion is elaborated.

It is only by the assumption of a hermaphroditic primitive
genital trace, together with the dependence of the somatic and
psychic sex characteristics upon the internal secretory activity of
the genital glands, that we can explain those cases in which com-
plete alteration of single sex characteristics, or even of the entire
sexual character, takes place during the life of the individual.
These cases appear to be by no means exceptional, though they
have not received the attention which they deserve.

A case of Friedrich-Grawitz's, recently described by Alberti,
is very interesting in this connection. The subject wras a girl
of 20, with clearly defined female habit, well-developed mammary
glands, and regular menstruation, who gradually reverted to the
masculine type, with cessation of the menses. The adipose tissue
diminished and the body became covered with hairs; the breasts,
which \vere previously very well developed, became soft ; the
hair of the head became short and thin ; the voice deepened ;
and thick, dark whiskers and moustache made their appearance.
Three years later she was operated upon for ovarian tumour ; and
she eventually died of peritonitis, the outcome of twisting of the
pedicle by rotation of a multilocular cystoma.

A large number of analogous cases have been described, in
which the female stigmata have, after puberty or even late in
life, reverted to the male type, and vice versa (Zambini, Freund,
Hegar, Wilson, Parhon and Goldstein, Hammond, Djemil-
Pascha). In some instances, there was more or less complete
disappearance of certain well-marked stigmata of the one sex,
their place being taken by corresponding characteristics of the
other. As a general rule, however, the alteration in the sex
characters followed pathological processes, of traumatic or idio-
pathic origin, in the genital glands.

Important evidence in favour of the hermaphroditic nature
of the primitive genital trace and of the dependence of the
characteristics of sex upon the internal secretion of the pre-
ponderating specific genital tissue, is provided by those not very

THE GENERATIVE GLANDS 365

rare cases in which the physiological cessation of the function
of the genital glands is followed by more or less alteration in the
sex characters. Women at the menopause have been known to
develop male characteristics, such as a deep masculine voice and
hirsute growth upon the face and body.

Castration late in life is not followed by any demonstrable
changes in the sex characteristics, and prepubertal castration, as
we shall see later, produces not heterosexualism, but infantilism.
But the perverted sex characteristics described above are the result
of the suppression of the ovarian function. These facts suggest
that in the case of castration, extirpation of the genital glands
includes the removal of the rudimentary portions of heterosexual
tissue ; while in cases of ovarian inadequacy, these heterosexual
rudiments have acquired a determining influence upon the de-
velopment of primitive beginnings which are present in in-
dividuals of both sexes.

The same theory accounts for the perversion of sex charac-
teristics in animals ; such are, male sheep and goats which yield
milk, and female goats and sheep with beard and horns; antlered
females among the cervidae ; hens with cock's plumage or
arrhenoidia, the reverse condition, thelyidia, in cocks, &c.

The phenomenon of cock's plumage in hens has been
extensively investigated by A. Brandt. It appears that the
changes are not confined to the plumage, but that these birds
acquire other male characteristics; they crow or sing and, in
the absence of the cock, thev lead the other females.

j

Brandt points out that arrhenoidia and thelyidia are normal
conditions in certain species of birds, where they occur in-
dependently of changes in the genital glands, as the expression
merely of variability of the external sex characteristics. They
are congenital, however, in hermaphroditism and in other
anomalies; they are acquired after loss or degeneration of the
internal genitals ; and they occur most frequently as accompani-
ments of senile degeneration of the ovaries with sterility, and of
obliteration of the oviduct.

A. Rorig has made antler formation and the manner in
which it is influenced by the reproductive organs the subject of
careful investigation.

The antlers of the stag are acquired secondary characteristics,
developed at a period when "the strong projecting canine teeth,
the original weapons of his forefathers, had proved an inadequate
means of defence, and the method of fighting forehead to fore-
head during the rutting season had been evolved."

The sexual character of the antlers is shown by the fact that
' these organs of aggression invariably attain to full development
at a period immediately preceding the rutting season, and that
they are shed a short time after its close."

Rorig brings forward a large amount of material, chiefly

366 INTERNAL SECRETION

anatomico-biological in character, to show that the absence of
one or both antlers does not affect the virility of the animal.
Absence of antlers may accompany abnormal formation of the
male sexual organs.

Old females, which have become sterile, incline to antler
formation, as do also females with diseased internal genitals.
The antler development of hermaphrodites is said to be more
influenced by the epididymis than the testes.

Rb'rig is unable to give a satisfactory explanation of abnor-
malities, and he closes his treatise with the remark that the
originating cause of the malformation of antlers will probably
remain a problem for some time to come.

Those cases in which the secondary sex characteristics are
changed on one side only, usually upon the same side as the
gland with which they correspond, may also be taken as evidence
in favour of the theory that sex characteristics are dependent
upon the genital glands.

The one-sided development of the mammary glands in men
and the development of a single antler in female cervidas are
frequently advanced as instances of one-sided pervertion of the
stigmata of sex. But that these deductions are inconclusive is
shown by the fact that very different accounts are given of
the manner in which the antlers of stags are affected by one-sided
castration. Some authors state that one-sided castration is fol-
lowed by loss of the antler on the same side ; others again affirm
that it is the antler of the opposite side which is lost.

A case described by M. Weber is frequently quoted as an
instance of asymmetry in the somatic sex characteristics. Weber
observed a finch (Fringilla coelebs] \vhich possessed a right testis
and had male colouring and plumage upon the right side; the
left side was female in colouring and plumage, and was furnished
with an ovary. This freak of nature is very difficult of explana-
tion. Halban, and later Pfliiger, regarded this bird as a one-sided
hermaphrodite, not only in regard to the arrangement of its
genital glands, but also in its somatic sex characters. Nussbaum,
on the other hand, regards this case as proof of the great influence
of the nerves upon the secondary sex characteristics. The stig-
mata of sex are usually arranged symmetrically upon both sides
of the body; but it is important to remember, in this connection,
that Vircho\v laid special stress upon the fact that, in the male
pseudo-hermaphrodite Katharina Hohmann, the left side of the
body, in which the genital anomaly was situated, was generally
(extremities, rump, face) less well developed than the right.

The results of castration in both man and animals have fre-
quently been advanced as evidence in favour of the congenital
origin of the characteristics of sex. It is an undeniable fact that,
if the genital glands are removed at the earliest possible date from
two individuals of the same species, but of different sex, these

THE GENERATIVE GLANDS 367

individuals will not show complete identity of habit, either imme-
diately after operation or later ; certain characteristics, such as
beard and the mammas, will develop in accordance with their
original sex. Castrated males grow a certain, though scanty.,
amount of hair on the face. These results are accounted for by
the fact, that the sexual differentiation of the tissues probably takes
place during fcetal life through the agency of the already dif-
ferentiated genital glands, and that after suppression of the
genital glands the primitive beginnings of individual stigmata
continue to grow and attain a certain imperfect degree of develop-
ment.

The same applies to Ondermann's much-quoted experiments
with Oeneria dispar, and those of Kellog with silk-worms. Cas-
tration of the caterpillar did not obliterate the signs of sexual
dimorphism in the butterfly.

In all these cases, castration was performed at so late a period
that the possible influence of the genital gland upon the develop-
ment of the somatic stigmata was not entirely excluded.

In order to decide the question as to whether the sex of the
soma is congenital or not, it would be necessary to extirpate the
undifferentiated sexual glands of the foetus. The only evidence
on this point is that supplied by Nature in the case of the so-
called parasitic castration of crustaceans.

It has long been known that certain crabs are attacked by
parasites which belong to the isopods of the family Bopyrida?.
These parasites are never found in fully-developed male crabs
and for this reason it has been asserted that female crabs are
their only hosts. Giard, who investigated this question very
thoroughly, found that the Bopyridas enter their host only during
the early youth of the latter ; that they attack both male and
female individuals; and that they effect the destruction of the
genital glands of their host. The result of this early gonotomy
is that the host does not develop sexual characteristics of any
kind, but becomes neuter in every sense of the term. Even more
interesting is the fact that, in certain orders (Slenorynchus), the
males which have been castrated in this manner, after casting
their shell several times, assume the habit of the female type so
completely, that for a long time they were believed to be females
or were regarded as of a different species. I believe myself that
this remarkable occurrence is explained by the fact that the
invading parasites are females only, which attain to sexual
maturity within the body of their host, and that the female genital
gland of the parasite has a determining influence upon the de-
velopment of the sex characteristics of the host.

It appears then, that we have to do here with an instance
of early castration accompanied by simultaneous transplantation
of the heterosexual genital gland, and the results seem to show
that the somatic sex characteristics are dependent upon the cells
of generation.

368 INTERNAL SECRETION

We are justified in assuming from the evidence which has
been brought forward that the stigmata of sex are, from their
earliest beginnings, dependent upon the genital gland, and that
for this reason they are very rightly termed " secondary." That
they attain to complete development by the agency of the cells
of generation only, is a point which has never been questioned.

That the somatic differences between the sexes are dependent
upon their genital glands is shown, in animals, by the signs
which accompany the periodic recurrence of the rutting period,
and in man by the phenomena of puberty. The maturity of the
organs of generation at the rutting period is accompanied by
remarkable changes in the structure and functional capacity of
the body, which last only so long as the increased activity of the
reproductive organs is maintained. Every one is familiar with
the brilliant coloration of the plumage, the rich, full song, and
the activity and love-play of birds in the mating season. In
other classes, the amphibia, for instance, the males and females
are distinguished by certain peculiarities during the mating
season in the spring and early summer. The male water-
salamander acquires a head-comb, the male batrachian, callosities
upon the thumbs.

Nussbaum's careful experiments have proved beyond all
doubt that, in the case of animals with recurrent mating season,
the internal secretion of the genital gland of the male has an
enormous influence, not only upon the genital apparatus, but
upon the rutting organs which are closely related to the processes
of reproduction. In the brown land-frog, Rana fusca, the seminal
vesicles, the thumb callosities, and certain of the fore-arm muscles
undergo annual cyclic changes which accord with the rutting
season. These organs swell up, become hypertrophied, and at
the expiration of the spawning period undergo involution.

The removal of the testicle from one side has no effect upon
the rutting organs, but if castration is performed during the
period of sexual quiescence, the rutting organs will not develop
at the next rutting season. Nussbaum introduced portions of
testicle into the dorsal lymph-space of such castrated male frogs,
with the result that the rutting organs began to hypertrophy in
exactly the same way as those of uncastrated animals. The
portions of testicle did not heal in but gradually became resorbed,
while at the same time the seminal vesicles, thumb-callosities and
forearm muscles diminished in size. These experiments prove
beyond any manner of doubt that the testicles supply a material
to the economy which promotes development ; in other words, they
elaborate an assimilatory hormone.

In the course of further experiments, Nussbaum discovered
that after resection of the nerve of one fore-arm, neither the
muscle of that fore-arm nor the papilla? and glands of the thumb-
callosity of that side underwent hypertrophy at the spawning-

THE GENERATIVE GLANDS 369

period, but that those of the sound side hypertrophied as usual.
He concludes from this that the testicular secretion stimulates
certain nervous centres and certain groups of ganglia only, and
that these produce, by means of centrifugal nerves, changes in
the form and the metabolism of the organs innervated by them.
It is not possible to adopt this assumption without further proof,
however. As Pfliiger points out, the arrest of the motility and
sensibility of the vaso-motor and secretory nerves produced by
resection, is sufficient in itself to account for the absence of hyper-
trophy. It is superfluous, at the very least, to assume that the
internal secretion of the genital gland produces its effect, not
directly, but by the agency of the nervous system.

In man, the secondary sex characteristics attain their full
development at puberty, that is to say, at a time when the genital
glands are fully developed, and the individual has attained to
sexual maturity. It is apparent, from what has gone before, that
the beginnings of the somatic sex characteristics are largely
present in the embryo, and that, like other tissues, they continue
to develop from birth until puberty.

It is a remarkable fact, however, and one which points to an
intimate association of the sex stigmata with the genital glands,
that several of the attributes of sex do not make their appearance
until the maturity of the genital glands is proclaimed by the
development of their external secretory processes (spermato-
genesis, menstruation, ovulation). The maturity of the secretory
function of the genital glands is shown, in boys, by a slight
enlargement of the testicle. In girls, it is expressed by the
menstrual haemorrhage which accompanies ovulation, that is, the
expulsion of the ovum ready for fertilization. Many of the
changes of puberty are common to both sexes ; such are the rapid
skeletal growth and the appearance of hair at the pubes and the
axilla? ; others, such as the growth of hair on the face, the altera-
tion in the voice, and the appearance of hairs all over the body,
are peculiar to the male; while others again, such as the develop-
ment of the mammary glands, the peculiar pelvic formation, and
the deposition of fat in certain localities are essentially feminine.

Among the secondary sex characteristics which make their
appearance at puberty, are those reflex nervous mechanisms which
are concerned in the performance of the sexual act. Through the
agency of the internal secretion of the genital glands, the
apparently low nerve centres which are here concerned acquire
a specific sensibility. Goltz showed that, during the spawning
season, the male frog reacts to every touch upon the skin of the
chest with the embracing reflex, and that this reflex may still be
obtained shortly after removal of the testicles and even after
decapitation. That the increase in reflex sensibility is not general,
is proved by the fact that the muscle-contractions are not obtained
in response to every kind of touch, but are only provoked by the

24

370 INTERNAL SECRETION

specific stimulation of the skin ; the reflex movement is confined,
moreover, to a certain group of muscles.

But the changes of puberty are not confined to the lower
centres of the spinal cord. That the functions of the cerebral
cortex are also affected is shown by the occurrence of sexual desire
and by the psychic changes which accompany the ' ' storm and
stress period."

That all the somatic and psychic characteristics of puberty are
dependent upon the maturity of the genital glands, is rendered
probable by coincidence ; the fact is made certain by the results
of castration.

Before passing on to this subject, however, it is expedient to
give a short description of the condition known as pubertas
praecox.

Both the older literature and that of recent date contain numer-
ous descriptions of premature puberty, especially in girls. Those
cases, formerly regarded as freaks, in which girls of very tender
age showed menstruation, development of the mammae, growth
of hair at the pubes and axillae, and excessive growth, have been
repeatedly brought together and criticized (Kussmaul, Ploss,
Gebhard, Strassmann, Neurath). According to Neurath (1909)
the known cases of precocious menstruation are eighty-three in
number, but the descriptions of these are not in every instance
complete. Precocity in boys has been observed in forty-three
cases, many of which have been wrongly described as gigantismus
infantilis. The similarity between these cases and gigantism is
apparent only, the sole common symptom being the early tallness
of the subjects. The abnormal skeletal growth is the outcome of
very different causes. Skiagrams show that, in pubertas praecox,
there is accelerated ossification, and a rapid approach of epiphysal
ossification to the stage when the synarthroses close (Neurath).
This finding is in accordance with that of physiological puberty,
for in the latter condition also, the proliferation of the epiphyses
soon ceases. Gigantism, on the contrary, is characterized in all
its forms by persistence of the epiphysal synarthroses and the
abnormal height to which this leads.

Pubertas praecox virilis is a condition affecting boys of 3 to 9
years of age. These children are remarkably large, heavy, and
well developed, and they show all the signs of puberty — com-
mencing growth of hair on the face, pubes and axillae, deep voice,
and strikingly large external genitals, the testicle being the size
of a plum when in accordance with the age it should not exceed
the size of a bean. The psychic development sometimes corres-
ponds to that of puberty, though the subjects are more frequently
mentally defective, or even idiotic.

The most important point in regard to the etiology of pubertas
praecox is whether or not the condition is primarily the outcome
of precocious development of the genital glands. We know that

THE GENERATIVE GLANDS 371

the development of the genital glands is influenced by a large
number of internal secretory organs, and we have to take into
consideration the fact that hypergenitalism, and the pubertic
precocity which accompanies it, may be the secondary results only
of the primary affection of other organs. This applies to cases
in which tumours were present either in the suprarenals or at the
base of the brain, and especially where these affected either the
pituitary or the pineal glands. Hypophysal affections are
frequently associated with perversions of growth in the direction
of gigantism, though as a general rule these are accompanied by
genital atrophy. The cases of pineal tumour which have so far
been described show all the signs of pubertas prascox; namely,
abnormal growth in height and premature genital and sexual
development, with corresponding mental precocity. The presence
of suprarenal tumour in sexual precocity is remarkably frequent.
Out of seventeen cases examined post mortem and four surgical
cases, suprarenal tumours were found in eleven, nine being girls
and two boys (Bulloch and Sequiera, Linser, Adams). All these
cases were remarkable for the exceptional development of the
body, considerable obesity, and physical precocity, together with
the habit of sexually mature persons, more especially extreme
hypertrichosis ; the functions of the sexual glands and certain
secondary sex characteristics, such as the mammae in girls, were
not, however, developed in proportion. In many instances, single
heterosexual characters were peculiarly well developed.

If we exclude these observations, a large number of cases
remain which cannot be explained otherwise than by primary
hypergenitalism.

Such is the case of the boy R. K., described by W.
Knopf elmacher (1903 and 1906), who, at the age of 6, was
132 cm. in height, and weighed 38.8 kg. The testicles were the
size of a plum, the secondary sex characters wTere almost fully
developed, the amount of hair at the pubes being especially
remarkable, while there was a distinct moustache, and the voice
was deep. Skiagrams (Schiiller) showed that the sella turcica was
normal in size, while the inner surface of the skull manifested no
signs of intercranial pressure.

The case described by Sacchi is even more instructive. The
patient was a boy of 9^, who, until the age of 5^, was both
physically and mentally normal. At that age, his entire being
underwent a gradual and progressive alteration. His bones grew
very rapidly, and his muscles became very much developed ; the
voice became deep ; hair appeared at the pubes and upon the face ;
and his mental condition changed. At 9^ years of age he was
143 cm. in height, and weighed 44 kg.; he had a lone black
beard and long hair upon the pubes, chest and legs. The left
testicle, owing to tumour formation, was enormously enlarged.
After removal of the diseased testicle, which the microscope

372 INTERNAL SECRETION

showed to be an alveolar carcinoma, the pubertic symptoms
gradually disappeared, and the boy became mentally and physic-
ally the same as other boys of the same age. In this case the
connection between the premature signs of puberty and the
pathological hypergenitalism is abundantly clear.

Before passing to a consideration of the influence which cas-
tration has upon the secondary sex characteristics, it is expedient
first to consider the significance of that organ which is regarded
as the pronounced characteristic of the female sex, but which has
no recognizable relationship to the function of reproduction,
namely, the mammary gland. This gland is present in the
embryonal beginnings of both sexes; in new-born infants it is
confined to a few ducts in the neighbourhood of the nipple, which
may produce a transient secretion known as " witches' milk '
(Hexenmilch).

A remarkable development of the mammary gland takes
place in female individuals at the period of puberty, though this
increase in size is largely the result of the deposition of fat. The
enlargement during puberty of the mammae of boys is probably
entirely due to fatty deposition ; and gynaecomastia — that is,
abnormal development of the mammae in males — is probably due,
in many instances, to testicular hypoplasia, or to atrophy of the
testicles as the result of pathological processes. Males which
show abnormal development of the adipose tissue at certain points
of predilection, are to be regarded as eunuchs or semi-eunuchs. An
extremely instructive instance of such pseudo-gynaecomastia is
described by Foges.

As far as the female mammary gland is concerned, there is
no doubt that its development at the period of puberty is
influenced by the genital gland. It has been proved experiment-
ally that the mammary gland does not develop in animals which
have been castrated in early youth ; while normal development
takes place after ovarian transplantation. That the influential
factor is supplied by the ovaries and not, as the simultaneous
uterine atrophy suggests, by the uterus, has been proved by
experiment (Foges).

The periodical swelling of the mammas observed in many
women during menstruation, and the occurrence of similar
phenomena in animals during the rutting period, are undoubtedly
attributable to the internal secretory activity of the ovaries.

The most important changes in the mammae are those which
take place during pregnancy. At the commencement of this
state, what must be regarded as a true hypertrophy takes place,
which continues until parturition.

There was at one time an all-prevailing view that the mam-
mary hypertrophy of pregnancy was the result of communication,
effected by way of the nervous system, between the mammary
planet and the pregnant uterus ; this theory has, however, long

THE GENERATIVE GLANDS 373

been disproved. An experiment by Goltz and Ewald is interesting
in this connection. These authors found that, after extirpation of
the entire lumbo-sacral portion of the spinal cord of a bitch, the
mammas underwent normal enlargement during pregnancy, and
that lactation after parturition was also normal. Ribbert trans-
planted the mammary gland of a guinea-pig into the neighbour-
hood of the ear, and found that it hypertrophied during pregnancy
and secreted milk after parturition.

There is, then, no doubt that the growth of the mammary
glands during pregnancy is the result of a chemically active
stimulant. The next step is to discover the source of origin of
this hormone. Pregnancy is associated with changes in the
ovary (formation of the corpus luteum verum) and in the uterus
(development of the muscles and mucosa) ; the foetus, moreover,
develops; and from the combined maternal and foetal tissue the
placenta, an organ by which the foetus obtains nourishment, is
formed. The active hormone may be the product of any one of
these four factors. Consideration of the clinical material which
the subject offers led Halban to the conclusion that neither the
ovary nor the uterus is the source of the hormone. In the first
place, castration early in pregnancy does not prevent the hyper-
trophy of the mamma?, and castrated women are able to suckle
their children ; in the second place, the development of the mam-
mary glands is constant in extra-uterine pregnancy, in which the
uterine hypertrophy is slight ; and in the third place, after
extirpation of the uterus, secretion of milk takes place in the same
way as under normal conditions.

It would appear from this that the cause of the hyperplasia
must lie with the ovum, that is to say, with either the foetus or
the placenta. From the fact that pregnancy changes take place
in the mammas where the embryonic body is absent, as, for
instance, in molar pregnancy, Halban concludes that the stimulus
cannot be supplied by the foetus; by a process of exclusion he
thus arrives at the result that the source of origin of the hormone
is the placenta, especially the trophoblast and the chorion
epithelium. Similarly, he regards the growth of the mamma? in
the foetus at the eighth lunar month, as due to reaction on the
part of the fcetal tissue to the stimulatory action of the placental
substance.

According to Halban, then, the substances supplied by the
ovary and the placenta produce similar results, those produced by
the placental substance being, however, much more intense.
During pregnancy, when the ovary ceases to be active, its internal
secretory function is undertaken by the placenta, by which it is
very much intensified.

Starling and Lane Claypon endeavoured to discover the origin
of the hormone by experimental measures. They injected extract
of foetus, ovarv, and uterine mucous membrane under the skin

7J4 INTERNAL SECRETION

^J I I

of virgin rabbits, with the object of obtaining hypertrophy of
the mammary glands. In six cases they actually succeeded in
producing a certain degree of hyperplasia with foetal extract, but
the experiments with extracts of placenta, ovary, and uterine
mucous membrane were negative in result. In one case, the
injection of the watery extract of 160 foetuses was followed by the
formation of secreting acini at the periphery of the mammary
gland.

The conclusiveness of Starling's experiments is disputed by
Halban, who regards the number as insufficient to establish proof ;
he also points to the possibility that the changes in the mammary
gland observed after injection of foetal extract were in reality
symptoms of rut. This pronouncement of Halban 's induced me
to submit the question to further experimental test, the experi-
ments being undertaken with the aid of Dr. R. Konigstein.

While our experiments were still in progress a communication
of Foa's appeared, in which he confirmed the findings of Starling
and Claypon, and supplemented them with the statement that the
action of the hormone is not confined to the species from which it
is derived. Thirty-five injections of an extract obtained from
fresh foetuses from cows produced swelling of the mamma? in a
virgin rabbit, and on isolated occasions a secretion resembling
milk was observed.

Our experiments, which will be fully described in another
place, showed that neither the repeated intraperitoneal injection
of placental extract, nor the implantation of fresh placentas of
rabbits in the abdominal cavity, produced histological changes of
any kind in the mammary glands of virgin rabbits. There was,
however, a more or less marked development of the mammary
glands of all virgin animals treated by means of intraperitoneal
injection of embryonal extract or by the intraperitoneal implanta-
tion of one or more embryo rabbits. Numerous glandular ducts
appeared, frequently with well marked branches, or, at the least,
formation of buds ; the lumen of the ducts became enlarged, con-
taining in some instances a cellular secretion ; the number of
epithelial layers usually increased; in nearly all cases there was
hyperaemia ; acini formation was isolated onlyj the excretory
ducts were enlarged and much more fully developed. The
intensity of these changes was in direct ratio to the amount of
extract injected or of material implanted. The glandular hyper-
trophy was more marked in animals treated by means of injection
than in those in which embryos were implanted.

The results of these experiments seem to show that, contrary
to the view expressed by Halban, the foetus is the source of origin
of the hormone which stimulates the growth of the mammary
glands.

K. Basch has recently published a work which is chiefly
concerned with the experimental investigation of those cases

THE GENERATIVE GLANDS 375

among animals, in which hyperplasia of the lactic -glands persists
for a short time after parturition. Basch states that he was
unable to obtain hyperplasia of the mammary glands of virgin
animals by the implantation of placental tissue. But the
implantation of the ovaries from a pregnant bitch under the skin
of the back of a i-year-olcl nulliparous bitch, was followed, fourteen
days later, by proliferation of the mammary gland of the latter ;
at the end of six weeks the enlargement was considerable ; and
after eight weeks secretion of milk was induced by the injection
of placental extract. Microscopic examination revealed the per-
fect picture of a gland in full secretory activity, while at the same
time the uterus retained its virgin character and the ovaries were
very small. Basch concluded that the hyperplasia of the
mammary gland in pregnancy depends upon certain chemical
substances, which are developed in the ovary, and which prepare
the gland for prolonged functional activity.

It is difficult to reconcile this assumption of Basch's with the
observations of other authors, which show that the internal
secretory activity of the ovary is inhibited during pregnancy. It
is, moreover, inconsistent with the fact that the hypertrophy of
the mammary glands is sometimes unaffected by castration at an
early stage of pregnancy. That the enlargement of the mammae
at puberty and during menstruation is the result of ovarian
influence, is not to be denied; but the cause of the hypertrophy
of pregnancy must be sought, not in the ovary, but in the foetus
which develops from the fertilized ovum.

Before solving the further question, namely, as to why the
secretion of the hyperplastic gland does not commence until after
parturition, we must consider what happens upon suppression of
the ovum, that is, of both foetus and placenta. It has long been
known that after intra-uterine death of the ovum milk forms in
the mammary glands and the lacteal secretion begins. The same
thing happens if the foetus is removed by surgical methods during
the second half of pregnancy. Halban concluded from this that
the important factor lay, not in the death or removal of the foetus,
but in the removal of the placenta, and that it was the biological
suppression of the placenta which supplied the impulse to the
secretion of milk. He and others find confirmatory evidence of
this theory in the "witches' milk" of new-born infants, which
they regard as the expression of the puerperal involution of the
fcetal organs, which had previously reacted to the conditions of
pregnancy.

Basch found that, by the subcutaneous injection of placental
extract, he was able to produce secretion of milk, sometimes in
considerable quantities, in animals in which the enlargement of
the mammae had persisted after the termination of pregnancy ; he
regards the results of these experiments as proof of the depen-
dence of the lactic secretion upon a substance found in the

o/

76 INTERNAL SECRETION

placenta. In so far as they illustrate the therapeutic uses of
placenta secretin, these experiments of Basch's are both important
and interesting, but they do not afford a satisfactory explanation
of the mechanism by which the impulse to secretion of
milk after parturition is supplied. If \ve assume that this
impulse is supplied by the placenta, we are faced with the
further problem, namely, that during the entire course of its
development in pregnancy, this organ fails to excite the secretion
of milk in the mammary glands; and that its activity in promoting
secretion is developed at the moment when its connection with
the uterine wall ceases. If the secretory hormone were elaborated
in the placenta, it w-ould be active during pregnancy. This
physiological inconsistence is not explained by the assumption
(Keiffer, Basch), that the amount of secretion supplied by the
placenta to the blood stream is very much increased during labour.

The secretion of the hyperplastic mammas is not difficult of
explanation, if viewed in the light of the theory laid down in
Part I. of this book. The growth of the gland is the expression of
an assimilatory increase of material with simultaneous inhibition
of disassimilatory decomposition. The growing gland produces
no secretion, or very little (colostrum). With the suppression of
the assimilatory hormone supplied by the foetus, that is to say,
at birth or by termination of the pregnancy during the second
half, disassimilatory decomposition, as expressed by the secretion,
is enabled to proceed unchecked.

The mammary gland is an organ which is present in the
primitive genital trace of both sexes ; during intra-uterine existence
it undergoes a certain degree of development, and later assumes
the part of a secondary characteristic of the female sex, attaining
to further development under the influence of the ripening female
genital g-land. The function of the mammary gland, so intimately
associated with the process of reproduction, does not become
apparent until after the formation (of the fcetus from the fertilized
ovum, for the developing fcetus supplies a hormone which pro-
motes hyperplasia of the glandular elements, and it is the
suppression of this hormone which permits the onset of the
secretory function.

THE RESULTS OF CASTRATION.

The operative removal of the sexual glands is followed by a
group of symptoms which, both in man and animals, has formed
a subject of exhaustive investigation. The results of castration
differ to a certain extent according to the age at which the opera-
tion is carried out.

The castration of young males is one of the oldest forms of
operation, and one which is still in frequent practice in the East.

THE GENERATIVE GLANDS 377

The castration of domestic animals, such as stallions, bulls, rams,
cocks, &c., is also frequently performed, and at an early age.

The first result of prepuberal castration is the defective
development of the genital apparatus. Post-mortem examination
shows that the seminal vesicles and the prostate of eunuchs are
small and atrophied. The penis does not, as a rule, become
atrophied, and for this reason it is customary to amputate the
penis of eunuchs employed as harem guards. Atrophy of the
seminal vesicles and prostate is observed in castrated animals,
especially in rats which have been deprived of their genital glands
at the age of 4 to 6 weeks (Steinach).

That the removal of the testes not only produces inhibition of
prostatic development, but leads to involution of the fully-formed
organ, is shown by a large number of animal experiments as
well as by Athanasow's careful histological investigations.
These observations suggested castration as a therapeutic measure
in the treatment of hypertrophy of the prostate; the method was
first carried out, with good result, by Ramm of Christiania in
1893.

The results which have since been obtained justify us in
regarding castration as a rational method of treatment in prostatic
hypertrophy and one leading to complete or partial cure. It is
somewhat difficult, however, to find a satisfactory explanation of
these results.

The inhibition of development in the case of the growing
organ is readily explicable. The hormone supplied by the testis
is essential to the normal development of the seminal vesicle and
the prostate. Walker showed that prostatic atrophy may be pre-
vented in castrated dogs by the subcutaneous injection of testicular
extract. In the case of hypertrophy of the prostate, which usually
appears at a time when the external secretory activity of the testis
is reduced, we have to assume an increase in the testicular internal
secretion. Otherwise we are compelled to refer the results of
castration in this condition to the operation of other momenta.
The suppression of the external secretion of the testis might also
lead to the atrophy of disuse in the secondary genital organs. It
was this view which suggested the operative treatment of prostatic
hypertrophy by the removal of one testis, and by the ligature or
resection of the vas deferens. Both methods were found to be
unsatisfactory and have been abandoned.

The etiology of hypertrophy of the prostate is to-day much
less obscure than formerly, when the internal and external secre-
tions of the testicle were regarded as functions of the same tissue,
namely, the spermatogenetic elements. Now that we know that
Leydig's cells in the interstitial tissue of the testicle are the
probable seat of its internal secretory activity, it is a rational
supposition that senile hypertrophy of the prostate results from
the over-production of the hormone in combination with a reduced

37& INTERNAL SECRETION

external secretion ; and that for this reason the total suppression
of the testicles may lead to the involution of the enlarged prostate,
a result which is not obtainable by the suppression of the testicular
external secretion only.

The secondary male characteristics do not as a rule attain
complete development where castration is performed before the
age of puberty. Observation of man and of animals of widely
different species shows, beyond any manner of doubt, that castra-
tion does not impart characteristics peculiar to the opposite sex,
and that transformation into the heterosexual type is never
observed (Tandler and Gross).

All eunuchs show one male skeletal characteristic, namely,
the development of the margo supraciliaris. The pelvis, moreover,
is not female, but infantile in type. The hair on the body is
scanty and is absent from the neighbourhood of the anus, but is
present, though in small quantity only, at the pubes and the
axillae. The face is usually hairless, though well-developed beard
and moustache may be present, especially in old age.

The larynx of eunuchs is not of the female type, but resembles
the enlarged organ of a child ; there is no prominentia laryngea,
and ossification has not taken place. For this reason the voice
retains its childish character and in no way resembles a woman's
voice ; it is a childish soprano which, late in life, undergoes the
changes in timbre and tone characteristic of mutation. The
general increase in the fat-body, which is sometimes very striking,
is the only feature which may give to the eunuch a somewhat
feminine appearance. Moreover, the mental and psychic develop-
ment after castration in no wray approaches that of the female,
though the quiet, phlegmatic temperament of castrated men and
animals is very characteristic.

The dependence of the secondary sex characteristics upon the
genital glands is well seen in the domestic fowl. The cock, the
male bird, is distinguished by well differentiated sexual signs,
and it has been customary from the earliest times to castrate the
cock in order, for domestic purposes, to produce the capon, in
which the male characteristics are merely rudimentary. That
there is a direct relationship between the genital gland and the
sex characters of the cock, is shown by Berthold's experiments,
but the incontestable proof of this w?as reserved for more recent
researches. It has further been shown by various authors
(Rieger, Sellheim, Foges) that the capons of commerce are not
physiological capons ; that is to say, they are not eunuchs, but
animals produced by a combination of factors ; namely, attempted,
but rarely complete, castration ; simultaneous removal of the
primitive origin of the external sex characteristics; and forced
feeding.

It may be remarked in passing that Sellheim showed that
castration is never really carried out with hens, for the reason

THE GENERATIVE GLANDS 3/9

that complete extirpation of the ovary is impossible. Poulards
are not castrated birds, but hens which have been crammed before
arriving at sexual maturity, the oviduct being severed at the same
time, so that the eggs are deposited in the abdominal cavity.

The true capon type is characterized by shrivelling of the
comb, wattles and spurs ; poor development of the neck and tail
feathers; hoarse voice; and excessive deposit of fat. This type is
obtainable only by the complete castration of young cocks.
Whether castration is perfect or not is revealed only post mortem.
Where the extirpation of the testicles is incomplete, the secondary
characters of the cock are retained ; in cases where these have
already attained a certain degree of development they will continue
to develop, provided that even a minimal amount of active testicu-
lar parenchyma is left in situ. Where, however, the amount of
tissue is less than minimal, the secondary characters will not
develop (Foges).

Transplantation of the entire testicle is invariably unsuccess-
ful in castrated animals, and this explains the negative results t)f
R. Wagner's experiments. According to Foges, it is possible
to get small portions of testicle to heal in so well, that months
later they contain living spermatozoa. Castrated cocks with
transplanted portions of active testicular tissue, do not acquire all
the characteristics of normal cocks, but they cease to be true
capons. The wattles and comb still retain their capon-like
character, but the plumage and the entire external appearance of
the bird, with the exception of the head, resembles that of the
true cock. Whether the incomplete character of the male stig-
mata is due to the small size of the implanted portions of testicular
tissue (Foges), or to absence of communication between them and
the vas deferens (Nussbaum), is at present unknown. The first
view finds support in the fact that A. Lowy observed a better
growth of the comb and wattles in capons fed with testicular
substance than in the control birds.

In the case of other animals (cattle, cervidas), the invariable
result of castration is insufficient development of the secondary
sex characters, never transformation into the heterosexual type.
A castrated cock never adopts the habit of a hen, a castrated
bull never resembles a cow, and in the same way castrated men
never resemble women.

When viewed in the light of the fact that cessation of the
function of the genital glands, whether physiological or patho-
logical, produces heterosexualism, the fact that castration never
produces the positive characteristics of the opposite sex but
results in a certain fixation of the infantile type, supplies a weighty
argument in favour of the hermaphroditic origin of the sexual
glands.

The information which we possess concerning the results of
castration before the age of puberty in women, is extremely

380 INTERNAL SECRETION

scanty. Roberts's observations in India have little value in this
connection, for the operation in his cases consisted in mutilation
of the external genitals only. It is known from the results of
experiments with animals (Hegar, Kehrer), that if both ovaries
are removed from female animals which have not reached sexual
maturity, the development of the entire genital apparatus will be
retarded, the uterus and Fallopian tubes remaining rudimentary.
By transplanting the extirpated ovaries under the skin, Halban
effected perfect development of the sexual apparatus, thus proving
that the protective influence of the ovaries is effected, not by
means of trophic nerves, but by the agency of an internal 'Secre-
tion.

Castration is frequently performed on women who have
passed the age of puberty. It is common knowledge that this
operation is followed by regressive changes in the secondary
genitals, shrivelling and atrophy of the uterus and vagina being
invariable findings. This atrophy was formerly explained by the
suppression of a trophic nerve centre supposed to be present in
the ovary. But Knauer's experiments have shown that, if the
ovaries are removed from their place .and implanted in another
part of the body, atrophy of the uterus will not take place. Fur-
ther experiment (Ribbert, Grigorieff, Rubinstein, Herlitzka,
Marshall and Jolly, Carmichael and Marshall, Daels, &c.) next
showed that the presence of even a portion of one ovary in any
part of the body is sufficient to maintain the complete anatomical
integrity and functional activity of the genital organs. Preg-
nancy may even occur after intraperitoneal transplantation of the
ovaries, and this result is a measure of the success which may be
obtained by ovarian transplantation in women.

The implantation of ovaries from animals of another species
has been repeatedly performed with successful results (Schultz,
Katsch, Carmichael and Marshall, Bucura). These ovaries (for
instance, those of the guinea-pig in a castrated rabbit, Bucura)
not only heal in but remain functionally active, for their follicles
become mature and atrophy of the uterus does not take place.
The implantation of testes into a female animal succeeds to this
extent, that the spermatogenetic tissue elements of the implanted
organs remain intact and spermatozoa may even be produced, but
the presence of the male genital gland does not prevent uterine
atrophy. The implanted testicle does, however, exercise a certain
influence upon the metabolism of the castrated female, the increase
in the weight of the body being considerably less in these cases
than after simple castration.

The subcutaneous injection of ovarian extract, whether from
the same or another species, does not prevent uterine atrophy
after castration (Jentzner and Beuthner). Bucura found that the
injection of ovarin into castrated animals was followed, not only
by atrophy of the muscles of the uterus, but by an increased dis-

THK GENERATIVE GLANDS 381

appearance of the interfascicular connective tissue. The exhibition
of ovarin 'merely reduces, to a certain extent, the obesity \vhich
follows castration.

The influence which the ovary has upon the uterus is further
shown by the fact that, after cessation of ovarian activity,
menstruation ceases in women, and the analogous rutting sym-
ptoms in animals disappear.

That menstruation is dependent upon the ovary was first
suggested by Sintema in the iSth century, though upon no
positive grounds. It was Bischoff (1844) who first suggested,
upon histological grounds, that ovulation, that is the periodical
maturity and release of the ovum, was coincident with menstrua-
tion, and that the latter was an expression of ovulation. Pfliiger
(1865) explained this relationship as follows : Stimuli accumulate
in the maturing Graafian vesicle which, acting reflexly through
the nerves, bring about a superfluity of blood in the genital
organs ; this causes the bursting of the follicle and release of the
ovum on the one hand, and on the other, the discharge of blood
from the uterus.

Strassmann succeeded in producing symptoms resembling rut
by increasing the blood-pressure in the ovaries of bitches, and
these results seemed to confirm Pfliiger's theory.

But isolated findings in both man and animals suggested the
possibility that the relationship between the ovary and the
phenomena of menstruation and of rut, was effected by a chemical
agent. Halban's experiments with apes proved that this assump-
tion was well founded. Female baboons (Cynocephalus) have a
menstruation similar to that of the human female. When the
ovaries of these animals were extirpated and implanted under the
cuticle of the abdomen, menstruation occurred in the same way
as under normal conditions; it ceased, however, as soon as the
implanted ovaries were removed. According to Marshall and
Jolly, the implantation in castrated bitches of ovaries in a state
either of, or preceding, rut, or the injection of the extract of such
ovaries, is followed by swelling of the vulva and other phenomena
of the rutting state.

It has frequently been found possible to maintain the process
of menstruation in women by the re-implantation or transplanta-
tion of the ovaries (Cramer, Pankow).

van cler Velde's statement that menstrual haemorrhage may
be procured at the physiological climacteric by means of ovarian
tabloids, must be accepted with a certain amount of reservation.

It is evident then, from what has gone before, that the hor-
mone which is formed in the genital glands and by them passed
on into the blood-stream, supplies stimuli which are necessary to
the normal development and subsequent anatomical integrity of
the genital organs, as well as to their physiological activity.

It is certain, however, that the influence of the genital glands

382 INTERNAL SECRETION

is not confined to the organs which are functionally related to
them ; that this influence extends to other physiological activities
is shown by the following observations.

The menstrual flow is sometimes accompanied by certain
nervous phenomena known as the molimen menstruale, and by
regular fluctuations affecting different functions, such as tempera-
ture, pulse, blood-pressure, and muscular power. For this
reason it is customary to speak of " undulations" in the female
vital processes. These menstrual waves are not dependent upon
the periodic loss of blood nor upon the activity of the uterus
during menstruation ; for the phenomena persist for a varying
length of time after hysterectomy. In such cases, moreover,
molimen menstruale without menstruation is also sometimes
observed. But both menstruation and the menstrual wave dis-
appear after suppression of the ovarian function, as at the meno-
pause ; after the operative removal of the ovaries ; and as an after-
consequence of hysterectomy (Mandl and Burger).

It is a common clinical experience (Chrobak, Landau) that
the symptoms which follow cessation of the ovarian function, all
the derangements, in fact, by which the climacteric is accom-
panied, are favourably influenced by the exhibition of ovarian
extract. Bucura has recently recommended the milk of rutting
cows in the management of the physiological or artificial meno-
pause.

THE SEXUALLY UNDIFFERENTIATED ACTIVITY OF
THE HORMONE IN THE GENERATIVE GLANDS.

The influence of the internal secretion of the generative
glands is not confined to the development of the secondary somatic
sex characteristics, but has a far-reaching effect upon a large
number of organs and upon the general metabolism. The pro-
found influence which this hormone has upon the organism is
apparently independent of sex, and is thus not specific to the
male or the female genital gland.

Of paramount importance is the effect of the genital glands
upon the growth of the skeleton. That this is the case in man
(eunuchs, and young males with atrophied testicles) was known
to, and pointed out by, the older authors. Sellheim found that
the castration of cocks has a modifying effect upon the growth of
the bones. Changes take place in the skull, in the pelvis, and in
the bones of the extremities; and these consist in increased longi-
tudinal growth with retarded ossification of the epiphysal carti-
lages. Similar changes were afterwards observed by Sellheim in
castrated dogs, horses, and cattle; and his results are confirmed by
Poncet, Briau, Pirche, Mobius, and many others, whose observa-
tions extended to animals of other species. Poncet found that
the entire skeleton was more powerfully formed; that the skull,

THE GENERATIVE GLANDS 383

as in eunuchs, was dolichocephalic ; and that the epiphysal carti-
lages persisted longer than in normal animals.

The experiments of Launois and Roy and those of Tandler
and Gross supply undoubted proof that in man, as in animals,
castration is followed by excessive longitudinal growth, a lack
of proportion between the length of the extremities and that of
the trunk, and persistence of the epiphysal synarthroses (as seen
in skiagrams) beyond the normal age.

Protracted epiphysal separation may result not only from
the operative removal of the generative glands, but also from
hypoplastic sub-development of them. The presence of this
symptom in combination with the persistence of other juvenile
traits, is described as immaturity of the organism or eunuchoidia
(Tandler and Gross). These cases do not altogether fall into the
group of pathological conditions classed as infantilism. For
infantilism is characterized by the small size of the skeleton and
its infantile proportions, namely, long trunk and short extremi-
ties. But hypoplasia of the genital glands is presumably accom-
panied by symptoms analogous to those of suppression ; namely,
abnormal longitudinal growth, especially in the legs, and con-
siderable increase in the fat-body. Thus the only true cases of
hypogenitalism would be those of infantile gigantism, already
described, which are characterized by abnormal growth of the
long bones, imperfect secondary sex characteristics, and deficient
mental development; and in \vhich the testicular atrophy and the
absence of any signs of pituitary disease justify the assumption of
primary hypogenitalism. Several authors (Alt, Schiiller) ascribe
mongolism to insufficiency of the genital glands. Moreover,
genital insufficiency may well play a part in the pathogenesis
of general hypoplasia (Bartel), for these cases are also charac-
terized by abnormal height, well developed fat-body, and
imperfect secondary sex stigmata.

That pregnancy is accompanied by reduced ovarian activity
is shown by the changes which take place in the skeleton. Young
women frequently grow in height during pregnancy (Halban),
and changes are known to take place in the pelvis in this con-
dition (Breuse and Kolisko).

According to Tandler, the age at which genital maturity takes
place has a paramount influence upon the growth of the skeleton.
The effect of late maturity, like that of genital hypoplasia, is to
increase the height, and especially the length of 'the legs; while
early maturity brings about premature closing of the epiphyses,
and is consequently associated with shortness of the legs. In
women, the upper part of the body is usually long in proportion
to the legs, and inhabitants of warm countries are generally small
of stature; these results are attributable to early sexual maturity.
Among animals, those which develop early are characterized by
the shortness of their extremities.

384 INTERNAL SECRETION

In pubertas prascox, the acceleration of growth is accom-
panied by premature ossification and closing of the epiphysal
synarthroses (Neurath). In chlorosis, precocity is said to be
expressed by shortness of the legs and premature disappearance
of the epiphysal synarthroses (Tandler).

A certain amount of evidence is also forthcoming concerning
the effect upon growth of the administration of extracts of the
genital glands.

Lowy showed that the skeletal pecularities described by
Sellheim are not observed if young capons are given testicular
substance, and that a premature arrest of skeletal growth may be
obtained in young hens by feeding them with ovarian substance.
Dor and Maisonave, Parhon and Antoniu, and Monziols describe
inhibition of bony growth after the subcutaneous injection of
testicular extract.

These observations all prove that there is an intimate relation-
ship between the development of the skeleton and the internal
secretory activity of the genital glands. In order to arrive at a
fuller understanding of this relationship, it must be borne in
mind that the increased skeletal growth is a secondary result, due
to the imperfect ossification of the epiphysal synarthroses ; this
fact suggests that the genital glands elaborate a hormone which
stimulates the processes of ossification.

The interrelationships which subsist between the genital
glands and those other internal secretory organs which are known
to influence the growth of the bones, are also very remarkable.
This nexus finds expression in the fact that castration is followed
by changes in the thyroid, thymus, and hypophysis ; and that,
further, the removal of the latter organs produces alteration in
the structure of the genital glands.

In a eunuch dissected by Tandler and Gross, the thyroid
apparatus was found to be remarkably small (weight 13 grm. as
against 45.8 grm. in normal persons) while thymus-persistency,
so frequently observed in animals after castration (Calzolari,
Henderson, Noel Paton), was observed in this instance also. By
means of skiagrams of living scopts these authors further dis-
covered hypophysal enlargement, their results being confirmed
by the fact that in the eunuch which they dissected there was
increase in the length, breadth, and depth of the sella turcica.

That the removal of the genital glands is associated with an
increase in the size of the hypophysis was first shown in the case
of animals by Fichera (1906), who succeeded in rapidly reducing
this enlargement by the injection of testicular extract.

It is very difficult to estimate the extent to which the skeleton
is directly influenced by the genital glands, owing to the fact
that the thymus, thyroid, and hypophysis all affect the growth of
the bones, their combined influence being extremely complicated,
in part antagonistic, and in part co-operative.

The same applies to the influence of the genital glands upon

THE GENERATIVE GLANDS 385

certain other organic systems. It is only in isolated instances
that we are acquainted with the mechanism by which the sexual
glands produce changes in localities far removed from them.
Thus, we are justified in ascribing certain developmental changes
of pregnancy, which are reminiscent of acromegaly, to primary
hypogenitalism and secondary hyperpituitarism ; while other
symptoms, we know, are due to secondary changes in the thyroid
apparatus.

Whether directly, or indirectly through the agency of other
hormone-producing organs, the genital glands exercise an influ-
ence upon the entire habit, as well as upon many of the functions,
of the animal organism. With the maturity of the genital organs
the juvenile habit makes its first appearance, and this is expressed
by a youthful freshness and vigour of the entire being, affecting
both the physical and mental capacities. The progressive physio-
logical diminution of the function of the genital glands is accom-
panied by senile changes in the cuticle and cuticular glands, in
the hair and teeth, and in the muscular and nervous systems.
Castration is followed by changes, even in young persons, which
largely resemble those of senile degeneration ; and it is evident
from this that senility, whether physiological or premature, bears
a relationship to hypofunction of the genital glands. As we have
shown in a previous chapter, senile decay is associated with
regressive changes in other internal secretory organs, and especi-
ally in the thyroid. There is, however, no justification for
ascribing a preponderating influence to one or more internal
secretory organs in the causation of senile cachexia, seeing that
we have as yet no definite information concerning the sequence
of the different processes.

The effect which the genital glands have upon the general
metabolism is very marked. That castration leads to increased
deposition of fat is one of the oldest pieces of human knowledge,
and has been utilized since very early times in the fattening of
animals for market purposes. That the localization of the fatty
deposit is dependent upon the sexual differentiation of the develop-
ing genital glands, and that it represents in part a sexual charac-
teristic, is shown both at and after puberty.

The suppression of sexual activity, in women during preg-
nancy and at the menopause, and in men with advancing age, is
accompanied by increased deposition of fat, the localization of
which is peculiar and, to some extent, characteristic in both sexes.
Certain forms of obesity, such as are observed in early childhood
and in boys of feminine habit with shrivelled or cryptorchidic
testes, and which are frequently associated with imbecility, should
probably 'be regarded as the outcome of primary hypoplasia of
the genital glands. It is frequently, however, a matter of extreme
difficulty to distinguish between obesity of genital origin and
that provoked by changes in the hypophysis.

25

386 INTERNAL SECRETION

Exceptional obesity of castrated males is not invariable in
man ; and cases of abnormal leanness have been observed. Never-
theless, the obese type is very frequent among eunuchs and scopts,
the entire fat-body being markedly over-developed and, at certain
sites, such as the mamma?, the ventral region, the nates and the
hips, attaining colossal proportions. Conspicuous obesity is
observed in women both after castration and at the menopause,
the percentage of cases in both classes being 42 to 52 per cent.

With the object of determining the nature of this change in
the nutritional conditions, as well as of discovering the cause of
the abnormal deposition of fat — which was presumably to be
sought in the changed manner of life, both physical and mental,
the alteration, in fact, of the entire temperament — Lowy and
Richter estimated the total metabolism (i.e., consumption of
oxygen and excretion of carbonic acid) of castrated dogs of both
sexes. They found that, aTter castration, metabolism was reduced
in the proportion of 14 to 20 per cent, per kilo of body-weight,
and that this reduction was maintained for months or even years.
They found, moreover, that not only was there a fall in metabolism
in proportion to body-weight, but that there was a considerable
reduction in the total metabolism apart from body-weight, the
latter frequently attaining a higher figure as the result of increased
adiposity. The authors concluded from these results that the
reduction of metabolism after castration is due to a diminution of
the processes of oxidation ; that the obesity is not necessarily
degenerative, but may be constitutional.

Pachtner (1906) confirmed the results of Lowy and Richter.
Liithje obtained different results from his experiments with a dog
and a bitch, but this is explained by the fact that obesity after
castration is by no means invariable, being present in only 50
per cent, of the cases under observation. L. Zuntz's statement
that, of four castrated women, only one showed reduced oxidation
during the resting stage, also offers no evidence against the theory
of Lowy and Richter, for Zuntz's subjects did not become obese.
This theory is very strongly supported, however, by the discovery
that it is possible to raise the depressed metabolism to as much as
30 to 50 per cent, above the normal by the exhibition, either sub-
cutaneously or by the mouth, of ovarian or testicular substance.
In normal, sexually mature animals, the exhibition of these sub-
stances is entirely negative. In the case of castrated animals,
both male and female, the ovarian substance was found to be the
more active, the effects of testicular substance being slight in
males and negative in females.

As far as the influence of the sexual glands upon the meta-
bolism of albumin is concerned, the experiments of Liithje,
Neumann, Vas, and others show that at no period of life does
castration lead to changes in Ihe metabolism of albumin ; and
that the increased excretion of nitrogen observed by certain

THE GENERATIVE GLANDS 387

authors after the exhibition of ovarian substance is to be ascribed
to increased administration of food containing nitrogen.

These experiments prove, then, that the increase in the
general metabolism which follows the exhibition of ovarian or
testicular substances is entirely due to the decomposition of sub-
stances in the body which do not contain nitrogen.

In view of the relationship which has been assumed between
osteomalacia and the genital glands, a certain interest is attach-
ing to the influence which these organs exercise upon the
metabolism of calcium and of phosphoric acid. The results
which have been obtained up to the present are inconclusive.
Curatolo and Tarulli, Neumann and Vas report reduction in the
excretion of calcium and phosphorus after exhibition of ovarian
substance ; while Falk and Schulz, as well as Llithje, were unable
to demonstrate any change in the metabolism of calcium, phos-
phoric acid, and magnesia.

Heymann's finding, that in ovariectomized rats there is a
marked progressive reduction in the total phosphoric acid con-
tents, especially of the bones, seems to contradict the well-known
fact that, in osteomalacia, castration inhibits the softening pro-
cesses in the substance of the bones, and thus brings about a cure.

The pathogenesis of osteomalacia, which is still very obscure,
requires a few \vords in passing. Fehling's theory that this
disease originates in pathological hyperfunction of the ovaries,
appeared to derive a certain support from the favourable effects
which were observed after castration. It is, however, rendered
practically untenable by the fact that the minutest histological
investigation has repeatedly failed to prove that osteomalacia is
accompanied by specific changes in the ovary, wrhether in the
follicular apparatus, the germinal epithelium, or the corpus
luteum. Wallart has recently observed peculiarly marked develop-
ment of the interstitial stroma cells in cases of osteomalacia in
both pregnant and non-pregnant individuals.

The discovery of the interrelationships which subsist between
the different internal secretory organs, especially between the
ovaries and the thyroid and suprarenal glands, suggested the
thyroid or suprarenal as the primary agent in the pathogenesis of
osteomalacia. The thyrogenic theory was first propounded by
Hoenicke (1904), and afterwards worked out by Parhon and
Goldstein. That this hypothesis rests upon very insufficient
foundation is shown by the fact that its authors have been unable
to decide whether osteomalacia is the manifestation of hyper- or
hypo-thyroidism.

Even more unsatisfactory is Bossi's theory, which explains
the pathogenesis of osteomalacia by an affection of the suprarenals.
That there is a relationship between the sexual glands and the
suprarenals, or rather the suprarenal cortex, is suggested by the
results of certain observations. There is no evidence to show

388 INTERNAL SECRETION

that the suprarenal cortex has a direct influence upon the meta-
bolism of the bones. The results of my own experience lead me
very strongly to contest Bossi's statement that total or partial
epinephrectomy is followed in animals by changes in the skeleton
resembling osteomalacia in man. The sole evidence in favour of
Bossi's view is the fact, which he observed and others have since
confirmed, that the subcutaneous injection of adrenalin produces
favourable results in osteomalacia. It is a question, however,
and one which must for the present remain unanswered, whether
this result is due, less to the pathogenetic significance of the
suprarenal, than to the pharmacodynamic action of adrenalin.

In the present obscure state of our knowledge, we are hot
justified in regarding osteomalacia as the expression of the patho-
logical affection of a definite internal secretory organ or organs.
We can only assume that several of these organs are concerned
in the production of osteomalacia; that the principal role is
played by the ovary (perhaps, also, as Bucura suggests, the
parovarium) and, judging by the incidence among men, by the
testis.

The supposed relationship between the ovarian function and
chlorosis led to investigation of the effect of castration upon the
composition of the blood.

Pinzani found that after castration there was increase of the
haemoglobin and red corpuscles in the blood of bitches, while
Liithje was unable to observe any change in these elements.
Breuer and Seiler carried out very exact experiments with bitches
which had been castrated at the commencement of sexual matur-
ity; they found that there was an invariable reduction in the
haemoglobin contents and in the number of erythrocytes, and that
this reduction disappeared again in the course of a few months.
Unlike the conditions which obtain in human chlorosis, it was
found that, in experiments with animals, the pigment contents
always diminished in direct proportion to the number of red
corpuscles.

From the earliest times, the ovaries have been credited with
a pathogenetic significance in chlorosis, and the condition has
been supposed to result from ovarian anomaly expressed by ner-
vous or humoral agency throughout the entire organism. Similar
views were held by the great physicians of antiquity, Hippocrates,
Galen, and Avicenna. The theory which prevails to-day is that
chlorosis is the manifestation of an alteration in the internal
secretory activity of the genital glands. The nature of this
alteration — whether hyper- or hypo-function — is, however, still
unknown. The premature disappearance of the epiphysal
synarthroses, as seen in skiagrams, is regarded as a sign of
genital precocity (Tandler). Of the later theories the most
interesting are those which attach a special significance to indi-
vidiual tissue elements of the ovary. According to Wallart, there

THE GENERATIVE GLANDS 389

is a connection between the internal secretion of the so-called
interstitial ovarian gland and the formation of the blood; while
Villemin regards chlorosis as a toxic condition, due to the presence
of the internal secretion of the corpus luteum, which has failed to
discharge itself with the menstrual flow. This theory is suggested
by the lipoid contents of the corpus luteum and the known
hasmolytic effect of the lipoid substances. There is yet another
hypothesis to which reference must be made in passing, that,
namely, of the polyglandular origin of chlorosis.

EXTRACT OF THE GENERATIVE GLANDS.

It was by means of the peculiar and characteristic activity of
testicular extract that Brown-Sequard obtained the first proof of
internal secretion, and it is proposed, for this reason, to enter
rather more minutely into the nature of the activity of the genital
substances.

Since that date, liquide testiculaire has found therapeutic
application in a large number of instances, but the scientific value
of these experiments is very small. The same may be said of
"spermin," first prepared by Poehl. The formula of this
substance is C5H14N2 ; it is not identical with the base, the phos-
phates of which form perfect crystals, which Schreiner originally
discovered in seminal fluid, but which has since been demonstrated
in other organic fluids. According to advertisements, this
' Sperminum Poehl" acts as a "physiological catalytic" and
ferment of intraorganic oxidation, and in this capacity is said to
improve the general condition and increase muscular energy and
cardiac activity, to promote appetite and sleep, and, above all,
to stimulate sexual activity. Up to the present, exact and care-
fully controlled experiments with this substance have not been
described. It has been largely employed by clinicians, but in
estimating the results which in certain instances have been
obtained, the suggestive influence of such measures is a factor to
be reckoned writh.

The influence of testicular extract upon muscular function
has been demonstrated by Zoth and Pregl, by means of con-
clusive experiments (1896). These authors systematically
excluded every possibility of error, including that of suggestion,
and they found that the subcutaneous injection of orchitic extract,
continued over a period of weeks, did not produce an increased
capacity for muscular energy ; but that when combined with
muscular exercises, there was an increase of as much as 50 per
cent, in the muscular performance, as shown by the ergograph
and by dumb-bell experiments.

The other effects of the genital substances have been discussed
in a previous chapter, where it was showrn that the administration
of these substances usually abolishes symptoms of suppression,

390 INTERNAL SECRETION

and that both metabolism and the functions of certain individual
organs may be intensified by this means.

According to the experiments of G. Loisel, extracts of the
ovaries and testicles of fishes, frogs, birds, and mammals, all
contain toxic substances and, when injected subcutaneously,
these extracts may provoke serious pathological symptoms or even
death (frogs, rabbits). Extracts of birds' eggs and, according to
Lambert, extract of the corpus luteum may produce toxic condi-
tions when injected under the skin of frogs.

The lesions produced in the Graafian follicles of normal
animals by the repeated subcutaneous injection of ovarian extract
obtained from animals of a different species, or even to a certain
extent of the same species, are also very remarkable. The
follicles may indeed be completely destroyed, while the rest of
the ovarian tissue remains unchanged (Bucura).

The effect described by certain authors which extracts of
the genital glands have upon the circulation of normal animals
can hardly be regarded as physiological. According to Baum,
spermin produces local vaso-dilation. According to Hallion,
extract of dried ovaries, when injected intravenously in quantities
of 5 mg. into dogs, produces a fall in arterial pressure with
reduction in the volume of the kidney and of the nasal mucosa ;
at the same time the thyroid gland undergoes a preliminary
diminution, followed by an enormous increase in volume, which
is said to result from active vaso-dilation. Hallion regards the
effect of ovarian extract in producing vaso-dilation writhin the
thyroid as specific. I have carried out very careful hasmo-
dynamic tests with ovarian extracts prepared in a variety of ways,
but, personally, I have never been able to confirm this finding.
The results which I obtained were never specific, but invariably
pointed to the presence in the extracts of substances which pro-
moted coagulation.

Serralach and Pares have made an interesting discovery,
namely, that the internal secretion of the testis plays a part in
the production of the genito-vesicular reflex. It is well known
that the ejaculation of semen is accompanied by the muscular
closing of the neck of the bladder, and by a relaxation of the
bladder walls, the capacity of the bladder being by this means
enlarged and the discharge of its contents at the same time
prevented. Serralach and Pares found that the intravenous
injection of a glycerine emulsion of testicular substance produces
the same changes in the bladder as the genito-vesicular reflex.

The chemical constitution of the genital hormone has received
as yet but little attention. A. Lowy's investigations are the first
in this field of inquiry. They show that the active substance of
the ovary must be an extremely labile body. The best effects are
obtained with the dry substance, even after ethereal extraction ;
glycerine extracts are also very active; extracts obtained with

THE GENERATIVE GLANDS 39 1

physiological saline solution are very much weaker ; and after
precipitation with acids the effects are very uncertain. Alcohol
seems to destroy the active principle.

According to Dixon (1901) the active constituents of testicular
extract are nucleoprotein and certain toxic bases. Loisel arrived
at a similar conclusion, as the result of his experiments with the
ovaries and testes of animals of different species.

THE INTERNAL SECRETORY TISSUE ELEMENTS OF
THE GENERATIVE GLANDS.

Although the correlative chemical activity of the generative
glands has long been known, the question as to whether this
internal secretion is the property of histologically differentiated
portions of the organ and which tissue elements are the ones
concerned, is of very recent date. The problem first arose about
ten years ago, but has only latterly formed the subject of investi-
gation. It was very generally assumed, though upon no very
definite grounds, that the secretory elements of the sexual glands
performed a double function ; that they elaborated the specific
external secretion, which was carried off by the excretory ducts;
and that they also produced specific substances, which were con-
veyed by the lymphatics or the vessels into the general circulation,
and which became active in distant parts of the organism. The
genital glands were regarded as typical instances of glands with
two surfaces, in which the epithelial cells elaborate both the
internal and external secretions. In 1906, Nussbaum adopted the
theory that the generative portion of the testis is the site of pro-
duction of the hormone. The coincidence of the development of
the rutting organs with the most rapid development of the sper-
matic cells, suggested that it was the secretion of the spermato-
gonia, namely, the spermatides, which at the rutting season sup-
plied the impulse to the development of the seminal vesicles and
other rutting organs.

It had long been known that, in addition to the seminiferous
tubules, the testis contained other morphological elements, but
owing to the nature of their genesis and structure, these were not
suspected of having an internal secretory function. It was not
until- after the most searching investigation in comparative
morphology, chiefly by Bouin and his co-workers, that the
biological differentiation of the elementary constituents of the
male sexual gland was recognized.

The situation in regard to the internal secretory element of
the ovary was more favourable. In this case also, it was at first
assumed that a double secretory function was performed by the
generative portion of the gland ; but the persistence of the
Graafian vesicle after the completion of ovulation suggested that
the internal secretorv function of this or^an was not simultaneous

392 INTERNAL SECRETION

with, but subsequent to, its external secretory function. Prenant
(1898), and later Born and Fraenkel, recognized that both in
genesis and structure the corpus luteum, which persists after the
ejection of the ovum and is of epithelial origin, possesses the
characteristics of an internal secretory gland. Later on, another
ovarian tissue formation of connective tissue origin, which had
long been known to histologists, but was first minutely investi-
gated by Limon (1902), was recognized by Bouin as possessing
internal secretory functions.

In describing the secretory elements in detail, it is expedient
that the male and female glands should be treated separately.

Testis, — The germinative portions of the testicle are the semi-
niferous tubules which, in addition to the spermatic cells (sperma-
togonia, spermatocytes, spermatides and sperma), also contain
the syncytium of Sertoli's cells. In addition to these, however,
the testis of all mammals contains peculiar elementary constituents
which are known as " interstitial " cells or " Leydig's between-
cells." These cells have formed the subject of repeated investi-
gation and it has been shown that they are characterized by
special genetic and structural features. They are of mesodermal
origin and appear in the primitive genital trace at a very early
phase of embryonal development, before the seminal cells have
assumed their cytological character. Enclosed in the cytoplasm
of Leydig's cells are granules which stain with osmium and
hsematoxylin-copper-lake (Regaud), acidophile and basophile
granules, pigment granules, and peculiar cell-crystals ; and these
enclosures give them a structural resemblance to secreting gland-
cells. Leydig's cells are situated in the interstitial tissue be-
tween the seminiferous tubules ; they are sometimes few in num-
ber, but they may be present in extensive clusters, especially
where, owing to lack of development or atrophy of the semi-
niferous tubules, there is room for fission to take place.

These between-cells were universally regarded as trophic
tissue elements, whose function it was to take up nutrient material
from the blood-vessels, and pass it on to the Sertoli's cells. This
theory received fresh support from the discovery by Regaud
(1901) that a substance passes from Leydig's cells to Sertoli's
cells. Reinke, however, who had proved that the cell crystalloid
discovered by him in the human testis passes into the capillary
lymphatics, suggested as early as 1896 that Leydig's cells might
elaborate an internal secretion which plays an important part in
the production of sexual instinct. Regaud and Policard, Loisel,
Mosselmann and Rubay also ascribed the internal secretory
function of the testis to this tissue element, but Bouin and Ancel
were the first to describe this tissue as the " glande interstitiellc
du testicule." In a large number of publications (1903-1904),
these latter authors brought forward the proofs in support of their
hypothesis, that this interstitial gland performs all the functions

THE GENERATIVE GLANDS 393

with which the internal secretion of the testicle has up to now
been credited.

This ingenious theory was based, partly upon observations
of the cryptorchidic testis, and partly on the results of experiment.
In the greater number of instances (man, pig, horse, dog, ram)
of cryptorchidic testicle, there is not only malplacement, but also,
as histological investigation shows, complete absence of sperma-
togenesis ; the cells of Sertoli in the seminiferous tubules are well
preserved and the cells of Leydig are more or less developed.
That animals with bilateral cryptorchidism are sterile has long
been known to breeders, but it is equally well known that such
animals possess normal, or even excessive, sexual instinct and
that all the male sex characteristics are well marked. The external
genitals and supplementary glands are fully developed. Where
the cryptorchidism is unilateral, the removal of the normal testicle
renders the animal sterile, but it retains its male appearance and
habit. The completely castrated stallion is, in Germany, called
"Walach," while the bilateral cryptorchis, or the unilateral
cryptorchis from which the normal testicle has been removed, is
called " Klopfhengst." Cryptorchidic individuals in man in-
variably show normal development of the external genitals and
male secondary stigmata.

Later histological investigation (Felizet and Branca, Cunneo
and Lecene, Nielsen, Tandler, &c.) confirms the finding that
cryptorchidism is invariably associated in both animals and man
with suppression of spermatogenesis, defective development of
the seminiferous tubules, and apparently normal development of
the cells of Leydig.

Similar changes are produced in the testicular tissue by
experimental ligature of the vas deferens. Spermatogenesis
ceases; the spermatocytes, and later the spermatogonia?,
degenerate and, at the end of a few months, they disappear. There
is at first no change in Sertoli 's cells of the seminiferous tubules,
and the cells of Leydig retain their morphological integrity. No
change is produced, however, in the manifestation of sexual
instinct, nor in the development of the secondary signs of sex.
Ligature of the vas deferens has frequently been performed by
veterinary surgeons in place of castration, but as the animals
retained the characteristics of the stallion, the results up to now
can hardly be regarded as satisfactory. Similar results have
occasionally been observed in cryptorchidic animals from which,
in place of the testicle, the enormously developed epididymis was
removed.

According to Shattock and Seligman, ligature of the vas
deferens of sheep and poultry does not prevent the development
of the secondarv sex characters.

Further evidence in support of Bouin's theory is supplied by
the results of clinical observation. Serious changes in the epidi-

394 INTERNAL SECRETION

dymis (tumours, inflammation leading to atrophy of the vas
deferens) do not inhibit sexual instinct nor do they affect the
male secondary traits.

These observations prove that the internal secretory function
of the testis does not lie in the generative elements. The question
which now arises is, in which of the two remaining elements,
Sertoli's cells or the cells of Leydig, is this function lodged. In
the hope of solving this problem, Bouin and Ancel endeavoured
by experimental measures to separate the functions of these two
groups of cells. Their course of reasoning was as follow<s. The
testicle resembles the other paired glands in that the removal of
one gland provokes compensatory hypertrophy of the other unit
of the pair. This hypertrophy presumably affects both the in-
ternal and external secretory tissue equally. If, however, the vas
deferens of the testicle left in situ is ligatured, the semen-forming
parts will be entirely destroyed \vhile the hormone-forming tissue
of the second gland will remain uninjured; such being the case,
the compensatory hypertrophy will be expressed in those cells
only the function of which is increased. Experiments with rab-
bits showed that, about six months after operation (unilateral
castration, ligature of the vas deferens of the other side), the
testicle left in situ appeared to be very much smaller, the semi-
niferous tubules contained a few spermatogonia^, and Sertoli's
cells were unchanged; while the interstitial gland was enormously
developed and showed signs of secretory hyperactivity. At the
end of ten to twelve months the seminiferous tubules had become
very much shrivelled, Sertoli's cells were degenerated, and the
entire testis was almost exclusively composed of extremely hyper-
plastic cells of Leydig.

. Tournade showed further that, in the case of rats, long-
continued ligature of the vas deferens leads ultimately to degenera-
tive destruction of Sertoli's cells.

Similar results were observed in the case of pigs with uni-
lateral cryptorchidism, from which the second normal testicle had
been removed before the age of sexual maturity. There was
complete absence of spermatogenesis and, in many instances, the
cryptorchidic testicle showed more or less marked hypertrophy,
the weight sometimes reaching double the normal. This hyper-
trophy was due to development of Leydig's cells, while Sertoli's
cells in the seminiferous tubules were unchanged. In three
cryptorchidic pigs, Bouin and Ancel found that the testicles had
remained at a primitive stage of development, Sertoli's cells being
absent, but Leydig's cells well developed. These animals were
typically male in appearance and the genital tract \vas fully
developed.

It is evident, then, that the presence or absence of Sertoli's
cells does not affect the secondary sex characters, and that the
internal secretory function is the sole property of the interstitial

THE GENERATIVE GLANDS 395

gland. This gland not only exercises a protective influence, but
it determines the appearance of the somatic male characteristics.

The behaviour of Leydig's cells during the embryonal period
and at other stages of existence points to the same conclusions.
The first appearance of Leydig's cells in the embryo precedes the
sexual differentiation of the primordial genital cells. The struc-
ture of the former indicates an exceptional degree of activity
during embryonal life. Bouin and Ancel thought it possible that
it is these cells which, by means of their specific internal secretion,
determine the sex of the generative cells — that it is their influence
upon the indifferent primitive genital trace which causes the latter
to take on the male aspect.

The sex of the somatic cells and, in consequence, the develop-
ment of the secondary genital organs and the further development
of all the male characteristics present at birth, are, then, de-
pendent upon the interstitial cells of Leydig. The normal
development of the secondary characteristics in the course of
post-uterine existence can only be ascribed to the function of this
tissue. From birth to about the beginning of puberty — at a time,
that is to say, when somatic sexual divergence is least clearly
marked — the' interstitial gland shows the minimum relative
development.

In quite young animals, ligature of the vas deferens does
not at first inhibit spermatogenesis (Griffiths), and the results of
the operation are first observed as secondary consequences at the
period of puberty, when formation of semen normally takes place.
Inhibition of development of the interstitial gland in early youth
leads to arrest of the development of the secondary sex charac-
teristics. In the course of their experiments with rabbits, Bouin
and Ancel observed certain animals which, after ligature of the
spermatic cord at the age of 7 to 8 weeks, developed the habit
and behaviour of castrated animals. Microscopic examination of
the testicle showed atrophy, not of the generative part only, but
also of the cells of Leydig. These cells were few in number, they
appeared reduced in size, and showed no cytological signs of
secretory activity; they contained a large quantity of pigment
granules. These investigators nre of the opinion that the differ-
ence in the condition of animals after ligature of the vas deferens
in early youth is dependent upon whether the excretory duct
only of the testicle is ligatured or whether the nerves which supply
the testicle are also included. Resection of the nerves contained
in the spermatic cord, without ligature of the vas deferens, may
lead to atrophy of the cells of Leydig. If the spermatic duct only
is ligatured, or if the resected nerve-fibres grow together again,
the lesion of the internal secretory tissue elements is either very
slight or is quite transitory. S. Vincent and Copeman also found
that complete suppression of both the internal and external secre-
tion of the testicle is only to be effected by the ligature of the

INTERNAL SECRETION

entire spermatic cord ; and that ligature of the vas deferens
destroys the generative portion of the gland only.

The changes of puberty are ushered in by an enormous de-
velopment of the cells of Leydig. In species with well-marked
rutting periods, this phenomenon invariably precedes sperma-
togenesis ; it is very marked in the testicle of the mole (Tandler).

Histological investigation shows that, in the testes of old
animals and of senile man, there is distinct diminution in the
number and size, together with atrophy, of the cells of Leydig.
The latter is expressed by the remarkable profusion of pigment
in the cytoplasm and the absence of other enclosures.

The observations which have been made in connection with
cryptorchidism are to be regarded as direct proof that the incep-
tion and development of the secondary male characteristics are
exclusively controlled by the interstitial cells of Leydig.

In addition to these findings, which are common to the large
majority of cryptorchids, further evidence is supplied by those
rare instances in which cryptorchidism in man is associated with
feminine secondary characters. Histologically, these cases show
complete sclerosis of the testis, while at the same time the cells
of Leydig are reduced to a few scanty groups (Felizet and Branca).
According to Benin and Ancel, cryptorchidism is peculiarly in-
teresting in pigs, such animals showing considerable difference in
the secondary sex signs, in sexual instinct, and especially in the
development of the genital tract. These differences depend upon
variation in the weight of the testicles, which in its turn results
from the different degree of development of the interstitial gland.
The genital tract is well developed in proportion to the number
of cells of Leydig which are present in the testes. In regard to
genital organs, sexual instinct, and somatic characters, the
cryptorchidic pig stands midway between the normal and the
castrated animal. As a general rule there is insufficient develop-
ment of the cells of Leydig in the testes, and the place which the
animal occupies between the two extremes is determined by the
degree of this insufficiency.

Tandler and Gross (1908) made use of the elective properties
of the Ro'ntgen rays to demonstrate the independence of the
secondary characteristics of sex of the function of the generative
portion of the testicle.

Since Albers-Schonberg, in 1903, reported that the Rontgen
rays exercise a profoundly deleterious effect upon the male genital
glands, numerous communications upon this subject have made
their appearance ; these were concerned, partly with the results of
experiments and partly with clinical material, but they all con-
firmed Albers-Schonberg's findings. Experimental work is
described by Selden, Buschke, Krause and Ziegler, Villemin,
Bergonnie and Tribondeau, Regaud and Dubreuil, Herxheimer
and Hoffmann. Clinical material is contributed by Philipp, and
bv Brown and Osgood.

THE GENERATIVE GLANDS 397

Upon all essential points these investigators are unanimous.
It is the specific cells of the testis, the spermatogoniai, which are
destroyed by the Rontgen rays; while Sertoli's cells, which take
no part in spermatogenesis, remain intact and the entire inter-
stitial tissue, with nerves and vessels, undergoes no change.

Tandler and Gross experimented with roebuck with perfectly
developed secondary sex characters and found that, after exposure
of the testicles to the Rontgen rays, the antlers remained perfect ;
while it is well known that castration results in the loss of these
male characters.

This elective destructive action of the Rontgen rays upon
the spermatic cells have recently been confirmed by Simmonds
by means of very careful experiments. He points out, however,
that even after prolonged exposure, isolated seminiferous tubules
remain intact. Of his conclusions the following deserve men-
tion :-

If the animal lives for a sufficient length of time after ex-
posure, regeneration of the seminiferous tubules will take place
and spermatogenesis may result. The destruction of the sper-
matic cells is almost invariably accompanied by proliferation of
the cells of Leydig, and this proliferation disappears after re-
generation of the spermatic cells.

Where the testicle had become withered by the action of the
Rontgen rays, the animals frequently became very obese later.
This obesity, like that which follows castration, must be regarded
as the outcome of the destruction of the genital glands.

From the results of his experiments, Simmonds concludes
that the maintenance of the sex characters, by means of an internal
secretion, is a function of both the spermatic cells and the cells
of Leydig ; that under normal conditions the cells of Leydig are
few in number, but, after the destruction of the spermatic cells,
there is vicarious intervention on their part, in consequence of
which they undergo proliferation.

If we summarize all that is known concerning the internal
secretory tissue of the male genital gland, we are led to the in-
evitable conclusion that the hormone which gives to the organism
its male characteristics, is elaborated in the cells of Leydig in the
interstitial tissue. In spite of their mesodermal origin, these cells
are able actively to produce certain specific substances and to
transfer these substances to the blood-stream ; such being the case
we are justified in describing them in their totality as an " inter-
stitial gland."

It is highly probable that, by the agency of its secretory pro-
ducts, this gland is responsible for the development of the male
sexual gland from the indifferent genital trace. That it has a
determining influence upon the normal development and maturity
of the generative portion of the sexual gland, upon the formation
of the secondary genital organs, and upon the existence and

398 INTERNAL SECRETION

persistence of those morphological and biological characters which
are the property of the male sex, is undoubted.

The part played by Leydig's cells in the general effects
produced by the genital hormone is still very obscure.
Castration leads to changes in the growth of the bones ; to modi-
fications in the structure of certain internal secretory organs, as,
for instance, the hypophysis ; and to profound metabolic altera-
tions which are, to a certain point, independent of sex and may
be reduced by the exhibition of homosexual or even heterosexual
genital gland extract. Up to the present, there is no evidence
to show that the hormone which produces these results is
elaborated in the cells of Leydig. In Simmond's experiments,
the animals frequently put on fat after exposure of their testicles
to the Rontgen rays, but there is no evidence to show that the
changes in the metabolism of fat are not due solely to the destruc-
tion of the generative parts. Further investigation is required,
especially of those effects produced by the genital gland which
are independent of sexuality, before the significance of the in-
dividual tissues of the testicle can be understood. It appears by
no means improbable that several hormones of different origin
are supplied by the testicle to the blood-stream.

Very little is known concerning pathological changes in the
cells of Leydig. According to Ancel and Bouin, this tissue
hypertrophies in acute disease, in prolonged cachexia it atrophies.
These investigators found that, in experimental intoxication or
infection, the cells of Leydig wrere hypertrophied at the commence-
ment of the condition, while in the final stages and in very severe
illness they were atrophied. They regard the hypertrophy of the
interstitial gland as a protective measure on the part of the
organism. This finding is confirmed by Voinov, but he regards
the increase in the number of Leydig's cells as a protective re-
action on the part of the genital glancl. It seems probable, from
the observations wh:<:h have been made up to the present, that
the multiplication of Leydig's cells is in some manner dependent
upon the behaviour of the semiferous tubules. Hyperplasia and
hypertrophy of Leydig's cells are accompaniments of both im-
perfect development and secondary atrophy of the seminiferous
tubules (Diirck). Hansemann believed that the cells of Leydig
are concerned in the production of testicular tumour.

Ovary. — In discussing the internal secretion of the ovary it
is necessary to consider this function in its relationship to three
different tissues : (i) the Graafian follicles; (2) the corpus luteum ;
and (3) those peculiar stroma cells which Bouin described col-
lectively as the glande interstitieHc de I'ovaire.

Of these tissues, the two first have long been known, and
investigation has revealed the nature of their interrelationship with
one another. The third has recently become the subject of con-
siderable attention. The epithelioid cells in the interstitial tissue

THE GENERATIVE GLANDS 399

of the ovary have, it is true, been minutely described and variously
named (granule ceils, migratory cells, plasma cells, medullary
cells), but the functions accredited to them have been purely local
and trophic in character. They were believed to he the renegera-
tive matrix of the ovarian parenchyma, or of the nutritional cells of
the membrana granulosa and of the ovum (Plato). Regaud and
Policard were the first to suggest that these cells might be secre-
tory glandular cells.

Bouin adopted the view that this cell-complex represented an
internal secretory gland, and his foundation for this belief is given
in a comprehensive work by Bouin's pupil, Limon (1902).
According to Limon, the interstitial tissue of the ovary is com-
posed of epithelioid cells, the protoplasm of which is filled with
granules resembling fat, which stain black with osmium, but
afterwards dissolve in Canada balsam. These cells are differently
placed in different animals ; they are sometimes arranged in com-
pact masses and cords, sometimes they are scattered without any
apparent arrangement. In the rabbit, the field-mouse, and the
guinea-pig, they are clustered together to form lobes which occupy
the major portion of the organ ; in certain other species they are
merely rudimentary. Concerning their genesis, Limon ascer-
tained that these cells are derived from the cells of the theca
interna folliculi, and are therefore of connective tissue origin.
The metamorphosis of the theca interna into interstitial tissue
accompanies the degeneration of the membrana granulosa and
of the ovum. When the ovum becomes destroyed, the cavity in
the vesicle becomes filled with young connective tissue and
shrivels; scarcely anything remains of the epithelium of the
membrana granulosa, and the ovum is recognizable only as a
small, shrivelled, hyaline lump in a mesh of the network of con-
nective tissue. At this stage, the metamorphosed vesicle re-
sembles a small corpus luteum, the structure of the cells of the
theca interna having a resemblance to those of the corpus luteum.
These metamorphosed vesicles may be termed spurious corpora
lutea, or, better, atretic vesicles, and, in their totality, they repre-
sent the interstitial ovarian gland.

The findings of Limon and Bouin, and the conclusions at
which these authors arrived, are confirmed by Cohn (1903), who
investigated the interstitial ovarian tissue of rabbits. From the
results of researches which he carried out (1905), Frankel came
to the conclusion that in many species, especially rodents, the
interstitial ovarian tissue is very perfectly developed, while in the
adult human female there are no traces of it; for this reason he
is unable to assign a physiological significance to this tissue.
Wallart and Seitz, on the other hand, observed changes in the
ovaries of pregnant women, such being enlargement, in many
follicles, of the theca interna cells and the presence of fat and
lutein in the protoplasm of these cells. These authors concluded

400 INTERNAL SECRETION

that structures genetically and morphologically analogous to the
interstitial gland of animals are present in man. Seitz does not,
however, believe that these cells possess an internal secretion.

In later investigations, conducted with the utmost care, Wal-
lart found that more or less well-developed interstitial tissue was
invariably present in the human ovary when growing vesicles
were also present. Similar cells are observed in new-born infants,
but there are no fatty enclosures in the protoplasm of the elements
of the theca interna. These fatty enclosures are invariably present
in older individuals, except such as have died from serious ex-
hausting diseases. The interstitial tissue continues to increase up
to puberty and even until the end of the second decade, but its
development is most marked and the cell agglomerations are
thickest during the period between infancy and puberty. At a
later stage, the development of this tissue is less marked than that
of the other parts of the ovary. The interstitial gland attains its
highest development during pregnancy. In many cases of patho-
logical pregnancy (hydatid mole, chorionic epithelioma), the
maximal development is attained. During menstruation an en-
largement of the gland takes place which is reminiscent of the
conditions during pregnancy. At the climacteric, the gland ceases
to develop, and remnants only are found in the ovaries, though
these persist for some time. According to Wallart, the situation
which is most favourable to the conversion of the theca interna
into the interstitial gland, is the portion of the ovary immediately
below the cortex, and it is here that the atretic follicles chiefly
undergo development.

Frankel was the first to assume a functional interrelationship
between the interstitial tissue and the corpus luteum ; he suggested
that the function of the corpus luteum might, under certain con-
ditions, be replaced by that of the tissue which is formed from
the atretic follicles. This assumption rests upon the presence of
a cell form, the lutein cell, which is apparently identical in both
tissues ; the theory is negatived, however, by the histogenetic
differentiation between the corpus luteum and the interstitial
gland — a point upon which Seitz laid special emphasis.

Seitz gave expression to his view in a new and eminently
appropriate form of nomenclature. He calls the lutein cells of
the interstitial tissue, which are formed from the theca interna,
theca lutein cells, in contradistinction to the granulosa lutein cells
of the corpus luteum, which, according to Sobotta's exact in-
vestigations with mice, are formed from the hypertrophic follicular
epithelium.

From the results of very careful observation of human ovaries,
Cohn recently settled the vexed question of the origin of the lutein
cells. According to Cohn, the development of the corpus luteum
and that of the atretic follicles are two essentially different pro-
cesses. Histogenetically, the lutein cell is not homogeneous.

THE GENERATIVE GLANDS 40 1

Lutein cells may be derived from epithelium and from connective
tissue. The lutein cells of the corpus luteum are derived from
the epithelium of the membrana granulosa. The connective tissue
framework of the corpus luteum is formed, by means of invasion
by connective tissue buds, from the theca interna. There is,
however, no fundamental difference between the formation of
the corpus luteum of pregnancy and that of the corpus luteum of
menstruation. The compact corpus albicans is probably a pro-
duct of the involution of the corpus luteum.

Atresia of the follicles is accompanied, both during and after
degeneration of the ovum and the epithelium, by proliferation of
the theca interna, which leads to the formation of a theca-lutein
layer. This layer is observed during pregnancy and in patho-
logical hypersemia of the genitals; it is also observed under
normal conditions. The atretic follicle is entirely a connective-
tissue structure.

Involution of the atretic follicle is accompanied by the de-
velopment of the theca-lutein cells into stroma cells, though in
some species this transformation is accomplished very gradually.
In such animals, the interstitial ovarian tissue is composed of
theca-lutein cells which have not, as yet, undergone degeneration.
The theca-lutein cell formation of the atretic follicles corresponds
in man to the interstitial ovarian tissue of certain animals.

These investigations supply a complete morphological pic-
ture of the tissues of which the ovary is composed. We know
that, in addition to the Graafian follicles, the ovary contains two
other tissues, both of which, from the nature of their structure,
might possess an internal secretory function, but which in their
origin differ fundamentally from one another. These are : The
corpus luteum, which is derived from the epithelium ; and the
interstitial stroma cells, which have a connective-tissue origin.
That the interstitial stroma cells possess a secretory function is
suggested by the presence of fat granules and other secretory en-
closures, as well as by a certain resemblance, commented upon
by many (Mulon, Wallart), to the cells of the suprarenal cortex.

Both tissues are present in a varying stage of development
in all mammals. The knowledge of this fact is of vital import-
ance to a right understanding of the ovarian secretory functions.
And of equal significance is a second fact, namely, that there are
no justifiable grounds for the distinction which has hitherto been
drawn between the true corpus luteum of pregnancy and the
'so-called spurious corpus luteum of menstruation. As Ravano
also points out, there is no difference whatever either in form and
contents or in genesis, between the two structures; both are true
corpora lutea, whether the ovum which proceeds from them is
fertilized or not.

In the face of these facts, it is not possible to concur in the
theory which Bouin and Ancel have recently advanced (1909).

26

402 INTERNAL SECRETION

These authors assume that the mammalia are divisible into two
groups, those in which ovulation is spontaneous, and those in
which it is provoked by sexual advances. The first group in-
cludes man, the dog, horse, pig, cow and certain other species;
females of this class possess, in addition to the corpus luteum
graviditatis, a second corpus luteum, which develops periodically,
is homologous to the interstitial gland, and fulfils the function
of the latter. The second group, which is represented by the
rabbit, guinea-pig, mouse and cat, is furnished with an enor-
mously developed interstitial tissue and with a corpus luteum
graviditatis, but possesses no periodic corpus luteum.

It is evident from the facts which have been advanced, that
there is no justification, either for such a classification of mam-
mals, or for any homology of the corpus luteum menstruationis
with the interstitial tissue. The corpus luteum is a homogeneous
structure, which proceeds from the epithelial portion of the
Graafian vesicle ; while the interstitial gland is another and dif-
ferent ovarian tissue element derived from the atretic follicles and
of connective-tissue origin, the elements of which have a structural
resemblance to true lutein cells and possess, moreover, a secretory
function.

In what does the function of these two tissues consist? It
is not possible, at present, to arrive at a satisfactory answer to
this question. We shall have occasion later to describe the
hypotheses which have been advanced concerning the functions of
the corpus luteum. In so far as the interstitial ovarian gland
is concerned, it is probable that this tissue, like Leydig's cells in
the testis, is the site at which the specific hormone is produced,
by which the correlative activity of the entire ovary is effected.
The material at our disposal is, however, insufficient to support
such a hypothesis, and the results of investigation are, moreover,
largely contradictory.

The interstitial gland attains very marked development, not
only before puberty and menstruation — that is to say, at the period
of increased ovarian function — but also during pregnancy (under
physiological and, to an even greater extent, under pathological
conditions) when, for many reasons, we are led to assume a
reduction of internal secretory function on the part of the ovaries.
It is during pregnancy that extensive cystic degeneration of the
follicles and formation of theca-lutein cells takes place (O. Fell-
ner, Cohn). On the other hand, Wallart recently observed cases
of osteomalacia unaccompanied by pregnancy, in which there was
marked development of the interstitial gland.

If the functional activity of the interstitial gland is estimated
in accordance with the degree of its anatomical development, it
appears probable that this tissue is active at puberty, during
menstruation, and in pregnancy ; up to the present, however, no
evidence is forthcoming to show the manner in which this internal
secretory activity affects the organism.

THE GENERATIVE GLANDS 403

That the secondary female sex characters, especially those
of the genital tract, are dependent upon the interstitial cells of
the ovary in the same way as the secondary male stigmata are
dependent upon those of the testis, is, at present, not proved. It
has been shown that uterine atrophy after castration may be
inhibited by the agency of the Graafian follicles alone, without
the co-operation of the corpus luteum or the stroma cells (Bucura).
But apart from this finding, Bouin, Ancel, and Villemin dis-
covered that exposure to the X-rays has an entirely different effect
upon the ovary to that which it produces on the testicle. The
X-rays also exercise an elective destructive action upon the ovary,
the specific tissue affected being the Graafian follicles. There is
a reduction in the volume of the ovary, and a diminution of the
follicles and corpus luteum ; the interstitial tissue, on the other
hand, not only remains intact, but it hypertrophies. The uterus
becomes atrophied in the same way as after castration. In the
case of the testicle, as we have already shown, the fact that the
interstitial tissue remains intact guarantees the integrity of the
genital tract and of the secondary characters.

From the knowledge which we at present possess, it appears
probable that the interstitial ovarian gland exercises a local
influence upon the physiological processes in the female genital
apparatus itself, and especially upon menstruation. The older
theory of an intimate connection between ovulation and menstrua-
tion is no longer tenable (Leopold and Ravano) ; moreover, the
careful investigations of Hitschmann and Adler have shown that
menstruation essentially consists, not in a haemorrhage, but in a
cyclic metamorphosis of the uterine mucosa. Hence we are
forced to assume a continuous production of the hormone by
which these changes are effected, the source of which can
only lie either in the Graafian follicle itself or in the interstitial
tissue. But the Graafian follicles are already present in the
immature ovary, and for that reason they can hardly be credited
with the same significance in this connection as the interstitial
gland, which attains its full development at puberty, shows signs
of a cyclic increase of function corresponding \vith menstruation,
and which, at the climacteric, undergoes involution.

The morphological and functional resemblance between the
premenstrual uterine mucosa and the decidua, suggests that the
menstrual alteration of the mucosa is in the nature of a prepara-
tion, that it prepares the ground for the nidation of the fertilized
ovum. It is interesting to note that, according to Keller's
investigations, rut in bitches corresponds with human menstrua-
tion in that it is accompanied by changes in the uterine mucosa
similar to those of the premenstrual period, though, in the case
of the animal, haemorrhage is absent or very slight. Thus, rut
is also a preparation of the uterine mucosa for the reception of the
fertilized ovum.

404 INTERNAL SECRETION

If the interstitial tissue elaborates the hormone which brings
about the uterine changes of menstruation and of rut, it is obvious
that this tissue plays a part, first in the nidation, and later in the
development, of the fertilized ovum. The assumption of a hyper-
function in this direction goes a long way towards explaining the
remarkable hypertrophy of the interstitial gland during preg-
nancy.

The further assumption of an antagonism betwreen the inter-
stitial cells and the other internal secretory tissues of the ovary—
in other words, if we assume that the anatomical hypertrophy of
the former takes place at the expense of the latter, the hyper-
secretion of the interstitial gland being associated with hypo-
secretion of the rest of the ovarian tissue — accounts for the signs
of inhibition of the activity of the ovarian hormone which are
observed in other organs during menstruation and pregnancy.
The stroma cell-complex affects the cyclic processes in the genitals
only, while hormones with other functions are elaborated in the
other ovarian tissues. This theory is quite as plausible as the
one which has gained credence up to now ; namely, that the
phenomena of menstruation, nidation, and development of the
fertilized ovum are all promoted by the agency of one tissue-
formation, the corpus luteum, which at the same time exercises
an inhibitory effect upon other correlative activities.

This brings us to a consideration of what is known as the
corpus luteum hypothesis.

Prenant (1898) was the first to regard the corpus luteum,
from the morphological peculiarities of its cellular elements, as
a ductless gland, whose peculiar function it is to guard against
the interruption of pregnancy, by preventing ovulation during
this condition as well as during the intervals between the rutting
seasons.

Gustav Born, the Breslau embryologist, suggested to L.
Frankel that, from the nature of its structure and developmental
processes, the corpus luteum verum graviditatis is an internal
secretory gland whose function it is to establish the ovum in the
uterus and promote its development.

L. Frankel undertook to supply the experimental evidence
necessary to the support of this theory. His experiments were
conducted with rabbits, the conditions governing their ovulation,
impregnation, and nidation being very well known. Rabbits
become pregnant every month, and immediately after littering
they become pregnant again. If fertilization fails to take place,
the rut occurs again at the end of about thirty-five days. The
mature Graafian follicles burst soon after littering, when the
animal immediately becomes ruttish and impregnation takes place.
This act is fruitful; three hours later the" spermatozoa have
reached the ovary, seventy hours later the fertilized ova have
passed down the Fallopian tubes into the uterus; upon the fourth

THE GENERATIVE GLANDS 405

to the seventh day, the blastula are formed in the uterus, and
upon the seventh day they become intimately connected with the
uterine mucosa.

Frankel discovered that pregnancy is prevented by bilateral
castration carried out between the first and sixth days, but that
the presence of one ovary is sufficient to ensure the development
of the ova. Destruction by galvano-cautery of all the corpora
lutea produced the same effect as bilateral castration, while
cauterization of other parts of the ovary had no influence whatever
upon pregnancy. It is evident then, that suppression of the
corpora lutea prevents the occurrence of pregnancy. But the
function of the corpora lutea is also to secure the development
of the already established ovum, for both bilateral castration and
the cauterization of all corpora lutea between the eighth and
twentieth days, are followed by involution of the embedded ova.
Further experiments showed that one corpus luteum is able to
perform the function of at least two or three; and further that
this trophic function is conveyed to the uterus by way of the
blood stream, in other words, through the agency of the internal
secretion of the corpus luteum. Frankel finds support for his
hypothesis in the hydatid moles and abortions which are by no
means infrequent accompaniments of ovarian tumour, and in the
corpus luteum cysts sometimes observed in tubular pregnancy.

In a further development of this hypothesis, Frankel adopted
the view that the corpus luteum menstruationis, which is formed
in women in every fourth week and in animals at varying inter-
vals, also possesses an internal secretion, and that it is the
function of this secretion in man to supply a nutritional impulse
of a cyclic nature to the uterus, and that this impulse prevents
the uterus from reverting to the infantile, or anticipating the senile,
stage. The mucous membranes are made ready for the reception
of the fertilized ovum ; if fertilization does not take place the
hyperasmia leads to the phenomena of menstruation and the
corpus luteum undergoes involution. As evidence of the part
played by the corpus luteum in the production of menstruation,
Frankel cites the fact that, in operative surgery, cauterization of
the recent corpus luteum prevents the occurrence of the next
menstrual period in six cases out of seven.

According to Frankel, the corpus luteum is an ovarian gland
which undergoes periodic regeneration, and which, from the time
of puberty until the menopause, regulates the nutrition of the
uterus.

The practical outcome of Frankel 's theory was the therapeutic
employment of lutein tabloids, prepared by him from the corpus
luteum of the cow, in the treatment of the clinical symptoms result-
ing from ovarian insufficiency. Frankel obtained better results
by this method than by the exhibition of ovarian tabloids.

The corpus luteum hypothesis, as propounded by Born and

4C>6 INTERNAL SECRETION

Frankel, supplied the incentive to extensive experimental and
morphological investigation, which produced no actual confirma-
tion of the theory, taut which supplied valuable information con-
cerning the sites of origin of the ovarian hormones.

The point in regard to which the least confirmatory evidence
is forthcoming, is Frankel's theory that the originating cause of
menstruation is to be sought in the corpus luteum. A small
number of findings have been described (Magnus, Lindenthal)
which seem to point to such origin; but the value of Frankel's
cautery experiments is disputed by the majority of authors, who
bring forward the well-known fact that, for no assignable reason,
menstruation frequently fails to appear at an expected date. The
hypothesis assumes that the bursting of the Graafian follicle takes
place ten to fourteen days before the commencement of menstrua-
tion, that corpus luteum being at the same time formed, the
secretory activity of which produces the menstrual period follow-
ing. Confirmation of this assumption was obtained in several
instances by Ancel and Villemin, \\lio found that, in ovaries
removed from women ten to twelve days before the date of the
next menstrual period, the Graafian vesicles were burst and quite
recent corpora lutea were present. This finding is less significant
than it appears, however, when we consider that the menstrual
swelling of the uterine mucous membrane takes place concurrently
with the ripening of the ovum in the Graafian follicle; that it cer-
tainly begins before the bursting of the follicle (Ahlfeld),and that it
cannot, for this reason, be due to the agency of the corpus luteum.
In one operation Mandl actually observed an ovary containing a
mature, but intact, Graafian follicle, together with a uterus in
which the mucosa had undergone premenstrual changes. The
experiments of Hitschmann and Adler, to which reference has
already been made, next proved conclusively that the haemorrhage
is the least important of the menstrual phenomena ; that it is, as
a matter of fact, merely an accompanying symptom of the cyclic
changes in the mucosa ; and that it is these which constitute the
essential feature of the menstrual process. It is hardly possible
that a stimulus of short duration, such as that provided by the
bursting of the Graafian vesicle, can be the forts et ori^o of the
entire cyclic process, nor can the haemorrhage itself be directly
due to that cause ; but the two processes, ovulation as well as
haemorrhage, must be regarded as the co-ordinated results of an
increased determination of blood to the q-enital organs.

The prevailing views upon the relationship between menstru-
ation and ovulation are in need of considerable revision in the
light of Leopold and Ravano's investigations. The material at
the disposal of these authors was very large, and the conclusions
at which they arrived are as follows :—

Menstruation, that is, the periodic emission of blood by the
uterine mucous membranes, depends upon the presence of the

THE GENERATIVE GLANDS 407

ovaries and the development of the uterine mucosa, and not
solely upon the bursting of a Graafian vesicle. In the greater
number of instances there is, both before and during the bursting
of the vesicle, a determination of blood to the ovary. This is, in
all probability, the reason why ovulation and menstruation are
frequently coincident. Ovulation may take place in accordance
with a specific periodic cyclic process, or its occurrence may be
irregular; as a general rule, however, its periodicity coincides with
that of menstruation.

In more than a third of instances, ovulation and menstruation
are not simultaneous. Ovulation may take place at any time,
and is not necessarily accompanied by uterine bleeding. This
fact makes it appear extremely probable that conception also can
•occur at any time.

Menstruation may take place without ovulation. At the
period when the ovaries undergo senile involution, they sometimes
contain normal Graafian follicles and corpora lutea, which seems
to show that the process of ovulation may outlast that of menstrua-
tion.

It is evident from the above statements that Frankel's theory
of the dependence of menstruation upon ovulation and upon the
internal secretory function of the corpus luteum, is untenable.
As Rcgaud and Dubreuil have shown, rut in rabbits has no
connection with the corpus luteum.

Frankel's further assumption that the corpus luteum regulates
the nutrition of the uterus from puberty to the menopause, is
also unfounded. This theory is based upon experiments in which
the destruction of the corpora lutea of rabbits was followed by
permanent nutritional disturbances of the uterus, similar to those
which follow bilateral castration. The results of exposure of the
•ovaries to the action of the X-rays — atrophy of the genitals,
accompanied by diminution in the size of the ovaries and dis-
appearance of the corpora lutea or Graafian follicles, with
persistence of the interstitial cells — have alreadv been described,
and these are advanced bv Bouin, Ancel, and Villemin as further
evidence in favour of the internal secretory function of the corpora
lutea. Vet the results of both sets of experiments really only
prove the functional importance of the corpora lutea and the
Graafian follicles in the maintenance of the anatomical integrity
of the genital tract. Both tissues are destroyed by the action of
the X-rays, and the possibility of damage to the Graafian follicles
by cauterization of the corpora lutea cannot be excluded. Bucura's
experiments, however, resulted in negative findings with regard
to the corpora lutea. These experiments proved that atrophy
after castration may be prevented by the transplantation of the
ovary from an animal of another species, provided that the ovary
contains developing Graafian follicles, the presence of an intact
corpus luteum being alone insufficient to affect the result. That

408 INTERNAL SECRETION

the Graafian follicles are the sole agents in the prevention of the
uterine atrophy, is proved in the most conclusive manner by a
case of Bucura's, in which a remnant of the ovary was left in
situ after castration, and in which atrophy of the uterus did not
take place. Examination of sections in unbroken series showed
that this remnant consisted solely of maturing Graafian follicles,
neither stroma cells nor any traces of corpus luteum being present.

Bern's original hypothesis, that the function of the corpus
luteum is to provide for the nidation in the uterus and subsequent
development of the fertilized ovum, finds considerable support in
the results of morphological investigation as well as in Frankel's
experiments. If the ovum, after its emergence from the Graafian
vesicle, becomes fertilized, lutein cells are formed from the
epithelial cells of the membrana granulosa, probably in the same
way as at the menstrual period ; but the corpus luteum of preg-
nancy persists and, in accordance with both its genesis and
structure, may be regarded as a secreting gland. What is the
nature of its function ? The similarity of structure and develop-
ment which subsists between the menstrual and the gestative
corpora lutea, inevitably suggests that the latter carries out, only
in a more intense degree, the function inaugurated by the former-
If the corpus luteum menstruationis prepares the uterine mucosa
for the reception of the ovum, the corpus luteum graviditatis is-
responsible for the nidation of the fertilized ovum and for its
further development. But, seeing that we are unable to attribute
the responsibility for the menstrual changes in the mucosa to the
corpus luteum menstruationis, the premises for the conclusion that
the corpus luteum graviditatis also possesses a preparatory
function cease to exist. On the other hand, Frankel's experi-
ments undoubtedly appear to bear this interpretation. These
experiments show that in the rabbit, suppression of the corpora
lutea in the first week after fertilization prevents the occurrence
of pregnancy, and that suppression between the eighth and
twentieth days terminates it. With regard to the latter point,,
however, Kleinhans and Schenk found by very careful experiments
that the removal of the corpora lutea after nidation does not
necessarily terminate a pregnancy of more than nine days' dura-
tion, and it seems evident from this that the corpus luteum has-
no significance in the after-development of the ovum.

The function of the corpus luteum could only be to safeguard
the nidation of the ovum. But even this manifestation of activity
seems improbable in the light of an experiment carried out by
Mandl. The left ovary of a pregnant rabbit was removed and
implanted between the fascia and the abdominal wall. After
littering, pregnancy again took place, and two days later the
second ovary was removed. The pregnancy ran a normal course,
in spite of the fact that a corpus luteum graviditatis could not
possibly have been present in the transplanted ovary, and post-

I

THE GENERATIVE GLANDS 409

mortem examination subsequently showed that there was no
" spurious " corpus luteum. It is very evident from this experi-
ment that the corpus luteum is not indispensable to either the
nidation of the ovum or to its after development. Frankel
explains the results of this experiment by assuming that, in this
instance, the function of the corpus luteum was vicariously under-
taken by an atretic follicle, but this assumption is a complete
departure from his own theory. For, as we know, the atretic
follicle is entirely a connective tissue structure and the theca-lutein
cells, formed in the course of its involution, compose the inter-
stitial ovarian tissue. This proves the importance of the inter-
stitial gland in the nidation of the ovum, while at the same time
it reduces the function of the corpus luteum to a probable partici-
pation in this process.

Having disposed of Born and Frankel's hypothesis, we return
to the view, first expressed by Prenant and since confirmed by
others (Sandes, Srobansky), that the internal secretory function
of the corpus luteum persistens consists in the inhibition of
ovarian activity and, more especially, in the prevention of ovula-
tion during pregnancy.

It is common knowledge that, as a general rule, neither
ovulation nor menstruation take place in pregnant women. In
the cow, persistence and hypertrophy of one corpus luteum are by
no means infrequent findings, and in such cases there is no
recurrence of rut at the usual intervals of twenty-one days ; if the
hypertrophied corpus luteum is removed by surgical means, how-
ever, the signs of rut will appear a few days later. In the case
of the mouse, the corpus luteum persists after littering, sometimes
until after the second or even third pregnancy (Sandes, after
Mandl).

Ravano shows that the current notion that, in women, the
corpus luteum graviditatis persists during the entire period of
pregnancy, is mistaken ; it may even completely disappear,
though the occurrence is rare. In about 5 per cent, of cases,
complete ovulation takes place during pregnancy, while a ten-
dency to ovulation is shown by the large majority of pregnant
women.

The material we at present possess supplies no decisive
evidence as to the part played by the corpus luteum in the
inhibition of ovulation and the other ovarian functions during
pregnancy. As we have previously shown, these processes may
result, with equal probability, from hyperfunction of the inter-
stitial cells and reduction of activity on the part of the other tissues,
particularly of the Graafian follicles. The atresia, which extends
during pregnancy to numerous follicles, consumes the material
for the maturing of the ovum.

It is evident from the above that the third and most con-
siderable tissue constituent of the ovary, the Graafian follicles,

4IO INTERNAL SECRETION

may possess important secretory functions. With the exception
of the cyclic symptoms in the genital iract, and certain processes
which take place during pregnancy which are referable to the
activity of the hormone of the interstitial gland, the Graatian
follicles are probably responsible for all the chemical correlation-
ships which are ascribed to the ovary as a whole. There is proof
that the maintenance of one important sex characteristic, the
female genital tract, is dependent upon these follicles. The
question as to which tissue is the primary origin of this, as of the
other, female .secondary characters, has scarcely as yet come under
discussion.

That the tissue which performs the function of external
secretion is also the site of production of the ovarian non-sexual
hormone, which exercises an alterative influence upon a large
number of tissues and functions, is suggested by analogy with
the male sexual gland.

In conclusion, reference must be made to Bucura's assump-
tion of an internal secretory function on the part of the parovarium
or epoophoron (remains of the Wolffian body), and his experi-
mental attempts to prove such secretion. Bucura's investigations
confirm the reports of earlier authors, that the epoophoron is an
organ which continues to develop after birth, that it attains the
summit of its development at puberty, that it apparently hyper-
trophies during pregnancy, atrophies with old age, and, from
the nature of its structure, may possess an internal secretory
function. He found that the uterus reacts differently to ovarian
extirpation if the parovarium is removed with it, and that both
these results differ from that which fellow's the customary method
of extirpating the uterine appendages. The difference in the
appearance of the uterus is due to the manner in which the con-
nective tissue is affected. Owing, however, to the extreme
scarcity of experimental material, it is impossible at present t<>
arrive at any definite conclusion concerning the function of this
appendage of the female genital gland.

INTERNAL SECRETION OF OTHER PARTS OF THE

GENITAL APPARATUS.

Prostate. — It is \\ell known that the prostate is a glandular
organ possessing an external secretion which promotes the activity
of the soermatozoa, partly by a specific stimulatory influence,
and partly by diluting and increasing the fluidity of the testicular
secretion (Fiirbringer, Exner, Steinach). From the results of
experiments and from clinical observation, Serralach and Pares
(1907) assumed an internal secretion on the part of the prostate.
They found that after removal of the prostate of dogs, there was
cessation of ejaculation of semen and suppression of the secretion
of the preputial glands, temporary cessation of spermatogenesis

THE GENERATIVE GLANDS 411

and atrophy of the testes. The administration of glycerine
extract of prostate subdued these symptoms or prevented their
occurrence.

The conclusiveness of Serralach and Pares' experiments is
questioned by |. P. Haberern on the justifiable grounds that
prostatectomy, as carried out by them, was not complete. As I
know from my own experiments, total extirpation of the prostate
of dogs is attended by considerable technical difficulties, and I
am prepared to support Haberern in his view, that the internal
secretion of the prostate can be proved only by extirpation experi-
ments which are free from objection, reinforced by the results of
the transplantation of the organ. The implantation site most
suited to the prostate is the bone tissue. Primary atrophy of the
prostate in man may cause aspermatism.

Glycerine or watery extracts of the prostate of bulls (Thaon,
Posner, and Kohn) and of dogs (Biedl) are extremely toxic. The
intravenous injection of a few cubic centimetres produces a marked
rise in arterial tension, followed by an equally marked fall ; there
is arrest of the heart's action and asphyxia. These symptoms are
most probably due to intravascular coagulation.

lrterus. — The difference in the symptoms of suppression
which follow extirpation of the uterus, extirpation of the ovaries,
and extirpation of both uterus and ovaries, led O. O. Fellner
(1908) to assume that the uterus possesses an internal secretion.
the action of which is both toxic and vaso-contrictor, and which
starts the menstrual wave. Fellner supposes that there is an
antagonism between the internal secretory activity of the uterus
and that of the ovary, the function of the ovarian secretion being
to neutralize the toxic product of the uterus. There is no experi-
mental foundation for this hypothesis. As far as is at present
known, extract of uterine tissue is physiologically inactive. As
Fellner himself pointed out, the toxic effect which is obviously
produced by the intravenous injection of homologous uterine
extract, is probably the result of intravascular coagulation,
brought about by the comparatively large amount of thrombo-
kinase present in the uterine mucosa. In the course of my own
experiments, I have been unable to confirm an effect of ovarian
extract which is described by certain French authors (Hallion,
Delille), namely, that it produces hypotension and has an elective
vaso-dilator effect upon the vessels in the thvroid gland. The
production of such a result by the intravenous injection of ovarian
extract could hardly be regarded, moreover, as proof of an intern il
secretory function on the part cf the ovaries, for, as we have
frequently pointed out, depressants are present in many tissue
extracts.

Placenta. — The internal secretion of this organ plays an
important part in the modern theory of eclampsia. We will
confine ourselves to a few brief comments upon the subject.

412 INTERNAL SECRETION

Schmorl's anatomical finding of emboli composed of placenta
cells in the lungs and other organs in eclampsia, paved the way
for Veit's syncytiolysin theory (1905). Syncytiolysin is
supposed to be an antibody, formed in the maternal
organism in consequence of the passage of albumin from
the syncytial villous coating. If the formation of this
antibody does not take place, or is insufficient to
combat the flooding of the organism with placental albumin,
the latter acts as a toxin and produces the toxic condition known
as eclampsia. Ascoli, on the contrary, regards the syncytiolysin
as the toxic substance, while, according to Weichardt, the
eclampsia toxin is a form of endotoxin which is liberated from
the placenta cells by syncytiolysin.

The premises for these different and entirely contradictory
hypotheses^ are provided by experiments which show that extracts
obtained by various means from placental tissue, have a toxic
effect ; that after intraperitoneal injection they produce albumin-
uria and other derangements ; and that after intravenous injection
they may cause death. A more careful investigation showed,
however, that the results are due in part to the action of albumin
obtained from animals of a different species (Lichtenstein), and
in part to intravascular coagulation (Dryfuss, Martin, Freund,
Mathes) caused by the presence of thrombokinase in the placenta.

Liepmann found that the normal human placenta is prac-
tically non-toxic to rabbits, while the eclampsic placenta is
extremely toxic, but Dryfuss was unable to confirm these results.
He, like Hofbauer, Dienst, and others, holds the view that
ferments, in certain cases in increased quantities, pass from the
placenta into the maternal blood-stream ; that these break up the
leucocytes and bring about increased formation of fibrin-ferments
and fibrinogen ; and in consequence of this thromboses and
degenerative processes occur in the liver and kidneys.

According to Massini, under normal conditions the placental
toxin is neutralized in the thyroid gland, and eclampsia takes
place only where there is thyroid insufficiency. According to
Vassale, eclampsia is a motor neurosis due to decreased function
of the parathyroid glands; he recommends the administration of
parathyroidin, and describes favourable results.

THE INTERNAL SECRETION OF THE

PANCREAS.

In the year 1889, v. Mering and Minkowski discovered that
extirpation of the pancreas of dogs is followed, not only by
digestive disturbances due to the absence from the intestine of
the pancreatic secretion, but by the continued presence of sugar

THE INTERNAL SECRETION OF THE PANCREAS 413

in the urine and by all those further symptoms (polyuria, poly-
phagia, emaciation ending in death) which we are accustomed to
associate with pronounced diabetes mellitus. An intimate rela-
tionship between diabetes and pancreatic disease had already been
suspected by several clinicians, who, upon anatomical grounds,
ascribed a pathogenetic significance to the pancreas in that
condition. Their hypothesis was now supplied with an experi-
mental foundation, while at the same time a new and previously
unknown function of the pancreas was brought to light.

A similar discovery to that of v. Mering and Minkowski was
made, at about the same time and quite independently, by de
Domenicis, though he failed to recognize the significance ol his
findings. The results have since been confirmed by means of
many hundreds of experiments, undertaken by numerous authors
(Lepine, Hedon, Gley, Thiroloix, Caparelli, Harley, Schabad,
Cavazzani, Sandmeyer, Selig, Rumboldt among others).

That glycosuria is a constant finding after extirpation of the
pancreas was disputed by isolated authors, but these exceptional
cases are fully explained by the, at first sight, remarkable fact,
that characteristic sequelae are observed only after complete, or
almost complete, extirpation of the organ. If one-third to one-
fifth of any part of the gland is left in situ, glycosuria will not
appear. If the remnant becomes destroyed by secondary pro-
cesses, or is removed by surgical means, serious diabetic sym-
ptoms will make their appearance. These observations pointed to
the fact that the cause of the metabolic derangement could not lie
in the digestive disturbances arising from the absence of the
pancreatic juice ; they showed, moreover, the relative unimpor-
tance of the changes brought about by operative intervention, in
the conditions governing the blood supply and the innervation
of the organ. Minkowski, followed by E. Hedon, whose work,
however, was quite independent, next showed by a well planned
series of experiments, that neither lesion of the vessels nor of the
nerves, nor suppression of the external secretion of the organ, is
the causative factor in the production of pancreatic diabetes. The
method employed was to remove that portion of the pancreas of
the dog which is situated in the mesentery of the duodenum, and
which Pfliiger named processus uncinatus, and to implant it,
together with its vascular peduncle, under the skin of the
abdomen. If this transplanted portion is sufficiently vascularized
and nourished, the rest of the pancreas may be removed by a
second operation without producing diabetes. But if, by a third,
very slight extraperitoneal operation, the transplanted portion of
the pancreas is also removed, serious diabetes will follow, and
death will ensue.

As the result of these experiments, pancreatic diabetes became
the subject of eager experimental investigation. Total extirpation
of the pancreas was next carried out with animals of different

414 INTERNAL SECRETION

species. Minkowski observed diabetes not only in the dog, but
in the cat and the pig, and Hedon observed the condition in apes.
Destruction of the pancreas is followed in rabbits by slight
diabetes expressed by alimentary glycosuria. In carnivorous
birds, removal of the pancreas is followed by slight diabetes
(Weintraud) ; while the herbivorous varieties show marked hyper-
glycaemia and reduction in the glycogen contents of the liver, but
no glycosuria (Kausch). Aldehoff found that, of cold-blooded
animals, the frog and the tortoise show glycosuria after pancreas-
ectomy. Markuse and Pfliiger also investigated the conditions in
frogs, and found that, if the liver is removed with the pancreas,
glycosuria does not appear. With regard to fish, in t\vo cases
out of eleven, Caparelli observed slight glycosuria in eels after
pancreatic extirpation, while Diamare observed constant hyper-
glycaemia and glycosuria in Torpedo m arm oral a.

The dog has formed the subject of the vast majority of
pancreatic experiments, and it was with this animal that an exact
experimental analysis in diabetes was first obtained.

Total extirpation of the pancreas of dogs is followed by sugar
in the urine in the course of a few hours or, at the most, a few
days. If, during the following days, the animals are fed, the
amount of sugar increases progressively, and, at the end of three
to five days, reaches the maximum of 8 to 12 per cent. If the
animals are kept fasting, the urine will contain sugar, but in
smaller quantities. Taking into consideration the fact that, in
addition to glycosuria, there is a very high degree of polyuria,
the absolute amount of sugar excreted is considerable. Dogs
weighing 10 to 15 kilos, and fed on a mixed diet containing
a large proportion of carbohydrates, excrete i to ij litres of urine
containing 8 to 10 per cent, sugar in twenty-four hours — that is,
about 1 20 to 150 grms. in the twenty-four hours. The other
diabetic symptoms evidenced by these animals are polyphagia
and polydypsia ; in face of the large amount of food taken, the
progressive emaciation is very remarkable. This is first shown
by a rapid decrease in the adipose tissue, but the fleshy parts also
soon show a marked falling away; and three to four weeks after
operation the animals are reduced to skeletons and perish of
extreme inanition. The emaciation, however, is attributable only
in part to the digestive derangements which accompany the sup-
pression of the external pancreatic secretion. The glycosuria
persists until the end, the sugar disappearing from the urine on
the day preceding death. In addition to sugar, the urine contains
acetone, aceto-acetic, diacetic, and /3-oxybutyric acid.

The duration of life depends, in the first place, upon the
operative technique; in the second, upon whether the removal of
the organ is effected without infective complications, especially,
as so frequently happens, duodenal necrosis with subsequent
peritonitis and perforation. It must also be borne in mind that,

T-HE INTERNAL SECRETION OF THE PANCREAS 415

owing to the long time which it takes to heal, the surgical wound
in experimental diabetes constitutes a certain danger to life. In
the absence of all by-factors, however, the metabolic disturbances
lead to death in three, or at most four, weeks after operation.
Should the animal live for a longer period, it is safe to assume
that extirpation was not complete, and that minute portions of
the pancreas were left in situ.

The autopsy shows that, with the exception of emaciation,
there are no noticeable changes in the organs. Fatty degenera-
tion is sometimes present in the liver and kidneys, dilatation and
hypertrophic changes are observed in the gastro-intestinal canal,
and, according to Boccardi, there are changes in the central
nervous system.

Partial Extirpation of the Pancreas. — If a portion only of
the pancreas is removed, a quarter or one-fifth of any part of the
organ being left in situ, glycosuria will not take place. An even
larger proportion of the pancreas may be removed and, provided
that the remaining portion is sufficiently well nourished and
vascularized, the glycosuria will be transient only. Whether the
remaining portion is left in situ, or is transplanted externally of
the abdominal cavity, is a matter of indifference. The trans-
plantation of the processus uncinatus with its vascular peduncle
to a position under the abdominal cuticle, prevents glycosuria.
Resection of the peduncle did not, in Hedon's experiments, pro-
voke glycosuria ; but Lombroso has recently shown that the
subsequent ligature of the peduncle produced slight transient
glycosuria. In one instance, where the implanted portion of
pancreas was efficiently vascularized by a large cuticular artery,
the removal of this portion eight days after implantation led to
serious diabetes, which terminated fatally.

Extirpation is sometimes partial as the result of accident,
small portions of pancreatic tissue being unintentionally left in
situ. Such conditions produce " slight " diabetes, sugar appear-
ing in the urine only after administration of the carbohydrates,
and disappearing again with a flesh diet. Tn many instances,
this remaining portion undergoes progressive degenerative
atrophy, in consequence of which the diabetes passes from the
slight into the severe form (Sandmeyer's diabetes).

METABOLISM IN PANCREATIC DIABETES.

The derangements of metabolism which follow extirpation
of the pancreas are expressed by the glycosuria and the hyper-
glycasmia of which it is the immediate outcome ; by the disappear-
ance of the glycogen reserve ; by the peculiar behaviour of the
organism with regard to the different carbohydrates; by the
increased formation of acetone bodies, due to the absence of the
carbohydrates ; by the over-charging of the blood with acids

41 6 INTERNAL SECRETION

(acidosis), with its attendant danger, coma diabeticum ; and by
changes in oxidation and general metabolism, as well as by the
secondary effects which these produce upon the nutritional con-
ditions (polyphagia and emaciation).

Glycosuria. — The characteristic symptom, which appears
-earliest after pancreasectomy and is most readily demonstrable,
is the presence of grape-sugar (dextrose) in the urine. The
amount and the intensity of the glycosuria is subject to immense
variation, partly the result of external factors, such as muscular
exertion, surrounding temperature, &c., chief among which is
the amount and nature of the diet. Assuming these factors to be
-equal, however, the condition falls into two distinct types con-
nected by transition stages, and these types correspond in all
essential particulars to the " slight " and " severe " clinical forms
of diabetes. The essential differences which Seegen pointed out
between the two clinical conditions are not observed in experi-
mental pancreatic diabetes. The differentiation is merely quan-
titative and depends upon the degree of pancreatic inadequacy.

The extirpation of relatively large portions of the pancreas
produces slight glycosuria; extirpation of the entire organ is
followed by severe glycosuria. If the portions left in situ
undergo secondary atrophy, the slight condition may pass into
the serious stage (Sandmeyer). Slight diabetes is characterized
clinically by the fact that sugar appears in the urine only after
a diet containing carbohydrates, and disappears rapidly if the
carbohydrates are excluded from the diet. In the severe form,
sugar is always present in the urine and, though the quantity
is diminished by fasting or by an exclusively meat diet, the
sugar never entirely disappears. As Minkowski showed, when
the metabolic derangement, after total extirpation of the pancreas,
has reached its height, the glycosuria has a certain definite in-
tensity, which may be estimated by the proportion between the
sugar and the nitrogen in the urine, and which, after fasting
or a diet free from carbohydrates, is expressed by the quotient
D:N=2.8:i. It has been shown by numerous subsequent ex-
periments that Minkowski's quotient of 2.8 varies but slightly in
diabetes produced by total extirpation of the pancreas of dogs ;
and that within the limits of this quotient, sugar is formed from
albumen. As we showed in a previous chapter, the previous or
simultaneous ex'tirpation of the thyroid of dogs without pancreas
raises the quotient D :N to 3.5, or even higher (Eppinger, Falta
and Rudinger).

Alimentation increases the absolute amount of sugar excreted.
Feeding with albumen is followed by a fluctuation of the sugar
contents in proportion to the amount of nitrogen present in the
urine (Minkowski, Berger, Lehmann, Bendix). The administra-
tion of fats does not, as a rule, increase the glycosuria, though
Falta, Eppinger and Rudinger observed a transitory, but very

THE INTERNAL SECRETION OF THE PANCREAS 417

marked, rise in the quotient D :N in dogs without pancreas after
feeding them with fats, and this result was intensified by the
injection of adrenalin.

With regard to the different carbohydrates contained in the
nutriment, Minkowski discovered that by far the greater number
(starch, grape-sugar, milk-sugar, cane-sugar) are excreted,
almost without residue, in the form of glucose. Levulose is the
only carbohydrate of which a large proportion is used up in the
organism. After the administration of levulose, a considerable
deposition of glycogen takes place in the liver and in the muscles.

These findings of Minkowski's were confirmed by Sand-
meyer and, more recently, by Pfliiger. According to Eppinger
and Falta, the pathological decomposition of albumin observed
in dogs without pancreas is reduced practically to the normal by
the administration of levulose; and it seems evident from this
that a portion of the levulose is really consumed.

Of the other factors which contribute to the intensity of the
glycosuria, the most important is the surrounding temperature.
According to Liithje, the quotient D:N is very high when the
surrounding temperature is low, and very low when the surround-
ing temperature is high. Minkowski and Allard, Falta, Mohr
were unable to confirm this relationship between the amount of
the glycosuria and the surrounding temperature.

The intensity of the glycosuria is influenced, moreover, by
the temperature of the body. The increased combustion and the
increased decomposition of albumin by which a heightened tem-
perature, especially fever temperature, is accompanied, may pro-
duce an intensified glycosuria. But, as a general rule, the be-
ginning of infective peritonitis and general sepsis in animals
after operation, is accompanied by a marked diminution or even
complete disappearance of the glycosuria. If experimental toxic
nephritis is induced (with cantharidin or chromic salts) in dogs
without pancreas, the condition wrill be accompanied by a con-
siderable decrease in the amount of sugar excreted in the urine
(Biedl). It is known that in spite of the fact that consider-
able hyperglycasmia is present, dogs with pancreatic diabetes
cease at the preterminal stage to excrete sugar (F'alta, Grote and
Stahelin). Similar findings in the clinical condition (reduction
in the sugar excretion with hyperglycaemia, in nephritis with
fever) are explained by v. Noorden as the result of the increased
impermeability of the renal filter to sugar; and this assumption
is accepted by L. Pollak in explanation of the reduction in the
glycosuria after repeated injection of adrenalin.

The effect which muscular exertion has upon the sugar
excretion in animals with pancreatic diabetes is at present insuffi-
ciently investigated. Heinsheimer observed that glycosuria — sub-
maximal, it is true— was favourably influenced by extreme mus-
cular exertion ; while Falta, Eppinger and Rudinger's dogs,

27

41 8 INTERNAL SECRETION

which were totally devoid of pancreas, showed rapid decline both
of the temperature and of the N. and D. excretion after an hour
in the treadmill, and a few hours later they died.

Hyperglyccemia. — The immediate cause of glycosuria in
pancreatic diabetes, as in all the experimental forms, except so-
called renal diabetes (phlorizin, renal toxins), is an abnormal
increase in the sugar contents of the blood. The renal filter is
impermeable to the normal sugar contents of the blood, which
are about .1 per cent.; but if the sugar contents of the arterial
blood exceed this figure, and especially if the hyperglycaemia is
maintained, the kidney is unable to withstand the sugar in the
blood and it passes, in consequence, into the urine. A high
degree of hyperglycaemia is invariably the result of extirpation
of the pancreas ; it is present also in those cases, such as herbi-
vorous birds, in which glycosuria is absent (Kausch). The cause
of hyperglycaemia lies in a derangement of the regulatory
mechanism by which the normal sugar contents of the blood are
guaranteed. It is not proposed to enter here into a discussion
of the nature of this derangement ; it will be sufficient for the
present purpose if we describe the phenomena by which hyper-
glycaemia is accompanied.

A factor of the first importance is supplied by the conditions
covering the glycogen contents of the body. Very early after
pancreas extirpation the glycogen in the liver is reduced until only
traces of it remain. In all cases of severe pancreatic diabetes,
the glycogen in the liver is reduced in the first few days to a
minimal amount and this does not subsequently disappear. Even
after generous feeding with carbohydrates only traces of glycogen
are to be found. In the slight form of diabetes, the liver may
contain considerable quantities of glycogen. Suppression of the
pancreas is also attended by a marked diminution in the amount
of glycogen in the muscles, though the muscles do not part with
their glycogen as readily as the liver. In face of the disappear-
ance of glycogen from the liver, the remarkably high glycogen
contents of the leucocytes is very striking (Ehrlich) ; the proba-
bility is that these become crammed with superfluous glycogen
from the blood. Not all the carbohydrates, however, escape con-
version into glycogen. As Minkowski proved, the administration
of levulose leads to a storing-up of glycogen in the liver and in
the muscles. It has been already pointed out that the administra-
tion of levulose does not increase glycosuria; certain later
observers (L. Pollak, Neubauer) regard this as the expression
of a greater resistency on the part of levulose-glycogen than upon
that of glucose-glycogen. As S. Fraenkel justly points out, the
administration of any one of the carbohydrates is invariably fol-
lowed by the formation of, the same glycogen substance, that,
namely, which directs the polarized ray to the right, and which,
after hydrolysis, yields dextrose. No one has, up to the present,

THE INTERNAL SECRETION OF THE PANCREAS 419

observed glycogen in another form, and for this reason the ex-
planation of the levulose experiments must lie in some cause
other than the formation of a different glycogen substance.
Fraenkel draws attention to Henri's experiments, which have
attracted little notice, and which show that levuiose has an in-
hibitory influence upon the action of invertin. This result sug-
gests that levulose may have an inhibitory effect upon the fer-
mentative processes in the liver.

Liberation of the glycogen reserves cannot be the only source
of the increased sugar contents of the blood, for these are
independent of the conditions governing glycogen in the organ-
ism. After the exhaustion of the glycogen reserves and the rapid
excretion of any carbohydrates which may have been present in
the food, the source of the surplus sugar in the blood can only lie
with the albuminoids and fats. Given a diet free from carbo-
hydrates and rich in albumin, it is possible that glycogen would
be formed as an intermediate stage in the conversion of albumin
into sugar. This line of argument is excluded where the diet
consists of fats, yet in this case also the glycosuria and hyper-
glycasmia are considerable.

The defective metabolism of the carbohydrates is the principal
cause of another important symptom of diabetes, namely, the
increase in the amount of the acetone bodies (oxybutyric acid,
aceto-acetic acid, acetone) present in the urine, or, as it is called,
the acidosis. Under normal conditions, the acetone bodies are
formed, in part from the amino acids of the albumin (Embden),
but principally free from oleic acids, as an intermediary product
in the conversion of fat into carbohydrates. Although the cause
is at present unknown, it is an undoubted fact that ketonuria,
that is, excretion of the acetone bodies in the urine, takes place
only when decomposition of the carbohydrates in the economy has
ceased. This explains the occurrence of acetonuria in inanition
and in those pathological conditions in which the nutritional con-
ditions in general, and the assimilation of the carbohydrates in
particular, are very much reduced. In severe diabetes, in addition
to the carbohydrates contained in the diet, the major portion of
the sugar obtained from other sources is also excreted; thus there
is an enormous increase in the formation of acetone substances
and, consequently, ketonuria of a very pronounced character.

The overloading of the blood with oxybutyric acid and aceto-
acetic acid gives rise to acid intoxication, which Naunyn and his
school regard as the cause of diabetic coma. The organism of
carnivora possesses a chemical protective substance in ammonia,
w7hich is formed by the decomposition of the albumin molecule,
and this substance is able to neutralize the superfluous acids. In
consequence of this, the increased production of acids increases
the ammonia in the urine at the expense of the urea. But the
amount of the ammonia is insufficient to combat the continued
formation of acids, and a demand is made upon the fixed alkalis

420 INTERNAL SECRETION

of the tissues ; the amount of the fixed alkalis, calcium, and
magnesia, present in the urine becomes increased (D. Gerhardt
and W. Schlesinger) ; while the alkalescence of the blood and
tissues in very much diminished; and, as a result of the alkaline
reduction, coma supervenes.

This theory of the origin of diabetic coma rests upon a sound
clinical and experimental basis, and to-day is very generally
accepted. The failure of the alkaline therapy, which \vas founded
on this theory, led v. Noorden to conclude that diabetic auto-intoxi-
cation is attributable, not only to the over-production of acids in
general, but also to the specific toxic action of isolated inter-
mediary products (oxybutyric acid and aceto-acetic acid).

Acetonuria is a constant symptom in dogs without pancreas ;
its presence is the more remarkable from the fact that acetone
bodies are not normally present in the urine of these animals,
while it is extremely difficult to obtain ketonuria experimentally.
The clinical picture presented by diabetic coma is by no means
rare in dogs which have lost their pancreas and, in many instances,
it is a terminal feature.

The general metabolism undergoes a fundamental change
after the extirpation of the pancreas. The accumulation of sugar
in the blood w7as formerly regarded as due to imperfect oxidation
of the carbohydrates and a lowering of the processes of oxidation
in general. Falta, Grote, and Staehelin (1907) showed, however,
that in dogs with pancreatic diabetes, the processes of oxidation
are enormously increased, for the metabolism of albumin of such
animals when in the fasting stage may attain to three times the
normal. The decomposition of fat is also very much increased.
These findings suggest a toxogenic decomposition of albumin.

According to Eppinger, Falta, and Rudinger, the increased
oxidation which follows removal of the pancreas is due to the
fact that, owing to suppression of the inhibitory influence nor-
mally exercised by that organ, the activity of the thyroid in
promoting metabolism is allowed to proceed unchecked.

It is certain that, owing to the increased metabolism, there
is a reduction in the amount of the albumin, and that this gives
rise to emaciation. The emaciation is further accounted for by
the permanent caloric deficiency, due to the defective metabolism
of the carbohydrates. The increased demand for, and consump-
tion of, food (polyphagia) does not entirely counteract the
deficiency in the caloric, and does not prevent the rapid emaciation
of the body. Dogs which have lost their pancreas become
extremely emaciated within quite a few weeks, and usually perish
of inanition.

THEORY OF PANCREATIC DIABETES.

Since it was first discovered that diabetes follows extirpation
of the pancreas, this condition has formed the subject of searching

THE INTERNAL SECRETION OF THE PANCREAS 42 1

and laborious investigation, as well as of lively discussion ; never-
theless, no final theory embodying a satisfactory explanation of
its causes has up to the present been forthcoming. We are com-
pelled, therefore, to confine ourselves to a short account of the
theories concerning the condition which have been advanced by
different authors.

v. Mering and Minkowski, the discoverers of pancreatic
diabetes, believed the condition to be the outcome of the cessation
of a specific function of the pancreas, a function which is essential
to the normal employment of sugar by the organism. After con-
sideration of the possible causes, Minkowski concluded that the
pancreas supplies some substance which aids in the decomposition
of sugar within the organism. He believed the cause of diabetes
to lie in a cessation of the internal secretory, or positive, pan-
creatic function, using the term in the sense in which v.
Hansemann employed it.

This conclusion was, however, opposed by de Domenicis,
whose discovery that glycosuria followed extirpation of the
pancreas was almost simultaneous with that of v. Mering and
Minkowski, though he worked independently of them. In his
opinion, glycosuria is not a constant result of pancreasectomy, but
is merely an expression of the serious nutritional disturbances
which are brought about by suppression of the external pancreatic
secretion. Owing to the absence of this external secretion, the
digestion of the nutrient material by the intestine is defective ;
toxins are formed and resorbed, and these disturb the chemistry
of the tissues, and thus give rise to the formation of sugar. In
the course of these earlier researches, de Domenicis discovered
that the intestinal extract of dogs without pancreas produces
glycosuria, though in a slight degree, in normal dogs. In a
recent publication he has asserted that severe, permanent glyco-
suria may be produced by the injection of the duodenal secretion
of dogs without pancreas. It is not to be denied that the external
pancreatic secretion has a certain influence upon the resorption
of nutrient substances in the intestine. Sandmeyer showed that
the administration of pancreatic tissue promotes digestion, and
resorption of nutriment. Similar results were observed by
Lombroso after the introduction of pancreatic juice into the
duodenum. In animals which have lost their pancreas, ho\vever,
this method merely increases the sugar excretion, and where
diabetes is precent in the slighter form it provokes true glycosuria.
The transplantation experiments carried out by Minkowski,
Hedon, and Thiroloix prove beyond any manner of doubt that
diabetes is not dependent upon the external pancreatic secretion.

The possession by the pancreas of an internal secretory
function \vas, however, denied for other reasons. In the case of
the pancreas, as in that of all organs with internal secretion, the
removal of which provokes pathological symptoms, the results of
extirpation were explained by the nervous injuries inseparable

422 INTERNAL SECRETION

from such operation. The brothers Cavazzani, as well as
Thiroloix, endeavoured to explain the results of pancreasectomy
by the injury to the nerves of the pancreas and liver ; their view
was based upon experiments in which extirpation of the solar
plexus, or of the nerves in the neighbourhood of the pancreas, was
followed by glycosuria. The theory of the nervous origin of
pancreatic diabetes has recently been warmly advocated by
Pfliiger. He points out that, in his experiments with frogsr
glycosuria followed, not extirpation of the pancreas only, but also
resection of the duodenum and resection of the mesentery between
the intestine and the pancreas; and that, in spite of the avoidance
of any injury to the pancreas or disturbance of the pancreatic
circulation, this result was constant. Herlitzka obtained similar
results. The experiments in which dogs showed glycosuria after
extirpation of the duodenum are not regarded as conclusive by
Pfliiger, for the reason that the duration of life in such animals is
very short ; but he draws attention to the earlier experiments by
de Renzi and Reale, in which permanent glycosuria lasting until
death was observed in dogs after resection of the duodenum.

That true diabetes follows duodenal extirpation was not con-
firmed, however, by Lauwens, Ehrmann, Rosenberg, and
Minkowski, who ascribe the occasional slight glycosuria which
they observed to nutritional derangement of the pancreas.
Minkowski's experiment with a dog — in which, after transplanta-
tion of the pancreas, the entire duodenum was excised, the animal
remaining free from glycosuria for four weeks, at the end of
which time the pancreas was removed, when severe diabetes made
its appearance — is decisive evidence against the occurrence of
duodenal diabetes.

The sole evidence in favour of the duodenum as a causative
factor in diabetes is supplied by two clinical cases of Zak's, in
which glycosuria followed cauterization of the duodenum ; as well
as by the results of certain experiments carried out by the same
author, in which, after cauterization of the duodenum, sugar was
found to be present in the urine and adrenalin present in the
blood (frog's eye test).

The results of experimental transplantation of the pancreas,
and of the extirpation of the organ when performed in several
sittings, have completely destroyed the theory that pancreatic
diabetes is the result of nervous lesions, Pfliiger suggested that,
in cases where the pancreas is implanted under the skin, a minute
nerve branch may remain intact, and that by this means the
resected nerve fibres mav resume their connection with the nerve
centres; this assumption is, however, almost too chimerical to
need refutation. Pfliiger himself has modified his views to this
extent, that in his latest publication he concedes a certain degree
of internal secretory activity to the pancreas. That this internal
secretion may be influenced by the nerves is readily conceivable.

THE INTERNAL SECRETION OF THE PANCREAS 423

That the pancreas possesses an internal secretory function
must be conceded upon general grounds. But the two-fold
significance attaching to the idea, and especially the earlier idea,
of internal secretion, namely, that of positive production together
\vith negative neutralization, suggests the possibility that the
regular pancreatic function may consist in the destruction of so-
called diabetogenic substances; that, after the extirpation of the
organ, these substances accumulate in the body ; and that they
have a deleterious influence upon the normal metabolism of the
carbohydrates. This is a theory which has been advanced by
several authors (Hedon, in his first publication, Tuckett), and
which seemed to derive support from Gaglio's statement, that
ligature of the thoracic duct prevents glycosuria after pancreasec-
tomy. This latter finding received no confirmation, however,
from later investigators (Lepine, Hedon, Biedl). The views of
Harley and of Vani are based upon de Domenicis's theory;
both authors believe that the suppression of the pancreatic func-
tion gives rise to an auto-intoxication, the essential features of
which are severe nutritional disturbances, glycosuria, and nervous
symptoms being among the manifestations of the latter. Accord-
ing to Vani, this auto-intoxication is due to suppression of the
endocrinal function of the pancreas.

The assumption that pancreatic diabetes is the outcome of an
auto-intoxication never obtained much support. It has since been
entirely abandoned; for the hypothesis that auto-intoxication
occurs as the result of organic suppression becomes more and
more limited in its application, owing to the fact that proof of
the existence of toxic substances has never, as yet, been obtained.
The possibility was recently suggested by Zuelzer that, after
extirpation of the pancreas, harmful substances are retained in the
economy which, under normal circumstances, would be excreted
or destroyed by the agency of that organ. Zuelzer's findings
permit, however, of a different interpretation.

All the known facts concerning pancreatic diabetes, and
especially the profound changes in the metabolism of the carbo-
hydrates to which it gives rise, point unequivocally to suppression
of an internal pancreatic secretion — which, under normal con-
ditions, plays a decisive role in the metabolism of the carbo-
hydrates as the originating cause of the condition.

As evidence against a positive secretory function and forma-
tion of hormones by the pancreas, it is pointed out that the
brilliant results expected of organo-therapy have been conspicu-
ously absent in pancreatic diabetes. From all 'accounts, the
results of the administration of fresh or dried pancreas and the
subcutaneous injection of pancreatic extract, seem to be uncertain
both in clinical pancreatic diabetes and in the parallel condition in
animals deprived of their pancreas. The reports are, however,
exceedingly contradictory. Positive results were observed by

424 INTERNAL SECRETION

Caparelli, Zuelzer, Dohrn and Mayer; negative results by Hedon,
Gley, Lepine, Forschbach, and others. For the reasons given in
the first part of this book, the failure of organo-therapy does not
necessarily disprove the internal secretory activity of the organ
under consideration. It is no more reasonable to expect a restora-
tion, by means of the administration of pancreatic extract, of the
injured metabolic processes of pancreasectomised animals, than
it is to expect the prolongation or the saving of life by means
of suprarenal extract in the case of suprarenalless animals.

In face of the results obtained by a far more practical method,
namely, that of pancreatic transplantation, the uncertain and
contradictory results of organo-therapy lose their value as
evidence against the formation of a pancreatic hormone. Instances
are supplied by Minkowski's experiments, in which portions of
the organ were transplanted together with their vascular stem ; at
a later stage, the vascular stem was severed and the healed in
portions of pancreas sufficed to avert diabetes. Pfliiger's unsuc-
cessful implantation of the pancreas under the skin of the back in
frogs has no bearing upon the question.

That the pancreas does possess an internal secretion has been
absolutely proved by Forschbach's parabiotic experiments. The
extirpation of the pancreas of one parabiotic dog wras followed by
slight glycosuria only. The manner in which the wound healed
and the absence of cachexia further showed that the metabolic
derangements characteristic of diabetes were absent. The
internal secretion of the one pancreas sufficed for the needs of
both animals. After separation, however, the animal which had
been robbed of its pancreas developed diabetes.

Lepine was the first to formulate a theory concerning the
nature and method of action of the internal secretion of the pan-
creas, and this supplied a new outlook in many directions and
offered a stimulus to fresh investigation. But a glance at the
results of nearlv twentv vears shows no discovery which in any

. ~? «' J *

way elucidates the causes in which diabetes takes its rise. Accord-
ing to Lepine's theory, a substance is formed in the pancreas
which is necessary to the normal metabolism of sugar. The sup-
position is that the normal sugar in the blood is broken up and
conveyed to the tissues by a glycolytic ferment, which is formed
in the pancreas, reaches the blood by way of the thoracic duct,
and attaches itself to the white corpuscles. By extirpating the
pancreas, the source of origin of this ferment becomes destroyed.
In both experimental pancreatic diabetes and in the spontaneous
clinical condition, the amount of the glycolytic ferment present in
the blood becomes very much diminished and, as a consequence,
the decomposition of the sugar molecule is less than in normal
blood. Thus an accumulation of sugar takes place in the blood
and the excess is excreted by way of the kidneys.

If we inquire more closely into the fact upon which Lepine

THE INTERNAL SECRETION OF THE PANCREAS 425

based his theory, namely, the diminution in clinical diabetes of
the glycolytic ferment in the blood, we are led to the conclusion
that the theory is untenable. Moreover, the disappearance at
blood-temperature of sugar from the blood is no proof of the
presence of a glycolytic ferment ; for, on the one hand, it is
difficult to ascertain the exact amount of sugar present in a fluid
containing albumin, while, on the other, the alkaline contents are
sufficient to account for an apparent decomposition of sugar
(Bendix and Bickel). It is evident, then, that Lepine's theory
is lacking in foundation.

Lepine himself, however, abandoned his original theory and
assumed the existence in diabetes of a substance inhibitory to
glycolysis. He and Boulud succeeded in isolating crystalline
bodies from the urine of diabetic and other patients, the exhibition
of which produced glyrosuria in healthy animals. This sub-
stance is said to become decomposed by passage through the
vessels of the pancreas. More recently still, Lepine again asserted
his belief in a pancreatic internal secretion with the function of
promoting glycolysis.

Although it was advanced against Lepine's theory that the
normal decomposition of sugar takes place, not in the blood, but
in the tissues, it seemed probable that the site of this decomposi-
tion lay in the pancreas. In such a case, absence of the pancreatic
parenchyma would give rise to insufficiency of the glycolytic
ferment and to consequent hyperglycasmia and glycosuria. This
view was adopted by Baldi and was supported by the results of
experiment. Pal, however, was unable to find a difference be-
tween the sugar contents of the arterial blood and those of the
venous blood in the pancreas. Baldi, on the other hand, found
a smaller amount of sugar in the pancreatic vein than in the
carotid artery ; he also found a diminution in the sugar contents
of blood mixed with dextrose, after it had been allowed to circulate
through the pancreas. Lepine discovered further that watery
pancreatic extracts have a glycolytic action, and that this action
is intensified by the addition of acids. From these findings
Lepine assumed" that a preferment was present in the pancreas,
and that this preferment was converted, by the action of the acids,
into a glycolytic ferment.

The presence of a destructive ferment in the pancreas has
been confirmed by a large number of authors, but it has since
been recognized that, not the pancreas only, but a number of
other organs, such as the spleen, liver, lungs, kidneys, muscles,
£<-., exercise a glycolytic influence. The decomposition of sugar
by the tissues even, was regarded as due to the action of oxidative
ferments distributed through them. According to later experi-
ments by Jacoby, Blumenthal, and N. Sieder, it seems probable,
however, that glycolysis is a process sui generis, the details of
which are still somewhat obscure. Stoklasa and his pupils re-

426 INTERNAL SECRETION

garded glycolysis, in both the animal and vegetable economies,
as typical alcoholic fermentation. Stoklasa found that, in addi-
tion to alcohol and carbonic dioxide, lactic acid, and later acetic
and formic acids, were formed by organic enzymes in the process
of the decomposition of sugar; according to him, the enzymic
processes in the protoplasm are as follows : (i) Primary, the
formation of lactic acid by lactolase ; and (2) the formation by
means of alcoholase, of alcohol and carbonic dioxide. The pro-
cess of decomposition is completed by the enzymes acetolase and
formylase, while combustion into carbonic dioxide and water is
effected by the addition of oxygen.

It is true that the processes by which the oxidation of sugar
is effected within the organism are in need of further investiga-
tion, yet this much may be taken as certain — that glycolysis is
a process carried out by ferments which are present in all the
tissues, and that in all probability the pancreas possesses no
specific function in this respect. As Ehrmann and Wohlge-
muth's very careful experiments have recently shown, the blood
in the pancreatic vein does not contain a larger proportion of
diastatic ferment than that in other vessels.

A specific function in the decomposition of sugar was
ascribed to the pancreas by O. Cohnheim, and simultaneously
with him but quite independently, by R. Hirsch. According to
Cohnheim 's experiments, neither the expressed juice of the
muscles nor that of the pancreas possesses any marked glycolytic
action when employed alone ; a complete destruction of glycogen
is effected only by the combined activity of the two. Cohnheim
assumes that the glycolytic ferment contained in the muscles is
rendered active by an agent present in the pancreas. This
' activator ' is not destroyed by boiling, it is soluble in water
and alcohol and insoluble in ether; hence it does not partake of
the nature of a ferment, but is an internal secretion. Cohnheim
investigated the activity of this a^ent in increasing quantities,
and found that its action was inhibited at excess; he regards
this as analogous to the complement deviation reaction.

Rahel Hirsch found that the glycolytic action of pounded liver
was considerably strengthened by the addition of pancreatic ex-
tract. She assumes that either a preferment or a kinase is sup-
plied by the pancreas, and that this lends to the liver a glycolytic
activity.

Cohnheim's results at first received a measure of confirmation
(by Arnheim and Rosenbaum and by Sehrt, whose experiments,
interesting to relate, were conducted with muscles from mummies
of a period previous to 300 B.C.): but Claus and Embden, who
carried out a series of very careful experiments in v. Noorden's
laboratory with the object of verifying Cohnheim's results, were
unable to find any proof of the existence of a pancreatogenic
activator, and they ascribe the disappearance of the suear to

THE INTERNAL SECRETION OF THE PANCREAS 427

bacterial impurity. Also J. de Meyer and Nanking were both
unable to confirm Cohnheim's results.

Like Lepine, J. de Meyer (1904) believed that the decom-
position of sugar took place in the blood. According to his
experiments, the glycolytic ferment is situated, not in the
muscles, but in the white blood corpuscles, and is rendered active
by the agency of the pancreas. He believes that the pancreas
contains a " sensibilizing substance," which changes a proferment
—which is present in the leucocytes and is secreted by them and
v. hich possesses properties analogous to those of the fibrin ferment
—into the active glycolytic ferment. De Meyer also believes that
the cause of diabetes after extirpation of the pancreas lies in the
suppression of the internal secretion, and that the latter is the
agent which activates the glycolytic ferment. The evidence
against this hypothesis is supplied by the arguments which were
advanced in disproof of Lepine's theory.

Vahlen (1908) was also unable to demonstrate the presence
in the pancreas of a substance which splits up sugar and thus
promotes oxidation. He believes it possible, however, that the
pancreas may contain a substance, at present unknown, which,
without giving rise to direct fermentative decomposition, may
yet bring about an increase in the decomposition of sugar in the
organism. He succeeded in isolating a constituent from the
pancreas which appreciably accelerated the alcoholic fermentation
of sugar, and, in the case of phlorizin animals, effected a con-
siderable reduction in the excretion of sugar. Vahlen did not,
however, carry out conclusive experiments with pancreasec-
tomized animals.

If we review the publications which, beginning with Lepine's
theory, have attempted to explain the nature of pancreatic dia-
betes, it is evident that conclusive proof of the assumption that
the pancreas supplies a substance which promotes glycolysis, or
which is essential to the general metabolism of sugar, is not
forthcoming. The generally accepted view, that pancreatic dia-
betes is a derangement of metabolism which consists in the arrest
of the normal conversion of sugar, has not, as yet, been suffi-
cientlv confirmed, and for this reason, has little positive value.

The older hypothesis, that diabetes is the expression of an
increased formation of sugar, has recently been revived; it is
reinforced by certain new arguments and has received a large
measure of support. This tendency marks a return to the teach-
ing of Chauveau and Kaufmann (1893) which, at the time of its
inception, found few supporters.

The central point round which the process of the metabolism
of the carbohydrates revolves, is what Claude Bernard described
as the " gly co genie animate"; the process, that is, by which
glycogen accumulates and sugar is formed in the liver. From
the carbohydrates derived from the nutriment, glvcogen is formed

428 INTERNAL SECRETION

in the liver and accumulates there as reserve material. It is
probable that, when the supply of carbohydrates is deficient, the
formation of glycogen from albumin also takes place in the liver ;
and here, also, the conversion of glycogen into the form in which
it is used by the tissues, namely, grape-sugar, takes place. The
sugar is withdrawn by the organs from the blood and is in part
employed directly in the performance of function ; in part, and
in the muscles more particularly, it is converted into glycogen.
The process of converting dextrose into a colloid polysaccharide,
of condensing the glycogen, and of again converting it into sugar,
is the common reversible function of the cells.

The sugar contents of the blood are dependent upon the
amount of sugar formed in the liver. According to Chauveau
and Kaufmann, this process is regulated and controlled by the
nervous system. These authors believe that two nervous centres
exist, one in the medulla oblongata and one in the cervical spinal
cord, and that by means of the centrifugal nerves contained in
the sympathetic, these regulate the formation of sugar, one centre
exercising an inhibitory, the other a direct stimulatory influence
upon the sugar production. According to the original theory of
these authors, the nervous impulses are first conveyed to the pan-
creas, whence they pass by way of the nerves to the liver, and
there bring about changes in the sugar production. Taking into
account the many facts which point to a chemical correlation,
these authors modified their view to this extent, that they ascribed
to the pancreas an internal secretion influencing the liver, which
was conveyed to the liver by the agency of the blood-stream.
The production of the secretion they believed to be under the
control of the nervous system.

Regarded in the light of our present knowledge, the theory
of Chauveau and Kaufmann signifies that the influence of the
internal secretion of the pancreas is exercised directly upon the
liver in part only; its main influence is directed to the nerve
centres which control the sugar production, the effect upon the
stimulatory centre being inhibitory and the effect upon the in-
hibitory centre stimulatory. In this way, a two-fold hindrance
to the formation of sugar in the liver is effected by the pancreas
with the aid of the nervous system. The suppression of the in-
ternal secretion of the pancreas not only abolishes inhibition, but
it also relieves the check upon stimulation, and, in consequence,
a pronounced glycosuria make its appearance. The suppression
of inhibition appears, however, to be the decisive factor; for
Hedon and Kaufmann discovered that the hyperglycaemia, or
rather the glycosuria, of pancreatic diabetes is by no means
maximal and may be increased by puncture of the floor of the
fourth ventricle, in other words, by irritation of the stimulatory
centre. According to this theory, then, pancreatic diabetes con-
sists in an increase in the sugar formation brought about by a

THE INTERNAL SECRETION OF THE PANCREAS 429

disturbance somewhere in the functional chain, that is to say, in
either the central nervous system, the pancreas, or the liver.

A similar view was expressed by Thiroloix and, more re-
cently, by Pfliiger. These authors assume that the sugar con-
tents of the blood are dependent upon two opposing factors, both
of which are under the control of the central nervous system.
Of these two factors, one is the mechanism by which sugar is
formed in the liver, which is governed by the centre in the
medulla oblongata. The other factor, antagonistic to the first,
is supplied by the so-called anti-diabetic activity, which limits
the production of sugar ; it is situated in the pancreas and is also
under the control of the nervous system. Thiroloix assumes that
the inhibitory action of the pancreas is performed by the agency
of an internal secretion which is regulated by the nervous sys-
tem ; Pfluger, on the other hand, believes that its anti-diabetic
property is supplied to the pancreas by nerves which originate
in the duodenum. This view is supported by Herlitzka. But
Pfluger concedes that the glandular substance of the pancreas may
play a part in Sandmayer's diabetes; he suggests that the
epithelial cells may possibly supply an anti-diabetic ferment to
the blood-stream.

It is evident from these theories concerning the nature of
pancreatic diabetes, that the conception of the pancreatic function
as an inhibition of the formation of sugar, lies at the root of all
the later teaching. Further information concerning the field of
activity of the pancreatic hormone, hence a new point of view
in regard to pancreatic diabetes, has recently been supplied by
the discovery of the relationship between the metabolism of the
carbohydrates and the activity of the other internal secretory

organs.

Particularly important was the discovery and analysis of
adrenalin glycosuria, for it showed the enormous influence of the
suprarenal, or rather of the adrenal system, upon the sugar
economy of the organism. Further, we know that adrenalin, by
mobilizing the reserve glycogen and thus promoting the forma-
tion of sugar from other material, raises the sugar contents of
the blood. The antagonism between the activity of adrenalin
and that of the pancreatic hormone is chiefly symptomatic in its
expression. The action of adrenalin is modified in certain direc-
tions by the internal secretion of the pancreas. In Zuelzer's
experiments, the effect of pancreatic extract in inhibiting adrenalin
glycosuria might be explained by the assumption that the excess
of sugar in the blood undergoes combustion by the agency of
the pancreatic hormone introduced into the economy. Zuelzer's
results permit, however, of another explanation. It may be that
the antagonistic effect of the two substances is the outcome of
their antagonistic influence upon the same physiological site; in
other words, the activity of an apparatus may be inhibited by

43° INTERNAL SECRETION

the pancreas and stimulated by the adrenal system. What we
know concerning the site of the activity of adrenalin suggests
that the pancreatic hormone has an inhibitory action upon the
nervous apparatus which regulates the formation of sugar. Lb'wi's
reaction also points to an inhibitory action, on the part of thi.'
pancreas, upon organs with sympathetic innervation.

The investigations of Eppinger, Falta and Rudinger, to
which frequent reference has been made, show that a certain in-
fluence is exercised by the thyroid apparatus upon the metabolism
of the carbohydrates, and that this influence is apparently brought
into play by the agency of the pancreas. The results of their
experiments seem to show that, while the activity of the thyroid
is opposed to the internal secretory activity of the pancreas, that
of the parathyroids is favourable to it. The assumption is that
the thyroid hormone stimulates the function of the vegetative
nervous system ; and that the pancreatic hormone affects that
function in the opposite sense.

From the data which have here been set forth, we are justified
in concluding that the pancreas, by means of its internal secretion,
inhibits the formation of sugar in the liver, and that this inhibition
is effected through the agency of certain nervous apparatuses.
Suppression of pancreatic activity abolishes the normal check
upon the formation of sugar, in consequence of which the glyco-
gen present in the organism is released; that is to say, the
glycogen derived from the carbohydrates in the food or, in de-
fault of these, from other material, is converted into glucose; and
as a consequence hyperglycasmia and glycosuria follow. The
pancreatic hormone appears to affect the same peripheral nervous
apparatus as adrenalin ; for, as Kaufmann showed, resection of
the splanchnic nerve is followed by pancreatic diabetes in exactly
the same manner as adrenalin glycosuria.

Attempts to isolate the pancreatic hormone have, up to now,
been fruitless. Nothing definite is known concerning its chemical
nature and we are forced to fall back upon hypothesis. The most
probable assumption is, that the substance is of the nature of a
ferment, and that it influences that process by which the decom-
position and new formation of glycogen take place in the liver.
The fact that, after extirpation of the pancreas, deposition of
glycogen in the liver may be effected by the administration of
levulose, suggests that suppression of the pancreatic function
does not prevent the formation of glycogen, but that it permits
the unchecked splitting up of this substance. The normal pan-
creatic hormone is a substance which inhibits the cliastatic con-
version of glycogen into sugar.

Many experiments have been undertaken with the object of
discovering the path along which the pancreatic hormone travels,
and the results were described by me in 1898. I discovered that
in the large majority of instances (66 to 86 per cent.), ligature

THE INTERNAL SECRETION OF THE PANCREAS 431

of the thoracic duct at the neck, or the diversion of the chyle
by means of a fistula, was followed by permanent glycosuria,
which was unaffected by either the fasting state or by feeding
with carbohydrates. The fact that the thoracic duct is not the
only channel by which the chyle is carried off, explains the
negative cases.

The results of these experiments led me to conclude that a
substance is contained in the chyle which influences the meta-
bolism of sugar in the organism. I resumed this line of in-
vestigation in association with Offer in 1907, and we discovered
that the instillation of adrenalin into the conjunctiva produces a
mydriasis, which, according to Lowi, is characteristic of pancreatic
diabetes. We discovered, further, that the chyle in the thoracic
duct possesses an inhibitory action in regard to adrenalin, and
that adrenalin glycosuria may be reduced, or even abolished, by
the subcutaneous injection of chyle, as well as by intensifying
the normal lymph secretion by means of lymphagogue substances.
It would appear from this that the substance contained in the
chyle which influences the metabolism of the carbohydrates, is
identical \vith the pancreatic hormone. The pancreatic substance
which possesses the property of inhibiting the formation of sugar,
reaches the circulation by way of the lymphatics.

Such being the case, then, it is to be expected that the in-
jection of chyle from the thoracic duct of normal dogs into the
veins of dogs without pancreas, will be followed by a diminution
of the glycosuria. As a matter of fact, positive results were
obtained in one case by Lepine, though Falta's results were
negative.

In my later experiments, the action of the chyle in reducing
glycosuria after pancreasectomy, w~as very clearly shown, the
best results being obtained in cases where, owing to the presence
of small remnants of pancreatic tissue in situ, the derangement of
metabolism had not attained the maximal. On the days upon
which large quantities (200 to 500 c.cm.) of chyle from healthy
dogs were injected subcutaneously, the animals showed a diminu-
tion of the quotient D :N to 1.5 or 1.2; while upon days when
no lymph was given the quotient reached 1.8, and later even 2.1.
It should be noted in passing that these results suggest the
therapeutic employment of chyle, or of lymphagogue substances,
in those cases of clinical diabetes which suggest pancreatic in-
adequacy, but not pancreatic suppression.

The analogy between the symptomatology of true clinical
diabetes and the experimental pancreatic form is so far-reaching,
that it is not surprising that \ve frequently encounter the opinion
that the metabolic disturbances of clinical diabetes are also pan-
creatogenic in their origin and are the expression of diminished
or internal secretory activity on the part of the pancreas or its
suppression. It should be borne in mind, however, that a

432 INTERNAL SECRETION

pathological alteration may take place at any point in the com-
plicated mechanism by which the sugar economy is regulated ;
and that a pathological condition of any one of the internal
secretory organs associated with the metabolism of the carbo-
hydrates, and consequent disturbance of their interrelationships,
may give rise to slight glycosuria or even to permanent diabetes.
But in these cases a relative insufficiency of the pancreas must
also be assumed.

Such being the state of affairs, the question as to whether
anatomically demonstrable changes take place in the pancreas in
clinical diabetes, acquires an increased significance. Lesions of
the pancreas in clinical diabetes were described before experi-
mental pancreatic diabetes had been discovered, and the patho-
genetic significance of these lesions was suggested by several
authors. The comparative scarcity of instances in which diabetes
is accompanied by serious anatomical lesions of the pancreas, and
the enormous preponderance of cases in which no anatomical
pancreatic lesion is demonstrable, together with the doctrine that
serious disease of the pancreas may be unaccompanied by diabetes,
are weighty arguments against the pancreas as a constant factor
in the pathogenesis of clinical diabetes.

The changes which are observed in the pancreas in diabetes
have recently become a subject of increased interest to anatomico-
pathologists. The morphological findings throw some light upon
the question as to which tissue element it is which elaborates the
pancreatic internal secretion. These, however, will be discussed
later. All we need say here is, that recent investigations show
that pancreatic lesions of the most varied description, chronic
inflammatory and degenerative changes, atrophy and neoplasms,
are observed in a comparatively large proportion (according to
v. Hansemann about 70 per cent.) of diabetic patients. It is
true that these are ahvays cases in which the disease is present
in its severest form ; information concerning the slighter aspect
of the disease, though its pathogenesis is far more interesting, is
very scanty. Negative anatomical findings in the pancreas can-
not be regarded as evidence against the pathogenetic significance
of this organ : the disturbance of the metabolism of the carbo-
hydrates may originate primarily in other links of the functional
chain, or the chemistry of the pancreas may be altered without
demonstrable morphological changes.

THE INTERNAL SECRETORY TISSUE ELEMENTS OF

THE PANCREAS.

As in the case of all glands possessing an external secretion,
it was at first assumed that the glandular cells of the pancreas
were bipolar, that is to say, that both the internal and external
secretory functions wTere performed by the same epithelial cells.

THE INTERNAL SECRETION OF THE PANCREAS 433

But in addition to the acini and their excretory ducts, it was known
from Langerhans's description (1869), that the pancreas contained
irregularly distributed cell groups, which were later named, after
their discoverer, the islands of Langerhans. The structure of
these elements suggested that they might possess an internal
secretory function.

The islands are composed of polygonal cells with ill-defined
boundaries, containing large round nuclei and comparatively
small and sparsely distributed granules. They are remarkably
well furnished with capillary blood-vessels which are intimately
associated with the cells, and they are surrounded with a delicate
connective tissue sheath (Flint, Laguesse).

A question of paramount importance in the determination
of function, namely, whether these islands contain lumina com-
municating with the excretory ducts of the pancreas, is not as yet
definitely decided. Lumina within the insular area have been
described by Gianelli and Giacomini in reptiles, by Dale in toads,
and by Vincent and Thompson in Kinosternon and in Amia
call) a. According to both Lewaschew and Mankowski, the islands
in mammals may be injected from the excretory ducts, though
this is denied by other authors (v. Ebner, Dogiel, Rossi).
Laguesse found that, in the snake, the islands contained lumina
which had an unbroken continuity with those of the acini. Well-
developed excretory ducts have also been occasionally observed
in the interior of the islands of the human pancreas. In his
investigation of the regenerative processes which take place in
portions of pancreatic tissue implanted in the spleen, Kyrle ob-
served proliferation of the epithelial cells of the excretory ducts,
in consequence of which the acini and the islands were formed
separately and excretory ducts were present in the islands when
fully developed. The embryological investigations of Weichsel-
baum and Kyrle led them to conclude that the islands of Langer-
hans are derived from the epithelium of the excretory ducts, and
that their formation takes place, not during foetal, but during the
early part of post-fcetal life.

The islands of Langerhans were regarded by the older scien-
tists, as well as many later authors, as lymph follicles to which
no particular functional significance was attaching. A more
exact knowledge of their genesis showed, however, that the cells
of the islands are of epithelial origin. By some authors (Gian-
nelli, Oppel) they are even regarded as the rudimentary remains
of an atavistic gland. Many scientists held the view that, though
the acini and the islands differ structurally from one another,
they are not functionally differentiated. Harris and Gow, Gibbes,
Gianelli and Giacomini assume that the islands play a part in
the production of the external pancreatic secretion, especially of
the diastatic ferment. Jarotsky observed signs of increased secre-
tory activity on the part of the cells of the islands after the ad-

28

434 INTERNAL SECRETION

ministration of carbohydrates in large quantities. According to
Lewaschew and Pischinger, the islands are really acini in a state
of functional exhaustion which, after a period of rest, resume
their secretory activity.

Laguesse (1893) was the first to adopt the view that the
internal secretion is elaborated by the cells of the islands of
Langerhans, the islands thus possessing an endocrinal function
which is of importance in the metabolism of the carbohydrates,
while the external digestive secretion is supplied by the acini.
The supposition is that a continuous transformation of acini into
islands, and vice versa, takes place, by which the two secretory
processes are carried out. Laguesse's theory principally depends
upon the presence of transition forms ; these he described with
extreme minuteness and his findings are confirmed by a large
number of observers (Mankowski, Gentes, Perdrigeat and Tri~
boudeau, Dale, Vincent and Thompson, Marrassini). Changes
in the number and size of the islands, and transition forms be-
tween acini and islands and vice versa, have been obtained by
certain experimental measures, such as the injection of secret! ne,
pilocarpine and phlorizin ; fasting; and over-feeding. But these
transformatory changes of acini into islands and vice versa have
been questioned by several authors, first by Vassale, then by
Diamare, Stangl, Rennie, and others, and more recently by
Weichselbaum and Kyrle.

In his critical survey, Lombroso arrived at the conclusion
that the morphological findings, obtained from experimental and
comparative anatomical investigation, were insufficient to justify
the theory of mutual transformation. According to Lombroso,
mutual transformation does not prove a sharp differentiation of
the internal and external secretions as functions of the two pan-
creatic tissues, acini and islands ; but it confirms his view that
both functions of the pancreas are undertaken by both tissues.

There are numerous authors, however (Kohn, Massari, Dia-
mare, Rennie, Opie, &c.) who deny Laguesse's theory of the
intimate morphological relationship between the acini and the
islands of Langerhans; who regard the latter as independent
tissue formations, but believe them to be ductless glands — epithe-
lial organs analogous to the parathyroids, the suprarenal cortex,
and the anterior lobe of the hypophysis — and whose property it
is to elaborate the pancreatic hormone.

Within the last fifteen years, clinical diabetes has provided a
certain amount of anatomico-pathological material, which has a
considerable bearing upon the internal secretory elements in the
pancreas.

The numerous investigations which have been made have
led, however, to very divergent results. The findings which they
observed led a number of investigators to adopt the insular theory
(Opie, Ssobolew, Herzog, Weichselbaum and Stangl, Sauerbeck,

THE INTERNAL SECRETION OF THE PANCREAS 435

Diamare, Visentini, &c.) ; while others (Hansemann, Gutmann,
Karakascheff, Herxheimer, Schmidt) ascribed the internal secre-
tory function to the acini. Others, again (Reitmann), adopted
the view that both pancreatic tissues are concerned in the etiology
of diabetes. According to Lombroso, the anatomico-pathological
findings are distinct evidence against the assumption that the
internal secretion of the pancreas is the function of one tissue
formation only, whether of the acini or of the islands of Langer-
hans.

Experiments undertaken with the object of ascertaining the
structural changes in the pancreas, which follow the exhibition
of substances believed to have an action in increasing or diminish
ing the hormone production, have also yielded contradictory
results. Ssobolew and Lepine found that, in the dog and the
guinea-pig, the intravenous injection of grape-sugar was followed
by a reduction in the size of the islands and by a diminution in
the number of granules in the island cells; while Diamare, on
the contrary, observed a remarkable profusion of granules in the
island cells of a Teleostean (Motella tricirrata), of frogs, and of
guinea-pigs. Marrassini describes hypertrophy of the islands of
Langerhans in rabbits, where prolonged administration of grape-
sugar was accompanied by continued glycosuria, and this hyper-
trophy was of so intense a nature that the neighbouring acini
were flattened, deformed and atrophied. The island cells con-
tained an enormous number of fine fuchsinophile granules. Re-
ports of the effects produced by the injection of phlorizin and
adrenalin upon the structure of the pancreas are equally con-
tradictory. After the repeated injection of phlorizin into dogs,
Ghedini observed a marked reduction in the volume of the pan-
creas, due to degenerative atrophy and necrosis of the acinous
tissue, no cell changes taking place in the islands. Lazarus
described marked hyperplasia and hypertrophy of the islands of
Langerhans in guinea-pigs after prolonged treatment with phlori-
zin and adrenalin, and here also the acinous tissue was unchanged.
After the administration of adrenalin, Herter and Wakeman found
necrosed foci in the pancreas and changes in the cells of the
islands of Langerhans; in chronic poisoning with arsenic, mor-
phia, and phosphorus, Carnot and Amet found hyperplasia, to-
gether with frequent fatty degeneration, of the islands. Lepine
and Vigliani observed absolutely normal histological conditions
after the exhibition of phlorizin ; and Tiberti reports similar
findings after the injection of phlorizin and adrenalin, as the
result of his very careful experiments with guinea-pigs and
rabbits. The latter author, like Heiberg, believes that the hyper-
trophied islands which Lazarus described are normal formations
in the pancreas of guinea-pigs.

A second experimental method of physiological differentiation
between the two tissues of the pancreas seemed to promise better

436 INTERNAL SECRETION

results. The method was based upon the known fact that ligature
of the excretory ducts of the pancreas, and the injection of foreign
substances into them, suppresses the external secretion and may
lead to more or less pronounced atrophy of those portions of the
gland by which the external secretion is elaborated. It was soon
found that glycosuria did not, as a rule, make its appearance in
experiments of this sort, and that the tissue of the islands of
Langerhans remained in comparatively good condition. After
ligature of the excretory ducts of the pancreas of guinea-pigs,
Schultze observed disappearance of the acini, with persistence of
the islands and absence of glycosuria ; similar findings were
described by Ssobolew in rabbits, dogs and cats ; and by Laguesse
in rabbits. Sauerbeck observed transient glycosuria in rabbits
after ligature of the pancreatic duct ; but the incidence, course
and intensity of the glycosuria was said to run parallel with
changes in the islands of Langerhans. Tiberti describes similar
findings, while different results were obtained by other observers
(Hansemann, Mankowski) who employed the same method.

From the results of his own experiments and those of other
scientists, Lombroso concluded that, after ligature of the pan-
creatic duct of rabbits, changes take place in the acini, but that
the acini do not entirely disappear, and that the islands also
undergo modification, though more slowly. Glycosuria is either
absent, or occurs in isolated instances only. He ascribes a par-
ticular significance to the fact that the resorption of nutriment
remains unchanged.

In pigeons, ligature of the excretory ducts produced changes
in the pancreas similar to those observed in rabbits ; but though
glycosuria was not present, the birds died after two to three
weeks, in consequence of the derangement of the absorption of
food. It must be remembered, however, that the absence of
glycosuria in birds is no proof of the continuance of the hormone
production ; the diabetic disturbance of metabolism which follows
extirpation of the pancreas is expressed only by hyperglycsemia,
though Lombroso failed to take this fact into consideration.

The numerous and very careful experiments which have been
carried out with the pancreas of dogs all show that, not only do
the acini not disappear after ligature or resection of the excretory
ducts, but that they do not undergo appreciable change. Lom-
broso found perfectly preserved normal acini fourteen days after
operation. This finding has been explained by the presence of
supernumerary excretory ducts, by which the passage of secretion
from the gland was facilitated (Hess and Sinn). Lombroso re-
jects this explanation, however, and he emphasizes the fact that
well-developed acini were present in .implanted portions of
pancreas which sufficed to prevent the occurrence of diabetes.

A consideration of all the available experimental material
led Lombroso to conclude that both the epithelial tissues of the

THE INTERNAL SECRETION OF THE PANCREAS 437

pancreas, namely, the acini and the islands of Langerhans, are
concerned in the internal secretory function of that gland.

According to this author, the internal secretion of the pan-
creas not only influences the sugar economy, but also plays a
part in the absorption of nutrient material. Previous to Lom-
broso, de Domenicis, as has been shown, believed the or/gin of
pancreatic diabetes to lie in the disturbance of absorption which
he observed after pancreasectomy. Abelmann's experiments
(1890) showed that the decomposition of fat is, in a quantitative
sense, only slightly affected by total extirpation of the pancreas,
but that the absorption of fat entirely ceases after this operation.
Fat absorption persists in a greater or less degree after ligf'ure
of the excretory ducts, as well as after partial extirpation and
transplantation of a portion of pancreatic tissue to a position
where it is in communication with the intestine. The absorption
of fat in the latter instance has been explained by the assumption
that the external secretion of the pancreas becomes re-absorbed
and reaches the blood-stream, whence it is conveyed to the in-
testinal mucosa.

Lombroso found that the capacity for the absorption of fat
was diminished by extirpation of the pancreas. The fasces of
animals without pancreas contain precisely the same amount of
fat as their food. If oleic acid is given, a portion becomes
absorbed and this is replaced by fat having a higher melting point.
After ligature of the excretory ducts, or where the pancreas has
ceased to discharge secretion into the intestine, the absorption
of fat amounts to about 80 per cent, of the amount of fat given.
This absorption is not due to the agency of an external secretion,
conveyed by some means into the intestine, but must be ascribed
to an internal pancreatic secretion, the activity of which is neces-
sary to the metabolism both of the fat in the tissues and that
introduced from the exterior.

It has been advanced against this conclusion that, in Lom-
broso's experiments, the measures taken to prevent the external
pancreatic secretion from reaching the intestine were insufficient.
Hess and Sinn suggest supernumerary excretory ducts ; Visenti
points to the possibilities of the ligatured ducts again becoming
passable, and of the formation of new ducts. Burckhardt, in one
instance, obtained contradictory results and he believes that, in
the case of animals with pancreatic fistula, the pancreatic secre-
tion may be returned to the intestine by the animals licking
themselves.

Lombroso's results have, however, been confirmed by Zunz
and Mayer, and more recently, by R. Fleckseder in a series of
extremely careful experiments carried out by methods designed
to obviate all sources of error. Fleckseder's conclusion is that
the absorptive power of the intestinal mucosa is chiefly dependent
upon the internal pancreatic secretion. There is, however, com-

438 INTERNAL SECRETION

pensation for the suppression of this secretion. Where the
function of the pancreas has gradually become completely sup-
pressed, the consequent severe diabetes may be unaccompanied
by derangement of absorption, and the assimilation of nutriment
may at this stage be better than where an active pancreatic fistula
is present.

Lombroso, also, believes the internal secretory function to
be the property of both pancreatic tissue formations.

THE INTERNAL SECRETION OF THE GASTRIC

AND INTESTINAL MUCOSA.

Claude Bernard's observation, which later formed the subject
of considerable investigation, first showed that the secretion of
pancreatic fluid is dependent upon the filling of the duodenum
and that it reaches its maximum when the ingesta have passed
from the stomach into the duodenum. From the results of
numerous experiments, admirable both in conception and tech-
nique, Pawlow came to the conclusion that the mechanism by
which the pancreatic secretion is elaborated is by a reflex process
on the part of the nervous system ; the impulse proceeding from
the gastric mucosa is carried by centripetal vagal fibres to a
centre in the medulla oblongata, and from this centre stimuli are
sent out which, travelling by way of the centrifugal vagus or
splanchnic nerve, cause the pancreatic gland to secrete.

Under Pawlow's direction, Popielski next showed that, if
acids are introduced into the duodenum, the pancreatic secretion
appears after resection of both the vagus and the splanchnic
nerves, after extirpation of the solar plexus, and even after
destruction of the spinal cord. Similar findings were observed
by Wertheim and Lepage and they, as well as Popielski, con-
cluded that the results were the outcome of a local peripheral
reflex.

Bayliss and Starling, however, discovered that the pancreatic
secretion is elaborated if acids are introduced into the lumen of
a coil of the duodenum which has been freed from all nervous
connections. This result showed very clearly that the release
of the pancreatic secretion depends upon a chemical substance,
and that chemical stimuli are conveyed to the pancreas by way
of the blood-stream. According to Wertheim and Lepage, the
direct introduction of acids into the blood-stream has no effect
upon the pancreatic secretion ; hence the only possible solution
was that, by the aid of acids, a substance was formed in the
mucous membrane of the intestine.

Bayliss and Starling obtained an extract by treating mucosa
scraped from the upper part of the small intestine with hydrochloric
acid, and this extract, when injected into the veins, provoked pro-

SECRETION OF THE GASTRIC AND INTESTINAL MUCOSA 439

fuse pancreatic secretion. To this active substance, which is not
a ferment because it withstands boiling and is soluble in alcohol,
they gave the name of " secretin." Bayliss and Starling
assumed that, by the hydrolytic action of the acids, secretin is
formed from " prosecretin," a precursor present in the cells
of the duodenal mucous membrane. The secretin formed in the
mucosa reaches the pancreas by way of the blood-stream ; for
Enriquez and Hallion succeeded in proving that, if the blood-
stream is conveyed from the vessels of a dog A into those of a
dog B, pancreatic secretion will make its appearance in B after
the injection of acid into the small intestine of A. These experi-
ments proved the existence of an internal secretion of the intestinal
mucosa, and they showed at the same time that there is a correla-
tion of function between the intestinal mucosa and the pancreas,
which is effected by the agency of hormones.

Bayliss and Starling's discovery has been subjected to
repeated tests, and the actual findings have received almost general
confirmation. The specific activity and the intimate chemical
nature of secretin have formed the subjects of a controversy, into
the details of \\hich we cannot enter here. Suffice it to say that
Popielski believes secretin to be identical with peptone, a product
of the decomposition of albumin ; while according to v. Fiirth
and Schwarz, secretin is not a homogeneous substance, but is a
mixture of several substances possessing the property of exciting
secretion, of which the most important is cholin.

A far greater interest is attaching to the manner in which this
discovery affects our conception of the mechanism by which the
external secretion of the pancreas is effected. Is the secretory
process entirely due to the agency of a hormone, as Bayliss and
Starling are inclined to believe ; or are the nervous reflexes, which
Pawlow's experiments revealed, also brought into play? This
question remains for the present unanswered. Several authors
(Fleig) assume, and apparently with justice, that two simultaneous
processes are concerned in the passage of the chyme into the
duodenum. Of these, one is the formation of secretin, which
induces, by chemical means, secretion of the pancreas; the other
is provided by the acid contents of the duodenum, which stimulate
the nerve-terminals, and the reflex action of these also leads to
pancreatic secretion.

According to Bayliss and Starling, the secretin formed in
the duodenal mucosa stimulates the secretion of bile and increases
its quantity.

With regard to the secretion of the intestinal juice, the succus
entericus, opinions are divided. The intestinal juice serves to
activate the proteolytic property of the pancreatic secretion, for
the trypsinogen contained in the latter is converted into the active
trypsin ferment by the agency of the endokinase in the intestinal
juice. The elaboration of the intestinal secretion is effected,

440 INTERNAL SECRETION

according to Pawlow, first, by the mechanical stretching of the
intestinal canal, and second, by. the presence of the pancreatic
juice. Bayliss and Starling believe it probable that the flow of
intestinal juice from the glands in the intestinal wall is provoked
by the chemical stimulus supplied by the pancreatic secretion ;
while Delezenne and Frouin hold the view that the discharge of
all the three secretions which are active in the upper part of the
small intestine, namely, the bile, the pancreatic fluid, and the
intestinal fluid, is effected by the same mechanism, namely, the
elaboration of secretin in the intestinal mucosa after the passage
into the intestine of the acid contents of the stomach.

According to Frouin, the elaboration of secretion by the
intestine may be increased by the intravenous injection of intes-
tinal fluid.

Pawlow's careful experiments have shown that the secretion
of the gastric fluid is largely the outcome of nervous impulses.
But two to three hours after food the gastric secretion becomes
increased; according to Pawlow, this increase is maintained after
resection of the vagi, and it appears to be dependent upon the
nature of the food.

Edkins next discovered that an extract is obtainable from
the pyloric mucous membrane by extraction with hydrochloric
acid, as well as by rubbing down with dextrose, maltose, or
peptone. When injected into the veins in repeated small doses,
this extract causes secretion of the gastric juice. According to
Edkins, the active substance, gastrin, is not destroyed by boiling
and appears to belong to the same class of bodies as pancreatic
secretin. This " gastric secretin," as Starling calls it, is present
only in the pyloric mucosa, extracts of the mucous membrane of
the fundus being inactive.

THE INTERNAL SECRETION OF THE KIDNEY.

The assumption of an internal secretory function on the part
of the kidney is among the earliest dicta of the Brown-Sequard
doctrine. As early as 1869, Brown-Sequard suggested that
uraemia either was not, or was not exclusively, the result of the
accumulation of urinary constituents in the blood, but was due to
suppression of the internal secretion of the kidney. Following
his first experiments with testicular extract, Brown-Sequard with
d'Arsonval endeavoured to obtain practical proof of his assump-
tion. A large number of clinical observations of anuria of long
duration, in which uraBmic symptoms were almost entirely absent,
led him to conclude that the occurrence of uraemia does not depend
solely upon the presence of urinary constituents in the blood, and
that it is not the result of stimuli supplied by the diseased
kidney; but that it is principally due to changes in the chemical
composition of the blood, brought about by suppression of the

THE INTERNAL SECRETION OF THE KIDNEY 44!

renal internal secretion. Experiment showed that animals die
much more rapidly after the removal of both kidneys than after
ligature of both ureters, in spite of the fact that the retention of
urinary constituents is the same in both cases, and this fact seems
to bear a similar interpretation. Brown-Se"quard and d'ArsonVal
further showed that if renal extract obtained from guinea-pigs and
rabbits is injected into the veins of nephrectomized animals of the
same species, symptoms of uraemia will appear later, and will be
less intense in these animals than in control animals which have
not received similar treatment. In animals treated with renal
expressed juice, the duration of life was as long, or longer, than
in animals with ligature of both ureters.

Lepine's observations have an important bearing upon the
passage of substances from the kidneys into the blood. He
found that the ligature of both ureters of rabbits produced a fall
in temperature, vomiting, and diarrhoea, terminating in death.
An entirely different symptom-complex resulted, however, when
the ureters were connected by means of cannulae with a vessel
containing normal saline solution, the pressure in the vessel being
higher than that in the ureter. This procedure produced, not a
fall, but a rise in temperature, dyspnoea and convulsions. Accord-
ing to Lepine, the filtrate of a kidney rubbed down in water, when
introduced into the blood, also produces a rise in temperature,
dyspnoea, and stronger movement ; and Lepine believes that
thermogenic and dyspnogenic constituents are present in renal
substance.

E. Meyer, a pupil of Brown-Sequard's, next discovered that
the blood of ura?mic animals is inactive in normal animals, but
that, in nephrectomized animals, it produces a remarkable
dyspnceic slowing of respiration. In a second series of investi-
gations, Neyer studied the periodic respiration, resembling the
Cheyne-Stockes type, of urasmic dogs ; he found that this remark-
able ura^mic symptom is reduced by the injection of renal
expressed juice, as well as by the injection of normal defibrinated
blood, the effect being so marked that for a short time the respira-
tion becomes normal. Blood from the renal veins is said to
produce particularly good and well-marked results.

These reports of prolonged life and improved ura?mic sym-
ptoms in nephrectomized animals after the administration of renal
extract or blood from the renal veins, have been tested by many
investigators (E. Vanni, Manzini, Vitzou, Ajello, and Parascan-
dalo, Mori, Bozzolo, Gilbert and Carnot, Spineanu, Maragliano,
Chatin and Guinard, Fiori), but with very conflicting results. A
definite pronouncement is hardly possible, however, seeing that
the duration of life in nephrectomized animals is, in any case,
very variable. As I know from my own experience, dogs and
rabbits sometimes live five to six days after the removal of their
kidneys, while other animals of the same species, operated upon

442 INTERNAL SECRETION

in a manner precisely similar, perish at the end of thirty-six hours.
In the second place, the appearance and course of the clinical
symptoms of uraemia is not, in such animals as these, a reliable
criterion of the condition. Many animals from which the kidneys
have been removed show no symptoms for two, three, or four
days, and then die, either suddenly or within a few hours, without
having shown any characteristic signs. In the case of other
animals, there is repeated vomiting and dyspnoea as early as the
first day after operation ; recovery is frequent, or there may be a
condition of chronic uraemia lasting for several days. Given
such conditions, I hardly think it possible to estimate the results
of any therapeutic measures at their proper value. Moreover, to
base a so-called physiological treatment of uraemia upon the
results of such experiments, and to apply this treatment, by the
exhibition of renal extract, to clinical nephritis, in my opinion,
shows a grave lack of judgment.

Attempts have been made to prove the elaboration of an
internal secretion by the kidneys by means of renal extract. Oliver
and Schafer proved that the kidney belongs to that class of organs
the extract of which, when injected into the veins, invariably
produces an increase in arterial tension. Tigerstedt and Berg-
man n next showed (1898) that a substance is obtainable with
cold water from the fresh kidney which, when injected into the
veins of rabbits, produces within a comparatively short time a
more or less marked rise in blood-pressure. This active substance,
to which the name of " renin " was given by the discoverers, is
derived from the cortex, and, in very small quantities, from the
medulla ; it is not dialyzable, it is soluble in water, in dilute saline
solution, and in glycerine; it is insoluble in absolute and in 50
per cent, alcohol; it withstands heat up to 54 to 56°, but is des-
troyed by heating in anvater bath and by boiling. A rise in
blood-pressure is produced by this substance in very small
quantities, and is due to the effect which it has upon the peripheral
vessels, upon the nerve terminals, and perhaps also upon the
muscles. From the results of two experiments, Tigerstedt and
Bergmann assume that, under normal conditions, renin is con-
veyed into the blood which circulates through the kidneys. In
these experiments, blood from the renal veins was injected in
quantities of 2 c.cm. into the veins of rabbits which had been
nephrectomized one to two days previously, and a rise in blood-
pressure of 13 to 25 per cent, followed. These experiments were
afterwards tested by Le\vandowsky, who found that the results
produced with 5 to 6 c.cm. of renal venous blood were in no way
different from those produced by the same amount of venous blood
from other parts of the body ; for this reason he is not prepared
to ascribe a specific vaso-contractor action to the blood in the renal
veins.

The effect which renal extract has in raising blood-pressure

THE INTERNAL SECRETION OF THE KIDNEY 443

had been confirmed by various authors (Riva-Rocci, Vincent and
Sheen, Batty Shaw), who believe that the tonic internal secretion
of the kidney forms the connecting link between renal disease on
the one hand, and arterial hypertension and cardiac hypertrophy
on the other. Seeing, however, that the hypertensive effect of
renal extract is not specific but is the property of extracts obtained
from a large number of other organs, it can hardly be regarded
as proof of an internal secretion on the part of the kidney, and
still less as a satisfactory explanation of the cardiac hypertrophy
of renal disease.

Rautenberg recently described marked cardiac hypertrophy
and sclerotic changes in the vessels of rabbits after temporary
ligature of the ureter.

The formation of what are known as ' autonephrotoxins,"
has been regarded as a further argument in favour of the passage
of the renal substance into the blood-stieam. Lindemann was
the first to show that, after the repeated injection of the expressed
juice of the kidney, an active poisons heteronephrotoxin, is
formed in the serum of immunized animals, which has a specific
and very injurious effect upon the kidney in animals of the same
species as that from which the expressed juice was obtained.
Nefediew next showed that blood taken from animals after ligature
of the ureters or of the renal artery, produced diffuse nephritis
when injected into animals of the same species. Lindemann 's
experiments showing that the blood of rabbits with chromian-
nephritis produced a parenchymatous nephritis in other rabbits,
provided further evidence in favour of the existence of auto- or
iso-nephrolysins.

As in the case of the other cytotoxic sera, however, these
autonephrolysins do not represent physiological processes; they
represent the toxic activities of substances formed under conditions
of immunization, and are probably not even organ-specific.

Timofeew, a pupil of Lindemann's, has recently endeavoured
to prove that nephritic oedema is chiefly the outcome of the
presence in the blood-stream of decomposed constituents of the
renal cells. These substances, which he calls " nephroblaptins,"
act in a manner similar to that of Heidenhain's lymphagogues
of the first class. According to Timofeew, the suppression of
renal activity which accompanies lesions of the renal parenchyma,
produces disturbance of the osmotic interbalance between the
organic fluids, and this leads to the retention in the tissues of an
excess of water. The substances which pass from the diseased
kidney into the blood-stream bring about changes in the blood
similar to those produced by lymphagogues of the first class;
and the consequent venous and capillary engorgement increases
the permeability of the vessel walls. The excess of fluid in the
organism, in combination with the increasing permeability of
the vessel walls, produces oedema.

444 INTERNAL SECRETION

Timofeew showed that the watery extract of healthy kidneys
(emulsions and filtrates), when introduced into the blood-stream
of healthy animals, increases the flow of chyle from the thoracic
duct to as much as eight to twenty-two times the normal. Normal
blood serum, whether obtained from the systemic arteries and
veins or from the renal vein, and blood from animals which have
undergone double nephrectomy and are dying of uraemia, have
no lymphagogue action. In animals in which only one renal
artery or one ureter is ligatured, the flow of chyle from the
thoracic duct is increased to twice or even eight times the normal ;
and the serum from animals such as these has a marked lympha-
gogue action upon normal animals.

Kast (1902) has already pointed out that the blood of indi-
viduals with nephritic oedema contains a lymphagogue substance.
Starling recognized that the cedematous fluid of persons with
kidney disease was a strong lymphagogue. Blanck discovered
(1906) that, if the serum or cedematous fluid from rabbits with
uranian nephritis is injected into rabbits which develop nephritis
without oedema after the exhibition of chromium or aloin, the
latter animals become cedematous. According to Timofeew, the
serum of nephrectomized animals is markedly toxic to healthy
animals, but it does not increase the flow of chyle. It is said
that sera from individuals with parenchymatous nephritis mani-
fest both properties when exhibited in man ; while, according to
Strauss, sera from individuals with interstitial nephritis have a
toxic property, but Kast does not believe it to be lymphagogue.
Timofeew assumes that the lymphagogue action of the serum
depends upon the presence of nephroblaptins, its toxic properties
upon the presence of other substances. Non-albuminous oedema
may occur without the participation of the kidneys, brought about
by the products of the decomposition of other organs which also
possess a lymphagogue action.

These results require further confirmation, but they suggest
that, where pathological changes take place in the kidneys, sub-
stances are supplied to the blood which may have a special
significance to the organism. One thing is clear, however, and
that is that these experiments supply no proof of a physiological
internal secretion on the part of the kidneys.

The following observations have an interest in this connection.
The experiments of J. R. Bradford (1899) showed that striking
changes in metabolism may be produced by the reduction of the
renal parenchyma. My own experiments, which have extended
over a period of years, but have not as yet been published, have
yielded interesting results. In dogs in which the nitrogen-
balance was maintained for weeks, and whose daily excretion of
urine was ascertained, the excision of a wedge-shaped portion of
the kidney, equal to about a quarter of the organ, led to the
following remarkable change, which was more pronounced after

THE INTERNAL SECRETION OF THE KIDNEY 445

removal of the other sound kidney. The daily excretion of urine
was considerably increased, and amounted to two, three, or even
five times the normal, v. Haberer also observed polyuria after
reduction of the renal parenchyma. The daily excretion of
nitrogen also increased, though the diet was unaltered. This
negative nitrogen-balance disappeared when the amount of food
given was very much augmented. The animals showed con-
spicuous thirst and considerable appetite, and by increasing the
amount of the food until the nitrogen was two to two-and-a-half
times the former quantity, it was found possible to maintain the
nitrogen balance. Reduction in the amount of the diet was
followed by a progressive decrease in the excretion of nitrogen
until a nitrogen deficit was again observed. The condition of
animals in which the renal parenchyma had been reduced in this
manner underwent no other change.

According to Bradford, the nitrogenous extractive substances
of the blood and tissues, and especially of the muscles, are con-
siderably increased in such animals ; he believes that there is rapid
decomposition of the tissues, particularly of the muscles. It is
expedient that mention of these metabolic changes should be
made here, though it is not possible at present to determine
whether they arise from suppression of the internal secretion of
the kidney or not.

LITERATURE.

The reference table, although very extensive, makes no pre-
tention to include the entire literature of the subjects dealt with.
The older literature, that anterior to about the middle of the last
century, has been omitted altogether. Detailed accounts of the
manner in which our knowledge concerning the individual internal
secretory organs has grown are given by various authors, and, as
a general rule, these accounts include summaries of the older
literature. To them the student is referred (Thyroid : Horsley,
Hellin, Langendorff, W. Scholz ; suprarenal: Pellegrino, Biedl ;
hypophysis cerebri : Caselli, Paulesco ; generative glands : Hegar,
Moebius).

The following list includes all the publications of which
mention is made in the text, together with all works of a physio-
logical or morphological nature. The clinical references include
only those works which may be regarded as fundamental ; while
very few of the numerous publications of a casuistic or therapeutic
nature have found mention.

In order to avoid repetition, the works are arranged, not
according to subject, but under the authors' names, which are
arranged in alphabetical order. The list of references is com-
plete up to the end of the year 1909; a few publications of the
year 1910 also find mention.

List of Contractions used in the Literature

References.

A. A. = Archiv f. Anatomic und Phy-
siologic. Anatomische Abteilung.

A. P. — Archiv f. Anatomic und Phy-
siologic. Physiologische Abteilung.

A. A. P. = Archiv f. Anatomic, Phy-
siologic und wissenschaftl. Medizin
von Joh. Miiller, Reichert und du
Bois-Reymond.

A. B. := Archives de Biologic.

A. d. F. •= Archivio di Fisiologia.

A. d. P. = Archives de Physiologic
normale et pathologique.

A. E. M. = Archiv f. Entwicklungs-
mechanik.

A. G. = Archiv f. Gynakologie.

A. H. = Archiv fiir Hygiene.

A. i. B. - Archives italiennes de
Biologic.

A. i. Ph. = Archives Internationales

de Physiologic.
A. J. A. = American Journal of

Anatomy.
A. J. P. ~ American Journal of

Physiology.
A. J. M. S = American Journal of

Medical Science.
A. k. Ch. = Archiv f. klinische

Chirurgie.
A. m. A. — Archiv fiir mikroskopische

Anatomic.
A. m. e. = Archives de medecine

experimentale et d'anatomie patho-
logique.

An. An. = Anatpmischer Anzeiger.
A. P. P. ~ Archiv fiir experimentelle

Pathologic und Pharmakolopie.

LITERATURE

447

A. V.=Archiv fur Verdauungskrank-
heiten.

B. C. = = Biochemisches Central-
blatt.

Bph. C. = Biophysikalisches Central-
blatt.

B. d. ch. G. = Berichte der deutschen
chemischen Gesellschaft.

B. G. G. Hegars Beitrage zur
Geburtshilfe und Gynakologie.

B. k. W. = Berliner klinische Woch-
enschrift.

B. Z. == Biachemische Zeitschrift.

C. a. P. = Centralblatt flir allgem-
eine Pathologic und pathologische
Anatomic.

C. f. B. = Centralblatt fur Bakterio-
logie.

C. Ch. = Centralblatt fur Chirurgic.

C. G =- Centralblatt fiir Gynako-
logie.

C. G. M. C. = Centralblatt fur die
Grenzgebiete der Medizin und
Chirurgie.

C. i. M. = Centralblatt fiir innere
Medizin.

C. k. M. = Centralblatt flir klinische
Medizin.

C. m. W. : Centralblatt fiir die
medizinischen Wissenschaften.

C. P. = Centralblatt fiir Physio-
logic.

C. r. A.. = Comptes rendus de 1'acade-
mie des sciences.

C. r. S. B. = Comptes rendus de la
societe de biologic.

D. A. k. M. = Deutsches Archiv fur
klinische Medizin.

D. Ch. = Deutsche Chirurgie.
D. K. = Deutsche Klinik.
Diss. = Inaugural-Dissertation.
D. m. W. == Deutsche medizinische
Wochenschrift.

D. Z. N. -Deutsche Zeitschrift fiir
Nervenheilkunde.

E. B. = Sitzungsberichte der physikal.
med. Societal in Erlangen.

E. P. = Ergebnisse der Physiologic
(Asher-Spiro).

F. M. = Fortschritte der Medizin.

G. m. = Gazette medicale de Paris.
H. B. = Hofmeisters Beitrage zur

cheniischen Physiologic und Patho-
logic.
I. M. — Internationale Monatsschrift

fiir Anatomie und Physiologic.
J. A. M. A. == Journal of American

Medical Association.
J. o. A. a. P. = Journal of

Anatomy and Physiology.
J. A. P. =: Journal de 1'Anatomie et

de la Physiologic.
J. B. Ch. = Journal of Biological

Chemistry.
J. K. — Jahrbiicher fiir Kinderheil-

kunde.

J. d. P. == Journal de la Physiologic
de riiomme et des animaux.

J. d. P. P. = Journal de Physiologic
ct de Pathologic generale.

J. E. M. == Journal of Experimental
Medicine.

J. o. P. =- Journal of Physiology.

J. o. P. B. =Journal of Pathology
and Bacteriology.

L. O. Lubarsch-Ostertags Ergeb-
nisse der allg. Pathologic und
patholog. Anatomie.

M. G. G. == Monatschrift fur Geburt-
shilfe und Gynakologie.

M. G. M. C. -= Mitteilungen aus den
Grenzgebieten der Medizin und
Chirurgie.

M. K. - Medizinische Klinik.

M. m. W. = Miinchener medizinische
Wochenschrift.

M. P. = Monatschrift fiir Psychiatric.

M. U. = Moleschotts Untersuchungen
zur Naturlehre.

N. C. — Neurologisches Centralblatt.

P. A. = Pfliigers Archiv fiir die
gesamte Physiologic.

P. m. — Presse medicale.

P. m. W. = Prager mediz. Wochen-
schrift.

P. R. S. == Proceedings of the Royal
Society of London.

P. V. — Prager Vierteljahrsschrift.

S. A. = Skandinavisches Archiv f.
Physiologic.

S. m. = Semaine medicale.

S. W. A. == Sitzungsberichte der k.
Akademie zu Wien. Mathematisch-
naturwissenschaftliche Klasse.

Th. G. : Therapie der Gegenwart.

Th. M. Therapeutische Monat-
shefte.

V. A. == Virchows Archiv fiir patho-
logische Anatomie und Physiologic
und klinische Medizin.

V. a. G. == Verhandlungen der ana-
tomischen Gesellschaft.

V. d. N. A. == Verhandlungen der
deutschen Naturforscher und Arzte.

V. d. p. G. =: Verhandlungen der
deutschen pathologischen Gesell-
schaft.

V. 10. C. M. = Verhandlungen des
10. Congresses fur innere Medizin.

V. g. M. Vierteljahrsschrift fur
gerichtliche Medizin und offentl.
Sanitatswesen.

V. H. ; Virchow-Hirsch" Jahres-
berichte.

W. B. = Sitzungsberichte der physi-
kal isch-medizinischen Gesellschaft,
Wiirzburg.

W. K. == \Viener Klinik.

\V. k. \\". == Wiener klinische Woch-
enschrift.

W. k. R. == Wiener klinische Rund-
schau.

448

LITERATURE

W. m. P. = Wiener medizinische

Presse.
W. m. W. - Wiener mediz. Wochen-

schrift.
W. V. = Verhandlungen der physi-

kalisch-medizinischen Gesellschaft,

Wiirzburg.

Z. A. == Zoologischer Anzeiger.
Z. a. P. - Zeitschrift f. allgemeine

Physiologic.

Z. B. -= Zeitschrift fiir Biologic.
Z. Ch. -= Zeitschrift fiir Chirurgie.
Z. e. P. = Zeitschrift fiir experiment-

elle Pathologie und Therapie.

Z. G. G. - Zeitschrift fiir Geburt

shilfe und Gynakologie.
Z. H. = Zeitschrift fiir Heilkunde.
Z. k. M. = Zeitschrift fur klinische

Medizin.
Z. ph. Ch. = Zeitschrift fiir physio-

logische Chemie.
Z. w. Z. = Zeitschrift fur wissen-

schaftliche Zpologie.
Ziegl. B. = Zieglers Beitrage zur

allg. Pathologie und pathologischen

Anatomic.
Z. r. M. — Zeitschrift fiir rationelle

Medizin.

ABADIE. Traitement chirurgical du goitre exophtalmique. La France

Med., No. 2, 1898.

ABDERHALDEN, E. Lehrb. d. physiolog. Chemie. 2 AufL, Wien, 1909.
ABDERHALDEN, E., and BERGELL, P. Uber Epinephrin. M. m. W., 1904.
- Zur Kenntnis des Epinephrms (Adrenalins). B. d. ch. G., 37, p. 2022,

1904.
ABDERHALDEN, E., and GUGGENHEIM, M. Weitere Vers. iiber d. Wirkung

der Tyrosinase aus Russula delica auf tyrosinhaltige Polypeptide u.

auf Suprarenin. Z. ph. Ch., 57, 1908.
ABDERHALDEN, E., and MULLER, F. Uber das Verhalten des Blutdruckes

nach intravenoser Einfiihrung von 1-, d- und dl-Suprarenin. Z.

ph. Ch., 58, 1908.
ABDERHALDEN, E., and THIES, F. Weitere Studien iiber das physiologische

Verhalten von 1-, d- und dl-Suprarenin. II. Mitt. Z. ph. Ch.,

59, pp. 22-29, 1909.
ABDERHALDEN, E., and SLAVU. Weitere Studien iiber das physiologische

Verhalten von 1-. d- und dl-Suprarenin. Z. ph. Ch., 59, pp. 129-

137, 1909.

ABDERHALDEN, E., and KAUTZSCH. Weitere Studien iiber das physio-
logische Verhalten von 1- und d-Suprarenin. Z. ph. Ch., 61, p. 119,

1909.
ABDERHALDEN, E., KAUTZSCH, and MULLER, F. Weitere Studien iiber das

physiologische Verhalten von 1- und d-Suprarenin. V. Mitt. Z.

ph. Ch., 62, 1909.

ABEGG. Zur Kenntnis der Addisonschen Krankheit. Diss., Tubingen, 1889.
ABEL, J. J. Further observations on the chemical nature of the active

principle of the suprarenal capsule. Bull, of Johns Hopkins Hospital,

No. 90, September-October, 1898.

- Uber den blutdruckerregenden Bestandteil der Nebenniere, das Epine-

phrin. Z. ph. Ch., 28, 1899.

- On epinephrin, the active constituent of the suprarenal capsule and

its compounds.

— On the formation and composition of highly active salts of epinephrin.
— - On the presence of cholin and neurin in the intestinal canal during its

complete obstruction. The Chemistry of the Melanins. A. J. P., 2,
March i, 1899.

- Further observations on epinephrin. Johns Hopkins Hospital Bull.,

No. 1 20, March, 1901.

— On the behaviour of epinephrin to Fehling's solution and other charac-

teristics of this substance. Ibid., No. 128, November, 1901.

- On a simple method of preparing epinephrin and its compounds.

Ibid., No. 130, 1902.

— On the elementary composition of adrenalin. On the behaviour of the

suprarenal gland towards Fehling solution. On the oxidation of
epinephrin and adrenalin with nitric acid. A. J. P., February 8,
1903.

— Weitere Mitteilungen iiber das Epinephrin. B. d. ch. G., 36, p. 1839,,

1903; and 37, p. 368, 1904.

LITERATURE 449

ABEL, J. J., and CRAWFORD, A. On the blood-pressure raising constituent

of the suprarenal capsule. Johns Hopkins Hospital Bull., No. 76,

July, 1897.
ABEL, J. J., and TAVEAU, R. On the decomposition products of epinephrin

hydrate. J. B. Ch., i, p. i, 1905.
ABELMANN. Uber die Ausnutzung der Nahrungsstoffe nach Pankreasexstir-

pation. Diss. Dorpat, 1890.
ABELOUS, J. E. Greffe de capsules surrenales sur la grenouille. C. r.

S. B., 44, P- 864, 1892.

- Contribution a 1'etude de la fatigue. A. d. P., pp. 437-446, 1893.

- La physiologic des glandes a secretion interne. Rev. gen Scienc.,

p. 273, 1893.
— • Des rapports de la fatigue avec les fonctions des caps, surren. A. d.

P., 1893-

Toxicite du sang et des muscles des animaux fatigues. A. d. P., 26,
1894.

— Sur 1'action antitoxique de corps surrenales. C. r. S. B., 47, p. 458,

15 juin, 1895.

- Des rapports de la fatigue avec les fonctions des capsules surrenales.

XI. Cpngres intern, a Romej and A. i. B., 22, 1895.

— Sur 1'origine musculaire des trouble consecutifs a la destruction des

glandes surrenales. C. r. S. B., 56, p. 951, 1904.

— Les troubles de pigmentation de la grenouille a la suite de la destruction

des glandes surrenales. Ibid., p. 952, 1904.

ABELOUS, J. E., and BARDIER, E. Action hypertensine de 1'urine de 1'homme
normal. Premieres recherches sur 1'urohypertensine. J. d. P. P.,
vol. x, p. 627, 1908.

- L'urohypotensine. J. d. P., vol. xi, p. 34, 1909.

— Uber Urohypotensine und Urohypertensine mehrere Mitteilungen in

C. r. S. B., vol. 64-66, 1908-1909.
ABELOUS and BILLARD. Recherches sur les fonctions du thymus chez la

grenouille. A. d. P., p. 898, 1896.
ABELOUS, J. E., and LANGLOIS, P. Note sur les fonctions des capsules

surrenales chez la grenouille. C. r. S. B., 43, p. 292, 1891.

— La mort des grenouilles apres la destruction des caps, surren. Ibid.,

P. 855-

— Note sur Faction toxique du sang des mammiferes apres la destruction

des capsules surrenales. Ibid., 44, p. 165, 20 fevrier, 1892.
— - Destruction des capsules surrenales chez le cobaye. Ibid., 44, p. 388,
7 mai, 1892.

- Capsules surrenales. Toxicite de 1'extrait alcoolique des muscles dc

grenouilles privees de capsules surrenales. Ibid., 44, p. 490, 1892.

— Rech. exper. sur les fonctions des caps, surren. de la grenouille.

A. d. P., 1892.

- Sur les fonctions des capsules surrenales. A. d. P., pp. 465-476, 1892.

— Sur les fonctions des capsules surrenales. C. r. S. B., 47, pp. 334-335,

1895.

ABELOUS, LANGLOIS, CHARRIN. Maladie d'Addison, Traces ergographiques.
Diurese par injections de capsules surrenales. C. r. S. B., 44,
p. 623, juillet, 1892.

- La fatigue chez les addisoniens. Ibid., p. 721 ; A. d. P., 24. 1892.
ABELOUS, J. E., and RIBAUT, H. Sur la substance hypertensive qu'on peut

extraire par 1'alcool des extraits de muscle putrefie. C. r. S. B., 64,
p. 907, 23 mai, 1908.

ABELOUS, RIBAUT, SOULIE and TOUJAN. Sur la presence dans des macera-
tions des muscles putrefies de subst. elev. la pression arterielle.
C. r. S. B., 58, i, 1906.

- Sur la presence dans les macerations des muscles putrefies d'une

ptomaine elevant la pression arterielle. Ibid., p. 530, 1906.
ABELOUS, SOULIE and TOUJAN. Dosage colorimetrique par le jode de
1'adrenaline. C. r. S. B., 57, i, p. 301, 1905.

- Sur la formation de 1'adrenaline par les glandes surrenales. Ibid.,

_ P- 533, 1905-

- Sur 1'origine de 1'adrenaline. Ibid., p. 574, 1905.

- Influence des extraits et des produits de 1'autolyse des organs et tissus

sur la formation de 1'adrenaline par les glandes surrenales. Ibid.,
57, ii, P- 589, 1905-
2Q

450 LITERATURE

ABELOUS, SOULIE and TOUJAN. Sur Tidentite d'action des extraits des sub-
stances corticale et meduliaire des capsules surrenales. Ibid., p. 530,
1905.

— Influence des extraits et des organes et des tissus animaux soumis a
1'autplyse sur la production de 1'adrenaline (2nd note). C. r. S. B.,
58, ii, p. 16, 1906.

- Sur un procede de controle de dosages chimique et physiologique de

1'adrenaline. Ibid., p. 174, 1906.
ABOTT, A. C. The adrenal gland and its active principle in their relation

to cytolysins and antitoxin production. C. f. B., 34, p. 696, 1903.
1 ABT. Le corps thyroide et la grossesse. These de Paris, 1904.
ACHARD, M. Recherches cliniques sur le cceur, le pouls et la tension

arterielle dans quelque convalescences. These de Montpellier, 1906.
ACHARD and LOEPER. Gigantisme, acrornegalie et diabete. Nouv. Icon.

Salpetr., 13, 1900.
ADAMI, J. G. The internal secretory activity of glands, &c. New York

Med. News, No. 19; and Montreal Med. Journ., May, '1897.

- The Myelins and potential fluid crystalline bodies of the organism.

J. A. M. A., 48, 1907.

- Principles of pathology. Phil, and New York, 1908.

ADAMI and ASCHOFF. On the myelins, myelin bodies and potential fluid
crystals of the organism. Proc. Roy. Soc., 78, p. 359, 1906.

ADAMS, E. W. A case of previous development. Trans. Path. Soc., Lon-
don, 1906.

ADDISON, THOMAS. On the constitutional and local effects of disease of
the suprarenal bodies. London, 1855.

ADELHEIM, R. Uber die Langerhansschen Inseln. Petersb. m. W., 30,

P- 359-
A.DLER, J., and HENSEL, O. Uber intravenose Nikotineinspritzungen und

deren Wirkung auf die Kaninchenaorta. D. m. W., 1906.
• — Intravenous injections of nicotine and their effects upon the aorta of

rabbits. Journ. of Med. Research, 15, p. 229, 1906.
ADLER, M., and MILCHNER, R. Untersuchungen des Kotfettes in einem

Falle von Pankreasdiabetes und dessen Beeinflussung durch

Pankreon. B. k. W., 1908.
ADLER, S., and THALER, H. Experimentelle und klinische Studien zur

Graviditatstetanie. Z. G. G., 62, p. 194. Diskussion zum Vortrag

Erdheim. W. k. W., 1906.
AFFANASSIEW, B. Uber den Bau und Entwicklung der Thymus. A. m. A.,

14, 1877.
AGADSCHANIANZ, R. Uber den Einfluss des Adrenalins auf das in der

Leber enthaltene Glykogen. B. Z., 2, p. 148, 1907.
AGOSTINI. Infantilismo distrofico e infantilismo mixedematoso. Riv. pat.

nerv., 1902.
AHLBECK, VICTOR, and LOHSE, J. E. Ein Versuch, das Eklampsiegift auf

experimentellem Wege nachzuweisen. Z. G. G., 62, p. 115.
AlCHEL, O. Uber die Entwicklung der Nebennieren bei Selachiern und

uber eine neue Homologie der Nebennieren in der Wirbeltierreihe.

E. B., H. 31, p. 86, 1899.

- Zur Kenntnis der Nebennieren. M. m. W., 1900.

- Vergleichende Entwicklungsgeschichte und Stammesgeschichte der

Nebennieren. i\. m. A., 56, 1900.

- Vorlaufige Mitteilung iiber die Nebennierenentwicklung der Sauger und

die Entstehung akzessorischer Nebennieren des Menschen. An. An.,
17, p. 30, 1900.

- Eine Antwort auf die Angriffe v. S. Vincent in London. Ibid., 18, 1900.
AIME, P. Les cellules interstitielles de 1'ovaire chez le cheval. C. r. S. B.,

58, ii, p. 250, 1906.
AJELLO, G., and PARASCANDALO, C. Contr. sperim. alia patogenesi dell'

uremia. Speriment, 1895.
D'AjUTOLO, G. Intorno ad un caso di capsula soprarenale accessoria nel

corpo pampiniforme di un feto. Arch, per le scienze, med., S,

pp. 203-306, 1884.
— - Su di una struma soprarenale accessoria in un rene. Bollet. delle sc.

med. di Bologna, Ser. 6, vol. xvii, p. 9, 1886.
AKOPENKO. Uber die Wirkung der Thyreoidektomie auf das Wachstum und

die Entwicklung des Knochen- und Nervens3rstems bei jungen Tieren.

L. O., 5, 1898.

LITERATURE 451

ALAIKE, P. Le role de la fonction interne de 1'ovaire et les essais de

1'opotherapie ovarienne en pathologie nerveuse et mentale. These de

Montpellier, 1906.
ALAMARTINE, M. H. La secretion interne du testicule et la glande inter-

stitielle. Gaz. des hop., 79, 1906.
ALBANESE. Recherches sur la fonction des capsules surrenales. A. i. B., 18,

1893.
— La fatigue chez les animaux prives des capsules surrenales. A. i. B., 17,

1892.
ALBARRAN, J., and BERNARD, L. Etude sur les cytotoxines renales.

A. m. e., p. 13, 1903.
ALBERS-SCHONBERG. Uber eine bisher unbekannte Wirkung der Rontgen-

strahlen auf den Organismus der Tiere. M. m. W., 1903.
ALBERTI. Kasuistik z. Hypertrichosis universalis. B. G. G., 9, 1905.
ALBERTONI and TIZZONI. Sugli effetti dell' estirpazione della tiroide.

Arch. p. le Scienze Med., x, p. i. 1886.
ALBRAND, M. Die Anlage der Zwischenniere bei d. Urodelen. A. m. A., 72,

1908.
ALBRECHT. Ein Fall von Pankreasbildung in einem Meckelschen Divertikel.

Ges. f. Morph. u. Phys. in Miinchen, 14, p. 52, 1901.

- Uber triibe Schwellung und Fettdegeneration. V. d. p. G., 6, 1903.

- Die Bedeutung myelinogener Stoffe im Zellleben. Ibid., 1903.
ALBRECHT, P. Ein Fall von Hypernephrom mit Metastasen. W. k. W.,

1904.

- Beitrage zur Klinik und pathologischen Anatomic der malignen Hyper-

nephrome. A. k. Ch., 77, 1905.

ALDEHOFF. Tritt auch bei Kaltbliitern nach Exstirpation des Pankreas
Diabetes auf? Z. B., 28, 293, 1894.

ALDRICH, J. B. A preliminary report on the active principle of the supra-
renal gland. A. J. P., 5, p. 457, August i, 1901.

- Is adrenalin the active principle of the suprarenal gland? A. J. P., 7,

P- 359, 1902.
ALESSANDRO. Influenza della macerazione acida di mucosa duodeno digiuuale

(contenente secretina) sulla secrezione lacrimale, sulla produzione

dell' umore aqueo e sulla circolazione del fondo dell' occhio. Arch.

di ott., 1907; Arch. f. Augenhk., 61, 1908.
ALESSANDRO, G., and BONAVENTURA, G. Le pouvoir secreteur du pancreas.

J. d. P. P., x, 219, 1908.
ALEXANDER. Behandlung d. Morbus Basedowii mit Antithyreodin Moebius,

M. m. W.j 1905.
ALEXANDER, A., and EHRMANN, R. Untersuchungen liber Pankreasdiabetes,

besonders Uber das Blut der Vena pancreatico-duodenalis. Z. e. P., 5,

P- 367-
ALEXANDER, C. Untersuchungen iiber die Nebennieren und ihre Beziehungen

zum Nervensystem. Zeigl. B., n, 1892.
ALEZAIS, H. Contribution a 1'etude de la capsule surrenale du cobaye.

A. d. P., 1898.
ALEZAIS and ARNAUD. Recherches experimentales sur la toxicite" des capsules

surrenales. Marseille medical, p. 637, 1889; pp. 81, 225, 1890.

- Sur le caractere du sang efferent des capsules surrenales. Ibid., 393,

1891.

- Recherches experimentales sur les capsules surrenales. Ibid., pp. n,

94, 131, 195, 1891.

- Etude sur la tuberculose des capsules surrenales et ses rapports avec

la maladie d'Addison. Revue de med., n, p. 283, 1891.

ALEZAIS and PEYRON. L'organe parasympathique de Zuckerkandl chez le
jeune chien. C. r. S. B., p. 1161, 1906.

- Particularites de devoloppement des paraganglions lombaires. Ibid., 1907.

- Sur les tumeurs dites gliomateuses des capsules surrenales. Ibid., p. 551.

- Un groupe nouveau de tumeurs epitheliales : les paragangliomes. Ibid.,

65, 1908.
ALLARA, V. Der Cretinismus, seine Ursache und seine Heilung. Ubersetzt

von H. Marian. Leipzig, 1894.
ALLARD, E. Uber die Beziehungen der Umgebungstemperatur zur Zuckeraus-

scheidung beim Pankreasdiabetes. A. d. P., 59, p. in, 1908.

452 LITERATURE

ALLARD, E. Die Acidose beim Pankreasdiabetes. Ibid., 59, p. 388, 1908.
ALLARIA, G. B., and VARANINI, M. Ricerche sul ricambio in un caso di

morbo di Addison curato con 1'opoterapia surrenale. Clinica med.

ital., p. 40, 1902.
ALLEN. Zur Frage der Tetanic bei Magendilatation usw. A. V., 5, 1898;

B. k. W., 1899.

ALLERS, R. Zur Kenntnis der wirksamen Substanz in der Hypophyse.

M. m. W., 1909.

ALMAGIA, M. Allattamento e funzione tiroidea. A. d. F., 6, p. 462.
ALMAGIA and EMBDEN. Uber die Zuckerausscheidung pankreasloser Hunde

nach Alanindarreichung. H. B., 7, p. 298.

ALONZO. Sulla funzione della glandola tiroide. Rif. med., vi, p. 208, 1891.
ALQUIER, L. Recherches sur le nombre et sur la situation des parathyreoides

chez le chien. C. r. S. B., 58, ii, p. 302, 1906.

- Sur les modifications de 1'hypophyse apres 1'exstirpation de la thyreoide

ou des surrenales chez le chien. J. d. P. P., 9, p. 492, 1907.
ALQUIER, L. and SCHMIERGOLD. Deux tumeurs de 1'hypophyse. L'en-

cephale, ii, No. 3.
ALQUIER, L., and THEUVENY, L. Etat du testicule de chiens ayant subi

diverses exstirpations partielles de 1'appareil thyro-parathyroidien.

C. r. S. B., 64, p. 663.

ALQUIER, L., and TOUCHARD, P. Lesions des glandes vasculaires sanguines

dans deux cas de sclerodermie generalisee. A. m. e., p. 687, 1907.
ALTERTHUM, E. Folgezustande nach Kastration und die sekundaren Ge-

schlechtscharaktere. B. G. G., ii, p. 13, 1899.
AMABILINO. Caso di morbo di Addison con lesioni dei centri nervosi.

Rif. med.j 1899.
D'AMATO, L. - - Sulle alterazioni prodotte dagli estratti di capsule surrenali

nei vasi sanguigni ed in altri organi. Giorn. internaz. d. scienze

mediche., 27 Ref. Bph. C., i.

- Weitere LJntersuchungen liber die von den Nebennierenextrakten

bewirkten Veranderungen der Blutgefasze und anderer Organe.

B. k. W., pp. 1 100 and 1131, 1906.

- Neue Unters. Uber d. exper. Pathologic d. Blutgefasze. V. A., 192,

1908.
D'AMATO, L., and FAGELLA, V. Delia natura e del significato delle lesioni

aortiche prodotte dagli estratti di capsule surrenali. Ref. Bph. C., I.
AMBERG. Uber die Toxizitat des wirksamen Prinzips der Nebennieren.

Arch, intern. Pharmacod., n, p. 57, 1902.
AMBROSIUS, W. Beitrage zur Lehre von den Nierengeschwiilsten. Diss.,

Marburg, 1891.
AMOUROUX. Etude experimentale de 1'atherome tabagique. These de

Toulouse, 1906.

AMPT. Uber das Parovarium (Epoophoron). Diss., Berlin, 1895.
ANCEL, P. Histogenese et structure de la glande hermaphrodite d'Helix

pomatia. A. B., t. xix, 1902.

- Les follicules pluriovulaires et le determinisme du sexe. C. r. S. B., 55,

p. 1049, 1903.

- Sur le determinisme cytosexuel des gametes. Periode de differenciation

sexuelle dans la glande hermaphrodite de Limax maximus. Arch, de
zool. exp., i, 1903.

ANCEL, P., and BouiN, P. Recherches sur le role de la glande interstitielle
du testicule. Hypertrophie compensatrice experimentale. C. r. A.,
decembre, 1903.

— L'apparition des caracteres sexuel secondaires est sous la dependence

de la glande interstitielle du testicule. Ibid., Janvier, 1904.

- Histogenese de la glande interstitielle du testicule chez le pore.

C. r. S. B.j 1903.

— Sur 1'existence de deux sortes de cellules interstitielles dans le testicule

de cheval. C. r. S. B., 56, i, p. Si, 1904.

- La glande interstitielle du testicule. Examen critique des essais de

verification experimentale de son role sur Porganisme. Ibid., p. 83.

- Sur la glande interstitielle du testicule des mammiferes. (Rep. a

M. G. Lpisel.) Ibid., p. 95.

Tractus genital et testicule chez le pore cryptorrhide. Ibid., 56, i,
p. 281, 3 fevrier, 1904.

le par le corps jaune. iDia., 07, p. 400, 1909.

LLEMIN. Sur la degenerescence de la glande seminale deter-

ar Pablation du feuillet parietal de la vaginale. C. r. S. B.,

LITERATURE 453

ANCEL, P., and BOUIN, P. L'infantilisme de la glande interstitielle du testi-
cule. C. r. A., i feVrier, 1904.

— Sur les relations qui existent entre le developpement du tractus genital

et celui de la glande interstitielle chez le pore. C. R. Assoc. des anat.
Toulouse, 1904.

— • Sur la fonction du corps jaune. I. Methodes de recherches. C. r. S. B.,
66, p. 454. - - II. Action du corps jaune vrai sur 1'uterus, p. 505.
III. Action du corps jaune vrai sur la glande mammaire, p. 605.
• IV. Demonstration experimental de Faction du corps jaune, sur
1'uterus et la glande mammaire, p. 689, 1908.

- Le developpement de la glande mammaire pendant la gestation est

determine par le corps jaune. Ibid., 67, p. 466,
ANCEL and VILL:
minee par
66, p. 6, 1907.

- Sur la cause de la menstruation chez la femme. Ibid., p. 200, 1907.

- Periode catameniale coincidant avec 1'epoque ou le corps jaune a son

maximum de developp. il est vraisemblable que la menstr. est sous
la dependance du corps jaune. Sur 1'ectqpie experimentale de
1'ovaire et son retentissement sur le tractus genital. Ibid., p. 227.
AXDERODIAS. Secretion interne. Journ. de Med. Bordeaux, pp. 450, 467,

497, Si3, 1900.

ANDERSON. Reflex pupil-dilatations by cervical sympathetic nerve. J. o. r.,
p. 15, 1904.

— The paralysis of involuntary muscles with special reference to the

occurrence of paradoxical contraction. I. Paradoxical pupil-dilata-
tion. Ibid., p. 290.
ANDERSON and BERGMANN. Einflusz der Schilddrusenbehandlung beim

gesunden Menschen. S. A., viii, p. 326, 1908.
ANDERSSON, O. Zur Kenntnis der Morphologie der Schilddriise. A. A.,

p. 177, 1894.
ANDREZIEN, L. Origin and evolution of the thyroid function. Brit. Med.

Journ., 1893.

— • The morphology of the pituitary body. Ibid., 1894.
ANGIOLELLA, G. SulP avelenamente sperimentale da tiroidina etc. Annali

dd Neurolgia, 15. Zit. N. C., 16, p. 644, 1897.
ANTON, G. Uber Formen und Ursachen des Infantilismus. M. m. W.,

1906.

— Nerven- und Geisteserkrankungen in der Zeit der Geschlechtsreife-.

W. k. W., 1904.

— Wahre Hypertrophie des Gehirns mit Befunden an Thymusdriise und

Nebennieren. Ibid., 1902.

— Vier Vortrage iiber Entwicklungsstorungen beim Kinde. Berlin, 1908.
ANZILOTTI, G. Sulle proprieta tossiche dei nucleoprot. renali. La Clinica

mod., No. 12, 1903.

— Sulle modificazioni indotte nel rene opposte della legatura dell' uretera.

Ibid., 19,03.
APERT. Les enfants retardaires. Actualites medicales, 1902.

— Hypertrophie parotidienne et insuffisance thyrqidienne. S. m., 28, p. 71.

— Infantilisme et hypertrophie des glandes salivaires. Soc. med. Hop.,

1908.
APOLANT, H. Uber Reizung der Nebennieren. C. P., 12, p. 721, 21 Januar,

1899.

ARGUSTINSKY. Uber einen Fall von Thyreoplasie. B. k. W., 1905..
ARNAUD, F. Les hemorrhagies des capsules surrenales. Arch. gen.

Med., 1900.
ARNDT. Untersuchungen liber die Ganglienkorper des N. sympathicus.

A. m. A., 10, 1874.
ARNOLD, J. Uber die Struktur des Ganglion intercaroticum. V. A., 33,

1865.

— Ein Beitrag zu der Struktur der sogenannten Steiszdriise. Ibid., 32,

1865.

— Uber die feinere Strukter und den Chemismus der Nebennieren. Ibid.,

35, 1866.

— Akromegalie, Pachyakrie oder Ostitis ? Ziegl. B., 10, 1891.

454 LITERATURE

ARNOLD, J. Weitere Beitrage zur Akromegaliefrage. V. A., 135, p. i, 1894.
ARNOZAN and VAILLARD. Contribution a 1'etude du pancreas du lapin.

A. d. P., 1884.
ARON, H., and SEBAUER, R. Untersuchungen iiber die Bedeutung der

Kalksalze fiir den wachsenden Organismus. B. Z., 8, 1908.
ARONHEIM. Ein Fall von ausgedehnter Phlegmone, verursacht durch

subkutane Injekt. einer Cocain-Adrenalinlosung bei einem yojahrigen

Manne. M. m. W., 1904.
ARONSOHN, E. Die Zuckerausscheidung nach Adrenalininjektionen und

ihre Beeinflussung durch klinstlich erzeugtes Fieber. V. A., 174, 1903.

- Das Adrenalin zur Kupierung von Asthmaf alien. D. m. W., 1903.
ARREN. Essai sur les capsules surrenales. These de Paris, 1894.
D'ARSONVAL. Note sur la preparation de 1'extrait testiculaire. A. d. P., 1893.
ARTHUS. Glykolyse dans le sang et ferment glycolytique. A. d. P., 1891

and 1894.
ASCHNER, B. Demonstr. hypophysektomierter Hunde. W. k. W., Dezem-

ber, 1909.
ASCHOFF, L. Cystisches Adenofibrom der Leistengegend. M. G. G., 9, 1899.

- Uber einen Fall von angeborenem Schilddrusenmangel. D. M. W.,

1899.

— tjber die Lage des Parophoron. V. d. p. G., vol. ii, pp. 433-439) IQOO.

— Uber das Vorkommen chromaffiner Korperchen in der Paradidymus und

in dem Parophoron Neugeborener und ihre Beziehungen zu den
Marchandschen Nebennieren. Orth. -Festschrift, September- Abdr.,
pp. 1-9, 1903.

- Uber Atherosklerose und andere Sklerosen des Gefasssystems. Beitr. z.

M. K., 1908.

— Zur Morphologic der lipoiden Substanzen. Ziegl. B., 47, 1909.
ASCHOFF and COHN. Bemerkungen zu der Schur-Wieselschen Lehre von

der Hypertrophie des Nebennierenmarkes bei chronischen Erkran-

kungen des Nieren- und Gefassapparates. V. d. p. G., 1908.
ASCOLI and FIGARI. Uber Nephrolysine. B. k. W., pp. 561 and 634, 1902.
ASCOLI, G. Vorlesungen iiber Uramie. Jena, 1903.
ASHER and WOOD. Einfluss des Cholins auf die Zirkulation. Z. B., 37,

PP- 307-320, 1898.
ASKANAZY, M. Die bosartigen Geschwiilste der in der Niere eingeschlossenen

Nebennierenkeime. Ziegl. B., 14, 1893.

— Path.-anat. Beitr. z. K. d. M. Basedowii, insb. lib. d. dabei auftret.

Muskelerkrankung. D. A. k. M., 65, 1898.

— Teratom und Chorionepitheliom der Zirbel. V. d. p. G. in Jena, p. 58,

1906.

— Kommen in den Zellkomplexen der Nebennierenwande drusenartige

Lumina vor ? B. k. W., 1908 (Gegen Stoerk bejahend).
ASKANAZY, M., and HUBSCHMANN, P. Uber Glykogenschwellung der Leber-

zellkerne besonders bei Diabetes. C. a. P., 18, 1907.
ATKINSON, R. T. The early development of the circulation in the suprarenal

of the rabbit. An. An., 19, pp. 610-612, 1901.
AXTINA. Porpora emorragica curato con 1'adrenalina. Gazz. degli osped.,

1904.
ATHANASIU, C., and GRADINESCO, A. La circulation artificielle dans les

muscles. Action de 1'adrenaline sur 1'endothelium vasculaire.

C. r. S. B., 64, p. 613, 1908.

- Les capsules surrenales et les echanges entre le sang et les tissus.

C. r. A., 149, 1909.

ATHAXASIU and LANGLOIS. Du role du foie dans la destruction de la sub-
stance active des capsules surrenales. C. r. S. B., 49, p. 575, 1894.

ATHANASOW. Rech. histol. sur 1'atrophie de la prostrate consecutive a la
castration, a la vasectomie et a 1'injection sclerogene epididymaire.
These de Nancy, 1898.

AUBERTIN. L'hypertrophie cardiaque dans les infections et intoxications
chroniques experimentales. C. r. S. B., 63, 1907.

- Hyperplasie surrenale dans 1'alcoolisme chronique exper. Ibid., 63,

p. 270, 1907.

— Hypertrophie cardiaque dans 1'alcoolisme exper. Ibid., p. 206, 1907.
AUBERTIN and AMAND. A propos de 1'hypertension arterielle. S. m., p. 63,

1904.

LITERATURE 455

AUBERTIX and CUNET. Hypertrophie cardiaque et hyperplasie medullaire
des surrenales. S. m., 1907; C. r. S. B., 63, p. 595, 1907.

AULD. Preliminary report on the suprarenal gland and the causation of
Addison's disease. Brit. Med. Journ., May 12, 1894.

- A further report. Ibid., p. 745, October 6, 1894.

- A third report. Ibid., ii, p. 10, July, 1896.

AUSTOM, A., and TEDESCHI, H. Sugli effetti degli estratti di ghiandolle
surrenali e di iporisi sul sangue. R. Accad. v. Padova Sed., January
29, 1909; Bph. C., iv.

AVERBECK, H. Die Addisonsche Krankheit. Erlangen, 1869.

AXENFELD. Sehnervenatrophie und Menstruatiqnsstorung. D. m. W., 1903.

AZAM, J. Syndrome d'insuftisance hypophysaire aux cours des maladies
toxi-infectieuses. These de Paris, 1907.

BABER. Researches as to the minute structure of the thyroid gland.

Philosoph. Trans, of the R. Soc. , 172, 1881.

BABES, V. Les rapports entre la graisse, le pigment et des formations

cristallines dans les capsules surrenales. C. r. S. B., 64, p. 83, 1908.

— - Lesions des capsules surrenales dans la tuberculose. Ibid., p. 194, 1908.

— - Lesions inflammatoires et microbiennes des capsules surrenales. Ibid.,

65, P- 235.

- Observat. asupra capsulelor suprarenale. Ann. Acad. Roman., Bucarest,

1908.

— La presence d'une hypertrophie et d'adenomes des capsules surrenales
dans des cas d'adenomes ou du cancer primitif du foie. C. r. S. B.,

66, p. 479, 1909.

BABES, V., and JONESCU, V. Distribution de la graisse dans les caps.

surren. Ibid., 1908.
BABINSKI and ONANOFF. Tumeur du corps pituitaire. Rev. neur. , 8, p. 531,

1900.
BACCARANI, U., and PLESSI, A. Ricerche cliniche sull' azione dell' estratto

di sostanza modolare delle capsule surrenali (paraganglina Vassale)

nell' atonia gastro-intestinale. Rif. med. , 19, Nos. 13 and 14, pp. 358,

376, 1903.
BADUEL. Sopra alcune ricerche dirette a produrre un siero antiparagan-

gliare. Boll. Soc. Eustach., vol. 3, Nos. 5-8, 1905; Ref. B. C. iv,

p. 952.

- Effetti delle iniezioni di adrenalina nell' arteria renale. Ibid.

- Le alterazioni delle capsule surrenali .nei cardionefropatici. Riv. Clin.

med., 1908.
— • Lesions vasculaires produites par 1'extrait d'hypophyse. II Policlinicor

5 juillet, 1908.
BAER and BLUM. Uber den Abbau von Fettsauren beim Diabetes mellitus.

A. P. P., 59, p. 321, 1908.

- Zur AVirkung der Glutarsaure auf den Phloridzindiabetes. D. m. W.»

1908.

- tiber die Einvvirkung chemischer Substanzen auf die Zuckerausscheidung

und die Azidose, II. H. B., xi, p. 101, 1907.
BAEZA. tiber Adrenalinum-Chlorid u. Anwendung in d. rhinolog. Praxis.

B. k. \V., 1902.

BAHRS, H. Beobacht. v. 38 Fallen v. Addisonscher Krankheit. Diss.h

Gottingen, 1905.

BAINBRIDGE, F. A. Effects of ligature of one ureter. J. o. P. B., n, 1907.

— • Prosecretin in relation to diabetes mellitus. Bioch. Journ., iii, 82, 1907.

BAINBRIDGE, F. A., and BEDDARD, A. P. Secretin in relation to diabetes

mellitus. Brit. Med. Journ., i, p. 429, 1906.
The effects of partial nephrectomy in cats. J. o. P., 35, 1907.
The relation of the kidneys to metabolism. Proc. Roy. Soc., Ser. B.,.

79, 1907.

BALDI, D. Rapporto fra glicosuria ed acetonuria nel diabete sperimentale.
Rif. med., 1892.

- Lo zucchero nell' organismo animale. Lo Sperimentale, 48, p. i, 1894.

- La glicosuria in rapporte con la funzione del pancreas. Arch, di

Farm., iii, 1895.

- De la tiroide distingga un veleno nell organismo. Ibid., vi, 1898.
BALDONI. Der Lungengaswechsel des Hundes nach Exstirp. d. Schilddriise.

M. U., i7. 1900

456 LITERATURE

BALFOUR, F. M. The development of Elasmobranch fishes. Journ. of
Anat. and Phys., vol. x-xii, 1876-1878.

- A monograph of the development of Elasmobranch fishes. London,

1878 and 1885.
— Uber die Entwickl. und die Morph. der Suprarenalkorper (i\ebenmeren).

Biol. CbL, No. 5, 1881.
Handbuch der vergleichenden Embryologie. Ubers v. Vetter. Jena,

1881.
On the nature of the organ in adult Teleosteans and Ganoids, which

is usually regarded as the head-kidney or pronephros. Quart. Journ.

micr. Sc., vol. xii, 1882.
BALLET, G., and ENRIQUEZ, E. Des effets de 1'hyperthryreoidization experi-

mentale. Lamed, moderne, 1895; S. m., 1894.
BALLET, G., and LAIGNEL-LAVASTINE. Un cas d'acromegalie avec lesions

hyperplasiques du corps pituitaire, du corps thyroide et des capsules

surrenales. Nouv. Iconogr. de la Salpetr., xviii, 2, p. 176, 1905.
BALP, ST. Resultati di alcune esperienze di tiroidismo sperimentale. Giorn.

di R. Acad. di Med. di Torino, Jhrg. 67, Nos. 9, 10.
BAMBERGER, H. Krankh. der Nebennieren u. d. chylopoetischen Systems.

Erlangen, 1864.
BANG, IVAR. Chemische Untersuchungen der lymph. Organe. H. B., 4

and 5, 1904.

- Biochemie der Zelllepoide. Asher. Spiro Ergeb., vi, 1907, and viii,

1909.

- Die biologische Bedeutung der Lepoidstoffe. Erg. d. inn. Med. u.

Kind., iii, 1909.

BARBA. Sulla glycosuria surrenale. Rif. med, 1902.
BARBERA, A. G. Uber den Einfluss des J. Jodnatriums und Jodothyrins

auf den Blutkreislauf. P. A., 73, 312, 1900.
BARBERA and BlCCl. Strukturverand d. Nebenniere. Boll. sc. med. Bologna,

n, 1900.
BARBIER. Des rapports entre les lesions des capsules surrenales, les lesions

nerveuses et la maladie d'Addison. G. m., 1892.
BARBIER, H., and CRUET. Opotherapie biliaire. Bull. gen. de Therap.,

1907.
BARDIER. Historique gdnerale du r61e antitoxique des organes. P. m.,

1896.
BARDIER and BAYLAC. De 1'action de 1'adrenaline sur la pression sanguine

des animaux atropinises. C. r. S. B., 56, ii, p. 485, 1904.
BARDIER and BONNE. Modifications produites dans la structure des sur-
renales par la tetanisation des muscles. C. r. S. B., 55, ii, p. 355,

1903.

- Note sur les modifications produites dans la structure des surrenales

par la tetanisation musculaire. J. A. P., 39, p. 296, 1903.
BARDIER and FRAENKEL. Action de 1'extrait capsulaire sur la diurese. C. r.

S. B., 51, p. 544, 1899; J. d. P. P., i, p. 950, 1899.
BARGIER, G., and JOWETT. Synthesis of substances allied to adrenalin.

Proc. Chem. Soc., 21, p. 205.
BARLET, J. M. A case of Addison's disease with hyperpyrexia. Lancet,

September 6, 1902.
BARNABO, V. Sur les rapports entre la glande interstitielle du testicule et

les glandes a secretion interne. II. Policlinico, mars, 1908.
BARON, A. Diabetes suprarenalis. Utschennija Sapisski. Imp. Zit. n.

Landau, 1906.
BARRAND. Etude de la vasoconstriction produite par 1'application locale de

1'extrait aqueux de capsules surrenales. These de Lyon, 1897.
BARTEL, J. Der normale und abnormale Bau des lymphatischen Systems

und seine Beziehungen zur Tuberkulose. W. k. W. , 1907.

- Uber die hypoplastische Konstitution und ihre Bedeutung W. k. W.,

1908.
BARTEL and STEIN. Uber abnormale Lymphdriisenbefunde und deren

Beziehung zum Status thymicoiymphaticus. A. A., p. 231, 1906.
BARTELS, M. Uber Plattengeschwiilste der Hypophysengegend Zeitsch.

Augenk., 16, 1906.
BARTSCH, H. De morbo Addisonii. Diss., Konigsberg, 1867.

LITERATURE 457

BARUCH, F., Ein Fall von Morbus Addisonii. Diss., Prag, 1895.
BASCH, K. tiber die Ausschaltung der Thymus. W. k. W., 1903.

— Bemerkungen zu R. Fischls experimentellen Beitragen zur Frage der

Bedeutung der Thymusexstirpation bei jungen Tieren. Z. e. P., ii,
p. 95, 1905.

— Beitrage zur Physiologic und Pathologic der Thymus. J. K., 64, 1906.
— • Beitrage zur Physiologic und Pathologie der Thymus, II. Uber die

Beziehung der Thymus zum Nervensystem. Ibid., 68, 1908.
— • Uber experimentelle Auslb'sung der Milchabsonderung. Monatsschr. f.
Kinderh., 8, No. 9, Dezember, 1909.

B-ASSO. Uber Ovarientransplantation. A. G., 77, p. 51, 1906.

BATES, W. H. The use of extract of suprarenal capsule in the eye. New

York Med. Journ., 63, p. 647^ May 16, 1896.

The use of the aqueous extract of the suprarenal capsule as a haemo-
static. New York Med. Record, p. 207, February 9, 1901 ; Arch,
of Ophthalmol., 28, 1900.

BATTELLI, F. Dosage colorimetrique de la substance active des capsules
surrenales. C. r. S. B., 54, p. 571, 24 mai, 1902.

- Preparation de la substance active des capsules surrenales. Ibid.,

p. 608, 1902.

- Quantite de substance active contenue dans les capsules surrenales de

differentes especes animales. Ibid., p. 928, 12 juillet, 1902.

- Comparaison entre les proprietes colorantes, toxiques et les modifica-

tions de la pression arterielle produites par la substance active des
caps, surren. Ibid., p. 984.

- Influence des injections intraveneuses continues d'adrenaline sur la

survie des animaux decapsules. Ibid., p. 1138, 18 octobre, 1902.

- Presence d'adrenaline dans le sang d'animaux. Son dosage. Ibid.,

p. 1179, 1902.

- L'adrenaline dans 1'organisme des animaux decapsules. P. nSo, 25

octobre, 1902.

Toxicite de 1'adrenaline en injections intraveineuses. 13 novembre, 1902.
Transformation de 1'adrenaline " in vitro." P. 1435, 13 decembre,

1902.
Transformation de 1'adrenaline dans 1'organisme. Ibid., p. 1518, 27

decembre, 1902.

- Quantite d'adrenaline existant dans les caps, surren. de 1'homme. Ibid.,

p. 1205.

- Influence du travail suivi de repos sur la quantite d'adrenaline existant

dans les capsules surrenales. Ibid., p. 1520, 27 decembre, 1902.

- Recherches sur les vasoconstrictiones du serum sanguin. J. d. P. P.,

vii, p. 625.
BATTELLI, F., and ORNSTEIN, S. La suppleance des capsules surrenales au

point de vue de leur richesse en adrenaline. C. r. S. B., 61, p. 677,

1906.
BATTELLI, F., and ROATTA, G. B. Influence de la fatigue sur la quantite

d'adrenaline existant dans les capsules surrenales. C. r. S. B., 54,

p. 1203, 8 novembre, 1902.
BATTELLI, F., and TARAMASIO, P. Toxicite de la substance active des

capsules surrenales. Ibid., 54, p. 815, 28 juin, 1902.
BATTEN, F. Haemorrhage into the suprarenal capsule. Transact, of Path.

Soc., London, 1898.
BATTIER. L'anesthesie dentaire au moyen de 1'extrait de caps. surr. S. m.,

1902.

BAUDOUIN, H. Myatonie congenitale (maladie d'Oppenheim). S. m., 1907.
BAUER, K. Der chemische Nachweis d. degenerativen Nervenkrankh.

H. B., n, 1908.

BAUM, H. Die Thymusdriise des Hundes. D. Zeitsch. f. Tierh., 17.
BAUM, I. Die ortliche Einwirkung von Nebennierensubstanz, Brenzkate-

chin und Spermin auf die Zirkulation. B. k. W., 1905.

- Zur Wirkung und Verwendung der Nebennierenpraparate, insbesondere

in der Dermatologie. Arch. Dermat. u. Syph., 74, p. 59, 1905.
BAUMANN, E. Uber das normale Vorkommen von Jod im Tierkorper.

Z. ph. Ch., 21, 319, 1896.

-- Uber den Jodgehalt der Schilddriise von Mensch und Tieren. Ibid.,
22, i, 1896.

458 LITERATURE

BAUMANN and GOLDMANN, E. 1st das Jodothyrin (Thyrojodin) der lebens-
wichtige Bestandteil der Schilddruse ? M. m. W., 1896.

BAUMANN and HERTER. Uber die Synthese von Atherschwefelsauren und
das Verhalten einiger aromatischer Substanzen im Tierkorper. Z. ph.
Ch., p. 244, 1877-78.

BAUMEL. Pancreas et diabete. Montpellier med., ser. i, 47, 134, 1882.

- Capsules surrenales et melanodermie. Paris, 1889.

— Nouvelle theorie pancreatique de diabete sucre. Montpellier med.,

1889.

BAYER, G. Methoden zur Verscharfung von Adrenalin- und Brenzkatechin-
reaktionen. B. Z., 20, p. 178, 1909.

— Uber den Einfluss d. Driisen mit innerer Sekretion auf die Autolyse.

S. W. A., 118.
BAYLAC. Atherome experim. de 1'aorte consecutif a Faction du tabac. C. r.

S. B., 1906.
BAYLAC and ALRAREDE. Recherches experimentales sur 1'atherome de 1'aorte

consecutif a 1'action 1'adrenaline. C. r. S. B., 56, ii, p. 640, 1904.
BAYLISS, W. M. On the local reactions on the arterial wall to changes of

internal pressure. J. o. P., 28, p. 220, 1902.

— Die Innervation der Gefasse. E. P., 5, 1906.

BAYLISS, W. M., and STARLING, E. H. The mechanism of pancreatic secre-
tion. J. o. P., 28, pp. 325-353) 1902; and ibid., 29, 1903.

— Die chemische ^Coordination der Funktionen des Korpers. E. P., 5,

1906.

BAYON, G. P. Erneute Versuche liber den Einfluss des Schilddriisenver-
lustes und der Schilddriisenfutterung a. die Heilung der Knochen-
bruche, W. V., 34, 35.

- Beitrag zur Diagnose und Lehre von Kretmismus, &c. Ibid., 30, 1903.

- Uber angeblich verfriihte Synostose bei Cretinen. Ziegl. B. 36.
BEADLES, C. Tumour of the suprarenal body. Transact, of Path. Soc.,

London, 1898.

BEARD, J. The development and probable function of the thymus. An.
An., 9, 1894.

— The sources of leucocytes and the true function of the thymus. Ibid.,.

i 8, 1900.

BEAUJARD, E. Les lesions surrenales dans les nephrites. S. m., 1907.
BECKER. Beitrag zur Thyroidinwirkung. D. m. W., 1895.
BECKER, Ph. F. Der mannliche Kastrat mit besonderer Berliksichtigung

seines Knochensystem. Diss., Freiburg i, Br., 1898.

- Uber das Knochensystem eines Kastraten. A. A., p. 83, 1899.
BECLERE. Opotherapie surrenale. Bull. Soc. med., p. 171, 25 feyrier, 1898.

- Le traitement med. des tumeurs hypophysaires, du gigantisme et de

1'acromegalie par la radiotherapie. Bull, de la Soc. med. des

Hopitaux, pp. 274-293, 1909.

BEEBE. Inhibition of tetany by extract of parathyroids. A. J. P., 19.
BEER, E. Die Nebennierenkeime in der Leber. Z. H., 25, 1904.
BEIER. Untersuchungen liber das Vorkommen von Gallensauren und

Hippursaure in den Nebennieren. Diss., Dorpat, 1891.
BEISSNER. Die Zwischensubstanz des Hodens und ihre Bedeutung. A. m.

A., 51, 1898.

BEITZKE. Zur Biologic der Nebenniere. B. k. W., 1909.
BELAWENTZ. Contribution a Fetude de 1'action de 1'adrenaline sur

1'organisme animal. Ref. J. d. P. P., 5, p. 721, 1903.
BELENOWSKY, G. Essai de preparation de serum anti-intestinal. C. r.

S. B., 63, p. 9, 1907.
BELL, W. B., and HICK, P. Observations on the physiology of the female

genital organs. Brit. Med. Journ., p. 517, 1909.
BENCE, J. Exper. Beitr. zur Entstehung der nephritischen Odeme. Z. k.

M., 67, 1909.
BENDA. Uber den normalen Bau und einige pathol. Veranderungen der

menschlichen Hypophysis cerebri. A. P., p. 373, 1900.

- Beitrage zur normalen und pathologischen Histologie der menschlichen

Hypophysis cerebri. B. k. W., 1900.

- Uber vier Falle von Akromegalie. D. m. W., 1901.

- Die Akromegalie. Deutsche Klinik, iii, 1903.

LITERATURE 459

BEXDA. Patholog. Anatomic der Hypophyse in Flatau-Jacobsohn-Minor.
Handb. d. path. Aunt. d. Nervensystems. Berlin, 1904.

- Die Arteriosklerose im Lichte exp. Forschung. Th. G., IQOQ.
BENDER and LERI. Atrophie des caps, surren. chez les foetus anencephales.

C. r. S. B., 1903.
BENDIX. Intermittierende Polyurie bei Addisonscher Krankh. D. A. kl.

M., 82, 1903.
— Beitrage z. Kenntn. des glykolytischen Fermentes. Z. f. diat. u. phys.

Th., 1899.
BENDIX and BICKEL. Experimentell kritische Beitrage z. Lehre v. d.

Glykolyse. D. m. W., 1902; and Z. k. M., 48, 1903.
BENEDICENTI, A. L'azione dell' adrenalina sulla secrezione pancreatica.

Giorn. della R. Accad. di. med. Torino, 1906; and A. i. B., 45, 1906.
BENEKE, F. W. Studien iiber d. Vorkommen, d. Verbreitung u. Funktion

von Gallenbestandteilen in d. tier. u. pflanz. Organismus. Giessen,

1862.
BENEKE, R. Zur Lehre von der Versprengung von Nebennierengewebe in

die Niere, nebst Bemerkungen zur allgemeinen Onkologie. Ziegl. B.,

19.

BENJAMINS. Uber die Glandulae parathyreoideae. Ibid., 31, 1902.
BENJAMIN, E., and A. v. REUSZ. Uber den Stoffwechsel bei Myxodem.

J. K., 67.

BENNET. Dangers in the use of adrenal preparations. J. A. M. A., 1906.
BENSEN. Beitr. z. Kenntn. d. Organveranderungen nach Schilddriisen-

exstirpation bei Kaninchen. V. A., 170, 1902.
BERARD and ALAMARTINE. Les glandules parathyro'ides et leur tumeurs.

Lyon. chir., 1909. Ref. C. Ch., 1909, p. 1019.
BERARDI, S. Contribute alia patologia del morbo di Addison. Arch. ital.

di. Clin. med., 35, p. 17, 1896.
BERDACH. Ein Fall von primarem Sarkom der Nebenniere. W. m. W.,

1889.

BERDACH and PAL. Zur Pathologic der Nebennieren. B. k. W., 1894.
BERDES. Contrib. a 1'etude des tumeurs des capsules surrenales. A. m. e.,

4, 1892.
BERGEAT. liber 300 Kropfexstirp. a. d. Brunschen Klinik. Bruns Beitr.,

15, 1896.
BERGER. Fall von Tumor der Hypophysengegend mit Sektionsbefund.

Z. k. M., 54, 1904.
BERGMANN, G. v. Der Stoff- und Energieumsatz beim infantilen Myxodem

und bei Adipositas universalis. Z. P. P., V. 43.
BERGONIE and TRIBONDEAU. Action des rayons X sur le testicule du rat

blanc. C. r. S. B., 56, ii. 12 novembre, 17 decembre, 1904; 57, i, 17

Janvier, pp. 154 and 155, 1905.

- Aspermatogenese experimentale apres une exposition aux rayons X.

Ibid., p. 282, 1905.

- Action des rayons X sur Fovaire de la lapine. Ibid., p. 284, 1905.

- L'aspermatogenese experimeu. des rayons X est-elle definitive? Ibid.,

p. 678.

- Lesions du testicule avec des doses de rayons X comment se produisent-

elles ? Ibid., p. 1029, 1905.

- Processus involutif des follicules ovariens apres roentgenisation de la

glande genitale femelle. C. r. S. B., p. 105, 1907.

- Alterations de la glande interstitielle apres rcentgenisation de 1'ovaire.

Ibid., p. 274, 1907.
BERKELEY and BEEBE. Extract of parathyroids. Journ. Med. Res.,

February, 1909.
BERKLEY, H. J. The nerve elements of the pituitary gland. Johns Hopkins

Hosp., 1894, and Brain, 1894.
BERNARD, CL. Legons de Physiologie exper. au College de France. Paris,

1855.
.Memoires sur 1'extirpation du pancreas. C. r. A., 1856.

- Legons de pathologic experimentale (au College de France, 1859-60),

publie 1871.

- Rapport sur les progres de la physiologic generale en France, 1865.

- Vorlesungen Uber Diabetes, libers. Berlin, 1878.

460 LITERATURE

BERNARD, CL. La science experimentale. Paris, 1890.
BERNARD, L. Les syndromes surrenaux. P. m., 1905.

- Du role des glandes surrenales dans les etats pathologiques. Rev. de

med., 1907.

BERNARD, L., and BIGART. Etude anatomo-pathologique des capsules
surrenales dans quelques intoxications experimentales. J. d. P. P.,
iv., pp. 1014-1029^ 1902.

- Sur les reactions histologiques generales des surrenales a certaines

influences pathogenes experiment. C. r. S. B., 54, p. 1219, 1902.

- Reactions histologiques des surrenales au surmenage musculaire.

Ibid., p. 1400, 1903.

- Sur activite fonctionnelle des glandes surrenales dans 1'intoxication satur-

nine experimentale. Ibid., 56, i, p. 59, 1904.

- Les processus secretoires dans la substance corticale de la glande

surrenale. Ibid., 57, ii, p. 504, 1905.

- Lesions des glandes surren. au cours de 1'intoxication biliaire experim.

Ibid., p. 410, 1906.
— Etude anatom. pathologique des glandes surren. des tuberculeux.

J. d. P. P., 1906.
BERNARD, L., BIGART, and LABBE. Sur la secretion de lecithine dans les

capsules surrenales. C. r. S. B., 55, ii, p. 120, 1903.
BERNARD, L., and LAEDERICH. Nephrites experimentales par action locale

sur le reins. C. r. S. B., p. 768, 1907.

BERNARDINI. Ipertrofia cerebrale e Idiotismo. Rivista sper. fren., 13, 1887.
BERNATZKIJ, S. S. Das Lecithin des Knochenmarks normaler und im-

munisierter Tiere und die Verteilung des Phosphats im Organismus.

Diss.j St. Petersb.j 1908.
BERNSTEIN, BOLAFFIO, and WESTENRYK. Uber die Gesetze d. Zuckeraus-

scheidung beim Diabetes. Z. k. M., 66, 378, 1908.
BERRUTTI and PEROSINO. Note sulle capsule surrenali. Giorn. dell' Accad.

med.-chirurg. di Torino, 1857 and 12 giugno 1863; A. per le scienz.

med., 1879.
BERRY, J. M. Influence of adrenaline chloride on toxic doses of cocaine.

A. J. M. S., 1905.
BERTEL. Zur Toxizitat des Adrenalins. Ost.-ung. Vierteljahrsschr. f.

Zahnh., 1905.
BERTHOLD. Transplantation der Hoden. A. P., p. 42, 1849.

- Geschlechtseigentiimlichkeiten. Wagners Handwort. d. Physiol., I,

Braunschweig, 1872.

BERTKAN, PH. Beschreibung eines Zwitters von Gastropacha Quercus.
A. f. Naturgesch., 55, p. 75, 1889.

- Beschreibung eines Arthropodenzwitters. Ibid., 57, p. 229, 1891.
BERTRAM, R. Betrachtungen liber Adenomknotchen an den Nebennieren

Neugeborener und liber Tumoren der Nebennieren. Orth. Festschr.,
1903.

BERTRAND, G. Sur la composition chimique et la formule de 1'adrenaline.
Ann. Inst. Pasteur, 18, p. 672; Bull. soc. Chim., 3, ser, t. 31-32,
pp. 1188, 1289, 1904.

- Sur les relations du chromogene surreaal avec la tyrosine. C. r. A.,

138, 649, 1903.

- Sur la composition chimique et la formule de 1'adrenaline. Ibid., 139,

12, p. 502, 1904.

BERTRAND, M. L'infantilisme dysthyroidien. These de Paris, 1902.
BESNIER. Degenerescence cancereuse complete des deux capsules surrenales.

Bull. soc. anat. de Paris, 1850.

- Melanodermie generalisee avec pigmentation des angles, de la muqueuse

buccale et du prepuce, sans signes certains de cachexie surrenale.

C. r. des reunions clin. de 1'hop. St. Louis, Paris, 1888-89.
BESSMERTNY, CH. Studien iiber antagonistische Nerven. Z. B. 47, p. 400,

1906.
BEST. Uber Glykogen, insbesondere seine Bedeutung bei Entziindung und

Eiterung. Zieglers Beitr., 33, p. 585, 1903.

- Uber lokale Anasthesie in der Augenheilkunde. Vossius' Samml.,

vi, H. 3, 1905.

BESTION. Le sue ovarien. Effets physiol. et therap. These, Bordeaux,
1898.

LITERATURE 461

BlAGI. L' azione del principio attivo della medollare della capsule surrenale

sulla fibra muscolare liscia dell' utero. Rassegna di Ostetr. e Ginec.,

1905; Ref. B. C., iv, p. 762.
BIASOTTI, A. Dell' influenza dell' estratto di ghiandiole surrenali sull'

acceleramento dell'ossificazion dello scheletro. Soc. ital. di ostetr. e

ginec., 1908; Pathologica, 1908.
BIBERFELD, J. Beitrag zur Lehre von der Diurese. XIII. Uber die

Wirkung des Suprarenins auf die Harnsekretion. P. A., 119, p. 341,

1907.

- Pharmakologische Eigenschaften eines synthetisch dargestellten Supra-

renins und einiger seiner Derivate. M. K., 1906; Pharmac. Journ.,
1908.

- Uber Dosierung des in den Wirbelkanal gespritzten Suprarenins.

D. m. W., 1907.

BIECK, P. Beitrage zur Kenntnis der Nierengeschwlilste. Inaug. Diss.,.

Marburg, 1886.

BIEDL, A. Uber die Centra der Splanchnic!. W. k. W., p. 915, 1895.

- Vorl. Mitt, uber die physiol. Wirkung des Nebennierenextraktes.

W. k. W., p. 157, 1896.

- Action de 1'extrait de capsules surrenales sur la pression sanguine.

S. m., 1896.

— • Beitrage zur Physiologic der Nebenniere. Die Innervation der Neben-
nieren. P. A., 67, 1897.

- Schilddriise und Jodothyrin. Hypophysisexstirpation. W. k. W.,

p. 195, 1897.
— Uber eine neue Form des experimentellen Diabetes. C. P., 12, p. 624,

1898.

— • Zur Schilddriisenfrage. W. k. W., p. 1278, 1901.
— • Theoretisches liber das Wesen und die Behandlung des Fiebers.

W. m. W.j 1902.
— • Innere Sekretion. Vorlesungen, 1902. Wein, 1903. Wiener Klinik, 29,.

1903.

- Diskussion zum Vortrage Erdheims. W. k. W., 26, 1906.

- Diskussion zum Vortrage Foges. W. k. W., 615, 1907.

- Diskussionsbemerkung (zu Moskowicz). W. k. W., p. 304, 1908.

- Diskussionsbemerkung (zu v. Haberer und Stoerk). W. k. W., p. 306,

1908.

- Die geschichtliche Entwicklung der Kenntnisse liber die Nebenniere

bis Addison (1885). Janus. Arch. int. pour 1'hist. et la Geogr. medic.,
.. 15 Jg-, iQio.

- Uber die Lipoide der Nebennieren.

BIEDL and BRAUN. Zur Pathogenese der experim. Arteriosklerose.
W. k. W., 1909.

- Das Bild der Kompressionsarteriosklerose.

BIEDL and DECASTELLO, V. Uber Anderungen des Blutbildes nach Unter-

brechung des Lymphzuflusses. P. A., 86, 1901.
BIEDL and KONIGSTEIN, R. Uber das Mammahormon.
BIEDL and KRAUS, R. Experimentelle Studien liber Anaph}daxie. W. k. W.,

1908 and 1909.
Wirkung intravenos injizierten Peptons beim Meerschweinchen. C. P.,

24, 1910.
BIEDL and OFFER, TH. R. Uber Beziehungen der Ductuslymphe zum

Zuckerhaushalt. Hemrnung von Adrenalinwirkung durch die Lymphe.

W. k. W., 1907.

BIEDL and REINER, M. Studien liber Hirnzirkulation und Odem. I. Mitt.
' Uber das Vagusphanomen bei hohem Blutdruck. P. A., 73, 1898,

II. Mitt. Die Innervation der Hirngefasze. P. A., 79, 1899.
— • Offener Brief an den Herausgeber (gegen v. Cyon). P. A., 83, 1900.
BIEDL and ROTHBERGER, J. Die Volhardsche Methode der klinstl. Atmung.

C. P., 23, 1909.
BIEDL and WIESEL, J. Uber die funktionelle Bedeutung der Nebenorgane

des Sympathikus (Zuckerkandl) und der chromaffinen Zellgruppen.

P. A. 3 91, 1902.

462 LITERATURE

BIEDL and WINTERBERG, H. Die Ammoniak entgiftende Funktion der

Leber. P. A., 88, IQOI.
BIEGLIO, A. II ricambio organico nella sindrome miotonica. II Policl. 14,

No. 8.
BIEHLER, R. Ein eigentiimlicher Fall von Morbus Addisonii. Diss.,

Rudolfstadt, 1892.
BIERRING and ALBERT. Secondary manifestations of hypernephromata.

A. M. A., 1904.
BlERRY. Serum nephrotoxique. C. r. A., mai, igoi.

- Recherches sur les nephrotoxines. C. r. S. B., 4 avril, 1903.

BlERRY, H., and GATIN-GRUZEWSKA. L'Adrenaline produit-elle la glycosurie
par son action sur le pancreas? C. r. S. B., 58, p. 904.

- Action physiologique de 1'adrenaline pure. Ibid., p. 902.

- Effets de Pinjection de 1'adrenaline sur les animaux decapsules. Ibid.,

p. 203, 1904.
BlERRY and LALON. Variations du sucre du'sang et du liquide cephalora-

chidien. Ibid., p. 253, 1904.
BIERRY, H. , and MALLOIZEL, J. Hyperglycemie apres decapsulation, effets de

1'injection d'adrenaline sur les animaux decapsules. Ibid., 65, p. 232,

1908.
BIERRY and TERRAINE. Sur 1'amylase et la maltan de sur pancreatique de

secretine. Ibid., 57, ii, p. 257, 1905.
BlESlNG, K. Uber d. Nebennieren u. d. Sympathicus bei Anencephalen.

Diss., Bonn, 1886.

BlGART and BERNARD. Serum surrenotoxique. C. r. S. B., 1901.
BILAND. Uber die durch Nebennierenpraparate gesetzten Gefasz- und

Organveranderungen. D. A. k. M., 87, p. 413, 1906.
BILHARZ, A. Die Genitalorgane schwarzer Eunuchen. Z. w. Z., x, p. 281,

1860.
BlNG, R. Nebenschilddriisen und spontane Tetanieformen. M. K., p. 677,

1908.
BINGEL, A., and STRAUSS, E. Uber die blutdrucksteigernde Substanz der

Niere. D. A. k. M., 96, p. 476, 1909.
BlONDl. Beitr. zur Struktur und Funktion der Schilddriise. B. k. W.,

1888.
— • Contribution a Petude de la glande thyreoide. p. 475. A. i. B., 17,

1892.
BlRCHER, H. Das Myxodem und die kretinische Degeneration. Volkmanns

Sammlung klinischer Vortrage, No. 357, 1890.

— Der endemische Kropf und seine Beziehungen zur Taubstummheit und

zum Kretinismus. Basel, 1883.

- Fortfall und Anderung der Schilddriisenfunktion als Krankheitsursache.

L. O., i, 1896.

— Zur Implantation von Schilddrlisengewebe bei Kretinen. Z. Ch., 98,

H., i.

BlRCHER, E. Zur Pathqgenese der kretinischen Degeneration. Berlin, 1908.

- Experimenteller Beitrag zum Kropf herz. M. K., No. 10, 1910.
BIRNBAUM. Ovarium und innere Sekretion, Sammelreferat. Z. a. P., 8,

1908.
BIRNBAUM and OSTEN, A. Untersuchungen iiber die Gerinnung des Blutes

\vahrend der Menstruation. A. G., 81, 1906.
BlSCHOFF, TH. Beweis der von der Begattung unabhangigen periodischen

Reifung und Loslosung der Eier, &c. Gieszen, 1844.
BITTORF, A. Die Pathologie der Nebennieren und der Morbus Addisonii.

Jena, 1908.

— Adrenalinamie bei Nephritis? Die Loevvische Reaktion. C. i. M.,

p. 33, 1909.
BIZZOZERO and VASSALE. Sur le tissu des glandes excretantes. A. i. B., 9,

1887.
BLACKBURN, W. Primary sarcoma of the adrenal gland. A. J. M. S.,

August, 1906.
BLACKBURN, J. Hypernephroma. A histological study of three cases of

hypernephroma of the kidney and one of the papilliferous adenoma.

New York Med. Journ., No. 7, 1907.

BLAIR, BELL. The pituitary body and the therapeutic value of the in-
fundibular extract in shock, uterine atony and intestinal paresis.

Ibid., p. 1609, 1909.

LITERATURE 463

BLAXCHARD. Note sur Fhistoire de la decouverte de la capsule surrenale.

C. r. S. B., 1882.
BLANCHETIERE and CHEVALIER. Sur la recherche de la choline dans la

pancreas et la thyroide. C. r. S. B., 67, p. 277, 1909.
BLANCK. Exp. Beitr. z. Pathogenese d. Nierenwassersucht. Z. k. M., 60,

p. 472, 1906.
BLEIBTREU. Fall v. Akromegalie (Zerstorung der Hypoph. durch Blutung).

M. m. \Y.j 1905.
BLEIBTREU, L. Uber Beziehungen von Fettgewebsnekrosen und Arterio-

sklerose zum Diabetes mellitus. P. A., 124, 1908; and B. k. W., 1908.
BLOCK, I. Einflusz von Jod, Thyrojodin und Thyroiden auf den Stoff-

wechsel. Wiirzburg, 1896.
BLUM, F. Die Schilddriise als entgiftendes Organ. B. k. W., 1898.

— Die Schilddriise als entgiftendes Organ. V. A., 158, 1899.

— Zur Cheraie u. Phys. d. Jodsubst. in d. Schilddriise. P. A., 77, 1899.

- Neue experimentell gefundene Wege zur Erkenntnis und Behandlung

von Krankheiten, die durch Autointoxikationen bedingt sind. V. A.,
162, p. 375, 1900.

- Uber Nierenveranderungen bei Ausfall der Schilddriisentatigkeit.

V. A., 166, 1901.

— Uber Nebennierendiabetes. D. A. k. M., 71, 1901.

— • Weitere Mitteilungen zur Lehre von dem Nebennierendiabetes. P. A.,

90, p. 617, 1902.

— Gefassdriisen und Gesamtorganismus. P. A., 105, p. 625.

— • Neues u. Altes z. Physiologie und Pathologic der Schilddriise. V., 23,

C. M., 1906.
BLUMENTHAL, F. Uber zuckerabspaltende Korper im Organismus. B. k. W.,

..

- Uber das giykolytische Ferment. D. m. Yv., 1903.

- Uber Organsafttherapie bei Diabetes mellitus. Z. f. diat. u. phys.

Ther. , i, 1898.

- Uber die nichtdiabetischen Glykosurien. Halle, 1909.

- Glykolyse. Eulenburgs Realenzykl., 5, 1909.

BLUMREICH", L., and JACOBY, M., Exp. Unters. liber die Bedeutung der
Schilddriise und ihrer Nebendriisen fur den Organismus. B. k. W.,
1896; P. A., 64, 1896.

BOAS, K. Zur Methodik des Adrenalinnachweises. C. P., 22, p. 825, 20
Marz, 1909.

— Uber den Wert der Sublimatreaktion des Adrenalins. Ibid., 23, p. 252,

1909.
BOCK and HOFFMANN. Uber eine neue Entstehungsweise der Melliturie,

Durchspiilungsglykosurie. A. P., p. 550, 1871.
BOHM, B. Fortgesetze Unters. liber die Permeabilitat der Gesfaszwande.

B. Z., 16, 1909.
BOEHM, R. Uber d. Wirkung d. Barytsalze. A. P. P., 3, p. 216, 1875.

— Uber d. Vorkommen u. d. Wirkung d. Cholins. A. P. P., 19, p. 87,

1885.

BOENINGER, M. Beitrag zur Frage des Nierendiabetes. D. m. W., 1908.
BOERMA. Zur therapeut. Verwendung des Antithyreoidin. Arztl. Rundsch.,

1905.
BOESE and LORENZ. Kropf, Kropfoperationen und Tetanie. W. k. W.,

1909.
BOTTCHER, B. Eine neue Synthese des Suprarenins und verwandten

Verbindungen. Chem. Ber., 42, p. 253, Januar, 1904.
BOGOMOLEZ, A. Zur Frage liber die Yeranderungen der Nebennieren bei

experimenteller Diphtherie. Zieglers Beitr., 38, p. 510, 1905.

- Zur Physiologie der Nebennieren. Folia Serol., iii, 1909.
BOGULJUBOFF, W. L. Zur Chirurgie der Nebennierengeschwiilste. A. k.

Ch., 80, 1906.

BOIXET. Resultats eloign. de soixante-quinze ablations de deux capsules
surrenales. C. r. S. B., 47, p. 162, 1895.

— Resistance a la fatigue chez les rats decapsules. Ibid., p. 273, 1895.

— Nouvelles recherches sur la resistance a la fatigue de rats decapsules.

P. 325-

- Ablations des capsules vraies et accessoires chez le rat d'egout. Ibid.,

p. 498.

464 LITERATURE

BOINET. Action comparee de la fatigue et de la decapsulation sur la toxicite
des extraits musculaires du rat. Ibid., p. 646, 1895.

- Maladie d'Addison experimentale chez le rat d'egout. Ibid., 48, p. 164,

1896.

- Action antitoxique des capsules surrenales sur la neurine. Ibid., p. 364,

1896.

— Nouveaux cas de la maladie d'Addison experimentale. Ibid., 49, pp.

439 and 473, 1897.

— - Diminution de resistance des rats decapsules a 1'action toxique de divers,
subst. p. 466.

- Rech. experim. sur les fonctions des caps, surren. Ibid., 51, p. 671, 1899.

- Troubles nerveux et tremblements observes, chez un Addisonien, a la

suite de trop frequentes injections de capsules surrenales de veau.
Ibid., 51, p. 891, 1899.

- Recherches experimentales sur la pathogenic de la maladie d'Addison.

Revue de med., pp. 136-143, 17 fevrier, 1897.

- Dangers de 1'adrenaline dans certains cas de maladie bronze d'Addison.

C. r. S. B., 55, pp. 1471 and 1474, 1903.

- La mort dans maladie bronzee d'Addison. Arch. gen. de med. I., 1903.

- De 1'Addisonisme. Ibid., ii, 1904.

BOLAU, H. Glandula thyrcoudea u. Gl. thymus bei d. Amphibien. Zool.

Jahrb., 12, 1899.

BOLDT. Glokosurie nach Kropfschwund. D. m. W., 1904.
DE BONIS. Action des extraits d'Hypophyse sur la pression arterielle et sur

le coeur normal ou en etat de degenerescence graisseuse et de la nature

du principe actif de 1'hypophyse. A. i. Ph., p. 211, 1908.
DE BONIS, W., and SUSANNA, V. tiber die Wirkung des Hypophysenex-

traktes auf isolierte Blutgefasze. C. P., 23, p. 169, 1909.
BONNAMOUR, S. Recherches histologiques sur la secretion des capsules

surrenales. C. r. assoc. anat. Montpellier, 1902.

— Etude histologique des phenomenes de secretion de la capsule surrenale

chez les mammiferes. These de Lyon, 1905.
BONNAMOUR, S. and PINATELLE. Note sur 1'organe parasympathique de

Zuckerkandl. Bibliogr. anat. T. xi, pp. 127-136, 1902.
BONNAMOUR, S. and POLICARD. Sur la graisse de la capsule surrenale de la

grenouille. C. r. S. B., 55, p. 471, 1903.
BONNAMOUR and THEVENOT. Variations de resistance des lapins a 1'adren-

aline. C. r. S. B., 66, p. 509, 1909.
Toxine diphterique et adrenaline dans la production de I'atherome

experimental. Ibid., pp. 66 and 387, 1909.

BONNET, R. Lehrbuch der Entwicklungsgeschichte. Berlin, 1907.
BORCHARDT, L. Experimentelles liber den Diabetes bei der Akromegalie.

Ref. D. m. W., 34, p. 946, 1908.

- Die Hypophysenglykosurie und ihre Beziehung zum Diabetes bei der

Akromegalie. Z. k. M., 66, p. 332, 1908.

- Diskussion zum Vortrage Hochenegg. Congr. d. G. Chirurg., 1908.

- Funktion und funktionelle Erkrankungen der Hypophyse. Erg. d. inn.

Med. u. Kinderh., iii, p. 288, 1909.
BORN, G. tiber die Derivate der embryonalen Schlundbogen und Schlund-

spalten bei Saugetieren. A. m. A., 22, 1882.
BORRMANN, B. Ein Fall von Morbus Addisonii zufolge entzundlich-hyper-

plastischer Wucherung der Nebennieren auf traumatischer Grundlage.

D. A. k. M., 86, 1906.

BORUTTAU, H. Erfahrungen iiber die Nebennieren. P. A., 78, 1899.

— Uber den jetzigen Stand unserer Kenntnisse von den Funktionen der

Blutgefaszdriisen. D. m. W., 1899.

- Zur Entstehung des Adrenalins im Tierkorper. C. P., 21, 1907.

- Innere Sekretion. Nagels Handb. der Physiologic, ii, 1907.

BOSSI, L. M. Die Nebennieren und die Osteomalacie. A. G., 83, p. 505,

1907.
Nebennieren und Osteomalacie. C. G., pp. 69, 172, 1907.

- L' influenza delle capsule surren. sulP ossificazione d. scheletro. Gin.

mod., 1908.

— The influence of the suprarenal glands on the bone skeleton in relation

to osteomalacia and rickets. Brit. Med. Journ., 1908.

LITERATURE 465

BOTEANO, E. R. Contr. la physiol. glandei pituitarc la brosca. These.

Bucarest, 1906. Zit. n. Paulesco.
BOTTAZZI, F. Azione dell'adrenalina sul tessuto muscolare liscio esofageo

di Bufo vulgaris. Atti della R. Accad. med. di. Geneva, XVIII;

C. P., IQ, p. 100, 1904.

- Sur quelques alterations de globules rouges du sang a la suite de la

thyroidectomie. A. i. B., 23, 1895.
BOTTAZZI and COSTAXZI. Nuove recerche sull' azione dell' Adrenalina (Clin.)

e della Paraganglina (Vassale) sui muscoli lisci. II torn., 1905;

Ref. C. P., 20, p. 279, 1905.
BOTTAZZI, D'ERRico and JAPPELLI. Wirkung des Adrenalins auf die Speichel-

und Harnabsonderung. B. Z., vii, p. 431, 1908.
BOTTAZZI, F., and TORRETTA, A. Azione dell'adrenalina sulla muscolatura

longitudinale dell' esofago di Bufo yulg. A. d. F., i, pp. 325-331, 1904.
BOUCHARD, CH. Involution senile. Traite de path, gen., 1900.
BOUCHARD and CLAUDE. Recherches experimentales sur Padrenaline.

C. r. A., p. 928, 1902.

BOUCHARDAT. Monographic sur le diabete. Paris, 1875.
BOUCHART. Infiltration de la cornee et mydriase persistante attribuables a

1'adrenaline. La clin. opht., 1904. - - Accidents attribuables a

1'adrenaline. Rev. d'opht., 1905.
BOUCHE, F. Gegenseitige Beeinflussung von Adrenalin und Verdauungs-

storungen. Diss., Freiburg, 1909.
BOON. Les deux glandes a secretion interne de 1'ovaire, la glande inter-

stitielle et le corps jaune. Rev. med. de 1'Est., 1902.

— L'infantilisme et la glande interstitielle du testicule. C. r. A., Janvier,

1904.

BouiN, P., and ANCEL, P. Sur les cellules interstitielles du testicule des
mammiferes et leur signification. C. r. S. B., 14 novembre, 1903.

- Sur la signification de la glande interstitielle du testicule embryonnaire.

C. r. S. B., 19 decembre, 1903.

- La glande interstitielle chez les vieillards, les animaux ages et des

infantiles experimentaux. Ibid., 13 fevrier, 1904.

- Recherches sur les cellules interstitielles du testicule chez les mam-

miferes. Arch, de Zool. exp. et gen., vol. i, 1903.

- Sur les variations dans le developpement du tractus genital chez les

animaux cryptorchides et leur cause. Bibl. anat., torn, xiii, fasc. 2,
1904.

— Sur 1'hypertrophie compensatrice de la glande interstitielle du testicule.

Reponse a M. G. Loisel. C. r. S. B., 56, ii, p. 97, 1904.

- Sur le determinisme des caracteres sexuels secondaires et de I'instinct

sexuel. Ibid., 56, ii, p. 335, 1904.

— La glande interstitielle a seul, dans le testicule, une action generale

sur 1'organisme. Demonstration experimentale. C. r. A., Janvier,
1904.

— Recherches sur la signification physiologique de la glande interstitielle

du testicule chez les mammiferes. J. d. P. P., vi, 1904.

— La glande interstitielle du testicule et la defense de 1'organisme.

Hypertrophie ou Atrophie partielle de la glande interst. au cours de
certaines maladies chez Thomme. C. r. S. B., 57, i, p. 553, 1905.
— - Hypertrophie ou atrophie partielle de la glande interst. dans certains
conditions experimentales. Ibid., p. 554.

- A propos du trophospongiu'm et des canules du sue. Ibid., 57, ii, p. 221,

1905.

— Differenciation d'une membrane propre d'origine epitheliale. C. r. S. B.,

65, 1908.

— Sur le follicule de de Graaf mur et la formation du corps jaune chez

la chienne. Ibid., p. 314.

- Sur les homologies et la signification des glandes a secretion interne

de 1'ovaire. Ibid., 67, pp. 464 and 497, 1909.

BOUIN, P., ANCEL, P., and VILLEMIN. Sur la physiologie du corps jaune de
Tovaire. Recherches faites a 1'aide des rayons X. C. r. S. B., 58,
ii, p. 417, 1906.

- Glande interstitielle de 1'ovaire et rayons X. Ibid., p. 337, 1907.

30

466 LITERATURE

BOULLEXGER. De Faction de la glande thyroide sur la croissance. These

de Paris, 1896.
BOULUD and FAYOL. Sur le dosage colorimetrique d'adrenaline. C. r. S. B.,

55, P. 358, 1903.
BOURNEVILLE. Comparaisons entre les enfants norm, et anormaux au p. d.

vue d. 1. persistance ou 1'absence du thymus. Progr. med., IQOO.

- Idiotie myxcedemateuse ou myxcedeme infantile. Traite de med. de

Brouarde et Gilbert, ix, 1902.

BOVERI, P. Uber die Wirkung des Jods auf das durch Adrenalin erzeugte
Atherom der Aorta. D. m. W., 1906.

- Arteriosclerose experimental chez le singe. C. r. S. B., 65, p. 597,

12 decembre, 1908.
BOYCE and BEADLES. Enlargement of the hypophysis cerebri in myxcedema,

&c. J. o. P. B., October, 1892, and February, 1893.
BOY-TESSIER. L'adrenaline dans 1'hypotension cardio-vasculaire. C. r. S. B.,

57, i, p. 880, 1905.

- Duree de 1'action de 1'adrenaline. Ibid., p. 1097.

Bozzi. Unters. uber die Schilddruse, £c. Zieglers Beitr., 18, 1895.
BOZZOTO. Rapport sur 1'opotherapie. Congr. med. de Turin, 1898.
BRA, M. La methode Brown-Sequard, Traite d'histotherapie. Paris, 1895.
BRACCI, C. Timo e ricambio del calcio. Rivist. di Clinica pediatrica, iii,
p. 572, 1905.

- L'echange du calcium et le calcium des os dans la Thyroidectomie

experimentale. Gaz. des malad. infant, et d'obstetrique, septembre,
1905.

BRADFORD, R. J. The results following partial nephrectomy and the in-
fluence of the kidney on metabolism. J. o. P., 23, p. 414, 1899.

v. BRAMAXX. Uber Schilddriisenimplantation bei Myxodem u. Kretinismus.
D. m. W., 1909.

BRAMWELL, BYROM. Acromegaly in a giantess. Brit. Med. Journ., p. 21,
1894.

- A case of tetania treated by thyroid extract. Ibid., p. 1196, 1895.
Two clinical lectures on Addison's disease. Ibid., January, 1897.

- Ansemia and some diseases of blood-forming organs and ductless glands.

Edinburgh, 1899.

- A case of Addison's disease in which great improvement took place

under open-air treatment and the administration of suprarenal
extract. Brit. Med. Journ., October 28, 1905.
BRANCA, A. Le testicule chez Paxolotl, en captivite. C. r. S. B., 56, p. 243.

- Cellules interstitielles et spermatogenese. Ibid., 350.

BRANDT, ALEX. Anatomisches und Allgemeines liber die sogenannte
Hahnenfedrigkeit und uber anderweitige Geschlechtsanomalien bei
Vogeln. Z. w. Z., 48, p. 101, 1889.

- tiber den Zusammenhang der Glandula suprarenalis mit dem Paro-

varium resp. der Epididymis bei Hiihnern. Biolog. Centbl., 9, 1890.
BRANHAM. Tetany following thyroidectomy3 &c. Ann. of Surg., August,

1908.

BRAT, H. Zur Wirkung des Chlorbaryums und Barutins. B. k. W., 1905.
BRAUER, A. Entwickelung der Excretionsorgane der Gymnophoinen.

Z. A., 23, 1900.

- Beitrage zur Kenntnis der Entwickelung und Anatomic der Gym-

nophionen. III. Die Entwickelung der Excretionsorgane. Zool.
Jahrb., xvi, pp. 1-176, 1902.

BRAUER. Beitrag zur Lehre von den anatomischen Veranderungen des
Nervensystems bei Morbus Addisonii. D. Z. N., 7, pp. 54 and 415,

1895-
BRAULT, A. Maladie du rein et des capsules surrenales. Traite de med.,

v, Paris, 1893.

BRAULT, A., and PERUCHET, E. Maladie d'Addison. S. m., 1892.
BRAUN, H. Uber den Einflusz der Vitalitat der Gewebe auf die ortlichen

und allgemeinen Giftwirkungen lokalanasthesierender Mittel und iiber

die Bedeutung des Adrenalins fvir die Lokalanasthesie. A. k. Ch., 69,
^ p. 541, 1903; and C. Ch., 1903.

- Cocain und Adrenalin. Berl. Klinik. Heft 187, Januar, 1904

- Uber einige neue ortliche Anasthetica (Stovain, Alypin, Novocain).

D. m. W.j 1905.

- Die Lokalanasthesie. Leipzig, 1905 and 2. AufL, 1907.

LITERATURE 467

BRAUN, H. Zur Freilegung der zentralen Teile usvv. Z. Ch., 87.
BRAUN, L. Zur Frage der Arteriosklerose nach Adrenalinzufuhr. W. k. W.,
1905.

- Uber Adrenalinarteriosklerose. S. W. A., 116, 1907.

- Zur Pathogenese und Behandlung der Arteriosklerose. M. K., 1908.
BRAUN, M. Das Urogenitalsystem der einheimischen Reptilien, entwick-

lungsgeschichtlich und anatomisch bearbeitet. Arb. a. d. zool.-zoot.
Inst., Wiirzburg, iv, p. 113, 1878.

- Bau und Entwicklung der Nebennieren bei Reptilien. Ibid., v, p. i,

1882.

- Uber Bau und Entwicklung der Nebennieren bei Reptilien. Z. A.,

1879.
BREARD. Contr. a 1'etude de myxoedeme spontane et son traitement. These,

Paris, 1899.

BREGMANN. Zur Klinik der Akromegalie. D. Z. N., 17.
BREGMANN and STEINHAUS. Zur Kenntnis der Geschwiilste der Hypophyse

und der Hypophysengegend. V. A., 188, p. 360, 1907.

- Deux cas de tumeurs de 1'hypophyse. J. de Neur. de Bruxelles, 1907.
BREISACHER, L. Unters. iiber die gland, thyr. A. A., Suppl., p. 509, 1890.

The clinical application of some thyroid gland experiments.

J. A. M. A., 1903.
BREMER. An improved method of diagnosing diabetes from a drop of blood.

New York Med. Journ., March 7, 1896.
BRETON. La syndrome infantilisme, sa nature dysthyro'idienne. These de

Lille, 1901-02.

BRETON, A. Note sur 1'adrenaline. Gaz. des hop., p. 761, 1903.
BRETON and MICHAUT. Deux cas d'acromegalie. Ibid., p. 142, 1900.
BREUER, R. Beitr. zur Atiologie der Basedowschen Krankheit und des

Thyreoidismus. \V. k. W., 1900.
BREUER and v. SEILLER. Uber den Einflusz der Kastration auf den Blut-

befund weiblicher Tiere. A. P. P., 50.

BREUSS and KOLISKO. Die pathologischen Beckenformen. \Yien, 1900.
BRIAN, O. Uber eine aus Knochenmark bestehende Geschwulst zwischen

Niere und Nebenniere. V. A., 186, p. 258, 1906.
BRIAU. L'innervation du corps thyroide. These de Lyon, 1897.

- De Tinfluence d. 1. castration test, et ovar. sur le developp. du squelette.

Gaz. hebd., 1901.
BRIGIDI, V. Delle capsule suprarenali accessorie. Lo Sperimentale, p. 581,

1882.
BRIN. De 1'evolution des tumeurs propres a la capsule surrenale. These

de Paris, 1892.
BRINCKMANN. Uber Therapie bei M. Basedowii. Inaug.-Diss., Mlinchen,

1905.
BRISSAUD. De Tinfantilisme myxoedemateux. Nouv. Icon, de la Salp.,

- Myxoedeme thyroidien et myxcedeme parathyroidien. P. m., 1898.

- Legons clin. sur les maladies nerveuses. 2e serie, p. 440, 1899.

- LTnfantilisme vrai. Nouv. Icon, de la Salp., 1907.
BRISSAUD and MEIGE. Gigantisme. Rev. neurol., p. 1101, 1904.

Type infantil du gigantisme. Nouv. Icon, de la Salp., 1904.
BRODIE. An experiment upon the glomerula function of the kidney. C. P.,

p. 492, 1901.
BRODIE and DIXON. Contributions of the physiology of the lungs and some

observations on the action of suprarenal extract. J. o. P., 30, p. 476,

1904.
BROOKS, H. and KAPLAN, D. M. The effect of prolonged adrenalin medi-

cation on the human circulatory organs with report of case. Med.

Rec., New York, p. 708, 1908.

BROTZ. Nebennieren und Geschlcchtscharakter. A. G., 88, H. 3.
BROWN-SEQUARD. Recherches experimentales sur la physiologic et la patho-

logic des capsules surrenales. C. r. A., T. xliii, p. 422, 25 aout, 1856.

- Recherches experimentales sur la physiologic des capsules surrenales.

Ibid., t. xliii, p. 542, 8 septembre, 1856; Moniteur des hopitaux, Paris,
1856.

- Recherches experimentales sur la physiologic et pathologie des capsules

surrenales. A, gen. demed., pp. 385-401, 572-598, 1856.

468 LITERATURE

BROWN-SEQUARD. Nouvelles recherches sur les capsules surrenales. C. r.
A., xlv, g fevrier, 1857.

— Nouvelles recherches sur 1'importance, des fonctions des capsules

surrenales. Ibid., t. xlv, p. 1036, 21 decembre, 1857; Journ. de phys.,
i, 1858.

— Des effets produits chez 1'homme par des injections souscoutanees d'un

liquide retire des testicules frais de cobaye et de chien. C. r. S. B.,
pp. 415, 420, 430 and 451, 1 889.

- Experience demontrant la puissance dynamogenique chez 1'homme d'un

liquide extrait de testicules d'animaux. A. d. P., p. 651, 1889.

- Expose de faits nouyeaux a 1'egard de 1'influence sur les centres nerveux

d'un liquide extrait de testicules animaux. A. d. P., pp. 201 and 443,
1890.

— Remarques sur les effets produits sur la femme par des injections

souscoutanees d'un liquide retire d'ovaire d'animaux. Ibid., pp. 456
and 651, 1890.

— Expose de faites nouveaux montrant la puissance du liquide testiculaire

centre 1'affaiblissement du certaines maladies et en particulier la tuber-
culose pulmonaire. Ibid., p. 224, 1891.

- Remarques sur la spermine et liquide testiculaire. Ibid., p. 401, 1891.

- Faits montrant 1'influence du systeme nerveux sur la nutrition et secre-

tions. Ibid., p. 747, 1891.

- Injections de liquide extrait de la gl. thyroide dans des cas de myxcedeme.

Ibid., pp. 178 and 752, 1892.

- Liquide testiculaire. Ibid., pp. 151, 406 and 754, 1892.

— Progres de nos connaiss. a 1'egard de liquide testiculaire. Ibid., pp. 205

and 796, 1893.

— Importance de la secretion interne des reins. Ibid., p. 778, 1893.

— Influence de 1'extrait aqueux des capsules surrenales sur des cobayes

presque mourants a la suite de 1'ablation de ces organs. C. r. S. B.r
p. 410, mai, 1892.

- Influence heureuse de la transfusion du sang normal apres 1'exstirpation
des capsules surrenales chez le cobaye. Ibid., p. 467, 14 mai, 1893.

BROWN-SEQUARD and D'ARSONVAL. Recherches sur les extraits liquides
retires des glandes et d'autres parties de 1'organisme. A. d. P., p. 491,
1891.

— • Injection dans le sang des extraits du pancreas du foie, du cerveau.
Ibid., 1892.

- Nouvelles remarques sur les injections souscutanees et intraveneuses

d'extraits organiques. Ibid., p. 200. 1893.

— Influence physiolog. et therap. du liquide orchitique sur Torganisme.

Ibid., p. 539, 1893.
BROWN, O. H., and GUTIIRIE, C. C. The effects of intravenous injections

of bone marrow extract upon blood-pressure. A. J. P., 14, p. 328,

1905.
BROWN and JOSEPH. The effects of intravenous injection of extract of the

bone marrow of swine on the blood-pressure in dogs. Ibid., i6T

p. no, 1906.
BRUCHANOW, N. Zur Kenntnis der primaren Nebennierengeschwiilste.

Z. H., 20, 1898.
BRUCKNER, J. Sur 1'absence de 1'adrenaline dans le sang des chiens thyroid-

ectomises. C. r. S. B., 64, pp. 1123-24, 1908.

- Sur la secretion thyroidienne. Ibid., 66, p. 481, 1909.

BRUCKNER, J., and JONNESCO, V. Sur la resistance globulaire apres thyreoid-

ectomie. Ibid., 64, 1908.
BRUCKNER, J., and GiASCU, A. A. Disparition de la graisse des capsules

surrenales apres fistule pancreatique chez le chien. C. r. S. B., 65,

p. 697, 1909.
BRUGSCH, Th. Der Einflusz des Pankreassaftes und der Galle auf die

Darmverdauung. Z. k. M.., 58, p. 518.
BRUGSCH, Th. and BAMBERG, K. Zur Frage der Azidosis beim Pankreas-

diabetes des Hundes. Ccntb. f. Phys. u. Path. d. Stoffw., 3, 1908.
BRUHN, J. Ein Fall von Addisonscher Krankheit. Diss., Kiel, 1869.
BRUN, VlTTORIO. Azione dell' estratto di ghiandole paratiroidi contro gli

effeti di veleni convulsivante. Lo Pediastrio, No. 6, 1908.
BRUNEI, L. Etat mental des acromegaliques. These de Paris, 1899.

LITERATURE 469

BRUNN, A. v. Ein Beitrag zur Kenntnis des feineren Baues und der Ent-
\vicklungsgeschichte der Nebennieren. A. m. A., 8, pp. 618-638, 1872.

- Uber das Vorkommen organischer Muskelfasern in den Nebennieren.

Nachr. d. K. Ges. d. Wiss. Gottingen, pp. 421-422, 1873.

- Verdauungsorgane. Ergebnisse der Anat. u. Entw., 4, 1894-5.
BRUXNER, H. Zur Chemie der Lecithine und des Brenzkatechins, Bestand-

teile der Nebennieren. Schweiz. Woch. f. Chem. u. Pharm., 1892.
BRUNNERj K. Experimenta nova circa Pancreas accedit diatriba di lymphae

et pancreatis usu. 1863.

BRUNO, J. Uber Morbus Addisonii. M. m. W., 1902.
BRUNS, P. Zur Frage der Entkropfungs-Kachexie. Bruns Beitr. , 3, 1888.

- Uber den gegenwartigen Stand der Kropfbehandlung. Volkmanns S.,

No. 76, 1884.

— Weitere Erfahrungen und die Kropfbehandlung mit Schilddriisenfiit-

terung. Beitr. k. Chir., 13, 1895 and 16, 1896.
BUBNOW. Beitr. z. Unters d. chemischen Bestandteile d. Schilddriise.

Z. ph. Ch., 8.
BUCHSTAB. Arbeit der Bauchspeicheldriise nach Durchschneidung der

Splanchnici und Vagi. Diss. St. Petersburg, Ref. B. C., i.
BUCURA, K. J. Nachvveis von chromaffinem Gewebe und wirklichen

Ganglienzellen im Ovar. W. k. W., 1907.

— Uber die Nerven in der Nabelschnur und in der Placenta. Z. H.,

1907.

— Beitrage zur inneren Funktion des vveiblichen Genitales. Z. H., 28,

1907.

- Zur Therapie der klimakterischen Storungen und der Dyspareunie

M. m. W., 1909.
BUDAY, K. Beitr. z. Cystenbildung in suprarenalen Nierengeschwiilsten.

Zeigl. B., 24, 1898.
BUDAY and JANCSO. Ein Fall von pathologischem Riesenwuchs.

D. A. k. M., 60, 1898.
BUNZ, R. Uber das Vorkommen von Cholesterinestern im Gehirn.

Z. ph. Ch., 46, 1905.
BURGER. Stoffwechsel d. gesunden Menschen b. Schilddriisenftitterung.

Diss., Halle, 1895.
BURGER and CHURCHMAN. Der Plexus coeliacus und mesentericus und ihre

Rolle beim Abdominalshock. M. G. M. C., 16, pp. 507-549, 1906.
BUKOFZER, M. Uber Adrenalin und seine Wirkung auf die Kapillaren und

deren aktive Kontraktilitat. Allg. med. Cent. Zeit., 1902.

- Die Reaktion der Nasen- und Kehlkopfschleimhaut auf Nebennieren-

extrakte (Adrenalin). D. m. W., 1903.

BULIUS. Osteomalazie und Eierstock. B. G. G., i, 1898.
BULKELEY, F. S. The serum treatment of exophthalmic goitre. Boston Med.

and Surg. Journ., clviiii, p. 626, 1907.
BULLOCH and SEQUEIRA. On the relations of the suprarenal capsules to the

sexual organs. Trans, of the Path. Soc., Ivi, London, 1905.
BULTSCHENKA and DRINKMANN. Blutunters. nach Exstirp. d. Schilddriise.

Allg. med. Cent. Z., 1897.
BUQUET, H. and PACHON, V. Sur 1'action vasoconstrictive de la choline.

C. r. S. B., 67, p. 218, 1909.

- Additions d'effets hypotenseurs de choline et d'adrenaline. Ibid., 67,

p. 274, 1909-
BURANI. Caso classico osteomalacia mascuile. Rass. d. scienc. med.

Modena, ii, 1887.
BURCHARD, O. Acromegalie und Myxcedem. St. Petersb. med. Woch.,

p. 481, 1901.
BURCKHARDT, G. Uber die Leistungen verlagerter Pankreasstucke fur die

Ausniitzung der Nalirung im Darm. A. P. P., 58, p. 251, 1908.

- Ein Beitrag zur Ovarientransplantation (Transplantation von Ovarien

in den Hoden bei Kaninchen). Zeiglers Beitr., 43, H. 3.
BURCKHARDT, L. Die klinische und pathologisch-anatomische Stellung der

malignen Nebennieren-Adenome der Niere. Z. Ch., 55, p. 91, 1900.
BURG. Die Nebenniere und der Morbus Addisonii. Berlin, 1863.
BURGHARD and Bu'MF.NTAL. Uber die spezifische Behandlung des Morbus

Basedowii. Th. G., 1903.

470 LITERATURE

BURNETT, T. C. On the production of glycosuria by the intravenous injec-
tion of seawater made isotonic with the blood. J. B. Ch., iv, p. 57,
1908.

— The inhibiting effect of potassium in sodium chloride glycosuria.

J. B. Ch., v, p. 351, 1908.
BURR. A Case of adiposis dolorosa with necropsy. Journ. of Nerv. and

Ment. Dis., 1900.
BURR, Ch. and REIZMANN, D. Un cas de tumeur pituitaire sans acrome-

galie. Ibid., xxvi, 1893.

BURRESI. Morbo dell Addison. Lo Sperimentale, 1880.
BURTON-OPITZ, R. Stromuhr fur d. Messung der Blutvolumina der Venen.

P. A., 121.

- Uber die Stromung des Blutes in dem Gebiete der Pfortader. I. Das

Stromvolum der Vena mesenterica. P. A., 124, p. 469.

— A method to demonstrate the changes in the vascularity of the sub-

maxillary gland on stimulation of the secretory nerves. J. o. P., 30,

p. 133, 1904.
BURY, S. and JUDSON. A case of Addison's disease in a child treated with

suprarenal extract without benefit ; characteristic lesions found post

mortem. Lancet, 1897.
BUSCH and v. BERGEN. Suprarenal transplantation with preservation of

function. A. J. P., 16, p. 144, 1906.
BUSCHAN. Kritik der modernen Theorien liber die Pathogenese der Base-

dowschen Krankheit. W. m. W., Nos. 51, 52, 1894 and No. i, 1895.
— • Die Basedow'sche Krankheit. Wien, 1894.

— Die Brown-Sequard'sche Methode (Organsaft-Therapie). Heuser, 1895.

— Myxcedem und verwandte Zustande. Leipzig, 1896.

— Schilddriisentherapie. Eulenburg Realenc., 1896.

BUSE, O. Uber Bau, Entwicklung und Einteilung der Nierengeschwiilste.

V. A., 157, 1899.
BUSSANO, G. Contribute alia fisiopatologia della ipofisi. II Tommasi, No.

23, 1908.

BUSSCHER. A propos d'opotherapie renale. La belg. Med., No. 4, 1904.
BUTLER, H. O. A practical experience with adrenalin as a cardial and

vasomotor stimulant. Lancet, March 3, 1906.

CACASE. Giorn. dell' ass. Napoli. dei medici e naturalist!, 1903 zit. nach

Morat u. Doyon.
CACCIOLA, S. Un caso di capsula surrenale accessoria aderente al rene. In :

Alcune osservazioni anatomiche. Padova, 1885.
CADEAC and GUINARD. Quelques fails relatifs aux accidents de la thyreoid-

ectomie. C. r. S. B., p. 468, 1894.

- Remarques sur le role du thymus chez les sujets atteints d'une altera-

tion du corps thyroide ou ethyroides. Ibid., p. 508, 1894.

- Modific. fonctionelles relevees chez les anim. ethyroides. Ibid., p. 509,

1894.
CAFIERO. Sulle alteraz. istolog. ind. nei tessuti da! succhi di organi e dai

sieri citotoss. Rif. med., Nos. 30 and 31, 1903.
CAGIATI, L. Sul rapporto fra le alterazioni delle capsule surrenali ed il

morbo d'Addison. Ibid., vi, 92, 1890.
CAGNETTO, G. Hypophyse et acromegalie. Arch. p. Scienze med., 31, p. 80,

1907.

- Anatomische Beziehungen zwischen Akromegalie und Hypophysentu-

moren. V. A., 176, 1904.

- Neuer Beitrag zum Studium der Akromegalie. Ibid., 187, 1907.
CAILLAU. Notice sur les glandes surrenales suivie d'un discours prononce

sur le meme sujet de Montesquieu en 1718. Ann. clin. d. 1. S. d.

med. de Montpellier, 1819.
CALCAR, R. P. VAN. Immunitatsreaktionen und einige_ ihrer praktischen

Verwendungen fiir Klinik und Laboratprium. Leipzig, 1908.
CALDERARA, A. Mixedema di atrofia della tiroide con ipertrofia della ipofisi.

Giorn. R. Ace. med. Torino, vol. 13, fasc. 7-8, 1907.
CALLARI. Gerodermie, infantilisme, feminisme. Gazz. d. osped., 1901.
CALOGERO. Nebennierenexstirp. und access. Nebennieren bei der Ratte.

These de Paris, 1901 ; C. r. S. B., 1903.

LITERATURE 47 T

CALZOLARI, A. Recherches experim. sur un rapport probable entre la

fonction du thymus et celle de testicule. A. i. B., xxx, i, S. 71.
CAMIA. Ricerche sulla funzione del timo nella Rana. Riv. di pat. nerv. e

ment. I, 3, 1900.
CAMIS. Sul consumo di idrati carbonic nel cuore isolate funzion. Z. a. P.,

8, 1908.
CAMPBELL, A. \V. Notes of two cases of dilatation of the central cavity or

ventricle of the pineal gland. Transact, of the Path. Soc. of

London, 50, p. 14, 1898.
CAMUS, L. Action de 1'adrenaline sur I'ecoulment de la lymphe. C. r. S. B.

56, 1905.

— Greffes parathyroi'diennes chez 1'animal normal et chez 1'animal par-

tiellement ethyroide. Ibid., p. 439, 1905.

- La secretine de 1'intestin du foetus. Ibid., 61, p. 59, 1906.

CAMUS and LANGLOIS. Secretion surrenale et pression sanguine. Ibid.,

52, p. 210, 1900.
CANALIS, P. Contribution a 1'etude du developpement et dc la pathologie

des capsules surrenales. I. M., 4, pp. 312-334, 1887.

- Contribute allo studio dello sviluppo e della patologia delle capsule

soprarenali. Atti della R. Accad. delle Scienze di Torino, xxii,

8 maggio, 1887.

CANNIZARO. Uber die Funktion der Schilddruse. D. m. \Y., 1892.
CANTANI. Trattato delle malattie del ricambio. II Diabete, Napoli, 1875.

Deutsch von S. Hahn, Berlin, 1880.
CANTER, Ch. Contr. a Tetude des fonctions de la gl. thyroide. Merc, med.,

1895.

CANTURI, A. Sul gozzo esoftalmico. Gazz. Osped. e Clin., No. 62, 1908.
CAPELLE. Ein neuer Beitrag zur Basedowthymus. M. w. M., 1908.
— • Die Beziehungen der Thymus zum Morbus Basedowii. Beitr. kl. Chir.,

58.
CAPOBIANCO, F. La pneumonite da tiroidectomia e quella da recisione del

vago nei conigli. Rif. med., p. 166, 1892.

- Sulle fine alterazioni dei centri nervosi e delle radici spinali dopo la

tiroidectomia. Rif. med., 1892; A. i. B., 18, p. 306, 1893.

— La tiroidectomia nei mammiferi. Congr. med. int. Roma, 1894; Rif.

med., 1895.

- Ricerche microsc. e sperim. su gli effetti della tiroidectoma. I. M., n,

1894.

- Sur les effets de la thyroidectomie chez les animaux. A. i. B., 22, 1895.

— Reperto rarissimo e presenza di fibre muscolare striate nelle glandola

tiroide. Rif. med., Ann. IX, vol. i, No. 73; Boll, di soc. di naturalisti
in Napoli.

— Dell' azione di alcuni estratti organici sul lavoro muscolare. Atti della

R. Ace. d. Sc. Fis. e Matem. Napoli, n giugno, 1904.
CAPOBIANCO, F., and MAZZIOTTI, L. Su gli effetti della Paratiroidectomia.

Giorn. intern, delle sc. med., 1897 and A. i. B., 31, 1899.
CAPOLONIGO. Sulla penetrazione per diffusione dell' adrenalina nella

camera anteriore. XVII. Ophthalmologenkongresz. Annalen der

Ophthalmologie, 1905-6; Bph. C., ii, p. 119.
CAPPARELLI. Zur Frage des experimentellen Pankreasdiabetes. Biol. Cbl.,

495, 1893.
CARBONE, T. Das Neurin und die Nebennieren. Congr. int. med., Rom,

1894; C. a. P., 5, 1894.

- Esperience sull' estirpazione della ghiandola timo. Giorn. della real.

Accad. di Torino^ ix, 7, 1897.

CARLE, A. Uber die Exstirpation der Schilddruse. C. P., p. 213, iSSS.
CARLES, J., and MICHEL. Du pouvoir nephrotoxique de la maceration

renale administre par ingestion. C. r. S. B., 58, p. 276, 1905.
CARLIER. Note on the structure of the suprarenal body. An. An., 8, 1893.
CARMICHAEL and MARSHALL. The correlation of the ovarian and uterine

functions. Brit. Med. Journ., 1907.

- Compensatory hypertrophy in the ovary. J. o. P., 36, 1908.
CARNOT. Diabete apres injection de culture bacterique dans le conduit

pancreatique. C. r. S. B., 1894.

CARNOT and AMET. De la degenerescence des ilots dc Langcrhans en dehors
du diabete. C. r. S. B., 57, ii, p. 359, 1905.

472 LITERATURE

CARNOT and DELION. Parathyroidie tuberculeuse. Ibid., 57, li, p. 321,

1905.
CARNOT and GILBERT. Action d'extrait hepatique sur la glycosune exp.

Ibid., 1896.
CARNOT and JOSSERAND. Sur la valeur hemostatique de 1'adrenaline.

Ibid., 54, p. 1346.

- Des differences d'action de Tadrenaline sur la pression sanguine suivant

les vois de penetration. Ibid., 54, p. 14/2, 1903.

- Influence du travail musculaire sur 1'activite de 1'adrenaline. Ibid.,

55, P- 5i, 1903-

CARO. Schilddrusensekretionen und Schwangerschaft in ihren Beziehungen
zu Tetanie und Nephritis. M. G. M. C., 17, 1903.

- Wechselwirkung der Organe mit innerer Sekretion. M. K., 1910.
CARPENTER, MACCARTY. Fall v. malignem Hypernephrom bei einem Kinde.

B. k. W., 1905.

CARRACIDO, R. J. Un dato quimico para la explicacion de la glucosuria

pancreatica. Revista ibero-americ. de ciencias medicas. T., xi,

p. 294, Madr., 1904.
CARRARO, A. Studio comparative sugli effetti delle inizioni di estratto

d'ipofisi e di ghiandofa surrenale. Arch. sc. med. Torino, 32,

pp. 42-80, 1908; and A. i. B., 32.

CARRARO and KUSCHNITZKY. Regeneration der Nebenniere. B. k. W., 1909.
CARREL, A., and GUTHRIE, C. C. Exstirpatipn et Replantation de la glande

thyroide avec reversion de la circulation. C. r. S. B., 57, ii, p. 413,

^1905.
CARRIERS, G. Structure et fonctions du corps pituitaire. Arch. clin. d.

Bordeaux, 1893.
CARRIERE, N. Des dangers de la medication thyroidienne. Nord. med.,

IQOI.

CARRIERE, G., and DELEARDE, A. Sur un cas d'epithelioma atypique
symetrique des capsules surrenales. A. m. e., 12, 1900.

CARRIERE and VANVERTS. Etude experim. sur Faction de la thyroidine dans
la consolidation des fractures. C. r. S. B., p. 535, 1900.

CASELLI, A. Studii anatomici e sperimentali sulla nsiopatologia della
glandola pituitaria. Reggio Emilia, 1900.

- Influence de la fonction de 1'hypophyse sur le developpement de

1'organisme. Riv. sper. di fren., 37, 1900.

- Hypophyse et glycosurie. Ibid., 38, 1900.

- Sui rapporti funzionali della glandola pituitaria colPappareggio

tiroparatiroideo. Ibid., p. 468, 1900.
CASPER, M. Stoffwechselregulierungsorgane bei Tieren. L. O., i, p. 522,

1896.
CASTAIGNE, J. De 1'elimination du pigment noir dans la maladie bronzee.

Bull, de la Soc. anat., xi, 13, p. 510, juin-juillet, 1897.
CASTEIGNE, J., and RATHERY, F. Ligature unilateriale de 1'artere renale.

C. r. S. B., 1901.

Sur les nephrotoxines. Ibid., 17 mai, 1902.

- Toxicite de la subst. renale et nephrotoxines. P. m., 13 aout, 1903.

- Action exercee in vitro sur Tepithel. renal par les serums. A. m. e.,

1903.

- Nephrites primit. unlat. et lesions consec. de 1'autre rein. Ibid., 14,

1902.
DU CASTEL, J. Thyroide et formula leucocytaire. C. r. S. B., 65, pp. 443-

444, 1908.
oASTIGLIONl, G. Un nouveau cas d'acromegalie emeliore par 1'opotherapie

hypophysaire. Gaz. med Italiana, March 23, 1905.
C.ATON and PAUL. Notes of a case of acromegaly, &c. Brit. Med. Journ.,

1893.
oAUSSADE, G. Consid. sur la pathogenic de la maladie d' Addison. Union

med., 1895.

Sur les effets de 1'injection souscoutanee cTextracts de capsules sur-
renales chez les animaux. C. r. S. B., 18 Janvier, 1896.
CAUSSADE and LANLERY, C. Sarcome de la glande pituitaire sans acrome-

galie. A. m. e., 1909.
CAVAZZANI, E. Le funzioni del pancreas ed i loro rapporti col la patogenesi

del diabete. 1892, Venezia.

LITERATURE 473

CAVAZZAM, E. Zur Physiplogie des Duodenums. C. P., p. 370, igoS.

- I nuovi dibattiti sul diabete pancreatico. Arch, di Farmacol., vii, igoS.

- II latte atiroideo nella cura del gozzo esoftalmico. Riv. crit. di clin.

med., ix, igoS.
CECCA, R. Ovar und Nebenniere. Soc. med. chirurg. de Boulogne, mars,

CECCA, R., and ZAPPI, F. Le ghiandole a secreziqne interna dal punto di

vista chirurgico. Boll. d. scienze med. di Bologna, Serie VIII,

vol. iv, H. 3.
CECIL, R. L. A study of the pathological anatomy of the pancreas in ninety

cases of diabetes mellitus. J. e. M., xi, p. 200, March, igog.
CECONI, A., and MICHELI. Intorno alia questione delle nefrolisine. II.

Morgagni, No. 4, igo4.
CECONI, A., and ROBECHI, P. Cytotoxina ovarica. Rif. med., iii, Nos. 65,

66, igo2.
CENI and BESTA. Proprieta terapeutiche specifiche del siero di sangue di

animali immunizzati con siero di animali stiroparatiroidiati. Riv.

Sper. di Freniatria, igp3.
CENTANNI, E. La citoprecipitina e il suo valore diagnostica. Rif. med.,

igoi, 10,02.

— Neurotoxin. Rif. med., igoo; C. f. B., p. gSS, igoi.

— Uber die Autozytoprazipitine. Ibid., pp. gi, 23g, 362, igo3.

- Uber Autozytoprazipitine. 2 Abteilung. Ibid., H. 5 and 6, igo7.

— Sugli edemi nefritici. Pathologica, No. i, igoS.

CERLETTI. Effets des injections de sue d'hypophyse sur 1'accroissement

somatique. A. i. B., 47, p. 123, igo7.

CERLETTI and PERUSINI. Journ. of Mental Pathology, vii, No. 5, igo6.
CERTENET DE DEMAY. Traitement des hemorrhoides par 1'adrenaline.

Journ. de Med de. Bordeaux^ No. 20, igo4.
CERVELLO, V. Notices preliminaires sur 1'action de la neurine. A. i. B.,

5, p. igg, 1884.

- Sur 1'action physiologique de la neurine. A. i. B., p. 172, 1886.
CESA, D. and BIANCHI. Osservazioni sulla struttura e sulla funzione della

cosidetta ghiandola interstiziale dell' ovaia. A. d. F., iv, H. 6.
CESARI, L. La choline dans le liquide cephalo-spinal du chien soumis a

1'epilepsie experimentale. C. r. S. B., p. 66, igo7.
CESARIS, DEMEL. Adenocarcinoma del pancreas. Arch, per le Scienze

mediche, iSgs.
CESTAN and HALBERSTADT. Epithelioma kystique de 1'hypophyse. Rev.

neurol., p. 1180, igo3.
CEVIDALLI, A. Di alcune reazioni dell' adrenalina. Lo Sperimentale, 62,

igoS.
CEVIDALLI, A. and LEONCINI, F. Ricerche sul comportamento post-mortale

del principio attivo delle capsule surrenali. Lo Sperimentale, p. 175,

igog.

— - La docimasia surrenale nella diagnosi medico-forense della morte in

compendio. Ibid., p. 733, settembre-ottobre, igog.
CHAMPXEYS, F. H. A note on the history of the toxsemia of pregnancy.

Journ. of Obstet. and Gyna;c., August, igoS.
CHAMPY, CH. Note sur les cellules interstitielles du testicule chez les

batraciens anoures. C. r. S. B., 64, p. 8g3, igoS.
CHANDLER, G. Hypernephroma as a result of traumatism. N. Y. Med.

Journ., igo4.
CHANTEMESSE and MARIE. Les glandes parathyroi'diennes de Fhomme. Soc.

med. Hop., 10, p. 202, i8g3.
CHARPENTIER, A. Ecrans testiculaires ayant pour base 1'extrait de glande

interstitielle. C. r. S. B., 56, p. 828.
CHARRIN, A. Sur les elevations thermiques d'origine cellulaire. A. d. P.

21, p. 683, iSSg.

— Les toxines; mecanisme de leur action. Rev. gen. des scienc.. pp. 24-32,

15 Janvier, iSgs.

— Les fonctions des capsules surrenales en physiologic pathologique.

S. m., i8g6.

— Les defenses naturelles de 1'organisme. Paris, i8gS.

- Les poisons de 1'organisme. 2 Bande, Encycl. scient., Paris.

474 LITERATURE

CHARRIN and LANGLOIS. Lesions des caps, surren. dans Uinfection.
C. r. S. B., p. 812, 1893.

- Action antitoxique du tissu des capsules surrenales. C. r. S. B., p. 410,

1894.

- Hypertrophie experimentales des capsules surrenales. C. r. S. B., p. 131,

1896.

- Du role ces caps, surren. dans la resistance a certaines infections.

Ibid., 1896.
CHARRIN and LEVADITI. Action d. pancreas sur la toxine diphtherique.

Ibid., 51, 1899.
CHASSEVANT and LANGLOIS. Des gaz du sang efferent des capsules surrenales.

C. r. S. B., p. 700, juillet, 1893.
CHATELAIN. De la peau bronzee ou maladie d'Addison. These Strassbourg,

1859; Ref. Canst. Jahresb., iv, p. 281, 1861.
CHATIN and GUINARD. De la secretion interne du rein. A. m. e., p. 137,

1900.
CHAUFFARD. Maladies du foie, etc. Traite de Med. Paris, i, iii. 1892.

- L'intoxication addisonienne. Sem. Med., p. 74, 1894.

CHAUVEAU and KAUFMANN. Le pancreas et les centres nerveux. C. r. A.,
p. 463, 1893.

- Pathogenie du diabete. Ibid., 226, 1893.

CHENU and MOREL. Localisation de 1'iode dans les glandules parathyroides

externes. C. r. S. B., p. 680, 1904.
CHESNEAU. Tuberculose des capsules surrenales et insuffisance capsulaire.

Paris, 1900.
CHEVALIER, J. L'adrenaline. Bull, de therap., p. 856, 15 juin, 1903.

- Sur la preparation et le tirage des produits opotherapiques. Ibid.,

1908.

CHEVASSU. Tumeurs de testicule. Paris, 1906.
CHEVREL, R. Sur 1'anatomie du systeme nerveux grand sympathique des

elasmobranches et des poisson osseux. These Paris, Arch. zool. exp.

et gen., v, Suppl. p. i, 1889.

- Recherches anatomiques sur le systeme nerveux grand sympathique de

1'esturgeon. C. r. A., 117, p. 441, 1893; Arch, de zool. exp. et gen.

ser., 3, i, ii, 1894.
CHIAJE, S. DELLE. Uber ein Zytotoxin, welches die Fettentartung des

Eierstocks hervorruft. C. G., p. 705, 1908.
CHIARI, H. Zur Kenntnis der akzessorischen Nebennieren d. Menschen.

Z. H., 5. 1884.

CHIARUGI. Di un organo epiteliale, &c. Mon. zool. Ital., 9, 1898.
CHIDICHIMO, F. Azione dell' adrenalina sui muscoli lisci (utero, stomaco

ed intestine). La Ginecol., ibid., 1906; Ref. B. C., v, p. 297.
CHIENE, G. L. Observations on the use of Eucain-B and Adrenalin as a

means of inducing local anaesthesia. Scott. Med. Journ., September,

1904.
CHIRIE, J. L. Les capsules surrenales dans Peclampsia puerperale et la

nephrite gravidique. C. r. S. B., 64, p. 799, 9 Mai, 1908; S. m., 1908.
CHOAY, E. Influence du mode de preparation sur 1'activite des extraits

opotherapeutiques. Bull. gen. de Therap., August, 1908.
CHRETIEN, H. De la thyroidectomie. These, Paris, 1887.
CHRISTENS. Insuffisance parathyroidienne chez la chevre. C. r. S. B., 57,

p. 337, 1905.
CHRISTOMANOS. Uber die Zahl der roten Blutkorperchen in z\vei Fallen

von Nebennierenerkrankung. B. k. W., 1899.

CHROBAK, R. Uber Einverleibung von Eierstockgeweben. C. G. , 20, 1896.
CHROBAK, R., and ROSTHORN, A. v. Die Erkrankungen der \veibl.

Geschlechtsorgane. Nothnagels spec. Path. u. Ther., Bd. xx, II.

Miszbildungen. Wien, 1908.

CHURTON. On the effects of total and of partial destruction of the supra-
renal bodies. Lancet, i, p. 245, 1886.
CHVOSTEK, F., SEN. Suppurative Entziindung der linken Nebenniere.

W. m. P., 1880.
CHVOSTEK, F., JUN. Storungen der Nebennierenfunktion. L. O., 3, 1896.

- Pathologische Anatomie der Nebennieren. Ibid., 9, 2. Abt. 1903.

- Bemerkungen zur Atiologie der Tetanic. W. k. W., 1905.

LITERATURE 475

CHVOSTEK, F., Jux. Beitrage zur Lehre von der Tetanie. Ibid., 1907.

- Myasthenia gravis und Epithelkorperchen. Ibid., 1908.
— • Die menstruelle Leberhyperamie. Ibid., 1909.

- Diagnose und Therapie der Tetanie. D. m. \V., 1909.

ClACClO, C. Sopra i canaliculi di secrezione nelle capsule sopraren. An.
An., 22, 1903.

- Sopra una nova specie di cellule nelle capsule surrenali degli anuri.

Ibid., 23, 1903.

- Ric. sui processi di secrezione cellul. nelle capsule surrenali. Ibid..
^ 23, 1903.

- Sui caratteri citologici e microchimici delle cellule cromaffini. Ibid.,

24, 1903.

- Sui processi secretorii della corteccia surrenale. Ibid., 28, 1906.

- Sur la fine structure et sur les fonctions des capsules surrenales des

vertebres. A. i. B., 43, p. 17, 1905.

- Rapporti istogenetici tra il simpatico e le cellule cromaffini. Arch.

ital. di anat., vol. v, F. 2, pp. 256-267, 1906.

— - Sur la secretion de la couche medullaire de la surrenale. C. r. S. B.,
1906.

- Sur la topographic de 1'adrenaline. Ibid., pp. 333, 334, 1906.

- Sur Penterokinase. Ibid., p. 676, 1906.

- tjber das Vorkommen von Lezithin, &c. C. a. P., 20, 1909.

- Contribute alia conoscenza dei lipoidi cellulari. An. An., 35, 1909.
GIANNI, A. Azione dell' adrenalina nel morbo maculoso di Werlhofi. Rif.

raed., 1906.
CIMORONI, A. Sull' ipertrofia dell' ipofisi cerebrale negli animali stiroidati.

Lo Sperim., 61, H. i, 1907; and A. i. B., 48, H. 13, 1908.
ClOFFl, E. Contribute alia patologia e terapia dell' uremia. XII. Kongr.

int. Med. in Rom, novembre, 1902. Ref. B. C. i, p. 94, 1903.

- Contribute sperimentale alia patogenesi e cura dell' uremia. G. i. d. s.

med., 1903.

- Sulla pretesa specificite delle nefrolisine. Clin. med. ital., 43, No. 5,

1904.

- Smidollamente delle capsule surrenali in due tempi. Clin. med. ital.,

H. 6, 1905; Bph. C., i, p. 270; Gazz. d. Osp., anno 26, No. 4.
CITRON, J. Uber die durch Suprarenin erzeugten Veranderungen. Z. e. P.,

1905.
CiUFFO, G. Azione antitossica sull' adrenalina del siero di animali scap-

sulati. Soc. fra i cultori delle sc. med. e. nat. Cagliari, June 18,

1905; Ref. B. C., iv, p. 752.
CIVALLERI, S. Glandula paratirodea dell' uomo. Policlinico, No. 3, 1902.

- L'hypophyse pharyngienne de rhomme. Anat. Kongr., Marseille, 1908.
CLAIRMOXT, P. Uber ein Hypernephrom-Impfrezidiv in den Bronchiallymph-

driisen. A. k. Ch., 73, 1904.

CLAUDE, H. Acromegalie sans gigantisme. L'Encephale, ann. ii, No. 3,
pp. 295-298, mars, 1907.

- Syndromes d'hyperfonctionnement des glandes vasculaires sanguines

chez les acromegalique. C. r. S. B., 57, ii, p. 362, 1905.
CLAUDE and BLANCHETIERE. La choline dans le sang. J. d. P. P., pp. 86-

101, 1907.
CLAUDE, H., and GOUGEROT, H. Sur 1'insuffisance simultanee de plusieurs

glands a secretion interne (insuffisance pluriglandulaire). C. r. S. B.,

p. 785, 1907.

- Les syndromes d'insuffisance pluriglandulaire, leur place en noso-

graphie. Rev. de med., No. 10, p. 861 ff . ; No. n, p. 950 ft"., 1908.

- Insuffisance pluriglandulaire endocrinienne (I. memoire). J. d. P. P.,

p. 468; ii, memoire, ibid., p. 505, 1908.

CLAUDE, H., and SCHMIERGELD, A. De 1'etat des glandes a secretion interne
dans 1'epilepsie. C. r. S. B., 65, S. 82, 1908.

- L'appareil parathyroiden dans 1'epilepsie (II. note). Ibid., p. 139, 1908.

- Etude de 17 cas d'epilepsie an point de veu de 1'etat des glandes a

secretion interne. Ibid., juillet, 1908; Congres de Dijon, aout, 1908.

- Les glandes a secretion interne dans 1'epilepsie (III note). L'hypophyse,

les surrenales, les ovaires. C. r. S. B., 65, p. 196, 1908.

- Les glandes a secretion interne chez les epileptiques. L'Encephale, 1909.

476 LITERATURE

CLAUDE, H., and VINCENT, CL. Un cas de myasthenie bulbo-^spinale se

rattachant peut-etre a une insuffisance surrenale. Soc. d. Neurologic,

2 juillet, 1908.
CLAUS, R., and EMBDEN, G. Pankreas und Glykolyse. H. B., vi, pp. 214

and 393.
CLAUS and v. d. STRICHT. Contribution a 1'etude anatomique et chnique

de 1'acromegalie. Ann. et Bull, de la soc. de med. de Gand, 1893.
CLEGHORN. The action of animal extracts, £c., on the mammalian heart

muscle. Amer. Journ. of Physiol., 2, p. 273, 1899.

CLEMENS, P. Zum Stoffwechsel bei Morbus Basedowii. Z. k. M., 59). JQ00-
CLEMENT. Les capsules surrenales secretent-elles de 1'acide formique ?

Lyon med. Ann. yj, pp. 1342-1343, 1905. Ref. V.-H., i, p. 16, 1905.
CLOPATT, V.-H. Jahresbericht, ii, p. 508, 1900; Finiska Lakaresell Hand-

lungen, 1899.
CLUNET, J. Accidents cardiaques au cours d'un causes thyroiden base-

dowisie. (Reaction parathyroidienne hypophys. et surrenale.) Arch.

des malad. du cceur, p. 232, 1908.
COATS, J. An adenoid sarcoma with cartilage originating in the pineal

gland. Transact, of the Pathol. Society of London, xxviii, p. 44,

1887.
COE, W. S., and KUNKEL, B. W. The female urogenital organs of the

limbless lizard Anniella. An. An., 26, pp. 219-222, 1905.
COENEN. tiber Nebennierenverpflanzung. A. k. Ch., Si, p. 288, 1906.
CORN, F. Zur Histologie u. Histogenese d. Corp. luteum u. d. interst.

Ovarialgewebes. A. m. A., 62, 1903.

- tiber das Corpus luteum und den atretischen Follikel des Menschen

und deren cystische Derivate. A. G., 87, p. 367, 1909.

COHNHEIM, O. Die Bedeutung des Diinndarms fiir die Verdauung.
B. C., i, p. 169, 1903.

- Physiologic der Verdauung und Aufsaugung. Nagels Handb. d. Phys.,

ii, p. 516.

— Die Verbrennung d. Kohlehydrate im Organismus und ihre Beein-

flussung durch d. Pankreas. Z. ph. Ch., 39, p. 336, 1903.

— Uber Kohlehydratverbrennung. II. Mitt. Die aktivierende Subst. d.

Pankreas. Ibid., 42, p. 401.

— Uber Kohlehydratverbrennung. III. Mitt. Ibid., 43, p. 547.

— Uber Glykolyse. IV. Mitt. Ibid., 47, p. 253.

COLASANTI, G., and BELLATI, L. Uber die Toxizitat des Harns bei der
Addisonschen Krankheit. M. U., 15, 1895.

— Toxicite urinaire dans la maladie d'Addison. A. i. B., xxii, p. 283,

1895.

COLEMAN, WARREN. Tuberculosis of the adrenal bodies unaccompanied by
bronzing. New York Med. Record, 46, 18, 3 November, 1894.

— Adrenal substance in the intestinal haemorrhage of typhoid fever.

Med. News, 1902.

COLLIN. Nervous impulses controlling menstruation and uterine haemor-
rhage. Am. Gyn. and Obst., 6, 1895.

COLLIN and LUCIEN. Nouveaux documents relatifs a 1'evolution ponderale
du thymus chez le foetus et chez 1'enfant. C. r. S. B., 57, ii, p. 716,
1905.

COLLINA. Sulla origine della gl. pituitaria. Riv. sper. d. fren., 1898.

- Sulla struttura d. gl. pituitaria. Riv. pat. nerv., 7, 1903.

COLLINGE, W. E., and VINCENT, S. On the so-called suprarenal bodies in

cyclostoma. An. An., 12, pp. 232-241, 1896.
The suprarenal bodies of the fishes. Nat. Sc., vol. x, No. 63, pp. 318-

322, 1897.
COLLINI, M. Siero citotossico dell' ipofisi. Nuovo Raccloglitore medico,

No. ii, 1902.
COLLMANN. Beitr. z. Kenntn. d. Chondrodystrophia foctalis. A*. A., 166,

1901.
COLMAN, H. A case of Addison's disease with associated Leucoderma.

Lancet, 1900.

COLZI. Sulla estirpazione della tiroide. Lo Sperimentale, 1884.
COMESSATTI, G. Contribute allo studio chimico clinico delle sostanze iper-

tensive. Gazz. Osped., No. 146, 1908.

- Beitrny; zur Kenntnis der drucksteigernden Substanzen. M. m. W.,

1908.

LITERATURE 477

COMESSATTI, G. Un metodo semplice per il dosamento dell' adrenalina
contenuto nelle capsule surrenali del cadavere. Riv. de chim. et
Microscop. Clin., ix, May, 1909.

- Beitr. z. chemischen Nachweis d. Adrenalins im Blutserum. B. k. \Y.,

1909.

- Methode zur Bestimmung des Adrenalins im Xebenmerengewebe.

D. m. \Y., 1909.

- Uber den Wert der Froschbulbusreaktion und einige Eigenschaften des

Adrenalins. A. P. P., 60, p. 233.

- Pankreasextrakt und Adrenalin. Ibid., 60, p. 243, 1909.

COMOLLI, A. Intorno al tessuto di sostegno del corpo surrenale. Monitore

zool. Ital. , an. xviii, Nos. 5 and 6, pp. 158-161, 1907.
COMTE. Contribution a Fetude de I'hypophyse humaine et de ses relations

avec le corps thyroide. These de Lausanne, 1898. Ziegl. B., 23,

1898.
COXDER, A. F. R. On Addison's disease, with two cases, and also a case

which presented the symptoms of disease of the suprarenal capsules.

Edinburgh Journ., p. 275, 1905.
COXTI, A., and CURTI, O. Potere ipertensivo degli estratti surrenali dell'

uomo in alcune forme morbose. Gazz. degli osped. 1906; Bph. C.,

ii, p. 113.

- Effetti fisiologici degli estratti tiroidei ed ipofisari sul circolo. Boll.

scienc. med., 1906.

COOPER, A. Anatomy of the thymus gland. London, 1832.

COPPEZ, H. Sur 1'emploi d'adrenaline en therapeutique oculaire. Journ.
med. Bruxelles, Xo. 51, p. 809, 1902.

CORIAT. The production of cholin from lecithin and brain tissues. A. J. P.,
December i, 1904.

CORXING. Uber Entwicklungsvorgange am Kopfe d. Anuren. Morph.
Jahrb., 27, 1897.

COROXA and MORONI. Contribute allo studio dell' estratto di capsule sur-
renali. Rif. med., Nos. 37-39, p. 433, May 16 to is, 1898.

COROXEDI, G. Innere Sekretion. Archivio di Fisiologia. Novembre,
1904.

- Rapporto fra tiroide e reni. Ricerche comparative interno all' azione

dei dieuretici e dell' estratto tiroideo sul rene del cane etiroidato.
Boll, scienz. med., 80, p. 121.

- Importanza biologica degli alogeni nella funzione tiroparatiroidea ;

contribute sperimentale e teorico. VI. Intern. Kongr. f. Physiol.
Bruxelles, September, B. C., iii, 1381.

— Studio intprno alia fisiologia della glandula tireoidea e delle glandole

paratiroidi. Estratto degli Studi Sassaresi. Anno v, ser. ii, 1-2.
Sassari. 1906-1907.

— L'ablazipne completa dell' apparecchio tiro-partiroideo nei conigli

nutriti con grassi alogenati. Atti dell' Accad. med. fis. Fiorcnt., 1903.

Ref. B. C., i, p. 789, 1903.
COROXEDI and LUZZATTO. L'ammoniaque dans 1'urine du chien thyroid-

ectomise. A. i. B., 47, 1907.
COROXEDI and MARCHETTI. Mixoedema sperimentale. Riv. vcn. di scicnze

med., 21, 10.
COSMA. Einige Worte liber das Adrenalin. Ref. Schmidts Jahrb., 282,

p. 250, 1904.

COSMOVICI. Secretion et excretion. C. r. S. B., p. 607, 1907.
COSTA. Goitre epidemique. These, Lyon, 1897.
DA COSTA, C. Cellulas chromaffinas e adrenalina. Polytechnia Lisboa, i,

pp. 16 and 137, 1905.

- Notes cytologiques sur les cellules corticales des glandes surrenales.

C. R. du XV. Congr. intern, de med. a Lisbonne, 1906.

— Extr. du Bull, de la Soc. Portug. de la Sc. nat. Seance du 29 octobre,

1907. Zit. n. Haberer.
DA COSTA and PERES, C. Glandulas suprarenales e suas homologas. Lisboa,

129 pp., 1905.
DE COULOX. Uber Thyreoidea und Hypophysis der Kretinen sowie liber

Thyreoideareste bei Struma nodosa. V. A., 147, 1896-1897.
COUNSELL, H. E. Case of Addison's disease without pigmentation. Lancet,

3 May, 1890.

478 LITERATURE

COUVEE, H. Die Ursachen des Todes nach doppelseitiger Nephrektomie.

Z. k. M., 54.
COUZIN, P. Accidents aigus de la tuberculose des capsules surrenales.

Paris, 1899.
Cozzi, C. Le alterazioni del fegato nei cani operati di paratiroidectomia

totale. Med. Ital., Iviii, No. 47.
COZZOLINO, O. Intorno agli effetti dell' estirpazione del timo. La Pediatria,

1903.

- Deformazioni dello scheletro in seguito all' ablazione del timo. Ibid.,

p. 620.

- La tetania infantile secondo le recenti vedute etio-patogenetiche. La

Liguria Medica, i, H. 15, 1907.
CRAMER, H. tJber die Verwendung des Adrenalins in der Gyna'kologie.

D. m. W., 1903.
Transplantation menschlicher Ovarien. M. m. W., 1906.

- Zur Physiologic der Milchsekretion. Ibid., 1909.

- Ovarium und Osteomalazie. M. m. W., 1909.

CRAMER, W. On prptagon, chqlin and neurin. J. o. P., 31, No. i, p. 30.
Note on the action of pituitary extracts upon the enucleated frog's eye.

Quarterly Journ. of Exp. Physiol., i, p. 189, 1908.
CREIGHTON, C. A. Points of resemblance between the suprarenal bodies of

the horse and dog and certain occasional structures in the ovary.

P. R. S., 26, 1877.

- A theory of the homology of the suprarenals. J. o. A. a. P., 13. 1878.
CRILE, G., and DOLLEY, D. H. An experimental research into the resus-
citation of dogs killed by anaesthetics and asphyxia. J. e. M., viii,
pp. 713-725, 1906.

CRILE. Experimental researches into the means of controlling the blood-
pressure. J. A. M. A., 1903.
CRISTIANI, H. Sur les glandules thyroidiennes chez le rat. C. r. S. B.,

p. 798, 1892.
Nouvelles recherches sur les organes thyroidiennes de rongeurs. Ibid.,

p. 441, 1893.

Remarques sur Tanatomie et la physiologic des glandes et glandules
thyroidiennes chez le rat. A. d. P., 1893.

- De la thyroidectomie chez le rat. Ibid., p. 39, 1893.

- Des glandules thyroidiennes accessoires chez la souris et la campagnol.

Ibid., p. 279.

- Effets de la thyroidectomie chez les lezards. C. r. S. B., 1894.

- Etude histologique de la greffe thyroidienne. Ibid., p. 716, 10 novembre,

1894-

- De la greffe thyroidienne et son evolution histologique. A. d. P., 1895.

- Vascularisation comparee des greffes thyroidiennes. Rev. med. de la

Suisse romande, 1901.

- De 1'accroissement des greffes thyroidiennes. J. d. P. P., iii, 1901.
Transplantation de thyroidien dans des regions transparentes. C. r. S.

B., p. 679, 1903.

- Infection streptococcique experimentale de greffes thyroidiennes. Ibid.,

713-

- Lesions inflammatoires microbiennes de greffes thyr. , p. 725.

- Injection de subst. bacter. necrosante et cTessence de terebenthe dans des

greffes thyr. Ibid., p. 726.

- Hypertrophie compensatrice de greffe thyr. Ibid., p. 782.
Vitalite des tissus separes de Forganisme. Ibid., p. 828.

- Reimplantation de greffe thyr. reussies. Ibid., p. 1457.

De la greffe thyroidiennes chez les oiseaux. Ibid., 56, i, p. 192, 1904.

- Conservation de tissu thyroidien vivant dans Teau salee physiologique.

Ibid., p. 191.

- De la greffe thyroidienne chez les poissons et les amphibies. Ibid.,

p. 227.
La greffe thyroidienne chez rhomme. Sem. med., p. Si, 1904.

- La guerison du myxrcdeme par la greffe thyroidienne. Ibid., 1905.

- Degenerescence et atrophie experimentale des greffes thyroidiennes

C. r. S. B., 57, i, p. 68, 1905.
Evolution des greffes thyroidiennes superflues. Ibid., 361.

LITERATURE 479

CRISTIANI, H. De la persistance des greffes des glandes parathyroides.
Ibid., 57, ii, p. 754, 1905.

- Proprietes differentes des tissus thyroiden et parathyroidien. Ibid., 57,
r, ii, P-. 756, .1905-

- Evolution histologique de greffes faites avec du tissu thyroidien con-

serve. J. d. P. P., T. 7, p. 261, 1905.
CRISTIANI, H., and A. Recherches sur les capsules surrenales. Ibid., 4.

pp. 838-847, IQ02.

- De la greffe des capsules surrenales. Ibid., 4, pp. 922, 979-982, 1902.

- Role preponderant de la substance medullaire des capsules surrenales

dans la fonction de ces glandes. C. r. S. B., 54, 1902.

- De Tinsuffisance fonctionelle des greffes des capsules surrenales. Ibid.,

1902.

- Degenerescence et atrophie experimentale des greffes thyreoidiennes par

ingestion a dose toxique des pastilles de glande thyroide. C. r. S. B.,
57, ii, 1905.

- Evolution comparee des greffes de jeune tissu thyroiden transplantation

sur des animaux d'age differ. Ibid., 57, i, 530, 1905.
CRISTIANI, H., and FERRARI, E. De la nature des glandules para-

thyroi'diennes. C. r. S. B., 49, 1897.
CRISTIANI, and MLLE. FRIGOFF. Alteration des greffes thyroidiennes

par Temploi de la " Subcutine " comme anesthesique local.

C. r. S. B., 57, p. 689, 1905.
CRISTIANI and KUMNER. Uber funktionelle Hypertrophie der iiberpflanzten

Schilddriisenstuckchen beim Menschen. M. m. W., 1906.
CRISTIANI, H., and OUSPENSKY. Effets de la cocainisation locale sur les

greffes thyroidiennes. C. r. S. B., 56, p. 40, 1904.

- Action des solutions de cocaine sur le tissu thyroidien vivant. Ibid.,

p. 42.
CROFTAN. Uber das diastatische Ferment der Nebennieren. P. A., 90, 1902.

- Notiz liber eine chemische Methode, Hypernephrome (Nebennieren-

Tumoren) der Niere von anderen Nierengeschwuisten zu unter-
scheiden. V. A., 169, 1902.

- Concerning sugar forming ferment in suprarenal extract, a preliminary

report on suprarenal glycosuria. American Medicine, 1902.
CROOM. Uberpflanzung des Ovariums mit nachfolgender Schwangerschaft

und Geburt. Wer ist die Mutter des Kindes ? Edinburgh. Obst. Soc.

Ref. C. G., 1907.
CROVELLI. Friihzeitige Entwicklung der Geschlechtsorgane bei einem 18

Monate alten Madchen. Journ. med. de Bruxelles, 1890
CROWE, S. J., GUSHING, H., and ROMANS, J. Effects of hypophysal trans-
plantation following total hypophysectomy in the canine. Quart.

Journ. Exp. Physiol., ii, p. 389, 1909.
CUENOT, L. Les moyens de defense dans la serie animale. Encycl. scient.,

Paris.
CULLEN, G. M. The Carter literature of the thyroid gland. Edinb. Med.

Journ., 1891-2, p. 531.
CUMMINS, W. T., and STOUT, P. S. Experimental arteriosclerosis by

adrenalin inoculations and the effect of potassium iodide. Univ. of

Pennsylvania. Med. Bull., xix, pp. 100-102, July, 1902; Ref. B. C.,

v, p. 702.
CUNEO and LECENE. Notes sur les cellules interstitielles dans le testicule

ectopique de 1'adulte. Rev. de chirurg., t. xxii, 1900.
CURATULO and TARULLI. Einflusz d. Abtragung d. Eierstocke a. d.

Stoffwechsel. C. G., 1895.

— Sulla secrezione interna delle ovarie. Ann. cli ostetr. e ginec, 1896.
CURTIS, F., and GELLE. De la sclerpse amorphe dissociante et de la

frequence des formes de transition des ilots de Langerhans dans
certaines lesions du pancreas diabetique. C. r. S. B., 57, p. 942, 1905.

— Histogenese de la sclerose amorphe dissociante du pancreas. Ibid.,

P- 943-

- De 1'importance des formes de transitions acmo-msulaircs ou insulo-

aciniques dans 1'interpretation des lesions du pancreas diabetique.
Ibid., p. 966.

GUSHING, H. The hypophysis cerebri. Clinical aspects of hyperpituitarism
and of hypopituitarism. j. A. M. A., 53, pp. 249-255, July 24, 1909.

480 LITERATURE

GUSHING, H. Sexual infantilism with optic atrophy in cases of tumours

affecting the hypophysis cerebri. Journ. of Nervous and Mental

Diseases, xi, 1906.
GUSHING, H., and LEWIS, L. REFORD. Is the pituitary gland essential to

the maintenance of life? Johns Hopkins Hosp. Bull., 20, p. 105, IQOQ.
CUSHNY, A. R. The action of optical isomers. III. Adrenalin. J. o. P.,

37, p. 130, iQoS.

- Further note on adrenalin isomers. Ibid., 38, p. 259, March 22, 1909.
CYBULSKI, N. Uber die Funktion der Nebenniere. W. m. W., 1896.

- Sur les fonctions des capsules surrenales. Gaz. lekarska, March 23,

..

- Uber den Kalkstoffwechsel des tetaniekranken Siiuglings. M. f.

Kinderh., 1906.
CYBULSKI and SZYMONOVICZ. Anz. d. Krakauer Akad. d. W., 4 Februar und

4 Marz, 1895.
CYON, E. v. Beitrage zur Physiologic der Schilddriise und des Herzens.

P. A., 70, 1898; and Bonn, 1898.

- Jodothyrin und Atropin. Ibid., 70, p. 511.

- Jodnatrium und Muscarin. Ibid., 70, p. 643.

- Die Verrichtungen der Hypophyse.- I. Mitt. Ibid., 71, 1898.

- Les glandes thyroides, 1'hypophyse et le coeur. A. d. P., 1898.

- Uber die physiologische Bestimmung der wirksamen Substanz der

Nebennieren. P. A., 72, p. 370.

- Die Verrichtungen der Hypophyse. II. Mitt. Ibid., 72, 635, 1898.

- Die physiologischen Herzgifte. I. Teil. Ibid., 73, p. 42.

— • Die physiologischen Herzgifte. II. Teil. Ibid., 73, p. 339.

— • Die Verrichtungen der Hypophyse. III. Mitt. Ibid., 73, p. 483, 1898.

— Die physiologischen Herzgifte. III. Teil. Ibid., 74, p. 97, 1898.

— Die physiologischen Herzgifte. IV. Teil. Ibid., 77, p. 215, 1899.

- L'innervation du coeur. Richet, Diet. d. Phys., 4, 1899.

- Die physiologischen Verrichtungen der Hypophyse. P. A., Si, 1900.

— - Die Beziehungen des N. Depressor zum vasomot. Centrum. Ibid., 84,

1901.

- Zur Physiologic der Hypophyse. Ibid., 87, 1901.

— • Zur Physiologic der Zirbeldriise. Ibid., 98, 1903.

- Einige \Yorte zur Untersuchung von J. Masay Uber die physiologische

Rolle der Hypophyse. Ibid., 101, 1904.
CYON and OSWALD. Uber die physiologischen Wirkungen einiger aus der

Schilddriise gewonnenen Produkte. Ibid., 83, 1901.

CZYHLARZ v. Tetanic nach partieller Kropfexstirpation. W. k. W., 1902.
CZECZOWICZKA. Zur Kenntnis der durch Zytotoxine im Tierkorper erzeugten

Verandejungen. Z. H., 24, 1903.
CzERNY, A. Hydrocephalus und Hypoplasie der Nebennieren. C. a. P., 10,

p. 281, 1899.
CziRFUSZ, D. Tonogen gegen Hamorrhoiden. Gyog yaszat, 1904.

DAGONET, J. Beitr. z. patholog. Anatomic d. Nebennieren d. Menschen.

Z. H., 6, 1885.
DAHL, F. Nierengeschwiilste, entstanden durch losgerissene (versprengte)

Nierenkeime. Hosp. Tidende, 6 and 7; Ref. Monastb. d. Harn- u.

Sexualapp., p. 125, ipoo.
DAKIN, H. D. The synthesis of a substance allied to adrenalin. P. R. S.,

B., 76, 1905.

- On the physiological activity of substances related to adrenalin. Ibid.,

p. 498.

- Physiological action of synthetical substance allied to adrenalin.

J. o. P., 32.

- Fractionary hydrolysis of optically inactive esters by lipases. J. o. P.,

32, p. 199, 1905.

- A synthesis of certain naturally occurring aliphatic ketones, with a

suggestion of a possible mode of formation of this substance in the
organism (Methyl-n-nonyl-ketone, Methyl-n-heptyl-ketone, Methyl-n-
amyl-ketone). j". Biol. Ch., iv, p. 221, 1908.

- A comparative study of the oxidation of the ammonium salts of

saturated fatty acids with hydrogen peroxide. Ibid., iv, p. 227, 1908.

- Note on the use of paranitrophenylhydrazine for the identification of

some aliphatic aldehydes and ketones. Ibid., iv, p. 235, 1908.

LITERATURE 481

DAKIN, H. D., and KOSSEL, A. Weitere Beitrage zum System der einfach-

sten Eiweiszkorper. Z. ph. Ch., 44, p. 342.
DAKIN, H. D., and RANSOM. Note on the treatment of a case of diabetes

mellitus with secretin. J. Biol. Ch., ii, p. 305, 1907.
DALCHE. Dystrophie ovarienne. Le Bull, med., IQOI.

- La puberte chez la femme. Paris, igo6.

- Hyper- et hypovarie. Gaz. d. hop., 1906.

DALCHE and LEPINE. Opotherapie ovarienne. Progr. med., 1902.
DALE, H. H. The islets of Langerhans of the pancreas. P. R. S., 73, p. 84,
London, 1904.

- Physiological action chrysotoxin. P. Pharmac. S., May 20; and J. o. P.,

32, 1905.

DALLEMAGNE. Trois cas d'acromegalie. A. m. e., 7, p. 589, 1895.
DALTON. A case of acromegaly with diabetes. Transact. Path. Soc., 48,

1897.
DANA. On acromegaly and gigantism. Journ. of Nerv. and Ment. Dis.,

1893 and 1894.
DANIELSEN. Erfolgreiche Epithelkorper-Transplantation bei Tetania para-

thyreopriva. Bruns Beitr., 66, 1910.

DANIELSEN and LANDOIS. Transplantation und Epithelkorper. M. K., 1910.
DANIS. De 1'inrluence de la glande thyroi'de sur le developpement du

squelette. These Lyon, 1896.
DANLOS, APERT and LEVY-FRANKEL. Cyphose heredofamiliale a debut

precoce. Anomalies multiples (mamelons surnumeraires, incisives

de troisieme dentition, acromegalo-gigantisme sur plusieurs membres

de la famille). Soc. med. Hop., 1909.
DANTEC LE, F. La sexualite. Scientia, No. 2, Paris.
DARBY. Anatomy, physiology and pathology of the suprarenal capsule.

Charleston Soc. Rev., xiv, pp. 318-334, 1859.
DARCAN-MOUROUX. Contr. a 1'etude de la menopause precoce. These

Paris, 1904.
DARIER. Nebennierenextrakt. Ophthalm. Ges., Heidelberg, 1896; S. m.,

1895-
DARRE. De 1'influence des alterations du rein sur les glandes surrenales.

These de Paris, 1907; J. d. P. P., p. 714, 1907.

DASTRE. Sur le sucre et le glycogene de la lymphe. A. d. P., p. 532, 1895.
DAVIDSOHN. Das Melanom der Nebenniere. V. d. p. G., xiii, p. 287, 1909.
DAVIS, TH. G. N. Y. Med. News, p. 263, August n, 1906.
DAVIS, A. N. A case of carcinoma of the suprarenal capsule, necropsy.

Lancet, October 3, 1896.
DEBOVE. Adipose douloureuse. Arch. gen. med., 1903.

- Du diabete hypophysaire. J. d. Prat., No. 50, 12 decembre, 1908.
DECKERS and MEESCEN. Suprarenin in der Chirurgie. Gaz. med. Belg.,

15, i, 1903.
DEHLER, A. Beitrag zur Kenntnis vom feineren Bau der sympathischen

Ganglienzellen des Frosches. A. m. A., 46, 1895.
DELAMARE, G. Glandes surrenales. Traite d'anat. p. Poirier et Charpy, iv,

2, 1904.

- Coloration de 1'hypophyse par le triacide d'Ehrlich. C. r. S. B., 56,

p. 743, 1904. .

- Recherches sur la senescence des capsules surrenales. Ibid., pp. 1433-

1483, 1904.
DELAUNAY. Etude sur le role fonctionnel de la glande thyroide. These

Paris, 1896.
DELBET, P. Semiologie des organes genitaux. Bouchard, Traite de path.

gen., v, 1901.
DELEZENNE, C. Activation du sue pancreatique par les sels de calciums.

C. r. S. B., 57, ii, p. 47.6, 1905.

- Action des sels de calcium sur le sue pancreatique, prealablement

dialyse. Ibid., p. 523.

- Sur 1'activation du sue pancreatique par les sels de calcium. Action

antagoniste des sels de potassium. Ibid., p. 614.
— Sur les roles de sels dans 1'activation du sue pancreatique. Specifite

du Calcium. C. r. S. B., 57, ii, pp. 478 and 481, 1905.

DELITALA, F. II fegato del cane dopo Tablazione completa dell' apparato
tiro-paratiroideo. Lo Sperimentale, anno xli, fasc. 4.

31

482 LITERATURE

DELILLE, A. L'hypophyse et la modification hypophysaire. Paris, ^1909.

Daselbst zitiert mehrere Arbeiten desselben Autors mit Renon,.

Monier-Vinard, Vincent. 1907-10.09.
DEMIEVILLE. Deux cas de maladie d'Addison. Rev. med. de la Suisse

rom., iv, No. 9, 1884.
DEMOOR, J., and A. VAN LINT. La serum antithyroidien et son mode

d'action. Memoires couronnes de 1'acad. de Belgique. Bruxelles,.

1903.
DERCUM. Adiposis dolorosa. Univers. med. Magaz., 1888.

- A subcutaneous connective tissue distrophy, &c. A. J. M. S., 1892.
DERCUM and CARTHEY. Autopsy in a case of adiposis dolorosa. Ibid., 1902.
DERRIEU, E. Troubles de 1 utilisation des noyaux aromatiques dans

1'insuffisance surrenale? Montpellier med., 2, t. 25, p. 589, 1908.
DESCROIZILLES. D'un cas de maladie bronzee. Union med., No. 53, 1893.

- Un cas de maladie d'Addison a evolution lente. G. m., 1893.
DESGREZ, A. Influence de la choline sur les secretions glandulaires.

C. r. S. B., p. 52, 1902.
DESGREZ, A., and CHEVALIER, J. Action de la choline sur la pression

arterielle. C. r. A., 146, pp. 89-90, 1908.
DESSY, S., and GRANDIS, V. Contribution a Petude de la fatigue. Action

de 1'adrenaline sur la fonction du muscle. A. i. B., 41, pp. 225-233,.

1904; Rev. Sud-Amer. de scienc. med., an. i, No. 2, April, 1903.
DEXLER. tiber endemischen Kretinismus bei Tieren. Berl. tierarztl. Arch.,.

1909.

DEZIROT, H. Etude sur la maladie d'Addison chez 1'enfant. Paris, 1898.
DHERE. Sur Fabsprption des rayons ultraviolet! par 1'adrenaline. Bull.

de la soc. chimique de France, 4, serie i, p. 834, 1907.
DlAMARE, V. I corpuscoli surrenali di Stannius ed i corpi del cavo.

addominale dei Teleostei. Notizie anatomiche e morfologiche.

Bollet. soc. natur. Napoli, ix, 1895.

— Ricerche intorno all' organo interrenale degli Elasmobranchi ed ai

corpuscoli di Stannius dei Teleostei. Mem. soc. ital. sc., x. Roma,
1896.

- Sulla morfologia delle capsule surrenale. An. An., 15, p. 357, 1899.

— Del valore anatomico e morfologico delle isole di Langerhans. An.

An., 16, 481, 1899.

— Sulla constituzione dei gangli simpatici negli Elasmobranchi e sulla

morfologia dei nidi cellulari del simpatico in generale. An. An., 20,
418, 1902.

- Metaplasma ed immagini di secrezione nelle capsule suprarenale.

Archivio zoolog., vol. i, pp. 121-178, 1903.

— Sullo sviluppo e morfologia delle capsule suprarenali. Bollet. soc.

natur. Napoli, vol. xvii, pp. 55-62, 1903.

- Varieta anatomiche dell' interrenale. Arch. ital. d'anat., vol. iv,

H. 2, pp. 366-369, 1905.

- Studii comparativi sulle isole di Langerhans. I. M., 16, 1899.

- Studii comparativi sulle di Langerhans. 2. Mem., I. M., 22, 1905.

- Zur vergleichenden Physiolo.gie des Pankreas. Versuche liber die

Total-exstirpation des Pankreas und weiters liber die Glykolyse bei
Selachiern. C. P., 19, 1905.

- Zweite Mitt, liber die physiologische Bedeutung der Langerhansschen

Inseln im Pankreas. Ibid., 19, No. 4.

— Sul nuovo indirizzo della questione del rapporto fra pancreas ed

economia del glucosio nell'organismo. Tommasi, 1907.

- Vergleichend-anatomische-physiologische Studien liber den Pankreas-

diabetes. 3. Mitt. C. P., 21, No. 26, 1908.

- Sullo funzione endocrine del pancreas e sugli element! che la dis-

impegnano. Arch, di fisiol., v, p. 253, 1908.

- La secrezione interna del pankreas. Tommasi, No. 9, 1909.
DICKINS, S. J. O. Notes on a case of acute goitre. Lancet, October 24,

1908.
DIDE, D'AuxERRE. Les giandes vasculaires sanguines chez alienes.

Congres de Dijon, aout, 1908.
DIECKHOFF. Beitrage zur pathologischen Anatomie des Pankreas. Diss.,

Rostock, 1894. -- Festschr. Thierfelder. Leipzig, 1895.
DIEM, M. Uber das Vorkommen mydriatisch wirkender Substanzen im

Harn. D. A. k. M., 94, 1908.

LITERATURE 483

DIENST, A. Die Pathogenese der Eklampsie und ihre Beziehungen zur
normalen Schwangerschaft, zum Hydrops und zur Schwangerschafts
niere. A. G., 86.

DIESING, E. Die Regulierung des Mineralstoffwechsels. V. 26 C. M.,
p. 127, IQOQ.

- Beitrage zur Kenntnis der Funktion der Stoffivechseldriisen. C. f. d. g.

Phys. u. Path. d. Stoffw. , iv, p. 209, 1909.

DIETEKLE. Die Athyreosis und die Skelettveranderungen. V. A., 184.
DIETRICH, A. Morphologische Veranderungen in der Autolyse. V. d. p. G.

iv, 1903, p. 8i._
— - Fettbildung. Ibid., ix, p. 212, 1905.

— Fettgehalt pathologischer Nieren. Ibid., xi, p. 10, 1907.

- Naphtholblausynthese und Lipoidfarbung. C. a. P., 19, 1908.

- Wandlungen der Lehre von der fettigen Degeneration. Arb. path.

Inst., Tubingen, 1904.

- Die Fettbildungen im implantierten Gewebe. Ibid., 1906.
DIETRICH and HEYLER. Morphologische Veranderungen bei Autolyse. Ibid.,

1904.

DIEULAFOY. Accidents uremique avec anurie, &c. Soc med. des. hop., 1892.
DIMITROWA, Z. Recherches sur la structure de la glande pineale chez

quelques Mammiferes. Le Nevraxe, ii, H. 3, 1901.
DlSSE, J. Die Nebennieren. In K. v. Bardelebens Handbuch der Anatomic

des M'enschen, vii, i, pp. 162-179. Jena, 1902.
DIXON, W. E. The composition and action of orchitic extracts. J. o. P.,

26, 1900-01.

- The innervation of the frog's stomach. Ibid., 28, 1902.

The paralysis of nerve cells and endings with special reference to the

alkaloid apocodeine. Ibid., 30, 1903.
DIXON, W. E., and HALLIBURTON, W. D. Der Pinealkorper. Quart.

J. e. P., ii, p. 283, 1909; Ref. B.C. IX.
DIXON, W. E., and HAMILL, P. The mode of action of specific substance

with special references to secretin. J. o. P., 38, p. 314, 1909.
DOBROWOLSKAJA, N. A. Zum Chemismus der Verdauung im tierischen

Korper XXII. Mitt. Die Bedeutung des Blutes fur die Magenver-

dauung. Z. ph. Ch., 56, p. 408.

— Contribution a 1'etude des hypernephromes. A. Sc. biol., xii, p. 359,

1907'.

DOBROWOLSKY. Uber Cytotoxine der Ovarien. Gyn. Rundsch., i, 3.
DOEBBELIN. Pseudoacromegalie und Acromegalie. Diss., Konigsberg, 1895.
DONITZ. Cocainisierung des Riickenmarkes unter Verwend. v. Adrenalin.

M. m. W., 1903.
DORNER. Uber Nebennierenblutungen bei Neugeborenen. V. g. M., 3, F.,

xxvi, p. 27, 1903.
DOESCHATE, A. ten. tTber das Vorkommen von Milchsaure bei Eklampsie.

Diss., Utrecht, 1907; Z. ph. Ch., 54, 1907.
DOGIEL, A. S. Die Ausfiihrungsgange des Pankreas des Menschen.

A. A., p. 117, 1893.

— Die Nervenendigungen in den Nebennieren der Saugetiere. Ibid.,

pp. 90-104, 1894.

DOHRN, A. L. Urgeschichte des Wirbeltierkorpers. V. Mitt. d. zool.
Station in Neapel, 1884.

DOLEGA. Ein Fall von Kretinismus. Zieglers Beitr., 9, 1891.

DOLLARD. L'Adrenaline et ses applications therapeutiques. These de Tou-
louse, decembre, 1902.

DOMENICIS, DE. Studii sperim. intorno agli effetti delle estirpazione del
pancreas. Giorn. int. dell, scienz. med., 801, 1889; Atti d. congr.
intern., 3, 391. Roma, 1894.

- Noch einmal iiber den Diabetes pancreaticus. M. m. W., 1891.

- Esperimenti intorno alia glicosuria ed al diabete. Ace. Med. Ch.,

Napoli, 1898.

— Patogenesi della glicosuria che segue all' esportazione del pancreas.

Ibid., 1908.

- Ricerche sperimentali per la fisiologia della capsule surrenali. Gazz.

surrenali. Atti d. R. Accad. medic, chirug. di Napoli, p. 268 ff.,
1892.

— Cause de la mort apres 1'exstirpation des capsules surrenales. A. d. P.,

p. Sio, 1894.

484 LITERATURE

DOMENICIS, DE. Richerche sperimentali per la fisiologia della capsule
surrenali. Gazz. degli osp. Milano, xvii, No. 140, p. 1474, 1896;
Ref. C. i. M., p. 1017, 1897.

— Experimentelle Untersuchungen zur Physiologic der Nebenniere.

Wirkung der Transplantation derselben. W. m. W., 1897.

DONATH. Beitrage zur Path, und Ther. der Basedowschen Krankheit.
Z. k. M., 1899.

DONATI. Ipernefroma maligno del fegato. Arch, per le sc. med., 29,
No. 8, 1905.

DONETTI. Les lesions des cellules du systeme nerveux central apres
Pablation des capsules surrenales. C. r. S. B., 29 mai, 1897.

DONKIN. Addison's disease of very rapid course; remarks. Lancet,
February 2, 1895.

DONZELLO, G., and VlTO TARDO, G. Linfoangiosclerosi da adrenalina.
Sperimentale, 68, 1909.

DOPTER and GouROD. Les capsules surren. dans Puremie experim.
C. r. S. B.j 1904.

DOR. De Faction vasoconstrictive exercee par 1'extrait de capsules sur-
renales sur le conjonctive oculaire. Sem. med., No. 36, 1896; Pro-
vince med.3 12 juillet, 1896.

DOR, MAISONNEUVE and MEURIDS. Ralentissement experimental de la
croissance par Popotherapie orchitique. C. r. S. B., 57, p. 673, 1905.

DORNHOFER. liber Addisonsche Krankheit. Diss., Wxirzburg, 1879.

DOSTOIEWSKY, A. Zur mikroskopischen Anatomic der Nebennieren. Diss
(russisch), Petersburg, 1884 and A. m. A., 27, 1886.

— Uber den Bau des Vorderlappens des Hirnanhangs. A. m. A., 26,

1886.
DOUGLASS. The effect of suprarenal preparation on living protoplasm.

Amer. Journ. Med. Science, 129, p. 98, January, 1905.
DOYON, M. Action compare de la choline et de la pilocarpine sur la teneur

en glycogene du foie. C. r. S. B., 64, 1908.
DOYON, M., and GAUTIER, CL. Action de 1'adrenaline sur la glycogene du

foie. Influence de 1'atropine. Ibid., 64, pp. 866-868, 16 mai, 1908.
DOYON, M., and JOUTY, A. Ablation des parathyroides chez 1'oiseau.

Ibid., p. n, 1904.
DOYON, MOREL and KAREFF. Action de Padrenaline sur le glycogene.

Ibid., 1904.

- Action de Padrenaline sur le glycogene hepatique et le sucre du sang.

Ibid., 1905.
— - Les parathyroides chez la tortue (tortue d'Afrique). Ibid., p. 719, 1904.

- A.ction de 1'adrenaline sur le glycogene du foie. J. d. P. P., vii, p. 998,

1906.

DRECHSEL. Die wirksame Substanz der Schilddrlise. C. P., 9, 704, 1896.
DREVET, Louis. Effets therapeutiques du corps jaune de 1'ovaire en par-

ticulier dans 1'hypofonction de la glande ovarienne, la menopause

naturelle, la menopause post-operatoire. These de Paris, 1907.
DREYER, G. P. On secretory nerves to the suprarenal capsules. A. J. P.,

2, 1899.
DREYFUS. Die Therapie des morb. Basedowii in den letzten Jahren. C. ges.

Th., xxi, 1905.
DROBNIK. Experimentelle Untersuchungen iiber die Folgen der Exstirpa-

tion der Schildruse. A. P. P., 25, 1888.
DRUMMOND. The histological changes produced by the injection of

adrenalin-chloride. J. o. P., 31, p. Si, 1904.
DRUMMOND and PATON, D. N. Observations on the influence of adrenalin

poisoning on the liver, &c. J. o. P., 31, 92, 1904.
DRYFUSS, J. Chemische Unters. lib. die Atiologie der Eklampsie. B. C.,

vii, 492, 1908.
DUBOIS, L. A. L'action des extraits de capsules surren. C. r. S. B., 1896.

- Des variations de toxicite des extraits de capsules surrenales. A. d. P.,

28, 1896.

- De la pathogenic et du traitement de la maladie d'Addison. Nancy,

1896.

- Action de Padrenaline et de Panagyrine sur la circulation des muqueuses

linguales et bucco-labiale. C. r. S. B., 56, p. 355, 1904.

— Les changements de la coloration de la muqueuse linguale comme

indicateur du mecanisme d'action des agents vasoconstricteur. Ibid.,
p. 562.

LITERATURE 485

DUBOIS, R. The ductless glands. Brit. Ass. Adv. of Sc., 1906; V. H. i,

1907-

DUBREUILLE. Un cas de melanodermie generalisee. Ann. de dermat., p. 76,

1891.
DUBS. Rech. histol. s. le pancreas diabet. et non diabetique. These Paris,

1907.
Du CASTEL. Melanodermie. Maladie d'Addison on acanthisis nigncans.

Ibid., p. 1282, 1896.
DUCCESCHI, V. Sur les albuminoides du sang chez le chien thyroidectomise.

A. i. B., 24, p. 23, 1896.

— Les processus d'oxydation de reduction et de synthese chez les animaux

thyroidectomises. Ibid., p. 209, 1896.
DUCCESCHI, V., and TALLARICO, G. Sulla determinazione sperimentale del

sesso. A. d. F;, i, 1904.
DUCHESNEAU. Contribution a 1'etude anatomique et clinique de 1'acrome-

galie. These de Lyon, 1891.
DUCLOS. Contribution a 1'etude des capsules surrenales dans la race negre.

Rev. gen. de clinique et de therapeut. Paris, 1890.
DUCROT, R. L. Etude sur le role secretaire du liquide cephalorachidien par

les plexus choroides. These de Bordeaux, 1905.

DUDGEON, S. L. The etiology, pathology and diagnosis of adrenal haemor-
rhage. A. J. M. S., 1904.
DUFOUR, G. La pathogenic capsulaire de la maladie bronzee. These de

Paris, 1894.
DUNCANSON, J. GRAY. A note on the therapeutic value of adrenalin. Brit.

Med. Journ., 1903.

— The danger of suprarenal treatment in haemophysis. Ibid., p. 603,

March 12, 1904.
DUNGERN, v. Histologie d. Nebennieren bei Morbus Addisonii. Diss.,

Freiburg i. B., 1892.
DUPAIGNE. Opotherapie surrenale chez les Addisoniens. These de Paris,

1896.
DUPRAS, A. Hypernephrome de la capsule surrenale droite. Exstirpation

Guerison. Etude chimique et anatomo-pathologique. Rev med. de la

Suisse rom., No. 3, 1906.
DUPRE and PAGNIEZ. Infant, degeneratif (type Lorain) complique de dys-

thyroidie puberale (type Brissaud). Nouv. Iconographie de la

Saltpetriere, No. 2, 1902.
DURCK. Atrophie und Hypoplasie der Hoden. Munch. Arztever., Ref. in

M. m. W., Marz, 1907.
DURIG. Ein Beitrag zur Serumbehandlung des Morbus Basedowii.

M. m. W., 1905.
DURST, H. Uber einen Fall v. kompensat. Hypertrophie d. Nebenniere.

Diss., Zurich, 1899.
DUTTO. Diabete pancreatico. Bull, della R. Accad. Med. di Roma, 283,

1893.
DUTTO and Lo MONACO. Sur le metabolisme chez les chiens prives du

thyroide. A. i. B., 24, 1895.
DWORNITSCHENKO. Uber die Thymus der Erwachsenen in gerichtlich

medizinischer Beziehung. V. g. M., 3, F., Bd. 14.

EASTERBROOK. Action of thyroid and parathyroid extract upon metabolism.

Lancet, ii, 1898 and Brit. Med. Journ., September, 1900.
EASTWOOD, A. Malignant tumours from adrenal remnants. Transact.

Path. Soc., 53, 1902.
EBERTH, J. C. Die Nebennieren. Strickers Handb. d. Lehre v. d. Geweben.

i, Leipzig, 1871.

— Intrakranielles Teratom mesodermalen Ursprungs. V. A., 153, 1898.
— - Die mannlichen Geschlechtsorgane. Bardelebens Handb. d. Anat.,

vii, 1904.
EBNER, V. v. Kollikers Handbuch der Gewebelehre. 6 Aufl., Bd., 3,

Leipzig, 1899.
EBSTEIN, \V. Peritonitisartiger Symptomenkomplex im Endstadium der

Addisonschen Krankheit. D. m. W., 1897.
ECKER, A. Der feinere Bau der Nebennieren beim Menschen und den vier

Wirbeltierklassen. Braunschweig, 1846.

486 LITERATURE

ECKER, A. Blutdriisen in R. Wagner's Handworterb. d. Phys., iv, p. 128,

1853-
ECONOMO, C. J. Zur Entwicklung v. Vogelhypophyse. S. A\ . A., 108,

1899.
EDEL. Uber einen giinstigen Erfolg durch Behandlung mit Nebennieren-

tabletten in einem Falle von Morbus Addisonii. M. m. W., 1900.
EDELMANN, J. A. Die Bewegungen des Magens und der Ubergang des

Mageninhaltes aus dem Magen in den Darm. Diss., 1906.
EDINGER. Bau der nervosen Zentralorgane. 7 Aufl., 1908.
EDKINS, E. S. The chemical mechanism of gastric secretion. J. o. P.,

34, P- 133, 1906.
EDKINS, E. S., and TWEEDY, M. The chemical mechanism of gastric

secretion. Ibid., 38, p. 263, 1909.
EDMUNDS, C. W. Experiments of, on the thyroid and parathyroid glands.

J. o. P., 1895- .

- Further observations and experiments on the thyroid and parathyroid.

J. of Path, and Bact., i, p. 64, 1899; ii, p. 71, 1901; iii, p. 288, 1903.
— - Thyroid of puppy of thyroidless bitch. Transact. Path. Soc. London,
51, p. 221, 1900.

— The pathology of exophthalmic goitre. Brit. Med. Journ., 1901.

- The parathyroid glands. Lancet, vol. 174, 1908.

The treatment of Graves's disease with the milk of thyroidless goats.

Lancet, April 10, 1909.
EDMUNDS, W. The influence of digitalis, strophanthus and adrenalin

upon the velocity of the blood current. A. J. P., 18, pp. 129-148,

1907.
EDSALL and MILLER. Chemical pathology of acromegaly. ALed. Bull.

Univ. Pennsylvania.
EECKE, A. VER. Corps thyroi'de et echanges organiques. A. int. de pharm.,

4, 1892.

- Modifications de la cellule pancreatique pendant la secretion. A. B.,

xiii, 1895.

- Nouvelle contribution a 1'anat. et phys. du thymus chez la grenouille.

Bull. d. 1'acad. R. d. med. de Gand, Belgique, t. 78, p. 103, 1899.
EGDAHL, A. A study on the effect of intravenous injections of solutions

of pancreatic tissue and the cause of collapse in acute pancreatitis.

J. E. M., 9, 1907.
EGGELING, H. Eine Nebenniere im Lig. hepatoduodenale. An. An., 21,

1902.
EHREXBERG, R. Uber alimentare Glykosurie bei Psychosen. M. Psych.,

25, pp. 1-13, 1909.
EHRHARDT, O. Uber epileptisches Auftreten der Tetania thyreopriva.

M. G. M. C., 10, 1902.
— • Morbus Basedowii. D. Ch., 38, IQOI.
EHRICH, E. Klin. u. anat. Beitr. z. Morbus Basedowii. Beitr. kl. Chir.,

28, 1900.
EHRMANN, R. Uber eine physiologische Wertbes.timmung des Adrenalins

und seinen Nachweis im Blut. A. P. P., 53, p. 96, 1905.

— Uber die Wirkung d. Adrenalins auf. d. Hautdriisensekr. d. Frosches.

Ibid., p. 137.

— Zur Physiologic und experimentellen Pathologie der Adrenalin-
__ sekretion. A. P. P., 55, p. 39, 1906.

- Uber d. Einfl. d. Ausschaltung des Zwolffmgerdarms auf die Zuckeraus-

scheidung. P. A., 119, 1907.

- tiber Substanzen, die die Zuckerausscheidung nach Injektion von

Adrenalin zu hemmen imstande sind. B. k. W., 1908.

- Beitrag zur Physiologic der Nebennieren und liber im Blut vorhandene

und andere pupillerierweiternde Substanzen. D. m. W., 1908.

— Zur Methode des qualitativen und quantitative!! Nachweises kleinster

Adrenalinmengen in Blut und Korperfliissigkeiten. D. m. W., 1909.

— Bemerkungen zu der Arbeit von R. H. Kahn zur Frage der inneren

Sekretion des chromaffinen Gewebes. P. A., 129, 1909.
EHRMANN, R., and LEDERER. R. Uber das Verhalten des Pankreas bei

Achylie und Anaziditat des Magens. D. m. W., 1909.

ElCHLER, F. Uber die adrenalinahnliche \Yirkung des Serums Nephrek-
^ tomisierter und Nierenkranker. B. k. W., 1907.

— Experimentelle Beitrage zur Diagnose der Pankreaserkrankungen.

Ibid, 1907.

LITERATURE 487

TIICHLER, F., and SILBERGLEIT. Uber Glykosurie, hervorgerufen durch

Veratzung und Verschorfung der Innenflache des Darmes. B. k. W.,

1908.
ElJSSELSTEYN, G. VAX. Een geval van Morbus Addisonii. Needed. Week-

blad, 14 Mai, 1898.
EISELSBERG, A. v. Uber Tetanic im Anschlusz an Kropfoperation.

Wien, 1890.
Weitere Beitr. z. Lehre von d. Folgezustanden der Kropfoperation.

Festsch. f. Billroth. Stuttgart, 1892.

- Uber Vorkommen und Behandlung der Tetania parathyreopriva beim

Menschen. Beitr. Phys. Path. Festschr. Hermann, pp. 1-21, 1908.
Uber erfolgreiche Einheilung der Katzenschilddriise in die Bauchhohle

und Auftreten von Tetanie nach deren Exstirpation. W. k. W., 1892.
Wachstumsstb'rungen bei Tieren nach friihzeitiger Schilddrusen-

exstirpation. A. k. Ch., 49, 1895.

- Schluszbemerk. zu H. Munks Aufsatz. V. A., 154, 1898.

- Diskussionsbemerkungen zum Vortrag von Exner. Ref. M. m. W.,

1909.

- Die Krankheiten der Schilddriisen. D. Ch., Lief, 38, 1901.

- Diskussion zum Vortrag Erdheim. W. k. W., 781, 1906.

- Uber operative Behandlung der Hypophysentumoren. W. k. W., 1907.
Diskussion zum Vortrage Hochenegg. Kongr. d. d. Ges. f. Chir.

Berlin, 1908.
EISELSBERG, A. VON., and FRANKL-HOCHWART, L. v. Operative Behandlung

der Tumoren der Hypophysisgegend. N. C., No. 21, 1907.
— Neuer Fall von Hypophysisoperation bei Degen. adiposo-genitalis.

W. k. W., 1908.
EISELT, R. Vymena latek pri onoemocneui Addisonoen (Uber den Stoff-

wechsel bei der Addisonschen Krankheit). Sbornik lekarsky, X. H. 5,

1909.

ElSENLOHR. Zur Kasuistik der Tumoren der Hypophysis. V. A.. 68, 1876.
ELLENBERGER, W. Vergleichende Histologie der Haussaugetiere. Berlin,

1887.
ELLINGER and SEELIG. Der Einflusz von Fieber, Infektion und Nieren-

schadigung auf die Suprarenin-Glykosurie. M. m. W., 1905.
Festschrift zum 60. Geburtstag von Max Jaffe, p. 347, Braunschweig,

i go i.
ELLIOTT. On the innervation of the ileocolic sphincter. J. o. P., 31, p. 57,

1904.

- Antiperistaltic and other muscular activities of the colon. Ibid., 31,

p. 272.
The action of adrenalin. Ibid., 32, p. 401, 1905; and Brit. Med. Journ.,

1905.
ELLIOTT and DURHAM. On subcutaneous injections of adrenalin. Ibid.,

34, p. 490, 1906.
ELLIOTT and TUCKETT. Cortex and medullar in the suprarenal glands.

Ibid., 34, p. 332, 1906.

ELOY, CH. La methode de Brown-Sequard. Paris, 1893.
ELSASSER, O. Uber die Haufigkcit und die Bedeutung der isolierten

primaren Nebennierentubcrkulose. Arb. a. d. Geb. d. path. Anat. u.

Bakt. v. p. 45, Tubingen, 1904.
EMBDEN and ALMAGIA. Uber Zuckerausscheidung pankreasloser Hunde

nach Alanindarreichung. H. B. , 7, p. 298, 1905.
EMBDEN, G., and FURTH, O. v. Uber die Zerstorung des Suprarenins

(Adrenalins im Organismus). H. B., 4, pp. 421-429, 1904.
EMBDEN and SALOMON. Uber Alaninfiitterungsversuche am pankreaslosen

Hunde. H. B., 5, 507; 6, p. 63, 1904.
EMBDEN, SALOMON, and SCHMIDT. Uber Azetonbilding in der Leber.

H. B., 8, 1906.
EMBDEN, LUTHJE and LIEFMANN. Uber den Einflusz der Auszentemperatur

auf den Blutzuckergehalt. H. B., 10, p. 265, 1907.
EMERSON, H. Cardiac insufficiency due to high arterial pressure. Proc.

Soc. Exper. Biol. Med., vol. v, pp. 1-3.
EMERY, C. Zur Morphologie der Kopfniere der Teleostier. Biol. C., i,

pp. 527-529, 1881.

- Studi interne allo sviluppo ed alia morfologia del rene dei Teleostei.

Mem. R. Accad. Lincei Roma, vol. xiii, pp. 43-50 (see also A. i. B.,
T. ii, 1882).

488 LITERATURE

EMERY, C. Zur Morphologic der Kopfniere der Teleostier. Erwiderung an
Herrn G. Grosglick. Z. A.., No. 212, Jahrg. 8, pp. 742-744, 1885.

- La determinazione del sesso dal punto di vista biologico. Bologna,

1904.
EMMERT, J. Die Wirkung subkutan einverleibten Adrenalins. V. A., 194,

p. 114, 1008.
ENDERLEN. Untersuchungen liber die Transplantation der Schilddriise in

die Bauchhohle von Katzen und Hunden. M. G. M. C., 3, p. 474,

1898.

ENGEL, C. Uber Diabetes insipidus. Z. k. M., 67, 1909.
ENGELBERTZ. Morbus Addisonii. Diss., Bonn, 1892.
ENGELMANN, F. Die Placentartheorie der Eklampsieatiologie. C. G., 33,

1909.

— - Adrenalinbehandlung bei Osteomalacie. Ibid., 32, 1908.
ENGELMANN, K. Uber die Beziehungen von Erkrankungen der Nebennieren

zu Morbus Addisonii. Diss., Wiirzburg, 1906.
ENGLANDER, B. Adrenalin bei Knochenerweichung (Osteomalacie). C. G.,

1909.
ENRIQUEZ, E., and LEREBOULLET, P. Un cas de melanodermie arsenicale

generalisee simulant la maladie d'Addison. Gaz. hebd., xlvi, 54,

juillet, 1899.
EPELBAUM. Contribution a 1'etude de 1'organotherapie. Corps thyroide.

Capsules surrenales. These Paris, 1895.
EPPIXGER, H, FALTA, W., and RUDINGER, C. Uber die Wechselwirkungen

der Driisen mit innerer Sekretion. Z. k. M., 66, 1908; vorl. Mitt.,

W. k. W., 1908.

- II. Mitteilung. Z. k. M., 67, 1909.

— Uber den Einflusz der Schilddriise auf Stoffwechs.el und Nervensystem.

V. 25, C. M., 1908.

- Bemerkungen z. Arbeit Tomaszewski u. Wilenko. B. k. W., 1908.

- Uber den Antagonismus sympathischer und autonomer Nerven in der

inneren Sekretion. W. k. W., 1908.

EPPINGER and HESS. Zur Pathologie des viszeralen Nervensystems. I.
Mitt., Z. k. M., 67, p. 345, 1909; II. Mitt., Ibid., 68, p. 205, 1909;
III. Mitt., Ibid., 69, p. 231, 1909.

- Zur Pathologie der Basedowschen Krankheit. 26 C. i. M., Ref. C. i. M.r

p. 539,, 1909.
Versuche liber die Einwirkung von Arzneimitteln auf liberlebende

Coronargefasze. Z. e. P., V. p. 622, 1909.
ERB, W. Acromegalie. D. A. k. M., 42, 1888.
ERB, W., JUN. Uber experimentell erzeugte Arterienerkrankung beim

Kaninchen. V. 21, C. M. April, 1904.

- Experimentelle und histologische Studien liber Arterienerkrankung nach

Adrenalininjektionen. A. P. P., 53, 1905.

- Uber Gehirnblutungen bei Kaninchen nach Adrenalininjektionen.

Zieglers Beitr., Festschrift fur J. Arnold, S. 500, 1905.
ERBEN, F. Notiz zur Therapie des Diabetes mellitus. P. m. W., 1908.
ERDHEIM, J. Beitr. z. Kenntnis der branchiogenen Organe des Menschen.

W. k. W., 1901.

— Zur normalen und pathogischen Histologie der Glandula thyreoidea,

parathyreoidea und Hypophysis. Zieglers. Beitr., 33, p. 158, 1903.

— Uber Schilddriisenaplaisie bei Cretinismus. Geschwiilste des Ductus

thyreoglossus. Uber einige menschliche Kiemenderivate. Zieglers
Beitr. 35, p. 366, 1904.

— Beitrage zur pathologischen Anatomic der menschlichen Epithelkor-

perchen. Z. H., 25, Abt. f. pathol. Anat., 1904.

- Uber Hypophysenganggeschwiilste und Hirncholesteatome. W. S.,

Ii3v3, 1904.

— Zur Kenntnis einiger Kiemenderivate. An. An., 29, 1906.
Tetania parathyreopriva. W. k. W., 1906; M. G. M. C., 16. 1906.

- Uber Epithelkorperbefunde bei Osteomalacie. S. W. A., 116, 1907.

- Uber einen Hypophysentumor von ungewohnlichem Sitz. Zieglers

Beitr., 46, 1909.

ERDHEIM and STUMME. Schwangerschaftsveranderung der Hypophyse. 37.
Chirurgen-Kongresz, Berlin, 1908. B. k. W., 25 Mai, 1908.

— Uber die Schwangerschaftsveranderung der Hypophyse. Ziegl. Beitr.,

46, 1909.

LITERATURE 489

ERLANDSEN, A. Exper. Unters. liber den Phloridzindiabetes. I. B. Z., 23,

igio.

ERLANGER. Les capsules surrenales. These de Paris, No. 162, 1902.
ESAU, P. Exper. Unters. liber den Phloridzindiabetes. M. G. M. C., 19,

igoS.
ESCHERICH, TH. Bemerkungen Uber den Status lymphaticus der Kinder.

B. k. W., 1896.

- Zur Kenntnis der tetanischen Zustande des Kindesalters. M. m. W.,

1907.

- Die Tetanic der Kinder. \Vien, 1909.

ESSEN-MOLLER. Doppelseitige Ovariotomie im Anfgang der Schwanger-
schaft. C. G., 28, 1904.

ESSER. Ein typischer Fall von Morbus Addisonii. D. m. W., 1899.

ETIENNE and FRITSCH. La role atheromatisant du chlorure de calcium dans
1'atherome experimental n'apartient pas a sa chaux. C. r. S. B.,
p. 937, 1909.

ETIENNE, G., and PARISOT, I. Action sur les vaissaux de 1'adrenaline em-
ployee simultanement avec les vaso-dilatateurs codes. Congr. franc..
Med., Paris, 1907.

- Atherome aortique et extract d'hypophyse. C. r. S. B., 64, p. 751, 7

avril, 1908.

- Les composes iodes jouissent-ils de proprietes anti-atheromatisantes.

Soc. de Med. de Nancy, 26 fevrier; Revue Med. de 1'Est, i juin,
1908.

- Pression arterielle et arterio-sclerose. Congr. de Med. Geneve, sep-

tembre, 1908.

- Action sur 1'appareil cardio-vasculaire des injections repetees d'extrait

d'hypophyse. Comparaison avec 1'action de 1'adrenalinc. A. m. e.,
20, 1908.

- La role de 1'elevation de la pression arterielle dans 1'etiologie de

1'atherome. J. d. P. P., x, pp. 1055-1065, 15 novembre, 1908.
ETTLINGER and NAGEOTTE. Lesions de cellules du systeme nerveux central
dans 1'intoxication addisonienne experimentale (decapsulation).

C. r. S. B., 48, 1896.

EULENBURG. Antithyreoidinbehandlung der Basedowschen Krankheit. B. k.

W., 1904.
EULENBURG and GUTTMANN. Die Pathologic des Sympathicus. Berlin,

1873-
EULER, H. Pulpentod, natiirliche und synthetische Nebennierenpraparate.

Diss., Wien, 1907.
EUSTACHI, BARTH. Opuscula anatomica. De renum structura officiis, ed

administratione. Cap. vi, Venezia, 1563.
EWALD, C. A. Die Erkrank. der Schilddriise. Nothnagels. Hdb., 1896;

2 Aufl. Wien, 1909.

- Klinische Vorstellung von Hypophysistumoren. M. m. W., p. 1853,

1908.

- Dercumsche Krankheit. Encyclop. Jahrb. , 16, 1909.

EWALD, J. R., and ROCKWELL. Exstirpation der Thyreoidea an Tauben.

P. A. 47, 1890.
EWALD, P. Fettgehalt und multiple Adenombildung in der Nebenniere.

Diss., Mlinchen, 1902.
EWANS, H. W. Addison's disease following enteric fever. Lancet, 19 June,

1900.
EXNER, A. Kehlkopfnerven und die Funktionen der Thyreoidea. P. A.,

68, 1897.

- Uber die durch intraperitoneale Adrenalin-Injektion veranderte Resorp-

tionsfahigkeit des tierischen Peritpneums. Z. H. 24, 1903.

- Uber durch intraperitoneale Adrenalininjektion verursachte Verzogerung

der Resorption von den In den Magen eingebrachten Giftcn. A. e. P.,
50, p. 313, 1904.

- Exstirpation der Hypophyse bei malignem Adcnom, gefolgt von Bes-

serung. W. k. W., 15 Januar, 1909; and V. d. N. A. Ref. in
M. m. W., No. 39, 1909.

- Beitr. z. Pathol. u. Pathogenese der Akromegalie. M. G. M. C., 20,

1909.

EXXER, S. Physiol. d mannl. Geschlechtsorgane. In Fritsch-Zuckerkandls
Hdb. d. Urologie.

49° LITERATURE

EXNCR, S. Mannlich und weiblich. Beitr. z. Geb. u. Gyn., Festschr.
Chrobak. Wien, 1903.

FABOZZI, S. Sugli effetti del succo di capsule surrenali negli animali scap-

sulati. II Morgagni, 42, p. 177, igoo; Gazz. d. Osp., xxi, p. 116,

Milano, 1900.

FABRITIUS, J. Uber Cysten an der Tube, &c. A. G., 50, 1896.
FAIRBAIRN. A renal tumour arising from adrenal remnants. Transact.

Path. Soc. London, vol. 53, p. 184, 1902.
FALK, F. Uber die durch Adrenalininjektionen a,n Kaninchen hervor-

gerufenen Gefaszveranderungen und deren experimentelle Beeinflus-

sung. Z. e. P., 4, p. 360, 1907.

— tJber Adrenalinveranderungen an den Gefaszen und deren experi-

mentelle Beeinflussung. M. m. W., 1907.

— Uber die Adrenalin-Arterionekrose. W. k. W., 1909.
FALKENBERG. Zur Exstirpation der Schilddrlise. V. 10, C. M., p. 502,

1891.

FALTA, W. liber den zeitlichen Ablauf der Eiweiszzersetzung im tierischen
Organismus. D. A. k. M., 86, p. 517.

- tJber die Gesetze der Zuckerausscheidung beim Diabetes mellitus. IV.

Mitt., Z. k. M., 65, p. 300; VI. Mitt., ibid., 65, p. 463; VIII. Mitt.,
ibid., 65, p. 489 and ibid., 66, p. 401, 1908.

- liber physiologische Bedeutung des Pankreas. W. k. W., p. 1559, 1907.

— Diskussion zum Vortrage Biedl-Offer. W. k. W., 1907.

- Beziehungen zwischen der inneren Sekretion der Schilddriise, des pan-

kreas und des chromaffinen Systems. V. 25, C. M., 1908.

— Uber den Eiweiszumsatz beim Diabetes mellitus. B. k. W., 1908.

- Weitere Mitteilung liber d. Wechselwirkung d. Driisen m. innerer

Sekretion. Ibid., 1909.

- Concerning diseases that depend on disturbances of internal secretion.

A. J. M. S., 1909.

- Uber die Bedeutung der Blutdriisen in der Pathologic des Diabetes

mellitus. P. m. W., 1910.

- Die Therapie des Diabetes mellitus. Ergebn. f. i. M. u. Kinderh., ii,

1908.

FALTA, W., and GiGON, A. Uber die Gesetze der Zuckerausscheidung beim
Diabetes mellitus. V. Mitt., Z. k. M., 65, p. 313, 1908.

- liber den Einfluss stickstofffreier Energietrager auf den zeitlichen

Ablauf der Eiweiszzersetzung. B. Z., 13, p. 267, 1908.
FALTA, GROTE and STAEHELIN. Versuche Uber den Kraft- und Stoffwechsel
und den zeitlichen Ablauf der Zersetzungen unter dem Einfluss
verschiedener Ernahrung beim Hund. H. B., 9, p. 333, 1907.

- Uber den Stoffwechsel u. Energieverbrauch bei pankreaslosen Hunden.

Ibid., 10, 1907.
FALTA, RUDINGER, BERTELLI, BOLAFFIO and TEDESKO. liber Beziehungen

der inneren Medizin zum Salzstoffwechsel. V. 26, C. M., 138-149,

1909.
FALTA and WHITNEY. Zur Kenntnis des Eiweisz- und Mineralstoffwechsels

pankreasdiabetischer Hunde. H. B., 11, p. 224, 1908.
FALTA and IvcoviC. Adrenalin als Antidot. B. k. W., 1909.

- Uber die Wirkungsweise des Adrenalins bei verschiedener Applikation.

W. k. W., 1909.
FANO, G., and Rossi, G. Sulla viscosita del siero sanguigno nelle lesioni

sperimentali dell' apparecchio tiroparatirioideo. A. di Fisiol., ii,

1905.
FARRINI, A., and VIDONI, G. Azione degli estratti di tiroide delle soluzione

di tiriodma, degli estratti di timo sistemo circolatorio. Lo Speriment.,

62; and A. i. B., 52, 1909.
FASSIN, L. Role de Tiode dans 1'augrnentation des proprietes du serum sous

1'influence des produits thyroi'diens. C. r. S. B., ii, p. 457, 20 mars,

1904.
FASSINI, R. Effetti terapeutici della paraganglino Vassale in alcune forme

dispeptiche della tuberculosi pulmonarc. Gaz. Osp. e Cliniche, 1908.
FAURE, L. Contr. a Tetude de la maladie d'Addison. These Paris, 1898.
FAURET-FREMIET, E. Sur une secretion interne chez le cochliopodium pellu-

cidium. C. r. S. B., 58, p. 905, 1906.

LITERATURE

FAVORSKI, A. V. Traitement de 1'acromegalie. Revue Neurcl, IQOO.
FEDERICI, F. Delia struttura delle capsule surrenali e delle alterazioni

consecutive alle infezioni sperirnentali. Lo Sperim., 58, p. 419, IQO4.
FEDOROFF, S. P. Uber Befund von Adrenalin in einem Nierentumor.

Folia Urologica, H. 5, 1908; Bph. C., iii, No. 1626.
FEHLIXG. Die Form des Beckens beim Foetus und Neugeborenen. A. G.,

10.
- tJber Wesen und Behandlung der Osteomalacie. A. G., 28. 1890 and

29, i SQL
FEILCHENFELD. Fall von Tumor cerebri (Gliosarkom) der Zirbeldriise.

N. C., 1885.

FELDK.IRCHNER, J. Zwei Falle von Morbus Addisonii. Diss., Lindau, 1871.
FELICINE, L. Beitrag zur Anatomic der Nebenniere. An. An., 22, p. 152,

..

- Uber die Beziehungen zwischen dem Blutgefaszsystem und den Zellen

der Nebenniere. A. m. A., 63, pp. 283-312, 1903; and Diss., Bern,
1905-
FELIZET and BRANCA. Histologie du testicule ectopique. J. A. P. 1898.

- Recherches sur le testicule en ectopie. Ibid., 38, 1902.

- Sur les cellules interstitielles du testicule ectopique. C. r. S. B., 53,

IQOI.

FELLNER, O. Uber die Tatigkeit des Ovariums in der Schwangerschaft.
A. G., 87, 1909.

- Die wechselseitigen Beziehungen der innersekretorischen Organe,

insbesondere zum Ovarium. Volkmanns Sammlung, No. 508, 1908.

- Zur Histologie des Ovariums in der Schwangerschaft. A. m. A., 73,

p. 288, 1909.

- Uber physiologische Graviditatserscheinungen bei Mutter und Kind.

Z. G., 1909.

- Uber intravasale Gerinnungen nach Injektion von Uterusextrakten.

C. P., 23, 1909.
FELLNER and NEUMANN, tiber Rontgenbestrahlung der Ovarien in der

Schwangerschaft. C. G., 30, 1906.
FENYVESSY, B. v. tiber die Wirkung Schilddriisenstoffe auf die Zirku-

lation, &c. W. k. W., 1900.
FEODOSSIEW, N. E. Hypertrophie der Nebennieren nach Entfernung

der Eierstb'cke. Russkij Wratsch., No. 5, p. 135, 1906; Ref. Bph. C.,

ii, p. 160.
FERE, C. L'instinct sexuel evolution et dissolution. Paris, 1899.

- L'adipose douloureuse, syndrome de Dercum. Rev. d. med., aout, 1901.

- Rapports des testicules avec le corps thyroide. C. r. S. B., 57, p. 436,

1905.
FERE and BECHASI. Etude de Faction du sue ovarien sur le cobaye. Gaz.

hebd., 44, .1897.

FERGUSSON, J. S. The veins of the adrenal. A. J. A., 5, p. 63, 1906.
FERRARI. Contr. a 1'etude des glandes parathyroi'diennes. These Geneve,

1897.
FERRANINI, L. Uber von der Schilddriise unabhangigen Infantilismus und

Stoffwechselbilanz in einem Fall von Mitralinfantilismus. Arch. f.

Psych., 38, p. 296.

- II geroderma genito distrofico. Policlin., Suppl. 1898 u. Congr. ital.

med., Roma, 1899.

- Gifte und Toxine auf das iiberlebende Saugetierherz. C. R. du XXI

Congr. de la Soc. ital. de chirurg., Rome, October 27-29, 1908;

J. d. P. P., xi, p. 341, March 15, 1909.
FEUILLE. Contribution a 1'etude de Tatherome experimental. These de

Lyon, 1905-1906.
FICHERA. Hypertrophie du corps pituitaire consecutive a la castration. II

policlinico, sez. chir., juin-juillet, 1905.

- Sur Thypertrophie de la glande ])ituitaire consecutive a la castration.

A. i. B., 43, p. 405, 1905; and Boll. Ace. med., Roma, 1905.

- Sulla distruzzione dell' ipofisi. Lo Sperim., 59, 1905.

FILATOW. Uber den Einfiuss der Blutscra auf das Auge. Diss., Odessa,

1908.
FILEHXE. Zur pathogenese der Basedowschen Krankheit. E. B., 14 Juli,

1878.

492 LITERATURE

FILIPELLO, G. R. Sopra un caso di acromegalia. Annali di frenatria, 12,

p. 57, 1902.
FlLlPPl. Azione della adrenalina sulla musculatura della stomaco di rana.

Sperimentale, p. 764, 1904.
FlNKELXBURG, R. Klinische und experimentelle Untersuchungen liber

Diabetes insipidus. D. A. k. M.. 91, 1907.
FlNOTTl. Zur Pathologic und Therapie der Leistenhoden nebst einigen

Bemerkungen tiber die groszen Zwischenzellen des Hodens. A. Ch.,

57, 1897.
FINOTTI, R., and TEDESCHI, S. Alterazioni delle capsule surren. e pellagra.

Rif. med., 1902.
FlORI, C. Legatura dell' uretere e suoi esiti. Clinic. Chirurg., Modena.

- L'azione dell' estratto renale e del siero di sangue sottoposti alia nefrec-

tomia bilaterale. Gazz. degli osp., 1903.

- Sull' azione delle iniezioni di sangue venosa emulgente e di emulsioni

di parenchyma renale negli animali della stessa specie. Pisa, 1903.

- Patologia sperimentale del rene. II policlinico, 1903.

FlSCHEL, A. Untersuchungen iiber die Wirbelsaule und den Brustkorb dcs

Menschen. Anat. Hefte, 31, p. 463, 1906.
FISCHER, B. Uber Arterienerkrankung nach Adrenalininjektionen. V., 22,

C. M., 1905.

- Experimentelle Erzeugung von Aneurysmen. D. m. W., 1905.

- Experim. Arterienerkrankungen durch Adrenalininjektionen. M. m. W.,

1906.

- Zur Frage der experim. Arterionekrose durch Adrenalininjektion.

B. k. W., 1907.

FISCHER. Ub. Veranderungen d. Pankreas u. d. Leber bei Diab. mellitus.

V. A., 172, 1903.
FISCHER, J. Die Schilddriise und der weibl. Genitalapparat. W. m. P.,

1895.
FISCHER, M. H. Uber die Hervorrufung und Hemmung von Glykosurie

durch Salze. P. A., 109, 1905.

FISCHER, PH., and HOPPE, J. tiber Pankreon. M. m. W., 1907.
FlSCHL, R. Experimentelle Beitrage zur Frage der Bedeutung der Thymus-

exstirpation bei jungen Tieren. Z. e. P., i, 1905.
FLACHER, F. tiber die Spaltung des synthetischen dl-Suprarenins in seine

optisch aktiven Komponenten. Z. ph. Ch., 58, 3, pp. 189-194, 1908.

— The resolution of synthetic suprarenin into its optically active com-

ponents. Pharm. Journ., January 9, 1909.

FLATAU. Die Ovariotomie wahrend der Schwangerschaft. A. G., 82, 1907.
FLECK. Zur Frage der inneren Sekretion von Ovarium und Plazenta.

C. G., 29, 1905.

FLECKSEDER, K. Uber die Rolle des Pankreas bei der Resorption der Nah-

rungsstoffe aus dem Darm. A. P. P., 59, 1908.
FLEIG, C. Essai de preparation d'une antisecretine. C. r. S. B.. 57, ii,

795, 1905.

- Les sues digestifs normaux et les sues d'hypersecretions provoques

artificiellement. C. r. S. B., 64, 1908.
FLEINER, W. Addisonsche Krankheit mit Nebennierenkrebs. B. k. W.,

_ 1889.

— • Uber die Veranderungen des sympathischen und cerebrpspinalen Nerven-
systems .bei zwei Fallen von Addisonscher Krankheit. V. 10, C. M.,
1891 ; D. Z. N., 2, 1892.

— Uber den heutigen Stand der Lehre von der Addisonschen Krankheit.

Volkmanns Sammlung, No. 38, 1892.

— Neuer Beitrag zur Lehre von der Tetanie gastrischen Ursprungs.

D. Z. N., 5, 1900.

- Zur Frage der Tetanie bei Magendilatation. A. V., 5, 1901.

- Uber die Tetanie gastrischen und intestinalen Ursprungs. M. m. W.,

1903.
FLEISCHMANN, L. Die Ursache der Schmelzhypoplasien. W. k. W., 1907,

und Osterr.-ungar. Viertelj. f. Zahnk., 1909.
FLEISCHMANN, P., and DAVIDSON, H. Tiber Zytotoxine. Folia serol., i,

p. 173, 1908.
FLEISCHER, M. S. Uber die Einwirkung von Jodopin und einigen anderen

Substanzen auf die durch Adrenalin hervorgerufenen Arterien-

veranderungen, sowie iiber die Wirkung sehr groszer Adrenalindosen.

Ca. P., 20, 1909.

LITERATURE 493

FLEMING, R. A., and MILLER, J. A family with Addison's disease. Brit.

Med. Journ., April 28, IQOO.

FLEMMING. A case of acromegaly. Clin. Soc. Transact., 23, p. 253, 1890.
FLESCH. Uber die Hypophysis einiger Sauger. V. d. N. A., Magdeburg,

1884.
FLINT, J. M. Reticulum of the adrenal. An. An., 16, 1899.

The blood-vessels, angiogenesis, organogenesis, recticulum and histology

of the adrenal. Johns Hopkins Hospital Reports, ix, pp. 153-229,

1900.
The framework of the glandula parathyreoidea. A. J. A., 4, 1905.

- Das Bindegewebe der Speicheldriisen und des Pankreas und seine Ent-

wicklung in der Glandula submaxillaris. A. A., p. 61, 1903.
FLOCKEMANN. Beeinflussung der Ausfallsersch. kastr. Frauen durch Ovarial-

praparate. M. m. W., 1901.
FLOERSHEIM, S. The use of suprarenal capsule in diseases of the lower air

passages. Med. Record, November 17, 1900; N. Y. Med. J., May 14

and 18, 1901.

- A report of forty-five unpublished cases of haemorrhage treated by the

internal administration" of the suprarenal capsule. Am. Med. News,

p. 17, January 4, 1902.

^ The status of suprarenal therapy. Med. News, p. 587, April i, 1905.
FOA, P. Contribuzione allo studio della malattia dell' Addison. Riv. chir.

di Bologna, 1874 and 1879.
FoA, C. Contr. anatomica e sperimentale alia patologia delle capsule sur-

renali. Arch. p. 1. scienze med., 24, No. 22, 1900, and 25, p. 437, 1901.

- SulP innesto delle ovaie e dei testicoli. Riv. gen. d. biol., 1901 ; and

A. i. B., 35.

- Contribution anatomique et experimentale a la pathologic des capsules
^ surrenales. A. i. B., 35, p. 250, 1901; ibid., 36, p. 237, 1902.

- Sui fattori che determinate la funzione della ghiandola mammaria.

A. d. F., 5, 1909.
FoA and GATIN-GRUZE\VSKA. Action de Padrenaline sur la reaction du sang.

C. r. S. B., 57, ii, p. 145,^1905.

-^ Influence de la piqure diabetique sur la reaction du sang. Ibid., p. 144.
L' OA and PELLACANI. Sur le ferment fibrinogene et sur les actions toxiques

exercees par quelques organes frais. Arch. p. 1. scienz. med., vii,

p. 9, 1883; A. i. B., iv, 1883.

- Interno agli effetti tossici delle diluzione aquose degli organi freschi.

A. per le scienz. med., iii, p. 24, 1879.

FODERA and PITTAU. Studi sull' Hypophysis cerebri. Pathologica I, 1909.
FODERE, F. M. Uber den Kropf und Cretinismus. Aus d. Franz, v. Lind-

mann. Berlin, 1796.
FOLGER, A. Untersuchungen liber die pathologische Anatomic der Neben-

nieren bei einigen Haustieren. Biolog. Ges. in Kopenhagen, 1907;

S. A., 21, p. 277, 1909.
FORSTER. Fall von Markschwamm mit ungewohnlich vielfacher meta-

statischer Verbreitung. V. A., 13, p. 271, 1858.
FORSTERLING, W. Kasuistische Beitr. z. Kenntnis d. Morbus Addisonii.

Diss., Berlin, 1898.
FOGES, A. Zur Hodentransplantation bei Hahnen. C. P., 1898.

- Schwangerschaftshypertrophie der Mammae und Nebenmammae. W. k.

W., 1901.

- Zur Lehre von den sekund. Geschlechtscharakteren. P. A., 93, p. 39,

1902.

- Ein Fall von Hermaphroditismus masculinus internus. Beitr. z. G. u.

G., Festschr. f. R. Chrobak. Wien, 1903.

- Ovarientransplant. in d. Milz. W. k. W., p. 615, 1907 and p. 271, 1908.

- Zur physiolog. Beziehung zwischen Mamma u. Genitale. C. P., 19,

1905 ; W. k. W., 1908.
FOISY. Nouveau precede d'anesthesie des tissus enflammes. C. r. S. B.,

55, IQ03-

FOXTANEL, P. L'Asthenie motrice bulbo-spinale. These de Lyon, 1905.
FORMAXEK, E. Action de la choline sur la circulation. Arch, intern, d.

Pharm., 10, 1903.
FORMANEK, E., and ElSELT, R. Uber die therapcutische Wirkung des

Nierenextraktes bei chronischer Nephritis. Ibid., xvii, p. 231, 1907.

494 LITERATURE

FORMANEK and HASKOVEC. Uber die Funktion der Schilddruse. Klin. Z.

u. Streitfr., g, Wien, 1895.
FORSCHBACH, J. Parabiose und Pankreasdiabetes. Vorl. Mitt. D. m. W.,

1908.

- Zur Pathogenese des Pankreasdiabetes. A. P. P., 60, 1909.

- Behandlung d. Diabetes mellitus mit Zuelzers Pankreasjiormon. D. m.

W., 1909.

FORSYTH, D. The Parathyroids. Quart. Journ. of Med., vol. i, p. 2, 1908.
The comparative anatomy, gross and minute, of the thyroid and para-
thyroid glands in mammals and birds. J. A. P., 42, 1908.

FOSSATTI, G. Di alcuna proprieta dell' estratto etereo dell' urine specie in
rapporte al puerperio ed all' allattamento. Ann. Ostetr. Ginec., 28,.
p. 88.

FOSTER, A. Case of Addison's disease treated with suprarenal extract.
Lancet, June 10, 1899.

FOSTER, N. S. Cases of diabetes treated with secretin. J. B. Ch., 2, p. 297,.
1907.

- Beobachtungen liber die Wirkung des Sekretins bei Diabetes und

Betrachtungen liber seine Anwendung. M. K., 1907.
FRAENKEL, A. Uber den Gehalt des Blutes an Adrenalin bei chronischer

Nephritis und Morbus Basedowii. A. P. P., 60, p. 395, Juni, 1909.
FRAENKEL, F. Ein Beitrag zur Therapie des Morb. Add. mit Nebennieren-

praparaten. Diss., Berlin, 1900.
FRAENKEL, L. Versuche tiber den Einfluss der Ovarien auf die Insertion des

Eies. V. d. d. Ges. f. Gyn., 1901.

- Zur Funktion des Corpus luteum. A. G., 68, 1902.

- Weitere Mitteilungen liber die Funktion des Corpus luteum. C. G., 28',

1904.

- Vergleichende histolog. Unt. Uber das Vorkommen driisiger Forma-

tionen im interstitiellen Eierstocksgewebe. A. G. , 75, p. 433, 190.

- Ovarialankorper und Osteomalakie. M. m. W., Nos. 25 and 26, 1908.
FRAENKEL and COHN, F. Experim. Unters. liber den Einfluss des Corpus

luteum auf die Insertion des Eies. An. An., 20, 1901.

FRAENKEL, S. Praparate aus der Nebenniere und Schilddruse. W. k. W.,.
1896.

— Beitrag zur phys. Chemie der Thyreoidea. W. m. Bl., Nos. 13-15, 1896.

- Beitrage zur Physiol. und physiol. Chemie der Nebennieren. Ibid.,

Nos. 14-16, 1896.

— Uber Gehirnchemie und die Phosphatide der Gewebe. W. m. \V., 1909.

- Gehirnchemie. E. P., 8, 1909.

— Uber Lipoide. VI. Mitteilung. Uber ein neues Verfahren der frak-

tionierten Extraktion der Gehirnlipoide. B. Z., 19, 1909.
FRAENKEL, S., and ALLERS, R. Uber eine neue charakteristische Adrenalin-

reaktion. B. Z., 18, p. 39, 1909.
FRANKEL, STADELMANN and BENDA. Klinische und anatomische Beitrage zur

Lehre von der Akromegalie. D. m. W., 1901, and Leipzig, 1901.
FRANCHINI, GUISEPPE. Beitrage zum chemischen und histologischen Studium

des Blutes bei Acromegalie. B. k. W., 1908.

- Contrib. a 1'etude de 1'acromegalie. Riv. sper. di fren., 33, p. 888, 1907.
FRANCHINI, G., and GIGLIOLI, G. J. Encore sur 1'acromegalie. Nouv. icon.

de la Salpetriere, No. 5, p. 325, 1908.

FRANCILLON, M. Essai sur la puberte chez la femme. These de Paris, 1905.
FRANCIS, E. Suprarenal extract in Addison's disease. Brit. Med. Journ.,

May 2, 1896.

- A case of haemophilia treated with adrenalin chloride. Ibid. May 28,

1904.
FRANCK, FR., and HALLION. Recherches sur 1'mnervation vasomotrice du

corps thyroide. J. d. P. P.} x, pp. 442-454, 15 mai, 1908.
FRANKE. Akromegalie. Th. M., p. 35, 1896.
FRANK and ISAAC, C. Die Bedeutung des Cholins und des Adrenalins fur

die Erforschung des Zuckerstoffwechsels. Z. e. P., vii, p. 326,

Oktober, 1909.
FRANKL, O. Zur Frage der Plazentartoxine. Gynaek. Rundsch., Bd. 3,

H. 3.
FRANKL, TH. tiber den Antagonismus der Chloride der Erdalkalien und

des Kaliums gegenliber dem Adrenalin. P. A., 130, 1909.

LITERATURE

FRANKL-HOCHWART, v. Die Tetanic der Erwachsenen. Wien, i8gi.
2. Aufl., 1907.

- Die Schicksale der Tetaniekranken. W. m. W., 1906; and X. C.,

Xos. 14 and 15, 1906.

- Diskussion liber Bergers Fall. Verein f. Psych, u. Neurol., 10 Mai,

1904.

- Die Diagnostik der Hypophysentumoren ohne Akromegalie. 16. Int.

med. Kongr., Budapest, 1909; \V. m. W., 1909.

- Uber die Diagnose der Zirbeldrusentumoren. D. Z. N. , 37, p. 455, 1909.
FRANKL-HOCHWART, v., and FROLICH. Uber die Wirkung des Pituitrins.

W. k. W., 1909.

FRANZ. Aus experimentellen Arbeiten liber Adrenalin, seine physiologische
Wertbestimmung und Wirkung. M. K., 1907 (Sammelreferat).

- Exstirpation eines groszen Nebennierentumors. \V. m. W., 1904.
FREDELI. Ricerche sull'azione terap. dell'ovarina in rapp. con una nuova

teoria della clorosi. Rif. med., 1896.
FRERICHS. Uber den Diabetes. Berlin, 1884.
FREUND, H. W. Beziehungen der weiblichen Geschlechtsorgane zu anderen

Organen. Z. Ch., 18, 1883; L. O., 3, 1898.

- Uber Akromegalie. Volkmanns klin. Vortr. , Nos. 329-330, 1889.
FREUND, H. Lokalanasthesie mittelst Eukain-Adrenalin. C. G., 1904.
FREUND, R. Zur plazentaren Eklampsie-Atiologie. B. k. W. No. 15,

p. 682, 1909.
FREY, H. On the suprarenal capsules. Todd, Cyclopaedia of Anat. and

Physiol., London, 1849.

FREY, v. Beitrage zur Kenntnis der Adrenalinwirkung. W. V., 1905.
FREYER, O. Zur Kenntnis der von versprengten Keimen der Nebenniere

ausgehenden Abdominalgeschwiilste, &c. Diss., Kiel, 1901.
FRIEDENTHAL. Zur Wirkung der Schilddriisenstoffe. Ai. m. W., 1908.
FRIEDJUNG, J. K. Erkrankungen der Thymus, Status lymphaticus und

plotzliche Todesfalle. Handbuch der Kinderheilk. von. Pfaundler

und Schloszmann, Bd. iii, 2. Aufl., 1910.
FRIEDLAND, F. Uber einen Fall von accessorischen Nebennieren in den

beiden Samenstrangen. P. m. W., 1895.
FRIEDLEBEN, A. Die Physiologic der Thymus in Gesundheit und Krankheit.

Frankfurt, 1858.
FRIEDMANN. Rhachitol bei Rachitis. Der Kinderarzt, 1900.

- Uber Nebennierensubstanz in der Therapie der Rhachitis. Th. G.,

p. 283, 1901.
FRIEDMANX, E. Die Konstitution des Adrenalins. H. B., 6, 1904; ibid., 8,

p. 95, 1906.
FRIEDMANN, F. Beitrage zur Kenntnis der Anato'mie und Physiologic der

mannlichen Geschlechtsorgane. A. m. A., 52, 1898.
FRIEDMANX and MAAS. Uber Exstirpation der Hypophysis cerebri. B. k.W.,

1900.

- Xoch einige Erfahrungen liber Exstirpation der Hypophysis cerebri und

liber Transplantation von Carcinom u. Thyreoidea auf die Hypo-
physis. B. k. W., !<)»;:.

FRIEDREICH. Psammoma kystomatosum haernorrhagicurr, der Glandula
pinealis in Kombination mit Medullarsarkom. V. A., 33, p. 165, 1865.

FRISCH, A. v. Adrenalin in der urologischen Praxis. W. k. WT., 1902.

FRISCO. Giorn. internaz. d. sc. med., Napoli, 1897.

FRITSCHE and KLEBS. Beitrag zur Pathologic des Riesenwuchses. Leipzig,
1884.

FROHLICH, A. Fall von Tumor der Hypophysis cerebri ohnc Akromegalie.
W. kl. Rundschau, 1901.

- Eine neue physiologische Eigenschaft des d.-Suprarenins. C. P., 22,

1909.
FROHLICH and LOEWI, O. Unters. z. Physiologic und Pharmakologie des

autonomen Nervensystems. A. P. P., 59, 1908.
FROMAGET, C. De Textrait aqueux de capsules surrenales en ophtalmologie.

Ann. de la Policl. de Bordeaux, V. 8, p. 613, mars, 1898.
FROMME, V. Experimentelle Untersuchungen zur parathyreoidalen Insuffi-

zienz in bezug auf Eklampsie und Tetanic mit besonderer Beriick-

sichtigung der antitoxischen Funktionen der Parathyreoideae.

AI. G. G., 24, 1906.

496 LITERATURE

FROUIN, A. Sur les variations de la secretion du sue intestinal. C. r. S. B.,

58, p. 653.

-Action du sue intestinal sur la secretion enterique. Ibid., p. 702;
C. r.j 140, p. 1 120.

- Action secretoire du sue gastrique sur la secretion stomacale. Ibid.,

p. 887.

- La secretion et 1'activite kinasique du sue intestinal ne sont modifies par

le regime. Ibid., p. 1025, 1905.

- Sur la presence et 1'origine d'acides organiques dans le sue gastrique

pur. Ibid., SQ, p. 392, 1905.

- Influence des produits de la digestion des albumino'ides et des sucres

Sur 1'action .secretoire de 1'HCl sur la secretion pancreatique.

C. r. S. B., 63, p. 519, 1907.

- Ablation des capsules surrenales et diabete pancreatique. Ibid., 64,

p. 216, 1908.

- Sur la possibilite de cqnserver les animaux apres 1'ablation complete

de 1'appareil thyroidien, en ajoutant des sels de calcium eu de
magnesium a leur nourriture. C. r. A., Bd. 148, p. 1622, 1908.

- Sur 1'asepsie du sue pancreatique. Arch. int. de Phys., vi, p. 253, 1908.
FROIN, G., and RIVET, L. Adenome des capsules surrenales et 1'hyperten-

sion dans I'hemorrhagie cerebrale. Gaz. des hop., No. 67, 1906.
FRUGONI, C. Adrenalin-Glykosurie und ihre Beeinflussung durch das
Extrakt und den Saft des Pankreas. B. k. W., 1908.

- La glycosurie adrenalinique et 1'influence qu'exercent sur elle Textrait

et le sue pancreatique. A. i. B., 50, p. 209, 1908.
FRUGONI, C., and GRIXOXI, G. Tubercolosi e tiroide. Riv. crit. clin. med.,

10.
• — • Einflusz der wirksamen Elemente der Schilddriise auf die experi-

mentellen, tuberkulosen und pseudotuberkulosen Infektionen. B. k. W.,

1909.
FRUGONI and STRADIOTTI. Interno alia funzione dell' isole del Langerhans.

Lo Sperimentale, 1909: and A. i. B., 51, p. 186, 1909.
FUCHS. Zur Friihdiagnose der Hypophysistumoren. W. k. W., 1903.

- Die Diagnose des Hypophysentumors. Jahrb. f. Psych., 26, 1005.
FURBRINGER. Die Storungen der Geschle^htsfunktionen des Mannes.

Nothnagels Handbuch, 19, 3. Teil.

FURTH, O. v. Zur Kenntnis der brenzkatechinahnlichen Substanz in den
Nebennieren. Z. ph. Ch., 24, p. 142, 1897; H. Mitt., ibid., 26, 1898;
III. Mitt., p. 105, IQCG

- Mahnung zur Vorsicht beim Gebrauche von Nebennierenpraparaten.

D. m. W., IQO2.

— Zur Kenntnis des Suprarenins. H. B., i, p. 243, 1901.

— Zur Kenntnis des Suprarenins (Adrenalins). S. W. A., 112, 1903.

- Neuere Untersuchungen iiber die chemische Zusammensetzung der

gefaszverengernden Substanz in den Nebennieren. B. C., ii. 1903.

— Die Beziehungen der Schilddriise z. Zirkulationsapparate. E. P., 8,

1909.

FURTH, O. v. and SCHWARZ, K. Tiber physiol. Wirkungen d. Jodothyrins.
W. k. W., 1908.

— tiber die physiologischen Wirkungen des Jodothyrins und der Schild-

driisenextrakte. V. 25, C. M. Wien, p. 400, April, 1908.

- tiber die Einwirkung d. Jodothyrins auf d. Zirkulationsapparat. P. A.,

124, 1908.

- tiber die Natur der blutdruckerniedrigenden Substanzen in den Schild-

driisen. P. A., 124, p. 361, 1908.

- Zur Kenntnis der Sekretine. P. A., 124, 427, 1908.

- Bemerkungen zur Jodothyrinfrage. C. P., 22, 1909.

- Zusatz zu der Abhandlung : fiber die Natur der blutdruckerniedrigenden

Substanzen in der Schilddriise. P. A., 125, 1909.
FUHR. Die Exstirpation der Schilddriise. A. P. P., 21, 1886.

- Der Kropf im Altertum. V. A., 112, 1887.

FUHRMANN, F. Der feinere Bau der Nebenniere des Meerschweinchens.

An. An., 24, p. 606, 1904, and Z. w. Z., 78, p. 522, 1905.
FURNIVALL. On a case of acromegaly, &c. Transact. Path. Soc., 49,

London, 1908.
FUSARI, R. Osservazipni sulle terminazioni nervose e sullo sviluppo delle

capsule surrenali. Rendic. d. Accad. dei Lincei, 6, p. 250, 1890; and

A. i. B., 16, p. 191, 1891.

LITERATURE 497

FUSARI, R. Contribuzioni alia studio dello sviluppq delle capsule surrenali
e del simpatico nelle polio e nei mammiferi. Arch. p. le scienze
med., 16, p. 14, 1892; and A. i. B., 18, pp. 161-182, 1893.

- Sullo sviluppo delle capsule surrenali. Accad. di sc. med. e nat. di

Ferrara, 1893.

- Sullo sviluppo degli organi paratiroide del uomo. Ac. med., Torino,

febbrajo, 1899.

GABBI. Casi clinici di Morbo dell' Addison Considerazioni sulla Genesi del
Pigmento. Rivista clin. di Bologna, p. 569, 1886.

- Forme fruste od incomplete del morbo di Addison. Clin. med. ital.,

1899.

GAGLIO, G. Sul diabete, che segue all' estirpazione del pancreas. Rif. med.,
1891.

- Ric. sper. sulle rane int. alle funzione della ipofisi. Acad. Pelorit.

Messin., 1900.

- Recherches sur la fonction de 1'hypophyse de cerveau chez les

grenouilles. A. i. B., 38, p. 117, 1902.

- Influenza della temperatura sulle glucosurie tossiche. A. P. P., p. 224,

Suppl., 1908.
GAHMIG, MAX. Uber einen Fall von Osteomalakie bei Mausen. Diss.,

Leipzig, 1907.
GAILLARD. L'hyperplasie surrenale dans ses rapports avec 1'hypertension

arterielle permanente la nephrite chronique et 1'atherome. C. r. S. B.,

63, p. 569, 1907.

- De Thyperplasie surrenale, &c. These de Paris, 1908.

GAMGEE, A., and JONES, W. Liber die Nukleoproteide des Pankreas, der

Thymus und der Nebenniere, &c. H. B., iv, p. 10, 1903; P. R. S.,

-i, p. 385, 1903.

GALDI. La glycosuria surrenale. II Tommasi, 1907.
GALEOTTI. Z. Kennt. d. Sekretionsersch. in den Epithelzellen d. Schild-

driise. A. m. e., 1896.
GAXGHOFXER, F. Uber plotzliche Todesfalle im Kindesalter. V. d. N. A.,

1902.
GANFIXI, C. Alcune particolarita morfologiche e topografiche delle

glandulae suprarenales dell' uomo. Arch. ital. d'anat., iv, F. i,

pp. 63-80, 1905.
GARBINI, G. La structure de la fonction de 1'hypophyse dans qq. formes

graves, congenitales ou consecutives, de psychopathic. Riv. di pat.

nerv., x, p. 449, 1905.

- Contr. clinique et anatomo-pathologique a la connaissance du myx-

cedeme postoperat., avec considerations sur la fonction de 1'hypophyse.

Ibid., xi, 1906.
GARDNER, W., and ALLEX. Azoospermia. Boston Med. and Surg. Journ.,

134, 1896.
GARXIER, CH. Les filaments basaux des cellules glandulaires. Bibliogr.

anat., 1897.

— De la structure et du fonctionnement des cellules glandulaires. J. A. P.,

1900.
GARXIER. Influence de 1'adrenaline sur le developpement des gangrenes

microbiennes. C. r. S. B., 54, p. 1440, 1903.
GARXIER, M., and THAOX, C. Action de 1'hypophyse sur la pression arterielle

et le rythme cardiaque. Ibid., 60, p. 285, 1906.

- Recherches sur 1'ablation de 1'hypophyse. Ibid., 62, p. 659, 1907.

— De 1'hypophyse sur la pression arterielle et le rythme cardiaque.

J. d. "P. P., 1906.

GARRE, Transplantationen in der Chirurgie. V. d. N. A., Stuttgart, 1906.

GARROD, A. E. Pineal cyst. Transact, of the Path. Soc. of London,
B. 50, p. 12, 1898.

GARROD, A. E., and DRYSDALE, J. Haemorrhage into both suprarenal cap-
sules. Ibid., 1898.

GASKELL, W. E. On the origin of vertebrates deduced from the study of
ammocoetes. Part II. The origin of the vertebrate body cavity and
excretory organs; the meaning of the somites of the trunk and of the
ductless glands. J. o. A. a. P., 27, 1903.

32

498 ' LITERATURE

GASKELL, W. E. The contraction of cardiac muscle. Schaefer Text-book

of Physiology, ii, London, 1900.

GASPERO, DI. Der psychische Infantilismus. A. f. Psych., 1907.
GATIN-GRUZEWSKA, J. Composition du foie des chiens nourris en vue de la

production de la quantite maximale de glycogene. C. r. S. B., 58,

p. 423, 1905.

— Influence de la dilution des solutions d'adrenaline sur la disparition du

glycogene dans le foie et dans les muscles. Ibid., 60, p. 940, 1906.
GATIN-GRUZEWSKA, J., and MACIAG, M. L'action de 1'adrenaline pure sur le

cceur isole. Ibid., 63, p. 28., 15 Janvier, 1907, and J. d. P. P., xi,

pp. 28-31, 1908.
GATTA. Sulla distruzione della ghiandola pituitariae tiroide. Gazz. degh

osped., 1896.
GATTI, G. Uber die von abgesprengten Nebennierenkeimen ausgehenden

Nierengeschwiilste. V. A., 144, 1896.

— Der Lecithingehalt der Grawitzschen Nierenstrumen. Ibid., 150, p. 417,

1896.
GAUDERER, L. Zur Kasuistik der Zirbeldriisentumoren. Diss., Gieszen,

1889.
GAUCHLER and ROUSSY. Sur un cas d'acromegalie avec lesions associees de

toutes les glandes vasculaires sanguines. Rev. Neur. , p. 356, 1905.
GAULTIER, R. Glycosurie experimentale par destruction etendue de la

muceuse duodenale a 1'aide d'un caustique. C. r. S. B., 64, 1908.

- Recherches sur la role de la tension arterielle dans la production de

Tatherome experimental par 1'etude de Faction simultane de 1'adrena-

line substance hypertensive et de " 1'extrait aqueux de gui " subst.

hypotensive. Ibid., 64, p. 1150, 1908.

GAUPP, E. Anatomic des Frosches. Braunschweig, 1901.
GAUSSEL. Un cas d'acromegalie. Nouv. Icon, de la Salpetriere, 19, p. 391,

1906.
GAUTHIER, G. Un cas d'acromegalie. Le Progr. med., p. 1109, 1890; p. 4,

1892.

- Les toxines microbiennes et animales. Paris, 1896.

- Localisation, elimination et origine de Farsenic chez les animaux.

Bull. acad. de med., 1900.

- Fonctions du corps thyr., pathogenie du goitre endemique, du goitre

sporadique, du goitre exophtalmique, &c. Revue de Med., 20, 1900.

- La fonction menstruelle et le rut animaux. Bull. ac. med., 1900.

- Les medications thyroidiennes. Paris, 1902.

- Reactions comparees de Fadrenaline et de la pyrocatechine avec le

permanganate de potasse. C. r. S. B., 66. p. 426, 1909.

- Remarques sur la reaction d'Ehrmann. Ibid., 67, p. 426, 1909.

- Application de la reaction d'Ehrmann a la mise en evidence de 1'adrena-

line dans les surrenales de la grenouilles. C. r. S. B., 67, p. 490,
1909.

GAUTRELET, J. Presence de la choline dans certains glandes. Action de
leur extrait sur la glycosurie adrenalinique. Ibid., 64, p. 174, 1908.

- Mecanisme de 1'action hypotensive de certains glandes. Ibid., p. 176,

1908.

- Choline et glycosurie adrenalique. C. r. S. B., 65, pp. 173-174, 1908.

- La choline dans 1'organisme antagonisme des appareils chromaffme et

cholinogene. Ibid., 65, p. 448, 1908.

- Du role hypotenseur de la choline d. 1'organisme. C. r. A., 148, 1909.

- La choline, son role hypotenseur dans 1'organisme. J. d. P. P., xi,

p. 227, 1909.

GAUTRELET, J., and THOMAS, L. Le serum normal neutralise la glycosurie
adrenalique. C. r. S. B., 66_, p. 438.

- L'ablation des surrenales supprime la glycosurie adrenalique, et gly-

cosuree phloridizine. Ibid., 66, p. 798, 1909.

- La respirations apres ablation des surrenales. C. r. S. B., 66, p. 1042.

- La choline dans le serum de chien de capsule. Ibid., 66, p. 1090, 1909.

- Contribution a 1'etude du cceur est de la pression arterielle chez le chien

decapsule. Ibid., 67, p. 231, 1909.

- Chez le chien decapsule, 1'excitation du splanchnique ne produit pas de

glycosurie. Ibid., p. 233.

- Action hypotensive du serum de chien prive de surrenales. C. r. A.,

149, 12 juillet, 1909.

LITERATURE 499

GAUTRELET, J., and THUAX. Influence de la polypnee sur la glycosurie

adrenalique. C. r. S. B., 04, 1908.
GAVME. Essai de pathogenic basedowienne. Dauphine medical, Nos. 8

and Q, 1899.

GEBHARD. Menstruatio praecox in Veils Handb. d. Gynakologie, 3, i, 1898.
GEDDES, A. G. Examination of the acromegalic subject. Edinb. Med.

Journ., IQOQ.

GEIS. The parathyroid glands. Annals of Surg., 47, p. 532, 1908.
GELLE. Du retentissement des lesions canaliculaires sur le parenchyme

pancreatique et leur importance dans la genese du diabete. J. d.

P. P., iv, p. 645.
GEMELLI, A. Contr. alia conosc. d. struttura d, ghiand. pituitaria. Bull.

Soc. med., Pavia, 1900.
Nuove ric. sull' anatomia e embriologla dell' ipofisi. Ibid., 1903.

- Structure du feuillet juxta-nerveuse d. la portion glandulaire de

1'hypophyse. Ibid., 55, 1903.

- Contribution a la physiologic de I'hypophyse. A. d. F., iii, novembre,

1905.

Les processus de la secretions de I'hypophyse des mammiferes. A. i. B.,
47, 1907.

- Nouvelle contribution a la connaissance de la fonction de I'hypophyse.

Societa milanese di medicina e biologica, December 13, 1907.

- Ulteriori contrib. alia conosc. della funz. d. ipofisi cerebrale. Rif.

med., 1908.

GENTES, L. Morphologic et structure des ilots de Langerhans chez quelques
mammiferes; evolutions et signification des ilots en general. These
de Bordeaux.

Ilots de Langerhans du Pancreas du chien. C. r. S. B., 54, 535; and
^ibid., 55, 334.
Note sur la structure du lobe nerveux de I'hypophyse. C. r. S. B.,

55, 1903.
Lobe nerveux de I'hypophyse et sac vasculaire. Ibid., 5 mars, 1907.

- L'hypophyse de vertebres. C. r. S. B., 63, 1907.

- La glande infundibuiaire des vertebres. Ibid., 3 juillet, 1907.
GEORGIEWSKY, K. Wirkung der Schilddriisenpraparate auf den tierischen

Organismus. Z. k. M., 33, 153, 1897.
GEORGOPULOS. Exp. Beitr. z. Frage d. Nierenwassersucht. Z. k. M., 60,

1906.
GERBER, H. Nebennierencarcinom mit in den rechten Vorhof reichender

Geschwulst. Thrombose der Vena cava. \V. m. W., 1904.
GERHARDT, D. Uber die Wirkungsweise d. blutdrucksteigernden Substanzen

der Nebennieren. A. P. P., 44, 1900.

- Diskussionsbemerkung zum Vortrage von Kocher. V. C. M., 1906.
GERHARDT and SCHLESINGER, W. Uber Kalk- und Magnesiumausscheidung

beim Diabetes. A. P. P., 42, 1899.
GERHARTZ, H. Geschlechtsorgane und Hunger. B. Z., 2, p. 154, 1906.

- Rudimentarer Hermaphroditismus bei Rana esculenta. A. m. A., 65,

10,05.

- Zur Physiologic des Wachstums. B. Z., 12, p. 97, 1908.

- Mannliche Geschlechtsorgane in Oppenheimers Handb. d. Bioch., iii,

i, 1909.

GESSARD. Sur le pigment des capsules surrenales. C. r. A., 138, 1904.
GETROWA, S. Uber die Thyreoidea von Cretinen und Idioten. Diss., Bern,

1905. _

- Uber die Glandula parathyreoidea. V. A., 188, 1907.

GHEDI.M, G. Untersuchungen tiber die Wirkung einiger Organextrakte.
C. f. B., 34, p. 721, 1903.

- Contrib. alia anat. patol. del pancreas. Rif. med., 933, 1904.

- Adipose non-douloureuse. Gaz. degli osp., p. 1639, 1907.

GHEDIM and MASCHERPA. Sulla glicosuria adrennlinica. Ace. med.,
Geneva, aprile, 1909; Pathologica, i, No. 12, i mai, 1909.

GHIKA, C. Etude sur le thymus. These de Paris, 1901.

GIACOMIXI, E. Sulle terminazioni nervpse nelle capsuli surrenali degli
uccelli. R. Accad. dei Fisiocritici di Siena. November, 1897;
A. i. B., 29, pp. 482-483, 1898.

- Sopra la fine struttura delle capsule surrenali degli Anfibii. Ibid.,

1898.

500 LITERATURE

GlACOMlNl, E. Brevi osservazioni intorno alia minuta struttura del cqrpo
interrenale e del corpi soprarenali del selaci. R. Ac. dei Fisiocritici
di Siena. 10, p. 835,, 1898.

— Sopra la fina struttura delle capsule surrenali degli Anfibii e sopra i

nidi cellulari del simpatico di questi vertibrati. Contribute alia
morfologia del systema delle capsule surrenali, 1902.

— Sull' esistenza delle sostanza midollare nelle capsule surrenali dei

Teleostei. Monit. zool. ital., anno 13, pp. 182-189, 1902; Ibid., 13,
7, 1903.

- Contribute alia conoscenza del sistema delle capsule surrenali dei

capsule surrenali dei Petromizonti. Ibid., pp. 1-20, 1902.

- Contribute alia conoscenza delle capsule surrenali dei Ganoidi e parti-

colarmente sulle esistenza della loro sostanze midollare. Ibid.,
anno 15, pp. 19-32, 1904.

— Contribute alia conoscenza delle capsule surrenali dei Ciclostomi. Sulle

capsule surrenali dei Missinoidi. R. Accad. delle sc. dell' Istituto di
Bologna, 29 maggio, 1904.

— Contribute allo conoscenza del sistema delle capsule surrenali dei

Telostei. Sulla sostanza midollare (organi soprarenali o tessuto
cromaffine) di Aiurus catus. R. Accad. delle Sc. dell' Istituto di
Bologna, pp. 183-189, 1905.

— Sulle capsule surrenali e sul simpatica dei Dipnoi. Ricerche in Pro-

topterus tanectens. Rendiconti della R. Ace. dei Lincei, vol. xv,
i° sem., ser. sa, fasc. 7°, 1906.

— II sistema interrenate e il sistema cromaffine (sistema feocromo) nelle

anguilla adulte, nelle cieche e nei leptocefali. R. Accad. d. Science
di Bologna. 24 maggio, 1908.

— A propos de 1'action physiologiques des capsules surrenales. Biol. med.

Ann., 6, pp. 133-158, 1908.
GIANNELLI, L. and GIACOMINI, E. Ricerche istologiche sul tubo digerente

dei rettili 3 nota. Intestina media e terminale, fegatopancreas. Ace.

d. Fisiocritici di Siena, 1896.
GIANNELLI, L. Sullo sviluppo del pancreas. R. Ace. dei Fisiocritici Siena,

ser. 4j 10, 1898.

— Sul valore morfologico degli accumuli di Langerhans. Ibid., 12, 1900.

— Sulla disposizipne degli accumuli di Langerhans nel Pancreas degli

anfibi urodeli. R. Ace. dei fisiocritici Siena, 1899; and Monit. Zool.
Ital., 12, p. 207, 1900.

- Pancreas interepatico negli anfibi urodeli. Monit. Zool. Ital., 10,

Suppl., 1899.
— • Ricerche istologiche sur pancreas degli uccelli. Monit. Zool. Ital., 13,

1902.

GIARD, A. De 1'influence de certains parasites rhizocephales sur les carac-
teres sexuels exterieurs de leur hote. C. r. S. B., 103, p. 84,^1886.

— Sur la castration parasitaire chez 1'Eupagurus Bernhardus Linne et chez

la Gebia stellata Montagu. Ibid., 104, p. 1113.

— Sur un Copepode (Cancerilla tubulata Dalyell) parasite de 1'Amphiura

squamata, Delle Chiaje. Ibid., 104, p. 1189.

- Sur la castration parasitaire de 1'Hypericum perforatum par la Ceci-

domya hyperici Bremi et par 1'Erysiphe Martii Leo. Ibid., 109, p.

324-

— Sur la castration parasitaire de Typhlocyba par une larve d'Hymen-

optere et par une larve de Diptere. Ibid., 109, p. 708.

- Comment la castration agit-elle sur les caracteres sexuels secondaires ?

C. r. S. B., 56, p. 4, 1904.
GIARD and BONNIER, J. Sur la philogenie des Bopyriens. C. r. A., 104,

p. 1309.
GIARD, A., and JULIE, A. La castration parasitaire et ses consequ. biolo-

giques. Rev. gen. de sciences, ann. v, No. 15, 26 aout, 1904.
GIBBES. On some points in the minute structure of the pancreas. Quat.

Journ. of Micrqsc. Science, 24, 183, 1884.
GIBELLI, C. La funzione delle capsule surrenali in rapporto col processo

di riparazione delle fratture e coll' etiologia dell' ulcera gastrica.

Pathologica, i, p. 131, 1909.
GIERKE, E. Das Glykogen in d. Morphologic des Zellstoffwechsels.

Zieglers Beitr., 37, p. 516, 1905.

LITERATURE 5OI

GlERKE, E. Das chromaffine System und seine Pathologic. L. O., 10,

P. 503, IQ06.

- Uber Knochenmarksgewebe in der Nebenniere. Ziegl. Beitr., Festsch.

Arnold, 1905.

- Die Persistenz und Hypertrophie der Thymusdriise bei Basedowscher

Krankheit. M. m. W., 1907.

- Driisen mit innerer Sekretion. Handb. d. path. Anat. von Aschoff, 2,

p. 751, 1909.
GIGON, A. Die Menge des aus Eiweisz entstehenden Zuckers beim Diabetes.

D. A. k. M., 97, p. 376, 1904.
Uber die Gesetze der Zuckerausscheidung beim Diabetes mellitus. III.

Mitteilung. Z. k. M., 63, 1907.
GILBERT and CARNOT. L'opotherapie, Paris, 1898.
GILBERT and CASTIGUE. Infection thyroidienne et goitre exophtalmique.

C. r. S. B., 51, p. 463, 1899.
GILDERSLEEVE, N. A study of the properties of the serum of rabbits treated

with the adrenal glands and erythrocytes of guinea-pigs. Univ. of

Pennsylvania, Med. Bull., 17, p. 183; Ref. B. C., iii, p. 169.
GlNSBURG. Contr. to the anat. of parathyroid bodies. Un. Pennsylv. med.

Bull., January, 1908.
GIOFFREDI, C. La distruzioni dell' adrenalina nel' organismo. Arch.

Farmac., vi, p. 145, 1907.
GIOFFREDI, C., and ZllNO, A. Contr. alia pathologia del Morbo di Addison.

Rif. med., 1895.
GIORDONI. Diagnostic des tumeurs de 1'hypophyse par la radiographie.

These Paris, 1906.
GiUFFRIDA-RuGGERl. Considerazioni antropologiche sull' infantilismo e

conclusioni relative all' origine delle varieta umane. Monit. zool.

Ital.j aprile and maggio, 1903.
GIZELT, A. Einflusz des Darmextraktes und des Pepton Witte auf die

Harnsekretion. P. A., 123, 1908.
GLASER. Untersuchungen Uber Cholesteatome und ihre Ergebnisse fur die

Lehre von der Entstehung der Geschwiilste. V. A., 122, 1899.
GLASERFELD, BRUNO. Die Epithelkdrperchen und ihre Beziehungen zur

Pathogenese der Tetanic. B. k. W., 1909.
GLASSNER, K., and PICK, E. P. Uber d. Ausscheidung d. Arenalins. V.

25, C. M., 1908.

- Unters. iib. d. gegenseitige Beeinflussung v. Pankreas und Nebennieren.

Z. e. P., 1909.

GLEY, E. Determination de la toxicite du serum sanguin chez les chiens
thyroidectomises. A. d. P., p. 283, 1894; 771, 1895.

- Sur les effets de 1'exstirpation du corps thyroide. C. r. S. B., 1891.

- Note sur les fonctions de la glandule thyroide chez le lapin, &c.

C. r. S. B., p. 843, 1891.

- Sur le diabete alimentaire chez les animaux prive du pancreas. Ibid.,

752, 1891.
Des effets de la thyroidectomie. Remarque a Moussu. Ibid., 1892.

- Des troubles tardifs consecutifs a la thyroidectomie chez le lapin.

Ibid., p. 666, 1892.

- Action d'un liquide extrait du pancreas sur les chiens diabetiques.

A. d. P., 753, 1892.

- Effets de la thyroidectomie chez le lapin. Ibid., 1892.

- Nouvelles recherches sur les effets de la thyroidectomie chez le lapin.

Ibid., 1892.

— Contr. e 1'etude des effets de la thyroidectomie chez le chien. Ibid.,

1892.

— Remarques sur quelques travaux de la phys. de la glande thvroide.

Ibid., 1892.

- Glandes et glandules thyroides du chien. Ibid., p. 217, 1893.

- Nouyelle preuve de 1'importance fonctionelle des glandules thyroides.

Ibid., p. 396.

- Accidents consecutifs a la thyroidectomie chez deux chevres. Ibid.,

p. 453, 1894.
Les resultats de la thyroidectomie chez le lapin. Ibid., 1893.

- La question des rapports entre la rate et la glande thyroide. Ibid.,

1894 and 1895.

- Des effets de 1'exstirpation des glandules parathyroides chez le chien

et le lapin. Ibid., p. 18, 1897.

502 LITERATURE

GLEY, E. Bemerkungen iiber die Funktion d. Schilddriise. P. A., 66, 1897.

— Glande thyroide et thymus. C. r. S. B., p. 1017, 1909.

Resume des preuves des relations qui exist entre la glande thyroide et

les glandules parathyroide. V. Physiol. Kongr. Turin. Progr. med.,
p. 251, IQOI.

— Essais de philosophic et d'histoire de la biologic. Pans, 1900.

Donnees exp. sur les correlations fonctionelles chez les animaux. Ann.

biol., i, p. 313,

GLEY and CHARRIX. Diabete experimental. C. r. S. B., 836, 1893.
GLEY and LANGLOIS. Sur 1'antagonisme reciproque de secretion deverses

dans le sang par divers glandes. C. r. S. B., p. 109, 1898.
GLEY and NICOLAS. Recherches sur les modif. histologiques, £c. Ibid.,

p. 216, 1895.
GLEY and PHISALIX, C. La nature des glandules thyroidiennes des chiens.

C. r. S. B., 1893.
Sur les effets de la thyroidectomie chez la salamandre. Ibid., 1894.

— Sur la fonction des glandules thyroides. Congr. med. int. Rome, 1894.
GLIKIN, W. Zur biologischen Bedeutung des Lecithins. B. Z., vii, 286,

1907.

GLUCK, TH. Thymuspersistenz bei Struma hyperplastica. B. k. W., 1804.
GLUZINSKI. Physiologische Wirkung der Nebennierenextrakte. W. k. \V.,

1895.
- Sur la toxicite de 1'extrait des capsules surrenales. Przelgrad lek.,

March 2, 1895.

— Einige Bemerk. z. klin. Bilde des Klimakteriums. W. k. W.. 1909.
GLUZINSKI and LEMBERGER. Einflusz der Schilddriisenbehandlung beim

gesunden Menschen. C. i. M., 1897.
GODALL, A. The postnatal change in the thymus of guinea-pigs. J. o. P.,

32, p. 191, 1905.
GODARD. Recherches sur les monorchides et les cryptorchides chez Phomme.

C. r. S. B., mars, 1856; and Ibid., 1857.
GODART. Recherches sur la transplantation de la glande thyroide. Journ.

d. med. Bruxelles, 49, 1894.
GOBELT. Versuche liber Transplantation des Hodens in d. Bauchhohle.

C. a. P., 9, 1898.
GORL. Em neues Feld fur Radiotherapie (Strumenbehandlung). M. m. W.,

1905.
GOETZE, J. Physiologic uncl Pathologic der Nebennieren. Diss., Berlin,

1897.
GOTZL and ERDHEIM. Zur Kasuistik der trophischen Storungen bei Hirn-

tumoren. Z. H., 1905.
GOLDBERG. Der Einflusz der Schilddriisenexstirpation auf die Entwicklung

junger Tiere. Podwyssozki' Arch. f. Path., 8, p. 912, 1897.
GOLDBERG, B. Das Prostatasekret bei d. Prostatahypertrophie. Folia

urolog., 1907.
GOLDSCHMIDT, A. Anwendung des Nebennierenextraktes in der Therapie

der Nasen- und Halskrankheiten. Monatsch. Ohrenhk., p. 358, 1902.

- Beit z. Kcnntnis der Pathologic d. menschl. Nebenniere. D. A. k. M.,

98, 1909.
GOLDSCHMIDT, B. Unters lib. d. Vorkommen v. alim. Glykosurie bei M.

Basedowii. Diss., Berlin, 1896.
GOLDSCHMIDT, S. Materialien zu einer Monographic iiber Nebennieren und

Nebennierentherapie. Dis,s., Halle, 74 pp., 1904.

- Adrenalin in der Urologie. D. m. W., 1902.

GOLDSTEIN, L. Die Krankheiten der Nebennieren. Zuelzers Handbuch,

1894.
GOLDZIEHER and MOLNAR. Bcitrage zur Frage der Adrenalinamie. W. k.

W., 1908.

- Pathologic der Nebennieren. Orvosi Hetilap, No. 16, 1908.
GOLODETZ, L. Neue Reaktionen fur Cholesterin und Oxycholesterin.

Chem.-Ztg., 1908.
GOLTZ. Einflusz des Nervensystems auf die Vorgange wahrend der

Schwangerschaft. P. A., 9, 1874.

GOMES. De Popotherapie ovarienne. These de Paris, 1898.
GOMEZ, OCANA. Nuevos hechos y viejas kysotesis sobre et aparato tireideo.

Riv. ibero-amer. d. sc. med., 1890; Ref. J. d. P. P., i, 1899.

LITERATURE 503

GOMEZ, OCAXA. Sur les secretions internes des glandes. Phys. Congr.,
Brussels, 1904.

- Assoc. font, entrc thyroidc et les testic. on les ovaires. Madrid, 1904

(Spanish).
GONIN. Du tractement de 1'uremie par les inj. souscout. de nephrine. Lyon.

Med., 1894.
GONTIER DE LA ROCHE. Modification histol. du pancreas apres exclusion

partielle chez le cobaye. Biol. anat., 11, 232, 1902; and These de

Lyon, 1903.
GONTSCHARNKOW. Uber die Herstellung eines fur die Schilddnise spezi-

fischen Serums. C. a. P., xiii, p. 121, 1902.
GOODSIR, J. On the suprarenal, thymus and thyroid bodies. Philos. Trans.

R. Soc., pp. 633-641. London, 1846.
GORDEEFF, J. M. Die sekretorische Arbeit der Magendriisen bei verschie-

denen Speisesorten. Arb. d. Ges. russ. Arzte, November, 1905.
GOTTLIEB, R. Beitr. z. Physiologic und Pharmakologie der Pankreas-

funktion. A. P. P., 33.

- Uber die Wirkung von Schilddriisenpraparaten an thyreoidektomierten

Hunden. D. m. \V., 1896.

- Uber die Wirkung der Nebennierenextrakte auf Herz und Blutdruck.

A. P. P., 38, pp. 99-112, 1896; and Ibid., 43, p. 286, 1899.

- liber Herzmittel und Vasomotorenmittel. V. 19, C. M., 1901.
GOTTSCHALK, S. Fall von akzessorischer Nebenniere im Ligamentum sus-

pensorum ovarii bei einer Erwachsenen. Z. G. G., 38, p. 332, 1898.

- Uber die Kastrationsatrophie der Gebarmutter. C. G., 1896.
C-OTTSCHAU, M. Uber die Nebennieren der Saugetiere und des Menschen.

^ W. B., pp. 454-462, 1882.

- Struktur und embryonale Entwicklung der Nebennieren bei Saugetieren.

A. A., pp. 412-488, Jg. 1883.

- Uber die Nebennieren der Saugetiere. Biolog. C., iii, pp. 565-576, 1883.
GOTTSTEIX. Versuche zur Heilung der Tetanie m. Implant, v. Schilddr.

D. Z. N., 6, 1895.
GOUGET, A. Maladie bronzde. Bull, de la Soc. anat., 5, p. 77, n juillet,

, 1897-.

- Saturnisme experimental. Hypertrophie considerable des capsules

surrenales Sclerose aortique. C. r. S. B., 55, pp. 1659 and 1953.

- Injections d'adrenaline et serum atheromatogene. C. r. S. B., 66, p.

375, 1909.
GOUIXET and AXDEXARD, P. Fonction clu thymus chez les bovides. Ibid.,

60, pp. 34^-344-
GOURFEIX. Recheches physiologiques et chemiques sur une substance

toxique, extraite des capsules surrenales. Rev. med. de la Suisse

rom., xv, 10, p. 513, 1895.

- Contribution a 1'etude pathologique des capsules surrenales. Ibid.,

Janvier, 1895.

- Recherches physiologiques sur la fonction des glandes surrenales. Ibid.,
^ xvi, 3, p. 113, 1896.

- Sur une substance toxique extraite des capsules surrenales. A gen. de

med., p. 500, 1895; C. r. A., 121, p. 311, 1895.

- La role de 1'autointoxication dans le mecanisme de la mort des animaux

decapsules. Ibid., 125, p. 188, 1897; C. P., p. 423, 1897.
Trav. du Labor, de Phys. de 1'Univers. de Geneve, 1900.
GOURLAY. The proteids of the thyroid and the spleen. J. o. P., 16, 1894.
GRAFEXBERG, E. Eine Nebcnnierengeschwulst der Vulva als eine Metastase

eines malignen Nebennierentumors der linken Seite. V. A., 194, pp.

13-32, 1908.

GRAESER. Adrenalin gegen Darmblutung bei Typhus. M. m. W., 1903.
GRAF, R., and LAXDSTEIXER, K. Versuche iibcr die Giftigkeit des Blut-

serums bei Eklampsie. C. G., 1909.
GRAFTS, L. M. Glandes a secretion interne et le metabolisme. J. A. M. A.,

1908.
CRAMEGXA, A. Un cas d'acromegalie traite par Radiotherapie. Rev.

Neurol., 1909.
GRAXDCLEMEXT. Comment et dans quel cas faut-il employer d'adrenaline

pour guerir le glaucome sans operation. Lyon. med., 37, 2, 1905.
GRAXDRV, M. Sur la structure de la capsule surrenale. J. A. P., 4, 225

and 389, 1867.

504 LITERATURE

GRANT-LAEHLAN. L'opotherapie centre Phemophilie. Lancet, 5 novembre,

1904.
GRASSI and MUNARON. Rendic. d. R. accad. dei Lincei, vols. xii and xiii,

1903 and 1904.
GRATIOLET, P. Systeme veineux des reptiles. L'Institut, 16 fevrier, 1853.

- Veine porte du rein dans les piseaux. Ibid., p. 386, 16 novembre, 1853.
— • Note sur les effets qui suivent 1'ablation des capsules surrenales.

C. r. A., 43, p. 468, septembre, 1856; A. de Med., 1856.
GRAUPNTER, R. Malignes Hypernephrom mit hyaliner Degeneration. Zeigl.

B. 24, 1898.

GRAVES, W. Uber Liickenbilding zwischen den einzelnen Zahnen, ein
friihdiagnostisches und bisher wenig bekanntes Zeichen der Akrome-
galie. M. f. Psych., p. 18, 1904.

GRAWITs, P. Die sogen. Lipome der Niere. V. A., 93, 1883.
— Die Entstehung von Nierentumoren aus Nebennierengewebe. A. k. Ch.,
30, 1884.

- Uber Wachstumsstorungen bei Kretinismus. D. m. W., 1885.

GRAY, A. M. H. On the development of the ductless glands in the chick.

Philos. Trans. R. Soc., pp. 205-309, London, 1902; Sem. med., 1902.

— - A case of myxocdema with unusual features. P. R. S., December, 1907.

GRAZIA, F. DE. Ricerche di ricambio nel diabete insipido. Rif. med., Bd.

23, No. 29.
GRECO. Nuova entita clin. geroderma genito distrofico. Riv. pat. nerv.,

1898.
GREEN, E., and MOORE. Report of a case of Addison's disease. New Y.

Med. Rec., 1902.

GREENHORD, E. H. On Addison's disease. London, 1866.
GREER, J., and WELLS, G. H. The absence of adrenalin in malignant renal

hypernephromas. A. int. Med., iv, p. 291, 1909.
GREGOR. Uber die Unschadlichkeit der Verfiitterung groszer Mengen von

Thyreoidea an Kinder. Monatsch. f. Kinderh., i, p. 318, 1902.
GREGOIRE. Physiologic du corps thyroi'de. Press, med., p. 162, 1901.
GRENET and TANON. Acromegalie et diabete. Soc. de Neurol., 1907; Rev.

neurol., p. 84.
GREY, E. G., and DE SANTELLE. The relation of the thyroid glands to

glycosuria. J. E. M., p. 659, 1909.
GRIFFITHS. The results upon the testicle of ligature or division of the vas

deferens. Lancet, April, 1895.
GRIGORIEFF. Die Schwangerschaft bei Transplantation d. Eierstb'cke.

C. G., 1897.

GRIMANI, E. Sugli effetti del trapianto del timo e sulle correl. funtim. fra
testicolo e timo. Arch. d. anat. patol., i, 1906; Ref. Bph. C.. i, 1569.

GROBER, J. Tiber den Einflusz von Muskelarbeit und Auszentempatur auf
das Masz der alimentaren Glykosurie. D. A. k. M., 95, p. 137, 1908.

GROBER. Massenverhaltnisse d. Herzens bei kiinstlich. Arterienstarre.
W. k. W., 1907.

- Zum erblichen Auftreten der Basedowschen Krankheit. M. K., 1908.

- Adrenalinerkrankung der Kaninchenleber. C. i. M., 1908.
GROSCHUFF, K. Bemerk. zu der Mitteilung von Jacoby usw. An. An., 12,

p. 20, 1896.

- Uber das Vorkommen von Thymussegm. der vierten Kiementasche beim

Menschen. Ibid., p. 161, 1900.

GROSGLICK, S. Zur Frage uber die Persistenz der Kopfniere der Teleostier.
Z. A., Jahrg. 9, No. 219, pp. 196-198, 1886.

- Zur Morphologie der Kopfniere der Fische. Ibid., 8, pp. 605-611, 1885.
GROSS, E. Beziehungen der Tetanic z. weiblichen Sexualapparat. M. m.

W., 1906.

- Zur Funktionspriifung des Pankreas. D. m. \V., 1909.

GRUBE, K. Uber chemische Korrelationen im Organismus. M. K., 1909.

GRUBER, W. Untersuchungen einiger Organe eines Kastraten. A. A. P.,
p. 463, Jahrg., 1847.

GRUNBAUM, O. F. F. A note on the effect of the administration of supra-
renal gland by the mouth in health and disease. J. o. P., 24, 2, p. 24,
1899.

Suprarenal gland extract as a haemostatic. Brit. Med. Journ., November,
1900.

LITERATURE 505

GRYNFELTT, E. Sur le corps interrenal des Plagiostomes. C. r. A., 135,
,, PP- 349-44i5 1902.

- Structure des corps suprarenaux des Plagiostomes. Ibid., 135, p. 373,

IQO2.

- Vascularisation des corps surrenaux chez les scillium. C. r. S. B.,

IQ02.

- Recherches anatomiques et histologiques sur les organes surrenaux des

Plagiostomes. Bulletin scientifique de la France et de la Belgique,
38, pp. 1-137; et These de Paris, 1903.

- Notes histol. sur la capsule surrenale des amphibiens. J. A. P., 40,

p. 180, 1904.

- Sur la capsule surrenale des amphibiens. C. r. A., 137, pp. 77 and 78,
, 1903.

Sur la capsule surrenale des amphibiens. Paris, 1904.

- Les organes chromaftines. Montpellier med., 1903.

GUALDRINI. Dell' emostasi nella chirurgia epatica e nuovo contributo col

cloruro di Adrenalina. Gazz. d. osped., p. 259, 1904.
GUARNIERI and MARiNO-Zuco. Recherches experimentales sur Faction

toxique de Pextrait aqueux des capsules surrenales. A. i. B., 10,

iSSS; and M. U., 14, pp. 59 and 617, 1892.
GUARNIERI and MAGINI. Etude sur la fine structure des capsules surrenales.

A. i. B., 10, 1888.
GUAY. Essai sur la pathogenic de la maladie d'Addison. These de Paris,

1893-
CUBLER. Fall von akuter maligner Akromegalie. Korrespbl. f. Schweiz.

A., 30, 1900.
GUNTZ, L. Einflusz der Kastration auf den respirator. Stoffwechsel.

Z. Ch., 44, 1908.
GURBER. Ub. d. Einfl. des Thyreoidins auf den Stoffwechsel. W. B., 1896.

- tiber die wirksame Substanz der Nebenniere. M. m. W., 1897; W. B.,

1897-

- Zur Kenntnis der wirksamen Substanz der Nebenniere. C. P., 1898.
GUERMONPREZ. Contribution a Petude de la maladie bronzee d'Addison.

These Paris, 1875.

GUERRINI, G. Sur les fines modifications de structure de quelques organes
dans le cours de la fatigue (fou, rein, hypophyse, capsules surrenales).
A. i. B., 49, pp. 161-170, 1908.

- Sulla funzione della ipofisi. Speriment., 58, p. 837, 1904.

- Sur une hypertrophie secondaire experimentale de Phypophyse. A. i. B.,

43, 1905-

- Uber die Funktion der Hypophyse. C. a. P., 16, 1905.

GUIART. Etude sur la glande thyroide, dans la serie des vertebres. Stein-

heil, Paris, 1896.
GuiEYSSE, A. La capsule surrenale chez la femelle du cobaye en gestation.

C. r. S. B., 51, p. 898, 18 novembre, 1899.

- La capsule surrenale du cobaye. J. A. P., 37; and These de Paris, 1901.
GUIHAL, E. Le syndrome addisonienses. Gaz. des Hop., IQOI.
GUILLAIN and ALQUIER. Etude anatomopathologique d'un cas de maladie

de Dercum. A. m. e., p. 680, septembre, 1906.

GUIXARD, L., and MARTIN, E. Action de 1'extrait capsulaire de Phomme
sain sur le rythme du cceur et sur la respiration. C. r. S. B., pp. 96 and
98, 4 fevrier, 1899.

- Action cardio-vasculaires du sue thyroi'dien. Ibid., p. 161, 4 mars, 1899.

- Contrib. a Petude des effets du sue surrenal. J. d. P., i, 744, 1899.
GUINDER. Uber Nierendekapsulation bei Eklampsie. M. m. W., KJO.S.
GUINON. Un cas d'acromegalie a debut recent. Nouv. Icon, de la Salp.,

3, p. 161, 1890.

- Infantilisme. Soc. de Pediatrie, 10 mai, 1901.

GUIZETTI, P. Modificazioni del glicogene delle paratiroidi umane nelle

malattie. Atti Soc. Ital. Progress. Sc. i Riun., Parma, pp. 283 and

284.
GULBENK. Deux cas de maladie d'Addison traites avec succes par Padren-

aline. Bull. gen. therap., 150, p. 88, 1905.
GULCKE, N. Verhalten der Nebennieren bei kongenitaler Syphilis. V. A.,

173, 1903-
GULL. A cretinoid state supervening in adult life in women. Transact.

Clin. Soc., London, 1874; and Brit. Med. Journ., November i, 1873.

506 LITERATURE

GULLAN, A. G. Exophthalmic goitre. Lancet, September 5, 1908.

- A contribution to the discussion on Exophthalmic goitre, with special

reference to the antithyroid treatment. Liverpool Med.-Chirurg.

Journ., July, 1908.
GULLAN, A., and GORDON. Two cases of Addison's disease and the effect

of the administration of suprarenal extract. Lancet, August 19, 1905.
GULLI, V. II diabete surrenale. Gl' Incurabili, 1905.
GUREWITSCH, R. Uber die Wirkung des Jodkaliums auf die Pulszahl.

Diss.,, Basel, 1907.
GUTMANN. Beitr. z. Pathologic d. Pankreas bei Diabetes. V. A., 172, p.

493, 1903; and 177, Suppl., p. 128, 1904.
GUTTMANN, P. Addisonsche Krankheit. Eulenburgs Real-Encyclopadie,

3 Aufl-

- Uber die Addisonsche Krankheit. Diss., Berlin, 1868; D. m. \V., 1885.

GUTZEIT, R. Ein Teratom der Zirbeldruse. Diss., Konigsberg, 1896.

HAAS, L. Uber die Addisonsche Krankheit. Diss., Wurzburg, 1862.
HABERER, i>. H. Experiment. Verlagerung der Nebenniere in die Niere.

A. k. Ch., 86, 1908.

- Exp. Unters. iib. Nierenreduktion u. Funktion d. restierenden Paren-

chyms. M. G. M. C., 17, 1907.
HABERER, v., and STORK. Beitrag zur Marksekretion der Nebenniere.

W. k. W., No. 9, pp. 305 and 338, 1908.
HABERERN, J. P. Physiol. norm, et path, de la prostate. Congr. intern.

d'urolog., ii, 1908.

HABERFELD, W. Die Rachendachhypophyse. Zieglers, B., 46, p. 133, 1909.
HABERFELD, W., and SCHILDER, C. Die Tetanie der Kaninchen. M. G.

M. C., 20, 1909.

HACKERT, H. Morbus Addisonii. Diss., Jena, 1884.
HAGENBACH, E. Exp. Studien iib. d. Funktion d. Schilddriise und der

Epithelkorperchen. M. G. M. C., 18, 1907.

- Schilddriisen und Epithelkorperchen. M. K., 1908.

HAHN, G. Uber die Wirkung der Nebennierenpraparate speziell des Adren-
alins mit besonderer Beriicksichtigung der Oto-, Rhino-. Laryngo-
logie. Diss., Leipzig, 1903.

HALASZ. Beitr. z. Kennt. d. hist. Veranderungen des Pankreas bei Pan-
kreasdiabet. C. f. norm. u. path. An., i, 1904.

HALBAN. Uber den Einflusz der Ovarien auf die Entwicklung des Genitales.
M. G. G. , xii, p. 496, 1901.

- Ovarium und Menstruation. S. W. A., no, p. 71, 1901.

- Die Entstehung der sekundaren Geschlechtscharaktere. A. G., 70,

1903; W. k. W., No. 28, 1903.

- Schwangerschaftsreaktionen der fotalen Organe und ihre puerperale

Involution. Z. G. G., 53, 1904.

- Die innere Sekretion von Ovarium und Placenta und ihre Bedeutung

fiir die Funktion der Milchdriise. A. G., 75, 1905.
HALBERSTADTER. Die Einwirkung der Rontgenstrahlen auf Ovarien.

B. k. W-, 1905.

HALLE, W. Uber die Bildung des Adrenalins im Organismus. H. B., viii,

1906.

HALLER, ALBERT, v. Elementa physiologiae corp. humani. Bernae 1765.
HALLER, B. Uber die Urniere von Acanthias. Morph. Jahrb., 29, 1901-2.

- Unters. iiber Hypophyse und Infundibularorgane. Ibid., 25, 1896.

- Uber die Hypophyse niederer Placentalier. A. m. A., 74, 1909.
HALLIBURTON. Report of chemical investigation of the tissues and organs

from cases of myxcedema in man and animals. Report on Myxcedema,
London, 1888.

The physiological effect of extracts of nervous tissues. J. o. P., 26,
1901.

- Die Biochemie der peripheren Nerven. E. P., 4, 1905.

- Handbook of Physiology. London, 1907.

HALLIBURTON and OSBORNE. The physiological action of cholin and neurine.

Proc. Phys. Soc., 171, 1899.
HALLIBURTON, CANDLEU, P. J., and SIKES, A. W. The human pituitary body.

J. o. P., 38, 1909.
HALLION, L. Corp thyroide et capsules surrenales. Arch, gen med., nouv.

ser. ii, p. 488, 1899.

LITERATURE 507

HALLION, L. Physiologic normale et pathologique du corps thyroide. Ibid.,
iv, p. 490, i goo.

- Corps thyroide et capsules surrenales. Ibid., vi, p. 604, K)OI.

- Effet vasodilatateur de 1'extrait ovarien sur le corps thyroide. C. r. S. B.,

1907.

- La fonction glycogenique du foie et sa regulation. Gaz. des hopitaux,

No. n, 1909.
HALLION, L., and ALQUIER, L. Modifications histologiques des glandes a

secretion interne par ingestion prolongee d'extrait d'hypophyse.

C. r. S. B., 64, p. 5, 1908.
HALLION and CARRION. Sur 1'essai experimental de 1'extrait opotherapeutique

d'hypophyse. Soc. de therap., 13 mars, 1907; Bullet, gen. de therap.,
_ p. 459, mars, 1907.

- Sur le traitement serotherapeutique du goitre exopht. d'apres la meth.

de Ballet et Enriquez. Presse med., 1905.
HALLION and LAIGNEL-LAVASTINE. Recherches sur Tinner vat ion vaso-motrice

des glandes surrenales. C. r. S. B., 55, p. 187, 1903.
HALLION and NEEPER. L'influence excito-motrice de la bile sur 1'intestin.

I. Action sur le rectum. Ibid., 63, p. 182, 1907. II. Action sur

1'intestin grele. Ibid., p. 254.
HALLOT, G. L'extrait de capsule surrenale et son emploi dans la therapeu-

tique oculaire. These de Paris, 1897.

HALMAGRAND. Etat actuel de Tinfantilisme. These de Paris, 1907.
HALPENNV, J., and THOMPSON, F. D. On the relationship between the

thyroid and parathyroids. An. An., 34, 1909.
HALSTED, W. S. An experimental study of the thyroid gland of dogs, &c.

Johns Hopkins Hospital Reports, vol. i, 1896.

- An experimental study of the thyroid glands of dogs, &c. Baltimore,

1896.

The transplantation of parathyroid glands in dogs. Proc. Path. Soc.,
Philad. ; and J. E. M., 5, pp. 74-77, 1908.

- Auto- and isotransplantation in dogs of the parathyroid glandules.

J. E. M., xl, p. 175, 1909.
HAMBURGER, W. The action of intravenous injections of glandular extracts

and other substances upon the blood-pressure. A. J. P., 11, p. 282,

1904.
HAMEL. Klinische Beobachtungen iiber z\vei Fiille von Morbus Addisonii

mit besonderer Beriicksichtigung des Blutbefundes. D. A. k. M., 71,

p. 240, 1901.

HAMM. Suprarenin (Hochst). D. m. W., 1904.
HAMMARj A. Uber die normalen Durchschnittsgewichte der mcnschlichen

Thymusdriise. V. g. M., 3, Folge, 37, p. i.

- Uber Thymusgewicht und Thymuspersistenz beirn Menschen. V. a. G.,

Genf, 1905.

- Zur Histogenese und Involution der Thymus. An. An., p. 23, 1905.

- Uber Gewicht, Involution und Persistenz der Thymus im Postfotalleben

des Menschen. A. A., 1906, Suppl.

— - 1st die Thymusdriise beim Frosch ein lebensvvichtiges Organ? P. A.,
1 10, 337-

— Zur Kenntnis der Tellostierthvmus. A. m. A., 73, p. i, 1909.
HAMON DU FOUGERAY. De Torigine rhino-pharyngienne de goitres. Progr.

med., No. 21, 1901.
HANAU, A. Versuche iibcr den Einflusz der Geschlechtsdriisen auf die

sekundaren Geschlechtscharaktere. P. A., 65, p. 516, i8<)(>.
HANDELSMANN. Experimentelle und chemische Untersuchungen iiber Cholin

und dessen Bedeutung fur die Entstehung von epileptischrn Kramp-

fen. Gazetta lekarska, Nos. 32-35; Ref. Virch-Hirsch' Jahresb. iiber,

1908, i, p. 131; D. Z. N., 35, 1908.
HANSEMANN, D. v. Uber Anaplasie, Spezifizitat und Altruismus der Zellen.

Berlin, 1891.

- Die Beziehungen d. Pankreas zum Diabetes. Z. k. M., 26, 181)4.

- Uber die sogenannten Zwischenzellen des Hodens und dercn Bedeutung

bei pathologischen Veranderungen. V. A., 142, 1895.

— Ein seltener Fall von Morbus Addisonii. B. k. W., 1896.

— Uber Akromegalie. Ibid., icScjj.

— Uber die Struktur und das \Vesen der Gefaszinseln des Pankreas.

V. d. p. G., 4, P- 187, 1901.

508 LITERATURE

HANSEMANN, D. v. Echte Nanps9mie. B. k. W., igo2.

- Demonstration eines kretinistischen Schakals. B. m. W., igoS.
HAPPEL. Ub. d. Folgen der Unterbindung d. Ausfuhrungsgange des Pankreas

beim Hunde. Diss., Marburg, 1906.
HARDMAN, W. A case of hypothyroidism. Brit. Med. Journ., August 20,.

IQ08.

HARLEY. An experimental inquiry into the function of the suprarenal cap-
sules and their connection with bronzed skin. Briefl. Mitteil. an
Virchow, November, 12, 1857; The British and Foreign Med. chir.
Review, No. 41, pp. 204-221 and No. 42, p. 498, 1858; Med. Times
and Gaz., p. 564, November 28, 1857.

- Living specimen of a rat from which both the suprarenal capsules and

the spleen had been removed. Trans. Path. Soc. London, vol. Q,
p. 401, February Q, 1858.

- Discussion in Roy. Med. and Chir. Soc., February 9, 1858.
The histology of the suprarenal capsules. Lancet, 1858.

HARLEY, W. Pathogenics of pancreatic diabetes. Brit. Med. Journ., 1892.

— Absorption and metabolism in obstruction of ductus pancreaticus.

J. o. P. B., 1895.
HARMER. Uber die Wirkung des Nebennierenextraktes auf die Schleimhaut

der Nase und des Kehlkopfes. W. k. W., 1901.
HARNACK, E. Zur Pathogenese des Diabetes mellitus. Diss., Dorpat, 1873.

— Uber von Cyons antagonistische Versuche mit Jodothyrin-Atropin, &c.

C. P., 1898.
HARRIS, I. Die Zerstorung des Adrenalins im lebenden Tier. Diss.,

Konigsberg, 1904.
HARRIS, V., and Gow. Comparative histology of the pancreas. J. o. P., 15,

349, 1894.
HART, K. Thymushyperplasie bei Morbus Addisonii. W. k. W., 1908.

— Thymuspersistenz und Thymushypertrophie. M. m. W., 1908;

C. G. M. C., 1909.
HARVEY, B. C. The chromaffine characters of certain parietal cells of the

stomach. Brit. Med. Journ., p. 1703, 1906.
HASKOVEC, L. Einwirkung des Schilddriisensaftes auf den Kreislauf.

W. m. Bl., 1896.

- Nouv. contrib. a la question de 1'action du liquide thyroidien sur le

systeme nerveux central. A. m. e., 13, 1903; and Arch, intern, d.

Pharmac., 8, 1901.
HAUSHALTER and LUCIEN, M. Polyurie simple et tubercule du 1'hypophyse.

Rev. Neur., 1908.
HAYEM and LESAGE. Pseudotuberculose bacillaire chez I'homme. Maladie

d'Addison. Bull, et mem. de la soc. med. des hop., Xo. 21. Paris,

1891.
HECKER. Zur Pathologic der Schilddriise und Nebenschilddriisen. Jahres-

ber. d. Ges. f. Naturheilk., p. 62, Dresden, 1906-1907; M. m. W.,

1907.
HEDBOM, K. Uber die Einwirkung verschiedener Stoffe auf des isolierte

Saugetierherz. S. A., viii, pp. 147 and 169, 1898.
HEDIXGER, E. Uber Beziehungen zwischen Status lymphaticus und Morbus

Addisonii. V. d. p. G., xi, 1907; Frankf. Zeitsch. Path., i, p. 527.

- Uber familiares Vorkommen plotzlicher Todesfalle, bedingt durch

Status lymphaticus. D. A. k. M., 86, p. 248, 1905.

— Uber experimentell durch Adrenalin und Hamostasin erzeugte Arteri-

enerkrankungen bei Kaninchen. Korr.-Bl. f. Schweiz. Arzt., 35, 20,
1905.

HEDINGER and LOEB. Uber Aortenveranderungen bei Kaninchen nach sub-
kutaner Jodkaliverabreichung. A. P. P., 56, p. 314, 1907.

HEDON, E. Sur la production du diabete sucre apres 1'exstirpation du pan-
creas. C. r. S. B., 1890.

- Exstirpation du pancreas; diabete sucre. A. m. e., i and 3 — 4 H.,

1891.

- Pathogenic du diabete maigre. Ibid., 1892.

- Exstirpation du pancreas. Les effets sur la nutrition generale.

A. d. P., 1891.

— Greffe sous-cutanee du pancreas. Ibid., p. 617, 1892.

— Les travaux recents sur la physiologic des glandes vasculaires san-

guines. Nouveau Montpellier medic., Supp., pp. 467-494, 1893.

LITERATURE 509

HEDOX, E. Physiologic norm, et path, du pancreas. Encyc. scient.,
Paris.

- Diabete pancreatique. Paris, 1898; and in Richet, Diet, de physiol.,

iv, IQOO.

- Experiences des transfusion reciproque par circulation carotidienne

croissee entre chiens diabetiques et chiens normaux. C. r. S. B., 66,

p. 60.9, 1909.
HEDOX, E., and FLEIG, C. Chloralose et inhibition. Arch, mternat. de

Phamac., 13.
HEGAR, A. Die Castration der Frauen. Volkmanns Samml., Nos. 136-138,

1878.

- Der Geschlechtstrieb. Stuttgart, 1894.

- Zur abnormen Behaarung. B. G. G., 4, 1901.

- Korrelationen der Keimdrlisen und Geschlechtsbestimmung. Ibid., 7,

p. 201, 1903.

HEIBERG, K. A. Ein Verfahren zur Untersuchung der Bedeutung der
Langerhansschen Inseln im Pankreas. Z. ph. Ch., 49, p. 243.

- Hypertrophie der Langerhansschen Pankreasinseln. M. m. W., 1907.

— Uber einige Probleme des Pankreas. Zeit. f. Phys. u. Path. d. Stoffw.,

1907.
HEIDEXHAIX, R. Die Bauchspeicheldriise. Hermanns Handb. d. Physiol.,

Bd. 5.
HEIDEXHAIX, L. Uber die Behandlung der peritonitischen Blutdrucksen-

kung mit intravenosen Suprareninkocksalzinfusionen. M. G. M. C.,

18, 1908.

HEIM. Dissertatio de renibus succenturiis. Berlin, 1824.
HEIXATZ. Altes u. Neues liber die Schilddruse. (Diss.) Russisch. Zit. nach

Georgiewsky, Z. k. M., 33, 164.
HEIXSHEIMER, F. Uber die Ursache der Zuckerausscheidung im Pankreas-

diabetes der Hunde. Z. e. P., 2, 1905.

HEIXZ, R. Handb. d. exper. Path. u. Pharmakologie. Jena, 1904-1906.
HELLIX. D. Struma und Schilddriise. Miinchen, 1893.

- Uber den wirksamen Bestandteil der Schilddruse. A. P. P., 40, 121,

1898.

HELLY, K. Studien uber Langerhanssche Inseln. A. m. A., 68, 124, 1905.

HEMET. L'opotherapie surrenale chez les Addisoniens. These de Paris,
1898.

HEMPEL. Ein Beitrag zur Pathologie der Glandula pinealis. Diss., Leip-
zig, 1901.

- Behandlung des Morbus Basedowi mit Anthyreoidinserum (Moebius).

M. m. W., 1905.
HEXDERSOX, L. J., and SriRO, K. Zur Kenntnis des lonengleichgewichtes

im Organismus. I. Teil. Uber Basen- und Sauregleichgewicht im,

Harn. B. Z., 15, pp. 105-113.
HEXDERSOX, J. On the relationship of the thymus to the sexual organs.

J. o. P., p. 38, 1904-
HEXGGE, A. Pseudohermaphroditismus u. sekundare Geschlechtscharaktere.

M. G. G., 1903.

HEXLE, J. Allgemeine Anatomic, pp. 996, 1004-1006. Leipzig, 1841.
— • Uber das Gewebe der Nebenniere und der Hypophysis. Z. r. M., 24,

1865.

— Handb. d. system. Anatomic. II. Blutgefaszdriisen. Braunschweig,

1866.

HEXRI, \T. Note sur Faction du sue pancreatique. C. r. S. B., 57 ii, 1905.
HEXROT. Des lesions anatomique et de la nature du myxoedeme. C. r. Ass.

franc., 82.
HEXSCHEX, K. Uber Struma suprarenalis cystica hsemorrhagica. Beitr.

z. klin. Chir., 49, S. 217, 1906.

HERBST, K. Formative Reize in der tierischen Ontogenese. Leipzig, 1901.
HKRLITZKA, A. Sul trapiamento dei testicoli. A. E. M., 9.

- Contribute allo studio del diabete duodenale di Pfliiger. Giorn. R.

Accad. di Med. di Torino, 71, p. 57, 1908; and A. i. B., 50.

- Zur Kenntnis des Pfliigerschen Duodenaldiabetes. P. A., 123, p. 331,

1908.

HERRIXG, P. J. The effect of thyroidectomy upon the mammalian pituitary.
Quart. Journ. of Exp. Physiol. London, vol. i, pp. 281-285; Brit.
Med Journ., 1908.

510 LITERATURE

HERRING, P. J. Action of pituitary extracts on the frog's circulatory system.

J. o. P., 31, p. 429.

The physiological action of extracts of the pituitary body and saccus
vasculosus of certain fishes. Quart. Journ. of Exp. Physiol., i, 187,
1908.

- A contribution to the comparative physiology of the pituitary body.

Ibid., p. 261.

HERMANN, G., and VERDUN, P. Persistance des corps postbranchi aux chez
1'homme. C. r. S. B., 1899.

— Remarques sur 1'anatomie comparee des corps postbranchiaux. Ibid.
HERMANN. O. Uber das Vorkommen und Veranderungen von Myelin-

substanzen in der Nebenniere. Arb. a. d. path.-anat. Inst. zu
Tubingen. V, 1906; piss., Tubingen, 1905.

HERTER, C. A. On adrenalin glycosuria and allied forms of glycosuria
due to the action of reducing substances and other poisons on the
cells of the pancreas. Med. News, So, 19, p. 865, May, 1902;
A. J. M. S., 1903.

— Note on the newly recognized sugar-controlling function of the supra-

renal glands. Amer. Med. News, October 25, 1902.
HERTER, C. A., and RICHARDS, A. N. Note on the glycosuria following

experimental injections of adrenalin. Med. News, T. So, p. 201,

February, 1902; Ref. Schmidt, 278, p. 118.
HERTER, C. A., and WAKEMANN, A. J. Uber Adrenalin-Glycosurie und

verwandte durch die Wirkung reduzierender Substanzen und anderer

Gifte auf die Pankreaszellen hervorgerufene experimentelle Gly-

cosurien. V. A., 169, p. 479, 1902.
HERTOGHE. De Phypothyroidie benigne chronique ou Myxcedeme fruste.

Nouv. iconog. de Salpet. , juillet-aout, 1899.

- Eine Reihe von Arbeiten in Bulletin de 1'Acad. royale de medecine de

Belgique, 10-13, 1895-1899.

- Die Rolle der Schilddriise bei Stillstand und Hemmung des Wachstums

und die Entwicklung und der chronisch gutartige Hypothyreoidismus.
Ubers. von Spiegelberg. Mtinchen, 1900.

HERZOG, M. Liefert das Pankreas ein dextrosespaltendes, Alkohol, und
CO2 lieferndes Enzym ? H. B., 2, 1902.

— Zur Histologie und Pathologic des Pankreas beim Diabetes. V. A.,

168, 1902.
HERVIEUX, C. Les ferments solubles de la glande interstitielle du testicule.

C. r. S. B., Bd. 60, pp. 653 and 683.
HERXHEIMER, G. Uber Pankreaszirrhose bei Diabetes. V. A., 183.

- Pankreas und Diabetes. D. m. W., 1906.

- Zur Frage des Verhaltens der Langerhansschen Zellinseln im Pankreas

bei Diabetes. Festschr. Orth., 1903.
HERXHEIMER, G., and HOFFMANN, K. F. Uber die anatomischen Wirkungen

der Rontgenstrahle auf den Hoden. D. m. W., 1908.
HESS, O. Beitrage zur Anatomic und Pathologic des Pankreas. Med.

naturw. Arch., Berlin, i, 1907.

— Die Ausflihrungsgange des Hundepankreas. P. A., 118, 1907.

HESSE, A., and MOHR. Uber Glykosurie und Glykamie des pankreaslosen

Hundes. Z. e. P., vi, p. 300, April, 1909.
HEYN. Ein Beitrag zur Lehre vom Myxodem. Arch. f. Psychiatric, 41,

1906.
HILDEBRAND, O. Uber den Bau gewisser Nierentumoren, ihre Beziehungen

zu den Nierenadenomen und zur Nebenniere nebst Mitteilungen iiber

den Glykogenbefund in diesen sowie in anderen Geschwiilsten.

A. k. Cli., 47, PP- 225-273, 1894.

- Adrenalin in der chirurgischen Praxis. B. k. W., 1905.
HlLDEBRANDT. Zur Lehre von der Milchbildung. H. B., 5, 1904.
HlLLEMAND, C. Organotherapie ou Opotherapie. Paris, 1899.
HINSELMANN, H. Glykogenabbau und Zuckerbilding in der Leber normaler

und pankreasdiabetischer Hunde. Z. ph. Ch., 61, p. 265, 1909.

- Uber das Wesen des Pankreasdiabetes. B. k. W., 1909.

HIPPEL. Ein Beitrag zur Kasuistik der Hypophysentumoren. V. A., 126,

p. 124, 1891.
HlRSCH, A. Die Geschwtilste der Nebennieren und Nebennierengeschwtilste

der Niere. Diss., Wiirzburg, 1902.

LITERATURE 511

HlRSCH, R. Uber das glykolytische Ferment der Leber. H. B., 4, 1903.

- Glykosurie nach Schilddrusenexstirpation bei Hunden. Z. e. P., ill,

1906.

- Schilddriise und Glykosurie. Z. P., v, p. 233, 1908.

- Innere Sekretion. Oppenheimers Handb. d. Bioch., Bd. 3, 1909.
HIRSCHEL, J. Beitrage zur Kenntnis des Morb. Basedowii. Jahrb. Psych.,

1Q02.

HlRSCHBERG, A. Beitrag zur Behandlung mit Oophorin. M. m. \V., 1908.
HiRTZ. Traitement de la maladie d'Addison par les injections de capsules

surrenales. Bull, de Therap., 30 juillet, 1902.
HlRZEL. Beitrag zur Kasuistik der Addisonschen Krankheit. Diss. , Zurich,

1860.
His, \V. Beobachtungen Uber den Bau der Saugetiereierstocke. A m. A.,

i, 1865.

- Der Tractus thyreoglossus und seine Beziehungen zum Zungenbein.

A. f. Anat. u. Entw. v. His und Braune, 1891.

- Beitrag zur Kenntnis der zum Lymphsystem gehorigen Driisen.

Z. w. Z., 10 and 1 1.

HlTSCHMANN, E. Ein Fall von " Gefasztod '' durch hamorrhagische
Zerstorung beider Nebennieren. W. k. W., 1902 ; Jahrb. f. Psych.,

21, IQ02.

HlTSCHMANN and ADLER. Bau der Uterusschleimhaut des geschlechtsreifen

\\'eibes mit besonderer Berticksichtigung der Menstruation. Berlin,

1908.
HOCHE, A. Kretinismus und Myxodem. Im Lehrbuch der Psychiatric von

Binswanger und Siemerlingj 1904.
HOCHENEGG, J. Geheilter Fall von Hypophysentumor. 37, Kongr. d. G.

Ch., 1908.

- Ablation von Hypophysenturnoren. W. k. \V., 1909.

- Zur Therapie der Hypophysenturnoren. Z. Ch., 100, IQOI.
HOCHSTETTER, F. Beitrage zur Entwicklungsgeschichte des Venensystems

der Amnioten. II. Reptilien (Lacerta, Tropidonotus). Morph.
Jahrb., xix, 3, H., pp. 428-501.

- Beitrage zur Anatomic und Entwicklungsgeschichte des Blutgefasz-

systemes der Krokodile. Sonderabdruck aus Yoelzkow, Reise in

Ostafrika in den Jahren, 1903-1905, Bd. iv, pp. 105-106. Stuttgart,

1906.
HODDIK. Uber die Behandlung der peritonitischen Blutdrucksenkung mit

intravenosen Adrenalin-Kochsalzinfusionen. C. Ch., p. 1193, 1907.
HODLMOSER. Tod durch Embolie der Pulmonalarterie, ausgehend von

einen in die Hohlvene gewucherten primaren Angiosarkom der

Xebenniere. Z. H., "25, 1904.
HONIGSBERGER. Behandlung der Rhachitis mit Nebennierensubstanz.

M. m. W., 1900.
HOENNICKE. Zur Theorie der Osteomalacie. B. k. W., 1904.

- Uber das Wesen der Osteomalacie. Halle, 1905.

- Uber experimentell erzeugte Strumen. Chirurgenkongresz, 1908.
HOSSLIN. Tumor der Hypophysis cerebri. M. m. W., 1894.

HOFBAUER, S. Beitrage zur Atiologie und zur Klinik der Graviditatstoxi-
kosen. Z. G. G., 61, H. 2, 1907.

- Uber experimentelle Beeinflussung von Graviditat. B. k. \V., 1908.
HOFFMANN, C. K. Zur Entwicklungsgeschichte der Urogenitalorgane bei

den Anamnia. Z. w. Z., 46, pp. 570-643, 1886.

— Zur Entwicklungsgeschichte der Tjrogenitalorgane bei ben Reptilien.
Ibid., 48, 1889.

- Etude sur le developpement de 1'appareil uro-genital des oiseaux. Verh.

d. Ak. d. \Yiss. Amsterdam, 1892.

- Zur Entwicklungsgeschichte des Sympathikus bei den Selachiern (1900),

bei den Urpdelen. Ibid., 1902.

HOFFM\XX, E. Uber Hypernephrometastasen. D. m. \V., 1907.
HOFFMANN, H. Yerwendung synthet. Suprarenins in der Lokalanasthesie.

M. m. \V., 1907.
HOFFMANN, J. Weiterer Beitrag zur Lehre von der Tetanie. D. Z. N.,

9, p. 278, 1897.
HOFFMANN, K. F. Uber den Einflusz der Rb'ntgenstrahlen auf den Kanin-

chenhoden. Diss., Bonn, 1908.

512 LITERATURE

HOFFMANN, R. Versuche mit Cholin. W. k. \V., 1905.

— Serumuntersuchungen bei Thyreoidose. M. m. W., 1908.

— Beitrage zur Lehre vom Morbus Basedowii. Z. k. M., 69, 1909.

— Antithyreoidin Moebius bei Osteomalakie. Z. G., 1908.

- Die Affinitat des Adrenalins zu Jod. M. m. W., 1909.
HOFMEISTER, F. Untersuchungen iiber die Zwischensubstanz in den Hoden

der Saugetiere. S. W. A., 65, Abt. 3, 1872.

HOFMEISTER. Zur Physiologie der Schilddriise. F. M., 10, 1892.
— • Exper. Unters. iiber die Folgen des Schilddriisenverlustes. Bruns.
Beitr., u, 1894.

— Zur Frage nach der Folgezustanden bei Schilddrusenexstirpation.

D. m. W., 1896.

- Uber Storungen d. Knochenwachstums bei Kretinismus. Fortsch. d.

Rontgenstr., i.
HOLLAND, C. J. The X-ray treatment of exophthalmic goitre. Liverpool

M. Ch. J., July. 1908.

HOLLINGER. tiber die Verteilung des Zuckers im Blut. B. Z., 1-^1904.
HOLM, F. tiber die nervosen Elemente in den Nebennieren. S. W. A., 53,

1866.

- Uber die chemischen Bestandteile der Nebennieren. J. prakt. Ch., i,

p. 150, 1867.

HOLMGREN, E. Uber die Saftkanalchen der Leberzellen und der Epithel-
zellen der Nebenniere. An. An., 22, p. 9, 1903.

- Weitere Mitteilungen iiber die Trophospongienkanalchen der Neben-

nieren vom Igel. Ibid., pp. 470-481, 1903.
HOLSCHEWNIKOFF. Ein Fall von Syringomyelie, verbunden mit trophischen

Storungen (Akromegalie). V. A., 119, p. 10.
HOLSTI. Ein Fall von Akromegalie. Z. k. M., 20, 298, 1892.
HOMBERGER, E. Uber Addisonsche Krankheit. Zeitschr. f. prakt. Arzte,

No. 4, 1897.

HONIGMANN. Adrenalin und Lokalanasthesie. C. Ch., H. 25, 1903.
HONORE. Recherches sur 1'ovaire du lapin. A. B., 16.
HOPPE-SEYLER, G. Uber chronische Veranderungen des Pankreas bei

Arteriosklerose und ihre Beziehung zum Diabetes mellitus. A. k. M.,

81, p. 119.
HORN, G. Beitrage zur Histogenese der aus aberrierten Nebennierenkeimen

entstandenen Nebennierengeschwiilste. V. A., 126, pp. 191-217, 1891.
HORNOWSKi, J. Recherches sur la pathologie du systeme chromaffine.

A. m. e., 21, 1909.

— Veranderungen im Chromaffinsystem bei unaufgeklarten postoperativen

Todesfallen. V. A., 198, p. 93, 1909.

HORNOWSKI, J. , and NEWICKI, W. Histologische Untersuchungen iiber die
Nebennieren bei Arteriosklerose sowie iiber den Befund in Neben-
nieren und Aorta von Kaninchen bei intravenosen Adrenalininjek-
tionen. V. A., 192, pp. 338-356, 1908.

HORSLEY. Die Funktion der Schiiddriise. Festschr. Virchow, 1891 ; Brit.
Med. Journ., i, 287, 1890.

— Remarks on the function of the thyroid gland. Repr. of the Dep. of

Path., Univ. Coll., London, 1894.

— Functional nervous disorders due to loss of tliyroid gland and pituitary

body. Lancet, i, p. 5, 1886; Brit. Med. Journ., vol. i, 323; vol. ii,

p. 411, 1906.
HOWELL, W. H. The physiological effects of extracts of pituitary body.

J. E. M., 3, pp. 215 and 245, 1898.
HOUGHTON, E. M., and MERRILL, C. H. The diuretic action of adrenalin

and the active principle of the pituitary gland. J. A. M. A., 51,

p. 1849, 1908.
HUCHARD and LANNOIS. Gigantisme acromegalique. Soc. med. d. hop.,

p. 1444, 1903-
HUDOVERNIG and POPOVICZ. Gigantisme precoce avec developpement pre-

coce des organes genitaux. Nouv. Icon. Salpetr. , No. 3, 1903.

- Un cas de gigantismo precoce, etude complementaire. Ibid., No. 4,

1906.

HURTHLE. Beitrag zur Kenntnis der Sekretionsvorgange in der Schiiddriise.
P. A., 56, 1894-

— Uber den Sekretionsvorgang in der Schiiddriise. D. m. W., 1894.

LITERATURE 513

HUISMANS, L. Uber Morbus Addisonii. M. m. W., IQOO and IQOI.

- Uber zwei Falle von mechanischem Thymustod. 13. k. W., iqoS.
HULST. Ein Tumor der Glandula parathyreoidea. C. a. P., 16, p. 103.
HULTGREN, E. O. Bemerkungen zu der Arbeit Olaf Scheel : Uber Neben-

nieren. V. A., 143, pp. 551-553, iQoS.
HULTGREN, E. O., and ANDERSSON, O. A. Studien zur Physiologic und

Anatomie der Nebenniere. Leipzig, 1899. S. A., ix, pp. 73-312.
HUNT, R. The comparative physiological activity of some commercial

suprarenal preparations. J. A. M. A., September 8, 1906.
— - Influence of thyroid feeding and of various foods and of small amounts

of food upon poisoning by acetonitril. Proc. Soc. Exp. Biol., New

York, October 18, 1905; J. B. Ch., i, p. 33, October, 1905.
HUNT, R., and SEIDELL, A. Studies on thyroid and the relation of iodine

to the physiological activity of thyroid preparations. Hygien. Lab.

Bull., No. 47, 1909.
HUNT, R., and TAVEAU, R. On the physiological action of certain cholin

derivatives and new methods for detecting cholin. Brit. Med. Journ.,

p. 1788, December 22, 1906.
HUOT, M. E. Sur les capsules surrenales, les reins et le tissu lymphatique

des poissons lophobranches. C. r. A., 124, pp. 1462-1464, 1897 and

126, p. 49, 1898.

- Recherches sur les poissons lophobranches. Ann. des sc. nat., t. xiv,

pp. 197-288, 1902.
HUSCHKE. Lehre von den Eingeweiden und Sinnesorganen des mensch-

lichen Korpers von v. Soemmering. Leipzig, 1844.
HUTCHINSON, R. The chemistry of thyroid gland and the nature of its

active constituent. J. o. P., 20, 1896; and Ibid., 23, 1898.
HUTCHINSON-WOODS. The pituitary gland as a factor in acromegaly and

giantism. Ref. C. a. P., ix, 1898.

IKEDA. Zum Einflusz des Ganglion hypogastricum auf die Geschlechts-

funktionen. C. P., 1907.
ILBERG. Das Zentr.-Nervensyst. eines Hemicephalus m. Aplasie d. Neben-

nieren. Arch. Psych. 36, 190,2.
IMBERT. Recherches experimentales sur les greffes des capsules surrenales

dans la rein. IV. Sess. de la soc. franc, d'urol., 1899; Proc. verb.,

p. 527, 1900.
IMMODA. Su 5 casi d'infantilismo maschile. Arch. d. Psychiatria, 17,

p. 526, 1896.
INABA-MASAMARO. Notes on the development of the suprarenal bodies in

the mouse. J. of the Coll. of Sc., Imp. Univ., Japan, vol. vi, Part i,

pp. 215-235, 1891.
INDEMANNS. Hel Antithyreoidin Moebus by de Behandlung van Morbus

Basedowii. Tijdschrift voor Geneseskunde, No. 17, 1904.
INGERMANN. Zur Kasuistik der Hypophysistumoren. Diss., Bern, 1889.
IRSAI, VAS and GARA. Thyreoideapraparate bei Strumakranken. D. m. W.,

1896.
IRVANCE, A., and PACE, C. Nebennierensubstanz und Rachitis. A. f. Kind-

heilk., 49, 1909.
ISAAC, S., and VELDEN, R. v. D. Kreislaufwirkung jodierter Eiweisz-

korper. Verh. d. Kongr. f. inn. Med., p. 307, 1907; und Med.-

naturwiss. Arch., i, 105, 1907.
ISCOVESCO, H. Pancreas et Catalase hepatique. C. r. S. B., 57, ii, p. 44,

1905.

- Les lipoides du corps thyroidea. Ibid., 65, pp. 84, 106, 218, 1908.
ISELIN. Tetanic jugendlicher Ratten nach Parathyreoidektomie. Steigerung

der tetanischen Reaktionsfiihigkeit jugendlicher Ratten bei Nach-
kommen parathyreoidektomierter Ratten. Z. Ch., 43, pp. 397-401.

- Wachstumshemmung infolgc von Parathyreoidektomie bei Ratten.

Ibid., p. 494, 1908.

ISRAEL, O. Experimentelle Untersuchung iiber den Zusammenhang
zwischen Nierenkrankheiten und sekundaren Veranderungen des Zirku-
lationssystems. V. A., 86, 1881.

- Zur Diagnose der Nebennierengeschwiilste. D. m. \V., 1905.

- Der akromegale Kauerauf. V. A., 164, p. 344, iqor.
ISSAKOWITSCH, A. Geschlechtsbestimmende Ursachen bei den Daphniden.

A. m. A., 69, p. 223, 1907.

33

514 LITERATURE

JABOULAY, M. Capsules surrenales accessoires dans un ganglion semilunaire

et au milieu du plexus solaire. Lyon med., pp. 300-302, 1890.
— - La greffe de corps thyroide et de capsules surrenales dans la maladie

de ces glandes. Ibid., 29, p. 399, 1897.
JACKSON. The prolonged existence of adrenaline in the blood. J. P., 23,

p. 226, 1909.
JACOBJ. Beitrage zur physiologischen u. pharmakologischen Kenntnis der

Darmbewegungen mit besonderer Beriicksichtigung d. Nebennieren.

A. P. P., 29, 1892.

JACOBS. Therapeutique ovarienne. La Policlinique, 1896.
JACOBY, M. Studien zur Entwicklungsgeschichte der Halsorgane der

Saugetiere und Menschen. Uber die Entwicklung der Kiemen-

derivate. Diss., Berlin, 1895.

- Uber die Entwicklung der Nebendriisen der Schilddruse und der Caro-

tisdriise. An. An., 12, 1896; and 13, 1897.

— Uber das Aldehyde oxydierende Ferment der Leber und Nebenniere.

Z. ph. Ch., 30, p. 135.
JACOPIM, G. La secrezione siderofila delle capsule surrenali. Clin. mod.,

p. 251, 1906.

JACQUES. Deux cas d'ectopie thyroidienne. C. r. S. B., 57, ii, p. 714, 1905.
JAGIC. Zur Behandlung des Asthma bronchiale. B. k. W., 1909.
JAKOBSON, J. H. Beitr. z. Kenntnis d. fotalen Entwickelung d. Steisz-

driise. A. m. Av 53, 1899.
JAKSCH and ROTKY. Uber eigenartige Knochenveranderungen im Verlaufe

des Morbus Basedow. Fortschritte auf dem Gebiete der Rontgen-

strahlen. Bd. xiii, 1908.
JANEWAY and OERTEL. Beitr. z. Pathologic der Zuckerharnruhr. V. A.,

171, 1903.
JANKOWSKI. Beitr. z. Entstehung des Corpus luteum d. Saugetiere. A. m. A.,

64, 1904.
JANNIN. Jodisme constitutionel, thyroidisme et maladie de Basedow. Revue

med. de la Suisse romande, 19, 1899.
JANOSIK, J. Bemerk. liber d. Entwickelung der Nebenniere. A. m. A.,

22, 1883.

— Histologisch-embryolog. Unters. Uber das Urogenilalsystem. S. W. A.,

91, 1885.

- Bemerkungen liber die Entwickelung des Genitalsystems. Ibid.,

99, 1890.

- t'ber die Entwickelung des Nachniere (Metanephros) bei den Ammoten.

A. A., pp. 23-82, 1906.
JANOWSKI, W. Primary suppuration of both suprarenal glands. Lancet,

1898.
JANOWSKY, TH. G. Nebennierenpraparate bei Erkrank. d. Osophagus.

A. V., 10, 1904.

JANUSCHKE, H. Adrenalin ein Antidot gegen Strychnin? W. k. W., 1910.
JAPPELLI, A. Untersuchungen iiber die Speichelabsonderung. Z. B., 51,

p. 405.
JAPPELLI, G., and D'ERRICO. Contribute alia linfogenesi. Arch, fisiol.,

iv, H. 4.
JAQUET. Note pour servir a 1'etude de la maladie d'Addison. A. P., 10,

pp. 679-691, 1878.

— Des effets de 1'extrait de rein dans le traitemcnt, &c. These de Lyon,

1897.

- Uber Schilddruse und Schilddriisenpraparate. Korr. Schweiz., Ae.,

1899.
JAROTSKY, A. J. Uber die Veranderungen in der Grosze und im Bau der

Pankreaszellen bei einigen Arten der Inanition. Diss., St. Peters-
burg, 1898.

JAYLE. Die Opotherapie mit Ovarium. Revue de gynec. vii, 1903.
JEANDELIZE. Insuffisance thyroidienne et parathyroidienne. These de

• Nancy, 1902.
JEANDELIZE and PARISOT. De la pression arterielle dans le goitre et Tinsuf-

fisance thyroidienne. IX. Congr. frang. de medec. Paris, 14-16

octobre, 1907.
JEANDELIZE, P., and PERRIN, M. Moindre resistance des lapins thyroid-

ectomises a 1'intoxication par 1'arseniate de soude. C. r. S. B. , 64,

p. 233, 1908.

LITERATURE 5 I 5

JENNER, W. Wirkung dcs Adrenalins bei Hamaturie. D. m. \V.. 1903.
JENTZNER and BEUTTNER. Exper. Unters. z. Frage d. Kastrationsatrophie.

Z. G. G., 42, 1900.
JOACHIMSTHAL. Uber Zwergwuchs u. verwandte Wachstumsstorungen.

D. m. W., 1899.

JOANNOVICS, G. Uber das Hepatotoxin. W. k. W., 1909.
— - Der Cytotoxine. Zeitschr. f. Immun.-Forsch. Ref. i, 1909.
JOESTEN. De glandularum suprarenalinum structura. Bonn, 1863.

— Der feinere Bau der Nebennieren. A. phys. Heilk., 5, 1864.

JOHN. Klinische Erfahrungen Uber intravenose Suprarenininjektion bei

schweren Herz- und Gefaszkollapsen. M. m. W., 1909.
JOHNSTON. Suprarenal extract in Addison's disease. Brit. Med. Journ.,

p. 419, 1900.
JOHNSTON and MANRO. Case of acromegaly. Glasg. Med. Journ., 50,

p. 112, 1898.
JOLIN. Uber den Jodgehalt der menschlichen Schilddriisen in Schweden.

Upsala Lakaref. Fort, xi, Suppl. ; Hammarsten Festschrift, No. 8,

1906, Ref. B. C., v.
JONES, PH. MILLS. Epinephrin, the active principle of the suprarenal

gland. California. Journ. of Med., p. 302, October, 1902.
JONES, W. On the enzyme of the thymus. On the enzyme of suprarenal

gland. A. J. P., x, No. 6, p. 24; and Z. ph. C., 41, p. 101.
JONES and WHIFFLE. The nucleo-proteid of the suprarenal gland. A. J. P.,

7, P- 423-
JONESCU, D. Notiz liber eine besondere Afrinitat der Xierengefasze zu

Adrenalin. \V. k. W., 1908.
JONSON, A. Studien liber Thymusinvolution. Die akzidentelle Involution

bei Hunger. A. m. A., 73, p. 390, 1909.
JORES. Uber Nebennierensarkome. D. m. W., 1894.

- Wesen und Entwicklung der Arteriosklerose. Wiesbaden, 1903.
JORIS, H. Contribution a Tetude de Fhypophyse. Mem. Acad. med. d.

Belgique, 9, 1907.

- Le lobe posterieur de la glande pituitaire. Ibid., 1908.

- L'hypophyse au cours de la gestation. Bull. Acad. med. d. Belg. , 1908.
JOSEPH, J. R. Further investigation upon the influence of organ extracts

of cold-blooded animals on the blood-pressure. J. E. M., 19, p. 606,

1907.
JOSEPH, J. R., and MELTZER. Eine Vergleichung der Giftigkeit der Chloride

des Magnesiums, Calciums, Kaliums und Natriums. C. P., 22,

p. 244, 1908.
JOSINE, R. Uber das Antithyroidin Moebius bei Morb. Basedoxvii.

M. m. W., 1904.

JOSSERAND, P. Contr. a 1'etude phys. de 1'adrenaline. Paris, 1905.
JOSUE, O. La vasoconstriction determinee par 1'adrenaline n'est pas due

aux centres sympathiques. C. r. S. B., 55, p^. 30, 1903.

— Atherome experimentale par injections repetees d'adrenaline dans les

veines. C. r. S. B., 55, p. 1374, 14 novembre, 1903.

- — La pression arterielle chez le lapin a la suite d'injections repetees
d'adrenaline dans les veines. C. r. S. B., 56, ii, 14 and 21 octobre,
10 decembre, 1904; 57, i, p. 319, 1905.

— Les capsules dans trois cas d'atherome artes. Soc. hop., 19 fevrier, 1904.

— Atherome arteriel et arteriosclerose. Press, med., 4 mai, 1904.

— Pathogenic de I'atherome arteriel. Congr. frang de medicine, 24

octobre, 1904.

— Contribution a 1'etude histologique de 1'atherome arteriel. J. d. P. P.,

p. 690, 1905.

Traite de Parteriosclerose. Bruxelles, 1908.
JOSUE and BLOCK. Action hypertensive de la couche corticale des capsules

surrenales. C. r. A., 144, p. 1295, 1907.
JOTEYKO, J. Action toxique curarisante de la neurine. S. m., p. 122, 1897.

- Influence de 1'adrenaline et de quelques autres produits glandulaire sur

la contraction musculairc. Journ. med. dc Bruxelles, Xos. 27-29,
pp. 417, 433, 449, 1903.

JOUCHTENKO, A. J. Influence de la thyroidine, de la spcrmine et de l.'adren-
aline, de 1'ablation du corps thyroide et des testicules sur les pro-
cessus d'oxydation, la toxicite urinaire et les echanges gazeux chez les
animaux. Russia Wratsch., 1907-1908; Ref. J. d. P. P., x, p. 1103,
15 novembre, 1908.

516 LITERATURE

JOUKOVSKY. Hydrocephalie et tumeur congenitale de la glande pineale
chez un nouveau-ne. Rev. mens. des maladies de 1'enfance, xix, p.

IQ7, IQOI.

JOUNG, J. A., and LEHMANN, J. E. Internal secretion of the suprarenals.

J. o. P., 37, 1908.
JOURDAIN, S. Sur le systeme V. porte renale. Ann. des sc. nat. ser., iv,

t. 12, 1859.
JOVANE, A., and PACE, C. Capsule surrenali e rachitismo. La pediatria,

B. xvii, p. 195.
JOWETT. Journ. of the Chem. Soc., p. 193, 1904; Jahrb. f. Tierchem., 34,

p. 581, 1904.
JULIEN. Rech. sur les suites eloignees de la castration chez la femme.

These de Lille, 1900.
JULIN, CH. Le systeme nerveux grand sympathique de 1'Ammocoetes (Petro-

myzon Planeri). An. An., pp. 192-201, 1887.
— • Recherches sur Tappareil vasculaire et le systeme nerveux peripherique

de 1'Ammocoetes (Petromyzon Planeri). A. B., vii, pp. 759-902, 1887.

KAESSMANN, F. Adrenalinbehandlung der Osteomalakie. C. G., 31,

p. 1376, 1907.
KAHLDEN, v. Beitrage zur pathologischen Anatomie der Addisonschen

Krankheit. V. A., 114, p. 65, 1888.

- tjber Addisonsche Krankheit. Zieglers Beitrage, 10; D. m. W., 1891.

- Uber Addisonsche Krankheit und liber die Funktion der Nebennieren.

Zusammenfassendes Ref. C. a. P., 7, pp. 464-509, 1896.
KAHN, R. H. Beobachtungen liber d. Wirkung d. Nebennierenextr. A. P.,

pp. 522-537, 1903-

- tlber Beeinflussung der Gefaszweite in der Netzhaut. C. P., 18, 1904.
— tJber die Beeinflussung des Augendruckes durch Extrakte chromaffinen

Gewebes. C. P., 20, No. 2, p. 33, 1906.

- Zur Frage nach der inneren Sekretion chromaffinen Gewebes. P. A.,

128, p. 519, 1909.

- Die Storungen der Herztatigkeit durch Adrenalin im Elektrokardio-

gramm. P. A., 129, 1909.
KAHN and LIEHEN. tiber d. scheinbaren Gestaltsanderungen d. Pigment-

zellen. A. P., 1907.
KAISERLIXG, D. Beitrag zur Wirkung intravenoser Suprarenininjektionen

auf die Kaninchenaorta. B. k. W., 1907.
KAISERLING, G., and ORGLER, G. Uber das Auftreten von Myelin in Zellen

und seine Beziehung zur Fettmetamorphose. V. A., 168, pp. 296-310,

1902.
KAJIURA, G. La choline se trouve-t-elle dans le liquide cephalo-rachidien

des epileptiques ? Quart. Journ. of Exper. Physiology, i, pp. 291-296,

1908.
KALAMKAROFF, J. G. Zur Frage liber experimentelle Atheromatose der

Aorta beim Kaninchen und liber die Wirkung der Jodverbindungen

auf diesen Prozesz. Diss., 1907; Ref. Bph. C., iii, No. 674.
KANTOROWICZ, L. Zur Histologie des Pankreas. Diss., Gieszen.
KAPLAN, D. On the hypodermic use of adrenalin chloride in the treat-
ment of asthmatic attacks. M>ed. News, 86, 19, p. 871, May, 1905.
KAPLAN and FEDOROFF. Adipose douloureuse. Rev. suisse d. med. , 1902.
KARAKASCHEFF, v. Beitrage zur pathologischen Anatomie der Nebennieren

(Atrophie, vikariierende Hypertrophie, Tuberkulose). Ziegl. Beitr.,

36, p. 401, 1904.
— Weitere Beitr. z. pathol. Anatomie der Nebennieren. Ibid., 39, p. 373,

1906.
- Uber das Verhalten der Langerhansschen Inseln des Pankreas bei

Diabetes mellitus. D. A. k. M., 82, 1904; and ibid., 87, 1906.
KAREWSKI. Zwei exstirpierte Nierentumoren. B. k. W. , 1904.
KARG. Uber Hautpigment und Ernahrung der Epidermis. An. An., p. 377,

1887.
KASAHARA. Uber das Bindegewebe des Pankreas bei Krankheiten. V. A.,

in, 1896.

KASCHKE. Cachexia thyreopriva und Myxodem. Diss., Berlin, 1892.
KASSEL, K. Epinephrinum solutum. Th. M., p. 422, August, 1903.
KAST. Uber lymphagoge Stoffe im Serum Nierenkranker. D. A. k. M., 73,

IQO2.

LITERATURE 5 I 7

KASTSCHENKO. Das Schicksal der embryonalen Schlundspalten bei Sauge-

tieren. A. m. A., 30, 18X7.
KASSOWITZ. Allgemeine Biologic. 4 Biinde, 1899-1906.

- Infantiles Myxodem, Mongolismus und Mikromelie. Wien, igo2.
KASTEN, F. Ub. d. therapeutischen Wert d. Nebennierensubstanz. Diss.,

Rostock, 1902.
KATZ, A. Harnuntersuchungcn in einem Falle von Morbus Addisonii.

W. m. BL, 1890.
KATZ and WINKLER. Experimentelle Studicn iiber Fettgewebsnekrose des

Pankreas. A. V., 4_, 289, 1898.
KATZENSTEIN. Uber Veranderungen in der Schilddriise nach Exstirpation

der zufiihrenden Nerven. A. P., 1897 and 1899.

- Uber exp. Beobachtungen an der Schilddriise. D. m. W., 1899.
KAUFMANN. Sur le diabete pancreatique et le mecanisme de regulation dp

la glycemie normale. A. d. P., p. 200, 1895.

- Mode d'action du systeme nerveux dans la production de 1'hyper-

glycemie. Ibid., p. 266.

KAUFMANN, E. Uber Zwischenzellengeschwtilste des Hodens. V. d. p. G.,
n, 1907.

KAUFMANN, M. Stoffwechselbeobachtung bei einem mit Nebennierensub-
stanz behandelten Falle von Morbus Addisonii. C. Stoffw. u.
Verdauungskr. , ii, 7, 1901.

- tiber Diabetes und Psychose. M. m. W., 1908.

- Organotherapie der Nephritis. F. M., pp. 633, 665, 1905.
KAUFMANN and MANNABERG. Diskussionsbemerk. zu Schur u. Wiesel.

W. k..W., 1907.
KAUSCH. Uber den Diabetes der Vogel nach Pankreasexstirpation.

A. P. P., 37, p. 274, 1896.
KEDZIOR and ZANIETOWSKY. Zur pathologischen Anatomic der Basedow-

schen Krankheit. N. Z., No. 10, p. 438, 1901.
KEHRER. Zur Menstruationslehre. B. G. G., 2, 1884.

- Versuche iiber Kastration und Erzeugung von Hydrosalpinx. Ibid.,

1887.
KEHRER, E. Physiologische und pharmakologische Untersuchungen an den

iiberlebenden und lebenden inneren Genitalien. A. G., 81, p. 129,

1907.
KEIBEL, F. Uber die Entwickelung des Urogenitalapparates von Echidna.

Erganzungsheft. An. An., 22, pp. 14-19, 1903.
KEISAKU-KOBUKO. Uber die kongenitale Syphilis der Nebennieren. C. a. P.,

14, 1903.
KEITLER. Uber das anat. und funkt. Verhalten der belassenen Ovarien und

Exstirpation des Uterus. M. G. G., 20, 1904.
KELLER, K. Uber den Bau des Endometriums beim Hunde. Anat. Hefte,

118, 1909.

KELLY, A. O. J. Uber Hypernephrome der Niere. Ziegl. Beitr., 23, 1898.
KENWORTHEY, WM. B. The use of suprarenal capsule in haemoptysis.

New York Med. Record, p. 415, 1901.
KERKIS, C. Les vasoconstrictions des serums normaux. These de Geneve,

1905.
KING, J. H. The influence of the thyroid on carbohydrate metabolism.

J. E. M., 1909.
KINNER. tiber die Behandlung der Rachitis mit Nebennierensubstanz.

Diss., Breslau, 1901.
KINNICUT, F. P., A clinical study of the therapeutic value of the calcium

salts in gastric tetany. A. J. M. S., 138, pp. i-io, 1909.
KINZLER. Uber den Kausalzusammenhang zwischen Zerstorung der

Nebennieren und Bronzed skin. Diss., Tubingen, 1895.
KlRKALDY, J. W. On the head-kidney of Myxine. Quart. Jour, of Micr.

Scien., 35, 1894.
KIRCH, R. tiber Adrenalinamvendung bei schweren Blutungen. D. m. W.,

1903.

KlSCH, H. Die Schilddriisentherapie bei Fettleibigkeit. W. m. P., 1899.
KlSHI. Beitrage zur Physiologic der Schilddriise. V. A., 176, 1904.
KLAPP, R. Experimentelle Beitrage zur Kenntnis der Wirkung der Neben-

nierenpraparate. Z. Ch., 71, p. 187, 1904.
KLEBS. Handb. z. path. Anat., i, Abt. ii, 1876; and Allg. Path., ii, 1897.

518 LITERATURE

KLEESTADT, W. Uber cystische Tumoren im Bereiche des Infundibulum.

Diss., Miinchen, 1906.
KLEIN. Uber die Bedeutung der bei Morbus Basedowii im Zentralnerven-

system nachgewiesenen pathol.-anatomischen Befunde. D. Z., p. 431,

1904.

- Neue Arbeiten liber sog. fotale Rachitis. C. a. P., 12, 1901.
KLEINHANS, F., and SCHENK, F. Experirnentelles zur Frage nach der

Funktion des Corpus luteum. Z. G. G., 66, p. 283.
KLEMPERER, G. Addisonsche Krankheit. In Eulenburg, Real-Enc.. 4. Aufl.,

i, 1907.
KLEMPERER, G., and UMBER, H. Z. Kenntnis d. diabetischen Lipamie.

Z. k. M., 65, 1908.
KLETT. Zur Beeinflussung der phototropen Epithelreaktion in der

Froschretina durch Adrenalin. A. A. Supplemented., p. 213, 1908.
KLIENEBERGER, C. Lib. d. Wirkung v. Nebennierenpraparaten auf die

Kaninchenaorta bei gleichzeitiger Anwendung von Jodipin und

Jodkali. C. i. M., 28, 1907.
KLOTZ. Experimental production of arterio-sclerosis. Brit. Med. Journ.,

1906; J. E. M., viii.
KNAFFL-LENZ, v. Beziehungen zw. Lipoidverflussigung und Zytolyse.

P. A., 123, 1908.
KNAUER. Einige Versuche von Ovarientransplantation am Kaninchen.

C. G., 20, p. 524, 1896.

- Uber Ovarientransplantation. W. k. W., 1899.

- Die Ovarientransplantation. A. G.. 60, p. 322, 1900.
KNOPFELMACHER, W. Alimentare Glykosurie und Myxodem. W. k. W.,

1904.

-- Demonstrationen. Ibid., 1903 and 1906.

KNY, E. Fall von isoliertem Tumor der Zirbeldriise. N. Z., p. 281, 1889.
KOCHER, TH. Uber Kropfexstirpation und ihre Folgen. A. k. Ch., 29,

1883.

- Vorkommen und Verteilung des Kropfes im Kanton Bern. Bern, 1889.

- Zur Verhiitung des Kretinismus. Z. Ch., 34.

- Die Schilddriisenfunktion. Korr. Schweiz. A., 1895.

- Zweitausend Kropfexstirpationen. A. k. Ch., 64, 1901.

- Die Pathologic der Schilddriise. C. i. M.3 Miinchen, 1906.
— Chirurgische Operationslehre, 1907.

KOCHER, A. Uber Morbus Basedowii. M. G. M. C., 9, 1902.

- Uber die Ausscheidung des Jods im menschlichen Harn und ihre

Beziehung zum Jodgehalt und zur Verkleinerung der Strumen.

M. G. M. C., 14, 359, 1905.

KOCUREK, R. Uber Zwergwuchs. V. d. naturf. V. Briinn, 45.
KOHLER. Einflusz der Auszentemperatur auf experimentelle Glykosurien.

Z. k. M., 1908.
KOLLIKER, y. Mikroskopische Anatomic oder Gewebelehre des Menschen.

Leipzig, 1854.

- Handbuch der Gewebelehre des Menschen. 2. Aufl., 1855; 3. Aufl.,

1859; 4. .Aufl., 1803; 5. Aufl., 1867.

- Entwicklungsgeschichte des Menschen und der hoheren Tiere. 2. Aufl..

1879-
Jber Z \vitterbildungen bei Saugetieren. VT. B., 1884.

- Uber die Nerven der Nebennieren. V. d. N. A., 66, p. 363. 1894.

- Uber die feinere Anatomic und die physiologische Bedeutung des

sympathischen Nervensystems. W. k. W., 1894.

KONIG. Uber ein Psammosarkom der Zirbeldriise. Diss. , Miinchen, 1894.
KONIGSTEIN. Anwendung des Extracturn suprarenale haemostaticum.

W. m. P., 1897 and 1898.
KONIGSTEIN, JUN. Demonstration von Sekretbildern im Epithelkorper.

W. k. W., p. 778, 1906.
KORBER, E. Kann Nebennierengewebe durch biochemische Reaktionen

nachgewiesen werden ? Diss., Greifswald, 1903.

- Uber die Croftansche Methode zur Erkennung von Nebennierengewebe

auf biochemischem Wcge. V. A., 142, p. 356, 1908.

KOHN, A. Studien iiber die Schilddriise. I, A. m. A., 44, 1895: II, Ibid.,
48, 1806.

- Die Nebennieren der Selachier nebst Beitragen zur Kenntnis der

Morphologie der Wirbeltiernebenniere im allgemeinen. A. m. A.,
53, PP- 281-312, 1898.

LITERATURE 519

KOHX, A. Uber die Nebenniere. P. m. W., pp. 104-105, 1808.

- Die chromaffinen Zellen des Sympathicus. An. An., 15, pp. 293-400,

1890-

- Die Epithelkorperchen. Erg. d. Anat. u. Entw., ix, pp. 194-252, 1899

and 1900.
Uber innere Sekretion. P. m. W., 1900.

- Uber Bau und Entwickelung der sogenannten Carotisdriise. A. m. A.,

56, 1900.

- Chromaffine Zellen, chromaffine Organe, Paraganglien. P. m. W.,.

1902.

- Die Paraganglien. A. m. A., 62, pp. 263-365, 1903.

- Das chromaffine Gewebe. Erg. d. Anat. u. Entw., xii, pp. 253-348,

1902 and 1903.

- Die Blutgefaszdriisen. P. m. W., 1903.

- t)b. d. Entwicklung d. sympath. Nervensystems d. Saugetiere. A. m. A.,.

70, 1907.
Uber das Pigment der Neurohypophyse des Menschen. Ibid., 75,

P- 33/J..IQIO.
KOLISCH. Uber sklerotische Veranderungen durch Phloridzinzufuhr.

G. d. A., 1905.
KOLISCH and PICHLER. Ein Fall von Morb. Addisonii mit Stoffwechsel-

untersuchung. C. k. M., 1893.

KOLLARITS. Hypophysentumor ohne Akromegalie. D. Z. N., 28, p. 88, 1905.
KOLLE, W. Uber Ziele, Wege und Probleme der Erforschung des

endemischen Kropfes. Korr.-Bl. Schweiz. Arzte, 1909.
Kox JUTAKA. Hypophysenstudien. Zieglers Beitrage, 44, 2, 1909.
Koi'LlK. Sporadic cretinism and its distinction from idiocy. N. Y. Med.

Journal, 1897.
KORAXYI, A. V. Uber die Wirkung des Jods auf die durch Adrenalin

erzeugte Arteriosklerose. D. m. W., 1906.

- Berichtigung zu meiner Mitteilung iiber die Wirkung des Jods auf die

durch Adrenalin erzeugte Arteriosklerose. Ibid., 1907.
KOSE, W. tiber das Yorkommen chromaffiner Zellen im Sympathicus des

Menschen und der Saugetiere. Lotos, No. 6, 1898.

Uber das Vorkommen einer Carotisdriise und der chromaffinen Zellen
bei Vogeln. An. An., 22, pp. 162-170, 1902.

- Uber die Carotisdriise und das chromaffine Gewebe der Vogel. Ibid.,

25, 1904.

- Die Paraganglien bei den Vogeln. A. m. A., 69, 1907.

KOSTLIVY, S. Leber- und Pankreaslasionen in ihren Beziehungen zum
chromaffinen System. M. G. M. C., 19, pp. 616-636, 1909.

KRAUPA, E. Untersuchungen iiber das synthetische Suprarenin. M. K.,
1908.

KRAUS, F. Uber die Zuckerumsetzung im Blute auszerhalb des Gefasz-
systems. Z. k. M., 21, p. 315, 1892.

- Uber das Kropfherz. W. m. W., 1899.

- Myxodem, Cachexie pachydermique. v. Mehrings Jahrb. d. inn. Med.,

1901.

- Uber Fettdegeneration und Fettinfiltration. V. d. p. G., 6, 1903.

- Pathologic der Schilddruse. V. C. M., Miinchen, 1906.

KRAUS, F., and FRIEDENTAL, H. Uber die Wirkung der Schilddriisenstoffe.

B. k. W., p. 1709, 1908.
KRAWKOFF. De 1'action des prep, jodees sur Tarterionecrose experim.

Wratsch., 1908; Ref. J. d. P. P., 10, p. 549, 1908.
KRECKE. Chirurgische Behandlung des Morbus Basedowii. M. m. W.,

1909.
KREHL, L. tiber die Storung chemischer Korrelationen im Organismus.

D. A. k. M., 88, pp. 351-384, 1907; and V. d. N. A, Stuttgart.
KRESS, K. WTirkungsweise einiger Gifte auf den isolierten Diinndarm.

P. A., 109, 1905.
KRETSCHMER, W. Uber den Mechanismus der Adrenalinwirkung und

dauernde Blutdrucksteigerung durch Adrenalin. A. P. P., 57, p. 348,

1907.

- Uber die Beeinflussung der Adrenalinwirkung durch Siiure. Ibid., 57,

p. 438, 1907.

KREUZFUCHS. Erfahrungen iiber innere Adrcnalindarreichung. W. m. P.,
1906.

52O LITERATURE

KRUCKMANN. Adipositas universalis bei 2 Geschwistern. D. m. W., iQo8.
KRUKENBERG, C. FR. W. Die farbigen Derivate der Nebennierenchromo-

gene. V. A., 101, pp. 542-571, 1885.
KRYCHTOPENKO, A. Caps, surrenales. These de St. Petersb., 1904;

A. d. sc. biol., 12, 1906.
KUDINZEW. Zur lehre von den Glandulis suprarenalibus. Wratsch., 1897;

Ref. St. Petersburger m. W., 22.
KUHN, A. Uber das Vorkommen von akzessorischen Nebennieren. Z. r. M.,

28, 1866.
KULBS. Exper. Studien iiber die Wirkung des Nebennierenextraktes.

A. P. P., 53, P- MO; M. m. W., 1905.
KtJLZ, E. Beitr. z. Pathologic u. Therapie d. Diabetes. Marburg, 1874

and 1875.
KULIABKO and ALESSANDROWITSCH. Wirkung verschiedener Substanzen auf

die automatischen Bewegungen des isolierten Darmes. C. P., 18,

p. 280, 1904.
KURSTEINER. Die Epithelkorperchen in ihrer Beziehung zur Thyreoidea

und Thymus. Anat. Hefte, 1898.
KtJSTER. Zur Entwicklung der Langerhansschen Inseln im Pankreas beim

menschlichen Embryo. A. m. A., 64, 158, 1904.

— Uber Gliome der Nebennieren. V. A., 180, pp. 117-130, 1905.

- Chirurgie der Nieren der Harnleiter und der Nebennieren. D. Ch., 52,

1902.
KUH, S. Treatment of acromegaly with pituitary bodies. J. A. M. A.,

p. 295, 1902.
KUMITA. Lymphgefasze der Nierenkapsel und der Nebenniere. A. A.,

p. 49, 1909.
KUMMER. Zur Kenntnis des Morbus Addisonii. Korresp.-Bl. Schw. A.,

No. 15, 1886.
KUNDRAT, H. Uber Wachstumsstorungen des menschlichen Organismus.

Wien, 1890.
KUPFFER, v. Die Deutung des Hirnanhangs. Sitzungsber. d. Gesellsch.

f. Morph. u. Phys. Miinchen, 1894.
KURDINOWSKI. Physiologische und pharmakologische Versuche an der

isolierten Gebarmutter. C. P., p. 323, 1904; A. P., Suppl. 3, 1904.
KUSMINE, K. Untersuchungen iiber die Lymphe. 6. Mitt. Uber den

Einflusz der Lymphagoga (Lebergifte) auf die Lymphe. Z. B., 46,

p. 554.
KUSSMAUL, A. Uber geschlechtliche Fruhreife. Wiirzb. med. Zeitschr. , 3,

1862.
KUTSCHERA, A. v. Zur Epidemiologie des Kretinismus. Off. Ber. iiber den

Amtsarzte-Kongresz. Deuticke, Wien, 1909.

- Das Groszenwachstum bei Schilddrusenbehandlung des endemischcn

Kretinismus. W. k. W., 1909.

KYRLE. Uber die Regenerationsvorgange im tierischen Pankreas. A. m. A.,
72, 1908.

LABADIE-LAGRAVE. Maladie bronzee ou maladie d'Addison. Traite des mal.
du sang, Paris, 1893.

— Toxicite urinaire chez la cobaye en gestation. C. r. S. B., 4 juillet,

1897.
LABADIE-LAGRAVE and DEGNY. Associations morbides de 1'acromegalie.

Arch. gen. de med., N. S., i, p. 129, 1899.
LABBE, H. V. Physiologic pathologique des diabetes sucres. Rev. de med.,

1907.
LABBE and GIRAUD, G. Dosage de Piode contenu dans les corps thyroides

des tuberculeux. C. r. S. B., 65, pp. 371-372, 1908.
LABZINE, M. M. De la regeneration des glandes surrenales. Arch, scienc.

biol., ii, p. 319, 1905; These de St. Petersbourg, 1904.
LAWEN, A. Quantitative Untersuchungen iiber die Gefaszwirkung von

Suprarenin. A. P. P., 51, p. 415, 1904-

- Experimentelle Untersuchungen iiber die Gefaszwirkung von Supra-

renin in Verbindung mit ortlich anasthesierendcn Mitteln. Z. Ch.,
74, p. 163, 1904.

- Die ortliche Anasthesie bei Zahnextraktionen, mit besonderer Beriick-

sichtigung der Cocain-Adrenalingemische. A. k. Ch., 72, p. 231, 1904.

LITERATURE 52 1

LAFOND, M. Sclerodermie et Corps pituitaire. These de Lyon, 1901-1902.
LAGUESSE, E. G. Sur la formation des ilots du Langerhans. 1893.

- Structure et developpement du pancreas. J. A. P., 1894.

- Sur la variabilite du tissu endocrine dans le pancreas. C. r. S. B.,

p. 900, 1899.

- Structure d'une greffe chez le chien. Ibid., p. 853, 1902.

- Sur la structure du Pancreas chez quelques Ophidien et particuliere-

ment sur les ilots endocrines. Arch, d'anat. microsc., 4, 1901.

- Ilots de Langerhans et secretion interne. C. r. S. B., 57, ii, p. 368, 1905.
Numeration des ilots endocrines dans le pancreas humain. Ibid.,

p. 504, 1905.
Lobule et tissu conjonctif dans le pancreas de 1'hotnme. Ibid., p. 539.

- Ilots endocrines et formes de transitions dans le lobule pancreatique,

P- 54--
Etude d'un pancreas de lapin, &c. Arch, d'anat. microsc., 9, p. 90, 1906.

- Le pancreas. Lyon, 1906-1907.

- Sur les rapports des ilots endocrines avec 1'arbre excreteur dans le

pancreas de 1'homme adulte. Ibid., 65, p. 139, 1908.

- Preuve exper. du balancement dans les ilots endocrines du pigeon.

^ Ibidv 67, p. 94, 1909.

- Sur 1'evolution des ilots endocrines dans le pancreas. Arch, d'anat.

microsc., n, 1909.
LAGUESSE and GOXTIER DE LA ROCHE. Les ilots de Langerhans apres

ligature. C. r. S. B., p. 584, 1902.
LAIGXEL-LAVASTINE. Application de Pimpregnation argentique de Cajal a

1'etude histo-chimique de la cellule medullo-surrenale. C. r. S. B.,

58, p. 661, 1905.

- Structure des cellules nerveuses de la substance medullaire de la

surrenale humaine. Ibid., pp. 697-700, 1906; pp. 331-332, 1905.

- Inclusion surrenale d'un ganglion solaire. Bull, de la soc. anat.,

Paris, No. 5, 1905.

- Les troubles glandulaires dans les syndromes neuropsychiques. Trib.

med., 1908.

- Des troubles psychiques par perturbation des glandes a secretion

interne. XVIIIe Congr. des medecins alienistes et neurologistes.
Dijon, 1908; Sem. med., 1908.

- La correlation des glandes a secretion interne et leurs syndromes pluri-

glandulaires. Gaz. des Hop., p. 1563, 1908.
LAIGXEL-LAVASTINE and AUBERTIX. Adenome medullaire de la capsule

surrenale. A. m. e., 20, 1903.
LAIGXEL-LAVASTINE and BLOCK. Syndrome de Basedow. Arch. gen. med.,

1904.
LAIGXEL-LAVASTIXE and HALBROX, P. Trois cas le tuberculose surrenale

sans melanodermie. Bull, de la soc. anat. Paris, Xo. 4, 1907.
LAMBERT. Sui Faction des extraits du corps jaune de Tovaire. C. r. S. B.,

62, p. 18, 1907.
LANCERAUX. Notes et reflexions a propos de deux cas du diabete Sucre avec

alteration du pancreas. Bull. acad. de med., III. ser., 7, 1215, 1877.

- Nouveaux faits de diabete sucre avec alteration du pancreas. Ibid., iSSS.
LANCERAUX and THIROLOIX. Le diabete pancreatique. C. r. A., 115.

- Les rapports des lesions des capsules surrenales et de la maladie

d'Addison. Arch. gen. med., p. 5, Janvier, 1890.

- Les glandes vasculaires. Sem. med., 1893; Cinquant. de la Soc. de

Biol., 1899.

- La trophoneurose acromegalique. Sem. med., 1895.

LANDAU, E. Zur Morphologic der Nebenniere. I. Mitt. Protokolle d.
Naturf.-Ges. b. d. Univ. Dorpat, 1901 ; II. Mitt. Allruss. Versamml.
d. Naturf. u. Arzte, St. Petersburg, 1901; III. Mitr. Sitzungsber. d.
Naturf.-Ges. b. d. Univ. Jurjew [Dorpat], 190;; IV. Mitt. I.M., 24,
pp. 431-446, 1907-

- Uber die anatomischen Veriinderungen in den Nebennieren bei Arterio-

sklerose. Z. k. M., 64, p. 237, 1907.

— Altersveranderungen des Venensystems der Xebennicrcn. Petersb. m.
W., 1908.

- Experimentelle Xebennieren-Studien. Dorpat, 1908.

LANDAU, M. Zur Behandlung der Beschwerden der natiarl. u. anticept.
Kiimax mit Eierstocksubstanz. B. k. W., 1896.

522 LITERATURE

LANDERER, P. Zur Kasuistik der Addisonschen Krankheit. Diss., Tubingen,

1878.

LANDO. Veranderungen der Pankreas bei Lebercirrhose. Z. H., 17.
LANDOIS, F. Die Epithelkorperchen. Erg. d. Chir. u. Orthop. I. IQIO.
LANDOLT. Uber die Verwendung des Nebennierenextraktes in der Augen-

heilkunde. C. Augenh., xxiii, p. 321, November, 1899.
LANDSTROM, J. Neuere Anschauungen iiber die Basedowsche Krankheit.

M. K., IQOQ.

LANE, M. A. The cytological characters of the areas of Langerhans.

J. A. Z., 1907.
LANGE, O. Uber die Anwendung des Adrenalin bei Blutungen. M. m. W.,.

1903.
LANGENDORFF. O. Beitrag zur Kenntnis der Schilddriise. A. A., Suppl.

218, 1889

- Altere unJ neuere Ansichten iiber die Schilddriise. Biol. C., 9, 1889.

— Uber Veranderungen in den periph. Nerven bei Cachexia thyreopriva.

V. A., 128, 1892.

- Uber die Innervation der Koronargefasze. C. P., 21, 1007.

LANGER, C. Wachstum des menschlichen Skeletts mit Bezug auf den Riesen.

Denkschrift d. Akad. d. Wiss. Wien, 31, 1872.
LANGERHANS. Beitrage zur mikr. Anatomie der Bauchspeicheldriise. Diss.,

Berlin, 1869.

- Nebennierenveranderungen beim Morbus Addisonii. V. d. p. G., 7,

p. 254, 1903.
LANGERHANS and SAWELIEW. Beitr. zur Physiologic der Brustdriise. V. A.,

134, 1893.
LANGHANS. Uber die epithelialen Formen der malignen Struma. V. A.,

189, 1907.
LANGLEY, J. N. Observations on the physiological action of extracts of the

suprarenal bodies. J. o. P., 27, p. 237, 1901.

- On the reaction of cells and nerve-endings to certain poisons. Ibid., 33,

p. 375, 1905; and 39, p. 235, 1909.

The sympathetic and other related systems of nerves. Schafer Text-
book of Physiol. ii, 1900.

- Das sympathische u. verwandte nervose System der Wirbelthiere. E. E.,

2, ii. p. 818.

LANGLOIS, P. Destruction des capsules surrenales chez le chien. C. r. S. B.f
p. 444, 1893; A. d. P., pp. 488-498, 1893.

- Maladie d'Addison. Richet Diction, de Phys., i, 1895.

- De 1'opotherapie dans la maladie d'Addison. P. m., 19 septembre, 1896.

- Action differente de Fextrait des capsules surrenales sur la pression san-

guine suivant 1'etat d'alteration morbide de ces organcs. C. r. S. B.,
p. 942, 1896.

- Sur 1'homologie fonctionnelle des capsules surrenales des grenouilles et

des mammiferes. C. r. S. B.3 pp. 184-186, Paris, 1897.

- Action des agents oxydants sur 1'extrait de capsules surrenales. Ibid.,

p. 524, 1897. •

- Du foie cornme organe destructeur de la substance active des capsules

surrenales. Ibid., p. 571, 1897.

- Physiopathologie des capsules surrenales. A. d. P., 30, p. 125, 1897.

- Les capsules surrenales. Paris, 1897. T. iv des travaux du labor, de

Phys. de Ch. Richet.

- Le mecanisme de destruction du principe actif des capsules surrenales

dans rorganisme. A. d. P., 30 Janvier, 1898.

- Sur 1'identite physiolog. des corps surrenaux chez les batraciens et les

mammiferes. A. d. P., 10, 1898.

- A propos de la destruction de Tadrenaline dans rorganisme. C. r. S. B.,

p. 93, 1904.
LANGLOIS and CHARRIN. Du role des capsules surrenales dans la resistance

a certaines infections. C. r. S. B., p. 708, 1896.
LANGLOIS and REHNS, J. Les capsules surrenales pendant la periode foetale.

Ibid., 1899.
LANGSTEIN, L. Behandlung d. Rhachitis mit Nebennierensubstanz. J. K..

53, 1901.
LANZ, O. Zur Schilddriisenfrage. Volkmanns Sammlung. Leipzig. 1801

— Uber Thyreoidismus. D. m. W., 1895.

LITERATURE 523

L \NZ, O. Zur Schilddriisentherapie des Kropfcs. Korr.-Bl. f. Sclnveizer
Arzte. No. 2, 1895.

- Ein Vorschlag zur diiitetischen Behandlung von Basedowkranken. Ibid.,

No. 23, 1899.

- Onderzoekingen over de afstammelingen van thyreopfiven. Nederl.

Tijdschr. voor Geneeskunde, No. 20. 1904.

- Progenitur thyreopriver Tiere. A. k. Ch.3 74, 1904.

- Adrenaline en heelkunde. AVeekblad, p. 1335, 11 Juni ; Virch.-Hirsch,
„ i, p. 736. 1904-

- Cachexia und Tetania thyreopriva. C. Ch., p. 339, 1905.

LAPIEXTE and LEZENE. Gliome primitif de la capsule surrenale. A. m. e.,

19, p. 59, 1907.
LARGUIER DES BAUCELS. Activation du sue pancreatique pur sous I'lnfluence

combinee des colloides et des electrolytes. C. r. S. B., 57, ii, p. 130,

1905.
LATTES, L. Uber die Zuckerbildung in der kiinstlich durchbluteten Leber

diabetischer Tiere. B. Z., 20, 1904.
LATZKO, W. Zur Diagnose und Frequenz der Osteoraalazie. M. G. G., i,

1895; and W. k. W., 1893 and 1894.

- Uber Nebennieren und Osteomalazie. W. k. W., p. 239, 1907.
LATZKO, \Y., and SCHNITZLER, J. Beitr. z. Organotherapie bei Osteomalacie.

D. m. W., 1897.
LAUB, M. Klinischer Beitrag zur Lehre vom Status thymicus. W. k. W.,

.. l899-.

- Uber die Wirkung °iniger dem Adrenalin verwandter Ketonbasen in der

rhinologischen Praxis. W. m. W., 1906.

LAUNOIS, L. D" 1'atrophie de la prostate. De la castration dans 1'hyper-
trophie de la prostate. Ann. d. mal. d. org. gen. ur. , 1894.

- Les cellules siderophiles de 1'hypophyse chez la femme enceinte.
^ C. r. S. B., 55, 1903.

- Glycosurie et hypophyse. Arch. gen. d. med., 1903.

- Recherches sur la glande hypophysaire de rhornme. These de Paris,

1904.

- La cellule pancreatique dans 1'intoxication par la pilocarpine. C. r.

S. B., p. 245, 1904.

- Diapedese et secretion pancreatique active. Ibid., 56, p. 2117, 1904.

- Action de la pilocarpine sur la secretion pancreatique. Ibid., p. 570.

- Contr. a 1'etude histophysiol. de la secretion pancreatique. A. i. Ph.,

3, 1905-

Traveaux recents sur 1'anatomie fine des capsules surrenales, particuliere-
ment en ce qui concerne la cellule chromaffine. Biol. med., No. 7,
pp. 265-283, 1905-

- Contribution a 1'etude du serum des animaux ethyroi'des. C. r. A., 147,

p. 263, 1908.

- Nouvelle contrib. a 1'etude du serum des animaux ethyroides. Ibid.,

147, 1908.

LAUXOIS and ESMEN. Essai d'interpretation du syndrome de Basedow. IXe
Congr. frangais des Medicins. 14-16 octobre, 1907.

LAUNOIS, EOEPER and ESMONET. La secretion graisseux de 1'hypophyse.
C. r. S. B., 56, 575, 1904-

LAUNOIS and MULON. Etudes sur 1'hypophyse humaine a la fin de la gesta-
tion. Arch, de gyn. et d'obstetr., 1904.

LAUNOIS and ROY. Etude biologique sur les geants. Paris, 1904.

- Gigantisme et infantisme. Nouv. Icon, de 1. Salp., 1902.

- Gigantisme et castration. Rev. intern, med., 1903.
LAURECK. Zur Kasuistik des Morbus Addisonii. Diss., Bonn, 1889.
LAUWENS, R. Exstirpation des Duodenum. Brief an den Herausgeber.

P. A., 120, 1907.
LWRONA. L'action de 1'iode sur les processus pathologiques experimentaux

provoques par 1'adrenaline dans les vaisseaux sanguins. Arch, scienc.

biol., 13, 1909.
LAWRENCE. Tumour of pineal body. Transact. Pathol. Soc. London, 50,

1898.
LAZARUS, P. Experimentelle Hypertrophie der Langerhansschen Pankreas-

inseln bei der Phloridzinglykosurie. M. m. W., No. 45 and Ncs. 51

and 52, 1907.

524 LITERATURE

LECKY, H. C. Notes on a case of Addison's disease, rapidly fatal, with

symptoms of acute toxaemia. Lancet, February 17, 1906.
LECONTE. Etude sur les hemorrhagies des capsules surrenales. These de

Paris, 1899.

LECORCHE. Traite du diabete. Paris, 1877.
LE DENTU. Affection chirurgicale des reins et des capsules surrenales. Paris,

1889.
LEFEVRE. Contribution a Fetude de la maladie d'Addison. These de Paris,

1890.

LEHMAN. Uber Adrenalin (Tierversuche). M. m. W., 1902.
LEHMANN, A. Beitrage zur Kenntnis der Zuckerbildung aus Eiweisz. Diss.,

Halle, 1902.

LEHMANN, O. Fliissige Kristalle. Leipzig, 1904.
LEHNERDT, FR. Zur Frage der Substitution des Calziums im Knochen-

system durch Strontium. Ziegl. Beitr., 47, 1909.
LEICHTENSTERN. tiber Mprbus Addisonii. D. m. W., 1891.
LEISCHNER, H. Uber Epitheikorperchen-Transplantationen und deren prak-

tische Bedeutung in der Chirurgie. A. k. Ch., 84, 1907.
LEMOINE and LAUNOIS. Lesions du pancreas dans le diabete. A. m. e., 3,

1891.

- Beitrage z. Pathologic u. Therapie d. Pankreaserkrankungen. Z. k. M.,

51 and 52, 1904.
LENHOSSEK, M. Das Problem der geschlcchtsbestimmenden Ursachen.

Jena, 1003.

LENNE. Die Zuckerkrankheit. Berlin, 1898.
LEONHARDT. Experimentelle Untersuchung iiber die Bedeutung der Schild-

driise fur das Wachstum im Organismus. V. A., 149, 1897.
LEOPOLD, J. S., and REUSS, A. v. Ub. d. Beziehungen d. Epithelkorper z.

Kalkbestand d. Organismus. W. k. W., 1908.
LEOPOLD and RAVANO. Neuer Beitrag zur Lehre von der Menstruation und

Ovulation. A. G., 83, 1907.
LEPINE, R. Sur la presence normale dans le chyle d'un ferment destructeur

du sucre. C. r. A., no, 1890.

- Etiologie et pathogenic du diabete sucre. A. m. e., 1891.

- Die Beziehungen des Diabetes zu Pankreaserkrankungen. W. m. P.,

1892.

- Sur une autointoxication d'origine renale. C. r. A., p. 991, 1889; and

S. m., 1893.

- Sur la participation du pancreas a la thermogenese consecutive aux

lesions cerebrales. C. r. S. B., 51, p. 835, 1899.

- Presence du glucose dans le liquide cephalo-rachidien. Sem. med.,

1 8 fevrier, 1903.

- De la glycolyse dans ses rapports avec le diabete sucre. Sem. med.,

1903.

- Serum antithyroi'den. Lyon med., 29 novembre, 1903.

- Etat du pancreas dans certaines glycosuries toxiques. C. r. S. B., 55,

pp. 161 and 1288, 1903.

- Excitation fonctionnelle du corps thyroiide au moyen de rayons X. Ibid.,

56, 1904.

- Sur la question du diabete renale. B. k. W., 1905.

- Le goitre exophtalmique devant la serotherapie. Revue du med., p. 984,

1906.

- Du role des secretions dans la pathogenic du diabete sucre. D. A. k. M.,

89, 1907.

- L'adrenaline agit-elle directement s. 1. fibres sympathiques ? C. r. S. R.,

65, 1908.

- Le diabete sucre. Paris, 1909.

LEPINE, R., and BOULUD. Sur la glycolyse dans le sang in vitro. C. r. S. B.,
p. 73, 1903.

- Influence de la maceration du pancreas sur la glycemie et sur le pouvoir

glycolytique du sang. Ibid., 57, ii, p. 160, 1905.

- Influence des globules blancs sur la glycolyse. Ibid., 58, i, p. 901, 1906.

- Sur le pouvoir glycolytique du sang des animaux phloridzines. Ibid.,

58, ii, p. 93.

- Effets sur la glycemie de la compression de 1'aorte pres de sa bifurcation.

Ibid., 62, p. 1108, 1907.

LITERATURE 525

LEPINE, R., and BOULUD. Sur la glycosurie sans hyperglycemie.

C. r. A. B., 143, ix Q4Q, 1907.
Sur le sucre total du sang. Ibid., 147, 1908.
LEPIXOIS, E. Etude sur le chromogene des capsules surrenales et sur

1'origine de la coloration rouge, que ces glandes prennent au contact

de Pair. C. r. S. B., 51, pp. 310, 315, 1899.
LERMITTE, A. Suprarenal gland extract as a haemostatic. Brit. Med. Journ.,

1899.
LERMOVEZ, M. Un grand medicament de 1'avenir : 1'adrenaline. Presse

med., No. 37, 1902.
LESAGE, J. Recherches experimentales sur 1'adrenaline. Arch. int. de

Pharmac., 13, 1904.
— - Toxicite de 1'adrenaline en injection intraveneuse pour le chien. C. r.

S. B.,^ 56, pp. 632 and 709, 1904.
Toxicite de 1'adrenaline en injection intraveneuse pour le chat. Ibid.,

pp. 665 and 754.

- Phenomene d'accoutumance du coeur du chat a 1'adrenaline. Ibid., 56,

p. 800, 1904.

- Effets physiologiques du sue pancreatique naturel en injection intra-

veneuse. Action sur la circulation et respiration. Ibid., p. 938, 1904.
LESNE and DREYFUS. Contr. a 1'etude du pouvoir glycolytique du sang.
Ibid., p. i 140, 1904.

- A propos de la pancreatectomie experimentale chez le chien. Ibid.,

p. 528, 1906.

LETIENNE. De la senilite. P. m., 1906.
LETULLE, M. Note sur la degenerescence graisseuse de la capsule surrenale.

Bull. soc. anat., pp. 263-264, 1889.

- Surrenalite nodulaire hyperplastique et adenomes, de la capsule sur-

renale. Ibid., pp. 314-337, 1892.

- Mort subite dans la tuberculose des capsules surrenales. Press med.*

1894-

- Adenomes de la glande surrenale. Arch, de scienc. med., i, i, p. 80,

1896.
LEVA. Zur Lehre des Morbus Addisonii. V. A., 125, 1891.

- tiber den Einflusz gewisser Gifte (Alkohol, Adrenalin, Nikotin) auf die

Produktion spezifischer Immunsubstanzen. M. K., 1907.

LEVI, DELLA VIDA. Sieri tossi specific! per le capsule surrenali. Lo Sperim.,
^ 58, 1904.

- Sulla particolare struttura del pancreas in un Lemuride. Ibid., 58, 1904.
LEVI, L., and DE ROTHSCHILD. Oedemes thyroidienne transitoires. C. r.

S. B., 29 decembre, 1906.

- Hypothyroidie et autpinfections a repetition. Ibid., 58, i, p. 797.

- Autotherapie thyroidienne de la grossesse. Ibid., p. 1018, 1906.

- Corps thyroi'de et intestin. Ibid., 62, p. 681, April, 1907.

— Intestin, thyroidin et ioncalcium. Ibid., 62, p. 703.
Traitement thyroidien. Ibid., 64, p. 932.

- Hyperthyro'ide basedowienne. Ibid., 19 decembre, 1908.

- Contrib. a 1'opotherapie hypophysaire. Soc. de Neurologic, 7 fevrier,.

1907.

Sur un cas de myppathie atrophique progressive ou de myatonie ameliore
par 1'opotherapie hypophysaire. Ibid., 6 juin, 1907.

— Etude sur la physiopathologie du corps thyroi'de et de 1'hypophyse.

Paris, 1908.

- Le syndrome oculaire de 1'instabilite thyroidienne. C. r. S. B., 66, 1909.
LEVY. Ein Beitrag zur Kasuistik der Hypophysentumoren. Diss, Berlin,

1890.
LEVY, A. G. The blood-changes after experimental thyroidectomy. Brit.

Med. Journ., 1898.

LE WALD. A case of Addison's disease. New York Path. Soc., p. 237, 1901.
LEWANDOWSKY, M. Uber die Wirkung des Nebennierenextraktes auf das,

Auge. C. P., 12, p. 599, 1898.

- Uber die Wirkung des Nebennierenextraktes auf die glatten Muskeln,

im besonderen des Auges. A. A., p. 360, 1899.

- Zur Frage der inneren Sekretion von Nebenniere und Niere. Z. k. M.,

37, 1899-

Wirkungen des Nierenextraktes auf die glatten Muskeln der Haut.
C. P., 14, 1900.

526 LITERATURE

LEWANDOWSKY, M. Das histologische Bild der Schilddriise in Beziehung

zu ihrer Funktiqn. Festschr. , Leyden, ii, 1902.
LEWASCHEW, S. W. Uber eine eigentiimliche Veranderung der Pankreas-

zellen warmbliitiger Tiere bei starker Absonderungstatigkeit der

Driise. A. m. A., 26, 953, 1886.
LEWIN. Studies on the blood of animals deprived of the adrenalin. A. J. P.,

p. 358, 1901.

- Physiologie und Pathologic der Hypophysis. Diss., Berlin, 1906.
LEWIN, C. Uber Epinephrin (Epirenan). Fortschr. d. Med., 23, p. 6, 1905.
LEWIN, G. Studien iiber die bei halbseitigen Atrophien und Hypertrophien

namentlich des Gesichtes vorkommenden Erscheinungen, mit beson-
derer Beriicksichtigung der Pigmentation. Charite-Annal.. pp. 619-
704, 1884.

- Uber Morbus Addisonii mit besonderer Beriicksichtigung der eigen-

tiimlichen abnormen Pigmentation der Haut. Ibid., pp. 630-726, 1885.
— Uber Morbus Addisonii. II. Teil. Ibid., 1892.
LEWIN, M. Das Suprarenin, ein ideal es Extraktions- und Dentinanasthe-

ticum. D. zahn-arztl. W., No. 16, 1904.
LEWIN and BOER. Quetschung und Ausrottung des Ganglion coeliacum.

D. m. W., 1894.
LEWIS. Hyperplasia of the chromophile cells of the hypophysis as the cause

of acromegaly. Bull, of the Johns Hopkins Hosp., 16, p. 157, 1905;

and J. M., 20, 102.

LEYDIG, F. Lehrbuch der Histologie der Menschen und der Tiere. Frank-
furt, 1857.
LlBORIO, P. GOMEZ. The anatomy and pathology of the carotid gland.

Amer. Journ. Med. Scien., 136, pp. 98-111, 1908.
LICHTENSTEIN. Kritische und experimentelle Studien zur Toxikologie der

Plazenta. A. G., 86, H. 2, 1908; C. G., p. 1639, 1908.

- Gegen die plazentare Theorie der Eklampsie-Atiologie. C. G., No. 8,

p. 265, 1909.

LICHTWITZ, L. Uber einen Fall von Skelodermie und Morbus Addisonii
nebst Bemerkungen liber die Physiologie und Pathologic des Sym-
pathikus und der Nebennieren. D. A. k. M., 94, 1908.

- Uber Wanderung des Adrenalins im Nerven. A. P. P., 58, p. 221, 1908.
LICINI. Der Einflusz der Exstirpation des Pankreas auf die Schilddriise.

Z. f. Ch., p. 107, 1909.

LIEBEN, S. Wirkung v. Extrakten chromaffinen Gewebes a. d. Pigment-
zellen. C. P., 20, 1906.

- Zur Physiologie der Tunica dartos. P. A., 124, 1908.

LIEBMANN, A. Uber die Nebennieren und den Sympathicus bei Hemi-

cephalen und Hydrocephalen. Diss., Bonn, 1886.
LlEFMANN, E., and STERN, R. Uber Glykamie und Glykosurie. B. Z., i,

p. 299, 1906.

LIEGEOIS. Des glandes vasculaires sanguines. These Paris, 1860.
LIEPMANN, W. Zur Technik und Kritik der Plazentarforschung. C. G.,

1909.
LlER, E H. VAN. Uber Adrenalin. Ned. Tijdschr. v. Geneesk., 1907. Ref.

B. C., VI.
LILIENFELD and MONTI. Sur la localisation microchimique du phosphore

dans les tissus. A. i. B., 19, 1893.
LlMON. Etude histologique et histogenique de la glande interstitielle de

1'ovaire. Arch, d'anat. micr., v, fasc. ii, septembre, 1902.
LINDEMANN. Uber das Verhalten der Schilddriise beim Ikterus. V. A.,

1897.

- Sur la mode d'action de certains poisons renaux. Ann. Inst. Pasteur,

p. 49, 1900.
LINDSTADT, C. Neuere Forschungen iiber die Verrichtung der Schilddriise.

Berlin, 1004.
LlNNERT, K. Vergleichend chemische Gehirnuntersuchungen. W. k. W.,

1910; and B. Z., 26.
LINOSSIER, G., and LEMOINE, G. H. Note sur 1'action nephrotoxique des

inj. de serum normaux. C. r. S. B.,25 avril, 1903.
LlNSER. Uber die Beziehungen zwischen Nebennieren und Korperwach-

stum, besonders Riesenwuchs. B. z. kl. Ch., 37, p. 282, 1903.
LIPSCHITZ, B. Uber Myxoedem. Diss., Berlin, 1897.

LITERATURE 527

LiSix, F. Rech. exper. sur les medicaments cardiovasculaires. Arch.

intern. Pharmacod., 17, p. 465, 1908.
LISSAUER, M. Experimented Arterienerkrankung beim Kaninchen. B. k.

W., 1 005.

- Zur Kenntnis der Nebennierenblutungen. V. A., 193, pp. 137-148, igoS.
LlSSER. Traitement du diabete par les lavements de pancreas. P. m., i8g6.
LiviNl. Parathyroi'des et lobules thymiques. A. i. B., 34, igoo.

Livox, CH. Secretions internes, glandes hypertensives. C. r. S. B., p. g8,
25 Janvier, iSgS.

- Corps pituitaire et tension sanguine. C. r. S. B., 51, p. 170, iSgg; and

C. r. A., iSgg.

- Danger du principe actif des capsules surrenales dialyse. Ibid., 54,

p. 1501, 1903.

- Action de 1'adrenaline sur les vaissaux. Ibid., 55, p. 271, 1903.

- Action des vieilles solutions d'adrenaline. C. r. S. B., 56, p. 125, 1904.

- Que devient 1'adrenaline dans 1'organisme ? Ibid., 56, p. 53g, igo4.

— • Destruction de 1'adrenaline dans 1'organisme. Ibid., 56, 26, p. mS,

1904-

— • A propos de la destruction de 1'adrenaline dans 1'organisme. Ibid., 56,
ii, p. 118, 1904.

- Sur le role de 1'hypophyse. C. r. S. B., 17 juin, igo7.

- Action differente des lobes hypophysaire sur le sang du chien. Ibid.,

p. 6 1 8.

- Presentation d'un chien hypophysectome. Ibid., 18 fevrier, 1908.

- Inexcitabilite de 1'hypophyse. Ibid., 64, p. 177, igoS.

— Penetration par la voie nerveuse de la secretion interne de 1'hypophyse.

Ibid., 65, p. 744, igpS.

— Sur 1'action des extraits du corps jaune de 1'ovaire. Ibid., 66, p. 54g,

igog.

— Contribution a la physiologic de 1'hypophyse. J. d. P. P., xi, pp. 16-27,

15 Janvier, igog.
LLOYD, J. Notes on a case of Addison's disease; recovering during the

administration of extract of suprarenal body. Brit. Med. Journ.,

August 24, iSg5.
LOBEXHOFFER. Beitrage zur Lehre der Sekretion in der Struma. M. G. M. C.,

20, igog.
LOCHTE, G. Zur Kenntnis der epithelialen Umwandlung der Thymus.

C. a. P., 10, i8gg.

LOCKHART MUMMERY, J. P., and SYMES, W. LF.GGE. Some points on the ex-
perimental production of the vascular atony of surgical shock. Brit.

Med. Journ., igoS.
LOCKWOOD, C. B. Upon the presence of adrenal structures in the inguinal

canal. J. o. A. a. P., pp. 7g-83, iSgg.
LODE, A. Zur Transplantation des Hodens bei Hahnen. W. k. W., iSgs.

- Uber Zahlen- und Regenerationsverh. d. Spermatozoiden. P. A., 50,

1891.

- Exp. Beitr. z. Physiologic d. Samenblasen. S. W. A., 104.

LODI, M. Sur un cas des germes aberrants des capsules surrenales dans les

ovaires. A. i. B., 27, pp. 486-487, igo2.

LOEB. Hypophysis cerebri und Diabetes mellitus. C. i. M., 1898.
LOEB, J. Vorlesungen iiber die D^namik der Lebenserscheinungen. Leipzig,

igo6.
LOEB, L. Influence of iodine preparations on the vascular lesions produced

by adrenalin. Ibid., 133, p. go3, June 6, igo7-
LOEB, L., and FLEISCHER. Vergleichende Untersuchung uber die Aus-

scheidung von Jod bei Verabreichung von Jodkali und Sajodin.

Z. e. P., iv, p. 716, igo7.

- Uber den Einflusz von Jodpraparaten auf die durch Adrenalininjek-

tionen hervorgerufenen Gefaszveranderungen. D. m. \V., igo7 ;

A. J. M. S., 133, P. Q03, igo7.
LOEB, L., and GITHEXS, TH. C. The effect of experimental conditions on

the vascular lesions produced by adrenalin. Ibid., 130, p. 658,

October, igos.
LOEB, M. Beitrag zur Lehre vom Diabetes mellitus. C. i. M., No., 35,

iSgS.
LOENIXG, K., and FUSS, S. Schilddriisenveranderungen bei Adipositas

dolorosa (Dercumsche Krankheit). V. 23. C. M., pp. 224-232, igo6.

528 LITERATURE

LOEPER. Action de 1'adrenaline sur les organs hematopoetiques. C. r. S. B.,
55, p. 1452.

- L'action de 1'adrenaline sur 1'appareil cardiovasculaire et sur la capsule

surrenale. Ibid., p. 1453, 1903.

LOEPER, M., and CROUZON, O. L'action de 1'adrenaline et des extraits
surrenaux sur le sang. Ibid., 55, p. 1376, 1903.

- L'action de 1'adrenaline sur le sang. A. m. e., 16, p. 83, 1904.

- Purpura hemorrhagique traite par 1'adrenaline, guerison. Bull, med.,

1903.
LOEPER and ESMONET. La secretion graisseuse de 1'hypophyse. These de

Paris, 1904; C. r. S. B., 56, p. 575, 1904.

LOEPER and OPPENHEIM. Maladies des capsules surrenales. Paris, 1906.
LOEPER and ROY. Glycosurie et hypophyse. C. r. S. B., 55, pp. 382-384,

1903.
— Gigantisme et acromegalie. Nouv. Icon, de la Salpetriere, 16. p. 163,

1903.
LOEWENSTEIN. Die Entwicklung der Hypophysisadenome. V. A., iSS,

p. 44, 1907.
LOEWENTHAL, N. Lesions cerebrales des chiens ethyroides. Rev. med.

Suisse rom., 1887.

— tiber eigentiimliche Zellengebilde im Sympathicus des Frosches. I. M.,

n, 1894.
LOWENTHAL and WIELRECHT. Die Behandlung der Tetanic mit Nebenschild-

driisenpraparaten. M. K., 1907-
LOEWI, O. Eine neue Funktion des Pankreas und ihre Beziehung zum

Diabetes mellitus. W. k. W., p. 747, 1907; and A. P. P., 59, 1908.

- Arzneimittel und Gifte in ihrem Einflusz auf d. Stoffwechsel. v. Noor-

dens Handb. d. Pathologic d. Stoffwechsels, ii, 1907.
LOEWI, O., and MEYER, H. Uber die Wirkung synthetischer dem Adrenalin

verwandter Stoffe. A. P. P., 53, p. 213, 1905.
LOEWIT, M. Diabetesstudien I. Kaltediabetes und Organfunktion. II. Em

Beitrag zur Lehre von der Adrenalinamie beim Frosche. A. e. P., 60,

p. I, 1909; ibid., 60, p. 420.

- Diabetesstudien. III. Mitt. D. Pankreasdiabetes b. Frosche. A. P. Th.,

62, 1909.

— Vorlesungen liber allgv Pathologic. Fieber, Jena, 1898.

LOEWY, A. Neuere Unters. z. Physiologic der Geschlechtsorgane. E. P., 2,

1903.
LOEWY and RICHTER. Sexualfunktion und Stoffwechsel. A. P., Suppl., 1899.

— Zur Frage nach dem Einflusz der Kastration auf den Stoffwechsel.

C. P., 1902.

LOHMANN, A. Cholin, die den Blutdruck erniedngende Substanz der
Nebenniere. P. A., 118, p. 215, 1907.

- tJber die Verteilung des blutdruckherabsetzenden Cholins in der

Nebenniere. C. P., 21, p. 139, 1907.

— Zur Physiol. d. Schilddruse. Sitzungsber. d. Gesellsch. Naturw. Mar-

burg, 25 Mai, 1908.

— tJber die antagonistische Wirkung der in den Nebennieren enthaltenen

Substanzen Suprarenin und Cholin. P. A., 122, p. 203, 1908.

— Neurin, ein Bestandteil der Nebennieren. P. A., 128, p. 142, 1909.
LOISEL, G. Grenouille femelle presentant les caracteres sexuels secondaires

du male. C. r. S. B., 53, p. 204, 1901.

— Terminaisons nerveuses et elements glandulaires de 1 epithelium

seminifere. Ibid., 54, p. 346,, 1902.

— Sur 1'origine embryonnaire et 1'evolution de la secretion interne du

testicule. Ibid., p. 952, and 1037, 1902.

- Etude sur la spermatogenese chez le monceau domestique. J. A. P.,

pp. 112-177, 1902.

— La sexualite. Revue scient. serie 4, t. xix, No. 22, mai, 1903.

— Croissance comparee en poids et en longueur des foetus male et femelle

dans 1'espece humaine. C. r. S. B., 55, pp. 1235 and 1237, 1903.
Les poisons des glandes genitales. Premiere note. Recherches

et experimentation chez 1'oursin. Ibid., 55, p. 1329, 1903.
Sur les secretions chimiques de la glande genitale male (a propos d'un

pretendue glande inter stitielle du testicule). Ibid., 56, p. 27, 1904.
Contributions a 1'etude des secretions chimiques des glandes genitales.

Les pigments elabores par le testicule du poulet. Ibid., 56, p. 104,

1904.

LITERATURE 529

LoiSEL, G. Les caracteres sexuels secondaires et le fonctionnement des
testicules chez la grenouille. Ibid., 56, p. 446, 1004.

- Sur 1'origine et la double signification des cellules interstitielles du

testicule. Ibid., p. 448.

- Recherches sur les ovaires de grenouilles vertes. Ibid., p. 504.

- Recherches comparatives sur les toxalbumines contenues dans divers

tissus de grenouille. Ibid., 56, pp. 883 and 88g, 1904.

- Les poisons des glandes genitales (suite.) IV. Recherches sur les

mammiferes. Conclusions generates. Ibid., 57, i, p. 77, 10,05.

- Conservation des poisons genitaux. Ibid., p. 80.

- Substances toxiques des ceufs extraites de tortue et de poule. Ibid.,

P- 133-

- Les phenomenes de secretion dans les glandes genitales. Revue generale

et faits nouveaux. J. A. P., ann. 15, pp. 536-562, 1904; and 41, p. 58,
1905.

- Sterilite et alopecie chez les cobayes soumis anterieurement a I'influence

des poisons ovariens de grenouille. C. r. S. B., 57, ii, p. 463, 1905.

- Recherches des graisses et des lecithines dans les testicules de cobayes

en evolution. Ibid., 57, ii, p. 584, 1905.

- Les substances graisses dans les glandes genitales d'oursin en activite

sexuelle. Ibid., p. 586.

- Considerations generates sur la toxicite des produits genitaux. Ibid.,

57, ii, p. 511, 1905.

- Experiences sur la toxicite des oeufs de canards. Ibid., 57, ii, p. 460,

1905.
Toxicite des oeufs de poule et de tortue. Ibid., p. 403.

- Croissance des cobayes normaux ou soumis a Faction du sel marin ou

du sperme de cobaye. Ibid., p. 506.

Toxicite du liquide seminale de cobaye, de chien et de tortue. Ibid.,
p. 509.

- Contribution a 1'etude de 1'hybridite. (Eufs de canards domestiques et

de canards hybrides. Ibid., p. 5^7 .

- Experience sur la toxicite des oeufs de canards. Toxicite des oeufs de

poule et de tortue. Ibid., p. 400.

LOMBROSO, U. Sul diabete sperimentale e la secrezione pancreatica esterna.
Giorn. R. Accad. Medic, di Torino, 1902.

- De I'influence des phenomenes lipolytiques dans 1'absorption des graisses

chez les chicns depancreatises. C. r. S. B., 55, p. 400, 1904.

— Observations histologiques sur la structure du pancreas du chien, apres

ligature et resection des conduits pancreatiques. Ibid., 57, p. 610,

1904.
— • Observations histologiques sur la structure du pancreas du pigeon, apres

ligature et resection des conduits. Ibid., p. 611.
— - tiber die Rolle des Pankreas bei der Verdauung und Resorption der

Kohlehydrate. H. B., 8, p. 51.

— Sui fenomeni consecutivi all' estirpazione del pancreas non piu funzion-

ante regolarmente. Giorn. della R. Accad. di Med. di Torino, ii,
anno 68, pp. 5-6, 1905.

— • Sur la structure histologique du pancreas apres ligature et section des
conduits pancreatiques. J. d. P. P., No. i, 1905.

- Sugli element! che partecipano alia funzione interna del pancreas. Arch.

di fisiol., 3, F. 2, 215, 1906.

— Sulla funzione del pancreas nel ricambio materiale. Torino, 1906.

— tiber die Beziehungen zwischen der Nahrstoffresorption und den enzy-

matischen Verhaltnissen im Verdauungskanal. P. A , 112, 1906.

- Uber die enzymatische Wirksamkeit des nicht mehr in den Darm

sezernierenden Pankreas. H. B., IT, Si, 1907.

- A proposito della nota del dottore Visentini : Sulla Funzione del pan-

creas. Gazz. med. Ital., No. 48, Pavia, 1907.

- Zur Beantvvortung von O. Hess : Die Ausfiihrungsgange des Hunde-

pankreas mit Bezug auf Fettresorption. Med. Naturwiss. Arch., i,
Heft, 3, Berlin.

- Zur Frage liber die innere Funktion des Pankreas mit besonderer

Riicksicht auf den Fettstoffwechsel. A. P. P., 56, 1907.

— Su gli elementi che compiono la funzione interna del pancreas. Arch.

Farmac., 5, 201, 1908.

34

530 LITERATURE

LOMBROSO, U. Sulla lipasi del secreto intestinale. Rend. R. Accad. del
Lincei, 17, ser. 3, 136. Roma, 1908.

- Kann das nicht in den Darm sezernierende Pankreas auf die Nahrstoffe

einwirken ? A. P. P., 60, p. 99, 1908. .

— Influenza di un segmento di pancreas cqmpletamente separate dai suoi

normal! rapporti nervosi. Boll. Associazione cultori Scienze mediche
e natural!. Roma, 1908.

— Sulla teoria umorale degli " Ormoni." II meccanismo della secrezione

pancreatica ed intestinale. Lo Sperimentale, 1908.

Zur Frage der Beziehung zwischen innerer Pankreasfunktion und

Nervenwirkung. Folia Neurobiologica, iii, No. 2, 1909.

— La secrezione interna del pancreas. II Tommasi, 1909.

— Die Gewebselemente, welche die innere Funktion des Pankreas besorgen.

E. P., IX, 1909.

LOMBROSO, N., and SACERDOTE, A. Sulle modificazioni istologiche del pan-
creas di coniglio dopo la ligatura del dutto di Wirsung. Rend. R.
Accad. di Lincei. Roma, 1908.

LOMER, R. Eigentuml. Verhalten der Nebennieren bei Hemicephalen.
V. A., 98, P- 366, 1884.

- Antithyreoidin Moebius bei Basedowkrankheit mit Psychose. M. m. W.,

Lo MONACO and V. RYNBERK. Sulla funzione dell' ipofisi cerebrale. Atti
Accad. dei Lincei, 10, pp. 117, 212 and 265, 1901.

- Ric. sulla funzione della ipofisi cerebrale. Riv. di Neuropath. Roma,

Nos. 9 and 10, 1901.
LONGWORTH, S. G. The action of some suprarenal preparations. Brit.

Med. Journ., 1902.
LORAND, A. Les rapports du pancreas avec la thyroide. Ibid., 56, p. 488,

25 mars, 1904.

— Pathogenic du diabete dans Facromegalie. Ibid., 56, p. 554, i avril.

— On the blood glands as pathogenic factors in the production of diabetes

and obesity. Transact, of the Path. Soc. of London, 57, i, 13, 1906.

— Klinische Beitrage zur Frage iiber die Beziehungen der Schilddriise zum

Diabetes. 79, V. d. N. A., pp. 40-41 ; Klin, therap. W., 1907.

— Sur les rapports de la thyroide avec les reins, avec consideration sur la

pathogenic de la goutte. C. r. S. B., 62, p. 129, 1907.

— Note sur la pathogenic de la narcose. Ibid., 6p, p. 908.

- Die rationelle Behandlung der Zuckerkrankheit. Berlin, 1909.

— Das Altern. 2 Aufl. Leipzig, 1909.

LORD. The pineal gland, its normal structure, some general remarks on its
pathology. Transact, of the Path. Soc. of London, 50, p. 18, 1898.

LORTAT-jACOB, L. Influence de la thyroidectomie partielle sur la gestation
et la lactation chez la lapine. C. r. S. B., 56, p. 61, 1904.

LORTAT-JACOB, L., and SABAREANU, G. Pathogenic de 1'atherome artenel et
thyroidectomie. Ibid., 19 novembre, 1904.

— Du role de la castration dans la production de Fatherome experimental.

Ibid., 57, P- 583, 17 avril, 1905.
LOTHRINGER. Untersuchung an der Hypophysis eimger Saugetiere und des

Menschen. A. m. A., 28, p. 257, 1886.
LUBARSCH, O. tiber die Abstammung gewisser Nierengeschwiilste von

embryonal versprengten Nebennierenkeimen. V. A., 137, 1894.

— Beitr. z. Histologie d. von Nebennierenkeimen ausgehenden Nieren-

geschwiilste. Ibid., 135, 1894.

— Allg. Pathol. u. path. Anatomie der Nebennieren. L. O., i, p. 488, 1896.

— Uber d. Vorkommen kristall. Bildungen in d. Zellen d. Hodens. V. A.,

145, 1896.

- Uber die Bedeutung der pathologischen Glykogenablagerungen. V. A.,

183, 1906.

LUBLINSKI. Jodismus acutus und Thyreoiditis acuta. D. m. W.,^1906.
— - Uber die Anwendung des synthetischen Suprarenins. B. k. W., 1907.
LUCIANI, L. Fisiologia dell' iiome. II. Le secrezioni interne protettive.

Milano, 1904.
LUCIBELLI. Contribute all fisiopatologia della capsule surrenali. Gazz. d.

osp., p. 1221, 1901.
LUCIEN, M. Thymus et athrepsie. C. r. S. B., 64, p. 559.

— Etude anatomo-pathologique sur Fhypertrophie du thymus. Ibid., 64,

p. Q2I.

LITERATURE 531

LUCIEN, M. Consideration anatomo-pathologiques sur 1'athrepsie. Reun.
biol. de Nancy, 10 juillet, igo8.

— Capsules surrenales et athrepsie. C. r. S. B., Marz, 1908.

LUCIEN and PARISOT. Etude physiologique et anatomique du thymus dans
1'athrepsie. Ibid., 64, p. 747.

— Variations ponderales de Thypophyse consecutivement a la thyroid-

ectomie. Ibid., 65, pp. 261 and 771, 1908.

— Influence de la thymectome sur la croissance. Soc. med. Nancy, 22

Juli, iQpS.

LUDKE, H. Uber Zytotoxine mit besonderer Berlicksichtigung der Ovario-
toxine und Thyreotoxine. M. m. W., 1905.

- Die Antikorperproduktion als zellularer Sekretionsprozesz. B. k. W.,

1905.

LUTHJE, H. Zur Frage der Zuckerbild. im tier. Organismus. M. m. W.,
1902.

— 1st die Zerstorung des Zuckers nach Pankreasexstirpation vollstandig

aufgehoben ? Ibid., 1903.

— Uber die Kastration und ihre Folgen. A. P. P., 48 and 50, 1903.
LUTZONE, E. Uber den Einflusz von diuretisch wirkenden Mitteln auf das

Zustandekommen der alimentaren Glykosurie. Diss., Gottingen, 1907.
LUFF, A. P. On the uses of the calcium salts in morbid conditions. Brit.

Med. Journ., 1909.
LUKSCH, F. Funktionsstorungen der Nebenniere bei Allgemeinerkrank-

ungen, Intoxikationen und Infektionen. W. k. W., 1905.

- Uber die Storung der Nebennierenfunktion bei Infektionskrankheiten.

B. k. \V., 1909.
LUNA, E. La morfologia delle ghiandole soprarenali dell' uomo nelle varie

fasi del loro sviluppo. An. An., 33, p. 383, 1908.
LUNDBORG. Die Entwicklung der Hypophysis bei Knochenfischen und

Amphibien. Z. A., 7, 1894.

— Spielen die Glandulea parathyroideae in der menschlichen Pathologic

eine Rolle ? D. Z. N., 27, p. 217, 1904.
• — Hypothese betr. d. Natur d. kataton. Symptomenkomplexe. Centbl.

f. Nervenh., 1905.
LUP6. Tiroidectomie. Alterazioni nei centri nervosi. Progresso med.,

Napoli, 1888. »

LUSCHKA, H. Die Steiszdruse des Menschen. V. A., 18, 1859.

— Der Hirnanhang und die Steiszdruse. Berlin, 1860.

— Uber die driisenartige Natur des sog. Ganglion intercaroticum. V. A.,

pp. 405-411, 1862.

LUSENA, G. Sulla patogen. del morbo di Basedow. Cron. d. Clin. med. di
Geneva, 1897.

— Sull' organoterapia paratiroidea. Ibid., 1898.

— Fisiopatologia dell' apparecchio tireoparatiroidea. Diss., Florenz, 1899.

- Sui rapporti funzionali fra la tiroide e la glandule paratiroide. Ibid.,

i goo.

- La resistenza alle intossicazioni bacteriche dopo 1'estirpazione delle cap-

sule surrenali. Boll, della R. Acad. med. di Geneva, anno xviii, No.
i, 1903; Ref. B. C., ii, p. 246.

— Nuove ricerche sull' apparecchio tireoparatiroidea. Rif. med., 1906.
LUSK, G. The influence of cold and mechanical exercise on the. sugar

excretion in phlorizin glycosuria. A. J. P., vol. 22, p. 163, 1908.

— The production of sugar from glutamic acid ingested in phlorizin gly-

cosuria. Ibid., p. 144.

LUSTIG. Sugli effetti dell' estirpazione del plesso celiaco. Lo Sperim.,
1890-1891; Arch, per le scienz. med., 13, p. 129, 1889; Zieglers Beitr.,
7, p. 431, 1889.

— Uber die Atiologie des endemischen Kropfes. X. Kongr. intern.

Berlin, 1890.

LYMAN GREEN, CH. Akromegaly associated with symptoms of myxcedema.
New York Med. Journ., October, 1905.

MAAS, O. Uber Veranderungen im Zentralnervensystem nach Unterbindung

der Schilddriisengefasze. B. k. W., 1902.
MAAS, P. Exper. Untersuchung liber die Innervation der Kranzgefasze.

P. A., 74, 1899.

532 LITERATURE

MACAROFF, G. Action mydriatique du serum et de 1'urine dans les nephrites
et chez les animaux nephrectomises. Presse med., 13 Janvier, 1909.

MACCALLEN, F. Adrenalin und Drucksteigerung. Engl. ophth. Ges., 6, 5,
1903.

MACCALLUM, W. G. On the production of specific cytolytic sera for thy-
roid and parathyroid, with observations on the physiology and path-
ology of the parathyroid gland, especially in its relation to exoph-
thalmic goitre. Med. News, October 31, 1903.

- Tumour of the parathyroid gland. Johns Hopk. Hosp. Bull., 16, No.
168, 1905.

— Die Beziehung der Parathyroiddriisen zu Tetanie. C. a. P., 76, igc-S-

— On the relation of the islands of Langerhans to glycosuria. Bull. Johns

Hopk. Hosp., 20, p. 265, 1909.

MACCALLUM, W. G., and VOEGTLIN, C. On the relation of the parathyroid
to calcium metabolism and the nature of tetany. Bull, of the Johns
Hopk. Hosp., 19, p. QI, March, 1908; and C. G. M. C., n, 1908.

— On the relation of tetany to the parathyroid glands and to calcium

metabolism. J. E. M., n, p. 118, 1909.

— On the relation of calcium metabolism to tetany and the cure of tetany

by administration of calcium. Proc. Soc. Exper. Biol. Med., vol. v,
P- 84.

MACCARRISON, R. Observations on endemic cretinism in the Chitral and
Gilgit valleys. Lancet, October 31, 1908.

— A summary of further researches on the etiology of endemic goitre.

P. R. S., vol ii, p. i, 1909.

— Further researches on the etiology of endemic goitre. Quart. Journ. of

Med., vol. ii, 7, p. 279, 1909.
MACCURDY, J. The influence of thyroidectomy on alimentary glycosuria.

J. E. M., xi, p. 798.
MACCRUDDEN. The effect of castration on the metabolism in osteomalacia.

A. J. P., xvii, p. 211.

The composition of bone in osteomalacia. Ibid., xvii, p. 32.
MACKENZIE, DAN. Suprarenal gland extract in the epistaxis of haemophilia.

Brit. Med. Journ., pp. 1009 and 1226, April 27, 1901.

MACLANTHLIN. Report of a case of Addispn's disease. Med. News, 1895.
MACLENNIN, A. An experimental investigation into the function of the

thymus gland. Glasg. Med.' Journ., August, 1908.
MACLEOD, J. J. R., and DOLLEY. Studies in experimental glycosuria. I.

On the existence of afferent and efferent nerve fibres, controlling the

amount of sugar in the blood. A. J. P., 19, p. 338, 1907.

— The effect of expressed tissue juices of muscle on the mammalian heart

beat. Ibid., p. 426.

— Studies in experimental glycosuria. II. Some experiments on the

nature of the glycogenolytic fibres in the great splanchnic nerve.
Ibid., 22, p. 373, 1908.

— Studies in experimental glycosuria. IV. The cause of the hyper-

glycaemia produced. by asphyxia. A. J. P., 23, p. 278, 1909.

— Experimental glycosuria. J. o. P., 32, July, 1905.

MACLEOD and Run. Studies in experimental glycosuria. III. The influence
of stimulation of the great splanchnic nerve on the rate of disappear-
ance of glycogen from the liver, deprived of its portal blood supply
or of both its portal and systemic blood supplies. A. J. P., 22, p. 397,
1908.

MACMUNN. Sulle funzione della capsule surrenali. II Morgagni, ii, No. 9,
p. 106, 1889.

MACWILLIAM, MACKIE, and MURRAY. Intravascular injection of salts and of
nucleo-proteid. J. o. P., 30, p. 381, 1904.

MADELUNG. Uber Verletzungen der Hypophysis. A. k. Ch., 73, p. 1066,
1904.

MAGENDIE. Rech. physiol. et cliniques sur les liquides cephalo-rachid.
Paris, 1842.

MAGNUS. Uber das anatomische Verhalten der Nebennieren, der Thy-
reoidea, Thymus und des Sympathicus bei Hemicephalen. Diss.,
Konigsberg, 1889.

- Ovariets betydning for svangerskabet med saerligt hensyntil Corpus
luteum. Norsk. Mag. f. L., Ref. in Frommels Jahresber., 1902.

LITERATURE 533

MAGNUS. Serumbehandlung von M. Basedo\vii. Norsk Magazin fur Lage-
videnskob., No. 7, 1905.

- Uber die Entstehung der Hautoedeme. A. P. P., 42, iSgg.

- Suprarenin bei Sipunculus, Wirkung auf glatte Muskeln. A. P. P., 50,

1903.

- Die Bewegungen des Darmkanales. Zusammenfassend. E. P., 7, igo8.
MAGNUS-LEVY, A. Uber den respiratorischen Gaswechsel und den Einfluss

der Thyreoidea, &c. B. k. W., 1895.

- Untersuchung zur Schilddrusenfrage, Gas- und Stoffwechseluntersuchung

bei Schilddrusenfiitterung, Myxodem, Morbus Basedowii und Fett-
leibigkeit. Z. k. M., 33, 1897.

- Uber Myxoedem. Ibid., 52. Die Therapie des Myxoedem. Th. G.,

1907.
Untersuchungen iiber Azidosis bei Diabetes mellitus. A. P. P., 45, 1901.

- Die Azetonkorper. Erg. d. inn. Med. u. Kind., i, 1908.

- Organtherapie und innere Sekretion. Mod. arztl. Bibl., Berlin, 1906.

— Der Stoffwechsel bei Erkrankungen einiger Driisen ohne Ausfiihrungs-

gang. Noordens Handb. d. Path. d. Stoffwechsels, ii, pp. 352-354,
1907.

- Der respiratorische Gaswechsel in Krankheiten. C. k. M., 1906.

— Chylurie und Diabetes. Z. k. M., 67, 1909.

MAGNUS and SCHAEFER. The action of pituitary extracts upon the kidney.

J. o. P., 27, p. 9, 1901-02.
MAKE. Essai sur le traitement de la maladie d'Addison. These de Paris,

1894.

MAHU and ICHARD. Adrenaline. Journ. de med., 10 avril, 1904.
MAIGNON, F. Mode de repartition du glycogene musculaire chez les sujets
alimentes et inanities. C. r. A., 145, p. 334, 1907.

- Du role des graisses dans la glycogenie chez les sujets sains et les

diabetiques. C. r. S. B., 64, pp. n and 14, 1908.
MAINZER. Vorschlag z. Behandlung d. Ausfallserschein. nach Kastration.

D. m. W., 1896.
MAIRET and BOSC. Recherches sur les effets de la glande pituitaire adminis-

tree aux animaux, a 1'homme sain et a 1'epileptique. C. r. S. B., p.

348, 1896; A. d. P., p. 600, 1896.
MAISCH, CH. O. Three cases presenting indications of Addison's disease

during infancy and childhood, with post-mortem and histological

reports on two. Postgrad, 14, 1899.

MAISONAVE. Contr. a 1'etude de 1'opotherapie orchitique. These, Lyon, 1903.
MAJ, A. Su di un caso di Morbo d'Addison venuto a guarigione. Clin.

med. Ital., 1901.

MALCOLM, JOHN. On the influence of pituitary gland substance on meta-
bolism. J. o. P., 30, p. 270, December, 1904.
MALSEN, H. v. Geschlechtsbestimmende Einfliisse und Eibildung des

Dinophilus apatris. A. m. A., 69, p. 63, 1907.

MALVOZ, E. Corps thyroide et immunite. C. r. S. B., 65, pp. 69-70, 1908.
MAMLOCK. Zusammenfass. iiber Adrenalin. Zietschr. f. diat. u. phys.

Ther. , 7, 1904.
MANASSE, P. Uber die hyperplastischen T.umoren der Nebenniere. V. A.,

133, 1893-

- Uber die Beziehungen der Nebennieren zu den venen und dem venosen

Kreislauf. Ibid., 135, 1894.

- Zur Histologie und Histogenese der primaren Nierengeschwiilstc.

V. A., 143, p. 278; ibid., 145, pp. H3-I57, 1896.

- Uber zuckerabspaltende phosphorhaltige Kb'rper in Leber und Neben-

niere. Z. ph. Ch., 20, p. 478, 1895.
MANCA, P. II rene del cane dope 1'ablazione completo dell' apparecchio

tiroparatiroidea. Arch, di biol. norm, e pathol., 59, 1906.
MANDL, L. Beitr. z. Kenntn. d. Funktion d. weibl. Keimdruse. Festschr.

f. Chrobak, 1903.

- Diskussionsbemerkungen zu Fraenkels Vortrag. C. G., 28, 1904.
MANDL, L., and BURGER, O. Die biolog. Bedeutung der Eierstocke nach

Entfernung der Gebarmutter. Leipzig, u. Wien,. 1907.
MANDLEBAUM, F. S., and CELLER, H. L. Contr. a 1'etude de 1'anatomie

pathologique de la myasthenie grave. J. E. M., x, 3, 1908.
MANICARDI G. La paraganglina Vassale nelle atonic gastro-enteriche. Rif.

med., 1903.

534 LITERATURE

MANKOWSKI, A. Nouvelles donnees sur la microphysiologie du pancreas, le
role des ilots de Langerhans. Seance du XIII. Congr. int. de med.,
a Paris, 1900, 3, p. 302.

- tiber die mikroskopischen Veranderungen des Pankreas nach Unter-

bindung einzelner Teile. A. m. A., 59, 286, IQOI.

— tJber die belebende Wirkung des Nebennierenextraktes bei drohendem

Chloroformtode. Wratsch., 1897, Ref. St. Petersb. med. W., 1897.

- Les moyens les plus simples pour preparer 1'extrait des capsules sur-

renales et son action sur 1'organisme animale. Arch. rus. de Path.,

iii. 3) P- 387, mars, 1898.
MANKOWSKY. Zur Frage nach den Zellgiften (Zytotoxinen). Russki

Wratsch, 1902; Russ. A. f. Path., xiv, i; Ref. in C. f. B., 32, No. 19.
MANKIEWICZ, O. Uber die bosartigen Tumoren der Nebenniere. Diss.,

Strassburg, 1888.
MANN, J. DIXON. On Addispn's disease. Lancet, p. 655, March 2.1, p. 711,

March 28, p. 764, April 4. London, 1891.
MANN, FR. Uber Bronzehaut. Diss., Greifswald, 1893.
MANOUCHINE. Blutgerinnung, Leukocyten und Pepton. Wratsch, J. d. P. P.,

xi, 1909.
MANSFELD, G. Die Verhiitung der Adrenalinarteriosklerose. W. k. W.,

p. 1650, 1908.
MANSFELD and RABDELEO. Die Verhinderung der Adrenalinarteriosklerose.

Orvosi Hetilap, 1908.
MARAGLIANO. Maladie d'A-ddison. Rif. med., 1894.

- La cosa della malattia di Basedow. Gazz. Osped., 1900.

- Note clinic, chim. e sperim. sulle nefriti. La Clinic. Med. Ital., p. 437,

1902.

MARASSINI. Dei fenomeni consecutivi all' estirpazione del plesso celiaco.
A. Sc. Med., Pavia 97, 1903.

- Ricerche sopra 1'azione tossica dei nucleo-proteidi del fegato. Con-

tributo allo studio del meccanismo d'azione delle cosidette citotossine
specifiche. Ref. B. C., i, p. 804, 1903.

— Contribution a 1'etude de la structure et de la fonction des capsules

surrenales. A. i. B._, 46, pp. 73-82.

- Sopra le modificaziqni che si hanno nelle capsule surrenali in rapporto

con alcune variazioni della funzione genitale e della funzione renale.
Lo Sperim., 40, p. 197, 1906.

- Sopra la minuta struttura dei vari element! delle capsule soprarenali

e sul loro probabile valore funzionale. Monit. zool. Ital., xvii, Nos. 2
and 3, pp. 42-60, 1906.

- Contr. sper. allo studio della funzione dell' isole di Langerhans. Riv.

d. Sc. Nat., Pavia, 1907.

- Sopra una particolare modific. delle glandule duoden. dopo 1'alla-

ciatura d. cond. d. Wirsung. Ibid., 1908.

MARBE, S. Les opsonines dans les etats thyroidiens. I. Les opsonines des
animaux hyperthyroiides. C. r. S. B., 64, p. 1058, 13 juin, 1908.

- II. Les opsonines des animaux ethyroides. Ibid., p. 1113, 20 juin, 1908.

- III. Les opsonines et la phagosytose chez les myxcedemateux. Ibid.,

12 decembre, 1908.

- IV. Actions directe, in vitro, du corps thyroi'de. Ibid. 13 mars, 1909.

— La phagocytose chez 1'animaux hyperthyr. et ethyr. Ibid., 26 Juni, 1909.
MARBURG, O. Die Adipositas cerebralis. Beitr. z. Pathol. der Zirbeldriise.

W. m. W., 1908.

Zur Kenntnis der nprmalen und pathologischen Histologie der Zirbel-
driise. Die Adipositas cerebralis. Arb. a. d. neurol. Institute a. d.
Wien Univ., xvii, 1909.

MARCHAND, F. Uber eine eigentumliche Erkrankung des Sympathicus der
peripherischen Nerven (ohne Bronzehaut). V. A., 81, 1880.

— Uber akzessoriche Nebennieren im Ligamentum latum. V. A., 92, 1883.

- Beitrage zur Kenntnis der normalen und pathologischen Anatomic der

Glandula carotica und der Nebennieren. Festschr. f. R. Virchovv,
i, p. 537, 1891.

- Uber den Prozesz der Wundheilung. D. Ch., Lief. 16. Stuttgart, 1901.
MARCHES:. La meccanica respiratoria dei cani tiroi'dectomizzati. Arch.

p. le Scienc. Med., 17.

MARCHETTI, S. Uber eine Degenerationszyste der Nebenniere mit kompen-
satorischer Hypertrophie. V. A., 172, pp. 472-47Q, 1903.

LITERATURE 535

MARCHETTI, S. Beitrag zur Kenntnis dcr pathologischen Anatomic der
Nebennieren. Ibid., 177, pp. 227-247, 1904.

- Schilddriisenprazipitine. Rif. med., 1907.

MARCUSE, \Y. Uber die Bedeutung der Leber fur das Zustandekommen

des Pankreasdiabetes. Z. k. M., 26, p. 225, 1894.
MARENGHI, G. Sull' esportazione delle capsule surrenali in alcuni mammi-

feri. Rendiconti del' Inst. Lombard., 2, 36, p. 543, 1903; Autoref.

in B. C., ii, p. 152; and Lo Sperim., 57, 1903.

MARESCH. Kongenitaler Defekt der Schilddruse, &c. Z. H., 19, 1898.
MARIANI, F. Ricerche sperimentali sulla funzione delle capsule surrenali.

Clin. medic. Ital., 1906.
MARIE. Sur deux cas d'acromegalie, hypertrophie singuliere non congenitale

des extremites superieures, inferieures et cephaliques. Rev. de med.,

p. 298, 1886.

- L'acromegalie. Nouv. Icon, de la Salpetrierc, i, p. 173, iSSS; 2, p. 45,

1889; Progres med., 1889.

- Acromegalie. Brain, 12, pp. 59-81, July, 1890; and Soc. m. Hopit.,

1896.
MARIE, P., and MARINESCO, G. Sur 1'anat. patholog. de 1'acromegalie.

A. m. e., 1891.
MARINE, P., and LENHARDT, C. H. Relation of iodine to the structure of

human thyroids. Relation of iodine and histologic structure to

diseases in general, to exophthalmic goitre, to cretinism and myx-

cedema. Arch. Int. Med., iv, p. 440, 1909.

- Effects of the administration or the withholding of iodine-containing

compounds in normal, colloid or actively hyperplastic (parenchy-

matous) thyroids of dogs. Ibid., iv, p. 253, 1909.
MARINESCO, G. De la destruction de la glande pituitaire chez le chat.

C. r. S. B., 44, p. 509, 1892.
Trois cas d'acromegalie traites par des tablettes de corps pituitaire.

Semaine med., p. jS'4, 1895.
Tetanic d'origine parathyroidienne. S. m., 1905.

- Contr. a 1'etude de la myasthenie grave pseudo-paralytique. Ibid., p.

241, 1908.
MARIXESCO and MIXEA, J. Note sur les changements morphologiques des

cellules des ganglions greffes sur des animaux prives de leur appareil

thyro-parathyroiden. C. r. S. B., pp. 239-241, 1908.
MARINESCO and PARHON, C. Sur 1'influence de la thyroidectomie sur la

survie des animaux en etat d'inanition. C. r. S. B., 67, p. 306, 1909.

- L'influence de 1'ablation de 1'appareil thyro-parathyroidien sur la graisse

surrenale. C. r. S. B., 64, p. 768, 1908.
MARINI, N. Considerazioni sulla patogenesi dell' ateromasia adrenalinica

e dell' ateroma in generale. Gaz. degli Osped., 26, 22, 1905.
MARlNO-Zucco. Recherches chimiques sur les capsules surrenales. A. i. B.,

10, 325, iSSS.

- Presence de la Neurine dans le sang. A. i. B., 21, p. 437, 1894.
MARINO-ZUCCO and DUTTO. Chemische Unters. iib. die Addisonsche Krank-

heit. M. I)., 14, p. 617, 1892.
MARlNO-Zucco, F., and S. Untersuchungen u'ber die Addisonsche Krank-

heit. Ibid., xiv, pp. 59-63, 1892. Ital. : Rif. med., viii, 64. 1892.
MARISCHLER, J. Ein Fall von lyrnphatischer Leukamie und einem Grawitz-

schen Tumor der rechten Niere. W. k. W., 1896.
MARRO. La puberte. Paris, 1900.
MARSHALL, C. F. A case of Addison's disease; necropsy; remarks. Lancet,

October 3, 1891.
MARSHALL, F. H. A., and JOLLY, W. A. Physiology of reproduction. Lancet,

1905. On the results of heteroplastic ovarian transplantation as com-
pared with those produced by transplantation in the same individual.

Quart. Journ. of Exp. Phys. , i and 2, 1908.
MARTIN, A. L'adrenaline dans le traitement des hemopthysies. Progr. med.,

p. 732, 1907.

MARTIN, CH. The nerve theory of menstruation. Brit. Gyn. Journ., 1893.
MARTINEAU. De la maladie d'Addison. Paris, 1864.
MARTINI, DE CH. Sur un cas d'absence congenitale des capsules surrenales.

C. r. A., 43, pp. 1052-1053, 1856.
MARTIN-MACRON and ORDONNEZ. Anat. et physiol. des glandes vase. sang.

These, 1860, Canstatts Jahrb., vi, p. 272, 1863.

536 LITERATURE

MARTINOTTI, C. Sull' estirpazione del pancreas. Giorn. R. Accad. Med. di

Torino, 348, 1888.
— Sui fenomeni consecutivi all' estirpazione del pancreas. Ibid., 338.

- Contribution a 1'etude des capsules surrenales. Giorn. della R. Ace. di

med. di Torino, Iv, pp. 299-301, 1892; A. i. B., 27, pp. 284-286.

- Sur les alterations des capsules surrenales consecutives a Pocclusion

des veines centrales respectives. A. i. B., 49, pp. 236-240, 1908.
MARUM, A. Uber die Beziehungen iiber den Glykogengehalt der Organe

und der Azidose beim Phloridzindiabetes. H. B., x, p. 105, 1907.
MASAY, F. L'Hypophyse. Etude de Physiologie pathologique. These de

Bruxelles, 1908.

- Recherches sur les effets d'un serum hypophyse toxique. Ann. de la

Soc. med. et nat., p. 91, 1908.

MASOIN, P. Influence de 1'exstirpation du corps thyroide sur la toxicite
urinaire. A. d. P., 1894.

- Influence de. 1'exstirp. du corps thyroide sur la quantite d'oxyhemo-

globine. Acad. de med. Belg., 1895.

MASSAGLIO, A. Contribute alia patogenesi del mixedema. Rivista di patol.
nervosa e mentale, /; and ibid., 13; A. i. B., p. 343, 1908.

- L'influenza della fatica nei cani parzialmente sparatiroidati. Gazz.

degl. Osp., 1907.

- II trattamento del mal di mare con la paraganglina Vassale. Gazz.

Osped., 1907.
MASSAGLIA, A., and SPARAPANI, G. Eclampsie experimentale et eclampsie

spontanee des animaux. A. i. B., 48, pp. 109-114.
MASSALONGO. Sull' Acromegalia. Rif. med., 1892.
MASSARI. Sul pancreas dei pesci. R. c. della R. Accad. dei Lincei, 7, 139.

Roma, 1898.
MASSINI. Contr. al estudio del patogen. de la ecclampsie. Ref. C. G. ,

1908.
MASSONE, M. II sistema cromaffine addominale in casi di " encephalos-

chisis." Pathologica, i, October i, 1909.
MASTRICHT INDEMANNS. Die Storungen der inneren Sekretion der Gefasz-

driisen und ihrer Beziehungen zueinander. Centrbl. f. Therap., Mai,

1909.
MATHES, P. Beobacht. an mit Plazentarsaft durchstromten Hundenieren.

Z. G. G., '62.

- Uber die Einwirkung des Oophorin auf den Stoffwechsel. M. G. G.,

1903.

MATTEI Di. Sull' iperplasia compensatoria delle capsule surrenali. Giorn.
Accad. d. med. di Torino, 3, xxxiv, 127, 1886.

- Sulle fibre musculari liscie delle capsule surrenali allo stato normale e

pathologic e sulle adenoma di questi organi. Ibid., 322-331.

- Sulla pretesa azione tossica delle diluzione acquose degli organi animali

freschi. Arch, per le sc. med., vi, pp. 245-288, 1883.
MATTEI Di, and Russo GILIBERTI. Sull' influenza dell' estirpazione delle

capsule surrenali sulP organismo. Ann. della soc. de scienz. natur di

Palermo, 1886.

MATHIEU. Action de 1'adrenaline sur le cceur. J. d. P. P., 6, p. 435, 1904.
MAURER, F. Die Schilddriise, Thymus und andere Schlundspaltenderivate

der Eidechse. Morph. Jahrb., 27, p. 119, 1899.

- Die Schlundspaltenderivate von Echidna. An. An., 16, Erganzungsb.,

1899.

- Die Entwicklung des Darmsystems. Hertwigs Handb. d. vergl. Ent-

wickl., 2, i, 1906.
MAUS, J. Glandula thyreoidea und Hyphophysis cerebri. Diss., Greifswald,

1895.
MAWIN, S. Uber die Glykosurie erzeugende \Virkung der Thyreoidea.

B. k. W., 1897.

MAY. Beitrage zur pathologischen Anatomic der Nebenniere. V. A., 108.
MAYER, A. Sur le mode d'action de la piqure diabetique, role des capsules

surrenales. C. r. S. B., p. 1124, 1906.

- Ablation des surrenales et diabete pancreatique. Ibid., 64, pp. 219-221,

1908.

MAYER, K. Zum thyreogenen Eiweiszzerfall. B. k. W., 1908.
MAYER, L. Urngekehrte Ecksche Fistel. M. m. W., 1907.

LITERATURE 537

MAYER, S. Beobachtungen und Reflexionen iiber den Ban und die Yerrich-
tungen des sympathischen Nervensystems. S. W. A., 66, Abt. 3, pp.
1-52, 1872.

— Das sympathische Nervensystem. Strickers Handb. d. Lchre v. d.

Geweb. ii, 1871.

— Die peripherische Nervenzelle und das sympathische Nervensystem.

Arch. Psych., vi, 1876.

— Zur Lehre von der Schilddriise und Thymirs bei den Amphibien. An

An., 3, 1888.

MAYO, CH. The Parathyroid Question. Ann. of Surg., July, 1909.
MAYOR, A. Uber intraarterielle und intravenose Injektionen. Th. M.,

1908.
MAZURKIEWICZ, W. Uber den Einflusz des Pankreassaftes auf den Blutdruck

und auf die Funktionen des Pankreas und der Submaxillardriise.

C. P., 20.

— Die festen Bestandteile des Bauchspeichels und die Theorie der Sekre-

tionstatigkeit des Pankreas. P. A., 121, 1907.

MECKEL, J. F. Abhandlungen aus der menschlichen und vergleichenden
Anatomic und Physiologic. I. Uber die Schilddriise, Nebennieren
und einige ihnen verwandte Organe, pp. 1-276; II. Fragmente aus
der Entwicklungsgeschichte des menschlichen Foetus, pp. 277-381.
Halle, 1806.

MEHRIXG, v. Uber experimentellen Diabetes. V. 5, C. M., 1886.

- Uber Diabetes mellitus. Z. k. M., 14 and 16, 1889.

MEHRIXG, V. and MINKOWSKI. Diabetes mellitus nach Pankreasexstirpation.

C. k. M., p. 393, 1889; A. P. P., 26, 1890.

MEIGE, H. L'infantilisme. Gaz. d. Hop., p. 207, fevrier, 1902.

- L'infantilisme chez la femme. Nouvelle Iconographie de la Salpetriere,

P. 2ig, IQO2.

- Le gigantisme. Arch. gen. med., 1902.

MlEGE and FEINDEL. Infantilisme myxoedemateux et maladie de Reckling-

hausen. Revue Neurologique, p. 837, 1903; Nouv. Icon, de la Salp.,

juillet-aout, 1903.

MEINERT. Tetanic in der Schwangerschaft. A. G., 55, 1898.
MEISEXHEIMER, J. Ergebnisse Uber einige Versuchsreihen von Exstirpation

u. Transplantation der Geschlechtsdriisen bei Schmetterlingen. Zool.

Anz., 32, 1908.

MEIXNER. Zur Frage des Hermaphroditismus verus. Z. H., 26, p. 318, 1905.
MELCHIORI. Nebennierentherapie bei Aorteninsuffizienz. Gazz. degli Osped..

No. _77, 1908.
MELLIX. Uber die Einwirkung einiger Gifte auf den kleinen Kreislauf.

S. A., 1904.
MELTZER, S. J. Geschichte der Schilddriisentherapie. New York med.

Monatsschr., 1895.

- Wandert Adrenalin in den Nerven ? A. P. P., 59, p. 458, 1908.

- Ideas and ideals in medicine. J. A. M. J., 50, p. 1577, 1908.

- Bemerkungen zur Wirkung von Adrenalin auf die Froschpupille.

D. m. W., 1909.

MELTZER and MELTZER-AUER. Ub. d. Einwirkung v. subkut. Einspritz. und
Eintrauf. in d. Bindehautsack von Adrenalin auf d. Pupille d.
Kaninchen. C. P., 17, 651.

- Ub. d. Einfluss des Nebennierenextraktes a. d. Pupille d. Frosches.

C. P., 18, p. 316, 1904.

- Studies on the " paradoxical pupil-dilatation caused by adrenalin."

A. J. P., xi, 1904.

The effect of subcutaneous injections and instillations of adrenalin upon
the pupils of rabbits. Ibid., p. 28.

- On the influence of subcutaneous injections of adrenalin upon the eyes

of cats after removal of the superior cervical ganglion. Ibid., p. 37.

- A discussion on the nature of the paradoxical pupil dilatation caused by

adrenalin. Ibid., p. 40.

The effect of suprarenal extract upon the pupils of frogs. Ibid.,
P- 449-

- Influence of suprarenal extract upon absorption and transudation.

Trans, of the Assoc. of Amer. Phys., 19, p. 208, 1904; Amer. Journ.
Med. Sc., p. 114, 1905.

LITERATURE

MELTZER and MELTZER-AUER. The action of ergot upon the stomach and

intestines. A. J. P., xvii, p. 143, IQOO.
MELTZER, S. J., and SALANT, W. Study on the toxicity of bile. The effect

of intravenous injections of bile upon blood-pressure. J. E. M., vii,

p. 280, 1905.
MENARD. De Porigine thyroidienne du rheumatisme chronique. These

Paris, 1908.
MEXDE, R. v. Ein Beitrag zur Anatomic der menschlichen Nebenniere.

Diss., Konigsberg, i, P. 1902.
MENDEL, E. Ein Fall yon Akromegalie. B. k. W., 1895.

- Obduktionsbefund eines Falles von Akromegalie. Ibid., 1900.

- Diskussionsbemerkung betr. operatives Eingreifen bei Akromegalie.

Ibid., p. 67, 1903.

MENDEL, K. Myxodem und Kretinismus. Diss., Berlin, 1896.
MENETRIER, P. Note sur les rapports des adenomes des caps. surr. avec la

nephrite interst. atroph. Soc. hop., 19 fevrier, 1904.

- A propos de la hypertension arterielle. Sem. med., 1904 and 1005.
MENGELBERG. Adrenalin und Atropin. Wochenschr. f. Ther. u. Hyg. d.

Auges. VI, 1902.
MERCKEL. Krankheiten der Nebennieren. Ziemsens Handb., viii, 2, pp.

281-314, 1875.
MERRIL. Adrenalindiurese und Hypophysisextraktvvirkung. J. A. M. A.,

NO. 22, 1908.

MESSEDAGLIA. Acromegalie et gigantisme visceral. Morgagni, mai, 1908.
METTENHEIMER, H. v. Zum Verhalten der Thymusdruse in Gesundheit und

Krankheit. Jahrb. f. Kinderheilk., 46, 1897 (1898).
METZGER, L. Zur Kenntn. d. wirks. Substanzen in den Nebennieren. Diss.,

"\Yiirzburg, 1897.

- Zur Frage von Nebennierendiabetes. M. \v. M., 1902.

METZNER, H. Beitrage zur Kenntnis der primaren Nierengeschwiilste.

Diss., Halle, 1888.
MEURON, PH. DE. Recherches sur le developpement du thymus et de la

thyroide. Recueil zoolog. Suisse, Bd. 4, 1886.
MEYER, A. Klinisches Bild des Infantismus und der Hypoplasie. M. w. M.,

1910.

Thymustumor und Myasthenie. M. m. W., 1908.
MEYER, E. Contrib. a 1'etude de la pathogenic de Turemie. A. d. P., p.

760, 1893.

- Faits relatifs a la secretion interne des reins. Ibid., p. 179, 1894.
MEYER, F. Beitrage zur Kenntnis der Diphtherievergiftung. A. P. P., 60,

1909.

- Beitrag zur Anatomic des Urogenitalsystems der Selachier und Amphi-

bien. Sitzungsber. d. Naturf.-Ges. Leipzig, Nos 2-4, pp. 38-44, 1875.
MEYER, H. Uber den Antagonismus der Gifte. W. k. W., No. 17, 1908.
MEYER, H., and GOTTLIEB. Experimentelle Pharmakologie. Wien, 1910.
MEYER, J. DE. Note a propos des experiences de M. Cohnheim. A. i. Ph.,

2, 131-
Note prel. sur la signific. physiol. de la seer, interne du pancreas.

Journ. med. de Bruxelles, 1904.

- Contr. a 1'etude de la seer. int. du pancreas et de 1'utilisation du glucose

dans rorganism. Ann. Soc. roy. de Bruxelles, 15, p. 155.

- Hyperglycemie et glycosurie provoque par injection d'un serum anti-

glycolytique. C. r. S. B., 63, p. 385, 1907.

- Glycolyse, hyperglycosurie, glycosurie et diabete. Ann. d. 1'Inst.

Pasteur, No. 10, 1908.

- Recherches sur le diabete pancreatique. Inhibition de la ?ecretion in-

terne du pancreas par un serum (36 mem). A. i. Ph., vii, p. 317, 1909.

- Contribution a 1'etude de la pathogenic du diabete pancreatique. Varia-

tions de la permeabilite pour le glycose. Relations entre le pancreas
et le rein. 4e mem. A. i. Ph., viii, p. 121, 1909.

- Nouvelle methode de circulation artificielle a travers le foie, appliquee

a 1'etude de la glycogenie hepatique. Ibid., p. 204, 1909.
MEYER, O. B. tiber einige Eigenschaften der Gefaszmuskulatur mit
besonderer Beriicksichtigung der Adrenalinwirkung. Z. B., 48, pp.
352-397, 1906.

- Versuche mit Kokainadrenalin und Andolin an iiberlebenden Blut-

gefaszen. Z. B., Bd. 50, p. 93, 1907.

LITERATURE 539

MEYER, R. Akzessorische Nebenniercn im Ligamentum latum. Verh. d.
Gesellsch. f. Gyniikol. u. Geburtsh. zu Berlin, 38, pp. 315 and 542,
1898.

- Die subserosen Epithelknotchen an Tuben, Ligamentum latum, Hoden

und Nebenhoden (sogenannte Keimepithel- oder Nebennieren-

knotchen). V. A., 171, 1903.
MEYER-THRAP. Ein Fall von M. Basedowii mit Blut und Milch von thy-

reoidektomierten Ziegen behandelt. Norsk Magazin f. Lagernd.,
.No. 7, 1905.
MEYERS, M. K. Die Wirkilng von intravenosen Injektionen von Hypo-

physenextrakt und Brenzkatechin, sowie von einmaligen Adrenalin-

injektionen auf die Aorta von Kaninchen. C. a. P., 20, 1909.
MEZNICESCU. Les modific. du sang apres 1'estirpation clu corps thyroide.

A. m. e., 1902.
MICHAEL, J. Zum Vorkommen der akzessorischen Nebennieren. A. k. Ch.,

43, 1888.
MlCHAELIS and ROXA. Untersuchungen uber den Blutzucker. B. Z., 14,

1908.

MICHALSKI. Die Therapie des Morbus Basedowii. Bruns Beitr., 49, 1906.
MlCHELSON. Uber die Wertlosigkeit des Zusatzes von Nebennieren-

praparaten bei der Lumbalanasthesie. M. m. W., 1907.
MIESCHER, F. Histochem. u. physiolog. Arbeiten. Leipzig, 1897.
MlESOWICZ, E. Untersuchungen iiber die Veranderungen in den inneren

Organen des Kaninchens nach intravenoser Injektion von Adrenalin.

Bull, intern. Acad. d. Sc. Cracovie, pp. 257-265, 1906.

- Uber experimentelle Herzhypertrophie. W. k. W., 1909.
MlESOWICZ, E., and MACIAG, A. Beobachtungen iiber das Verhalten der

mydriatischen Substanzen im menschlichen Serum. Gazeta lekarska,

No. 49, 1908; Fol. serol., ii, Januar, 1909.
MlGXOX. Neue Verwendungsart des Adrenalins in der Rhinologie. A. int.

Laryng., 1903.
MlHALCOVICS, V. v. Untersuchungen uber die Entwicklung des Harn- und

Geschlechtsapparates der Amnioten. I. M., 2, 1885.

- Beitrage zur Anatomic und Histologie des Hodens. Ber. d. sachs.

Ges. d. Wiss., 1873.

- Entwicklung des Gehirnanhangs. C. m. W., 1874.

- W'irbelsaule und Hirnanhang. A. m. A., u, 1874.

MIKA. Infantilisme (Type Lorain). Revue Neurolog., p. 250, 1902.

MIKLASSEWSKI, W. Neuere Anschauungen iiber das Wesen der Addi-
sonschen Krankheit nebst einem selbst beobachteten Falle. Kronika
Lekarska Warschau, Nos. 17-19, 1899; V.-H., ii, p. 57, 1899.

MIKULICZ. Uber die Resektion des Kropfes. C. Ch., 1885.

- Uber Thymusfiitterung bei Kropf und Basedow. B. k. W., 1895.
MILIAN, M. G. Le prurigo dans la maladie d'Addison. Gaz. hebdom.,

No. 45, 1897.

MILLER, J. L. The action of the extract of the suprarenal gland and the
method and indications for its use. J. A. M. A., 48, pp. 1661-1664,
May 18, 1907.

- Experimental arterial degeneration. Ibid., p. 593, April, 1907.

Uber Lebererkrankungen nach intravenosen Adrenalininjektionen beim

Kanninchen. M. K., 1908.
MILLER, J. L., and BENXET. Dangers in the use of adrenal preparations.

Brit. Med. Journ., 1906.

MILLS. Adrenalin in hsematemesis. Brit. Med. Journ., March 28, 1903.
MIXELLI, SPARTAEO. Sopra un casp di angiosarcoma primitive di una

capsula surrenale con metastasi. Gaz. med. ital., 38-39, p. 372, 1904.
MIXERVIXI, R. Des capsules surrenales. J. A. P., 40, pp. 449-492. 634-667,

1904.
MINERBI and A.LESSANDRI. Akromegalie und Adams-Stokes' Symptom.

M. m. W., 1908.
MINKEL. Beitrag zur Kenntnis der Addisonschen Krankheit. Diss., Bonn,

1893-
MINKIEWITSCH. Tetania parathyreopriva und Hyperparathyreosis. Diss.,

Basel, 1908.
MlNKOWSKlj O. Untersuchungen iiber den Diabetes mellitis nach Pankreas-

exstirpation. A. P. P., 31, 1893.

54° LITERATURE

MlNKOWSKI, O. Storungen des Pankreas als Krankheitsursache. L. O.,
i, 1896.

- Diabetes nach Pankreasaffektion. B. k. W., 1899.

- Bemerkungen liber den Pankreasdiabetes zur Abwehr gegen Eduard

Pfliiger. A. P. P., 53, p. 331, September, 1905.

- Die Totalexstirpation des Duodenums. A. P. P., 58, p. 271, 1908.

- Zur Kenntnis der Funktion d. Pankreas beim Zuckerverbrauch. Ibid.,

Suppl., 1908.

MINNICH, W. Das Kropfherz. Leipzig and Wien, 1904.
MlNOT, CH. S. Morphology of the suprarenal capsules. Proc. of the Amer.

Assoc. for the Advance, of Science, xxxiv, 1885.

- Lehrbuch der Entwicklungsgeschichte des Menschen. Deutsch von

S. Kastner, 1904.

MlRONESCU, TH. Beitrage zur Wirkung des Adrenalins und Euphthalmins
auf den Blutdruck beim Kaninchen. Romania med., 1905 and 1907;
Th. M., 20, p. 39, 1906.

- Sur qq. lesions des glandes parathyroides chez les pellagreux. C. r.

S. B., 64, p. 515.

MITSAKURI, R. B. On the development of the suprarenal bodies in mam-
malia. Quart. J. Micr. Sc., 22, pp. 17-29, 1882.

MITTENZWEIG. Traumatische Verblutung aus den Gefaszen der rechten
Nebenniere. Zeitschr. Medicinalb., p. 616, 1893.

MIWA, SA., and STOLTZNER, W. 1st das Jod ein notwendiger Bestandteil
der normalen Schilddriise ? Jahrb. Kinderh., 45, 1897.

MLODZEJEWSKI, W. K. Zwei Falle von Morbus Addisonii (russisch.)
M. Rundsch., 1895.

MODENA. L'Acromegalia. Riv. sperim. di Fren., xxix, 1895.

— Un cas d'acromegalie avec Myxoedeme suivi d'autopsie. Annuario del

Manicomio provinciale di Ancona, 1903.

MODRAKOWSKY, G. Zur Innervation des Pankreas. Wirkung des Atropins
auf die Bauchspeicheldriise. P. A., 114, 1906.

- Uber das gegenseitige Verhaltnis der Wirkung von Atropin und Physo-

stigmin auf das Pankreas. P. A., 118, p. 52, 1907.

- TJber die physiologische Wirkung des Cholins. Ibid., 124, pp. 601-632,

1908.
MODUGNO, G. Sui nidi cellulari del simpatico della Rana. Contribute

alia conoscenza dei caratteri citologigi delle celluli cromaffini. Boll.

Soc. Natur. Napoli, Bd. 20, p. 42.
MODIUS, P. J. Schilddriisentheorie. Schmidts Jahrbiicher, 210, p. 237,

1886.

- liber das Wesen der Basedowschen Krankheit. N. Z., p. 8, 1887.

- Uber Morbus Basedowii. D. Z. N., i, 400, 1891.

- Die Basedowsche Krankheit. Nothnagels Handb., 22, 1896.

- Uber das Antithyreoidin. M. m. W., 1903.

- Uber die Wirkungen der Kastration. Leipzig, 1903; and Halle, 1906.
M6LLER, J. Om Adrenalinet Nordisk Tijdskrift f. Terapi Copenh. Ref.

V.-H., ii, 1903.
MoLLER, S. Kritisch-experimentelle Beitrage zur Wirkung des Neben-

nierenextraktes (Adrenalin). Th. M., 19, pp. 547, 622, 1905; 20,

pp. 25, 85; Diss., Wiirzburg, 1906.
MONCKEBERG. Die Tumoren der Glandula carotica. Zieglers Beitr., 38,

1905.

- Uber die reine Mediaverkalkung der Extremitatenarterien und ihr

Verhalten zur Arteriosklerose. V. A., 171, p. 141, Jg., 1903.
MOERS. Uber den feineren Bau der Nebenniere. V. A., 29, pp. 336-358,

1864.
MOFFIT, H. C. Kidney tumours of adrenalin origin. Ref. V.-H., i, p. 731,

1904.
MOHR. Bemerkungen zur Behandlung der Hydrocele. Adrenalinein-

spritzungen in den Sack. M. m. W., August, 1908.
MOHR, L. Uber die Herkunft des Zuckers im Pankreasdiabetes von

Hunden. Z. e. P., ii, 1906.

- Uber die Zuckerbildung aus Eiweisz. Ibid.

— Uber die Beziehungen der Fette und Fettsauren zur Zuckerbildung.

Ibid.

- liber die Ausscheidung von Aminosauren im diabetischen Harn. Ibid.

— Untersuchungen iiber den Diabetes mellitus. Z. e. P., iv, p. 910, 1907.

LITERATURE 541

MOHR, L., and FREUND, R. Exper. Beitr. zur Pathogenese der Eklampsie.

B. k. W., 1908.
HOLLOW, TV. Uber Yorkommen von Mundschleimhautpigmentierung.

M. K., 1909.
MOLNARj V. Uber die interne Anwendung des Adrenalin mit besonderer

Riicksicht auf die scarlatinose hamorrhagische Nephritis. W. k. R.,

1904; Orv. Hetilap., 1904.

MOLON, C. Sulla glicosuria adrenalinica. Gazz. d. Osped., 1908.
MONERY, A. Sur un nouveau cas de concretion osseuses dans la glande

thyroide. J. d. pharm. et d. Ch. (6), IQ, p. 203.

- Recherches sur la fonction jodee de la glande thyroide. Ibid. (6), 19,

p. 288.

- Etudes nquvelles sur le metabolisme de 1'iode dans 1'economie et sur

la fonction thyroidienne. J. d. P. P., Bd. vii, p. 611.
MONTUORI, A. Sulla termo secretina. Gazz. med. int. di med., No. 13,

, 1905-

- Sull' importanza del fegato nel diabcte pancreatico. Gazz. d. Osped.,

1895-
MONTUORO. Sulle cellule midollari dell' ovaje del coniglio. Arch. d.

Anat. e. Embr., 1903.
MOON, R. O. Acromegaly with illustrative cases. Lancet, p. 27, January 2,

1909.
MOORE, B. On the chemical nature of a physiologically active substance

occurring in the suprarenal gland. J. o. P., 17, 1895.

- On the chromogen and on the active physiological substance of the

suprarenal gland. Ibid., 21, pp. 382-389, 1897.

MOORE, EDIE, and ABRAM. On the treatment of diabetes mellitus by acid
extract of duodenal mucous membrane. J. B. Ch., i, p. 28t 1906.

- Further observations on the treatment of diabetes mellitus by acid

extract of duodenal mucous membrane. Ibid., p. 446, 1906.
MOORE, B., and PURINTON, C. On cardiac thrombosis following complete
removal of the suprarenal glands. A. J. P., 4, pp. 51 and 57, 1900.

- On the effects of complete removal of the suprarenal glands. A. J. P.,

5, p. 182, 1901.

- On the absence of the active principle and chromogen of the suprarenal

gland in the human embryo and in the child at birth. Ibid., 1900.

- Uber den Einfluss minimaler Mengen Nebennierenextrakts auf den

Blutdruck. P. A., Si, 1900.

MOORE, B., and VINCENT, S. The comparative chemistry of the suprarenal
gland. P. R. S., 61, pp. 280-283, 1897.

- Further observations upon the suprarenal capsules with remarks upon

the non-existence of suprarenal medulla in Teleostean fishes. Ibid.,

62, pp. 252-256, 1898.

MOORE, F. C. Cholesterin. Medical Chronicle, December, igo7.
MORACZEWSKI. Stoffwechsel bei Akromegalie, &c. Z. k. M., 43, p. 336,

igoi.

MORANO. Studio sulle capsule s'urrenali. Napoli, 1870.
MORANDI. Ricer. sulP istologia norm, e patol. della ipofisi. Arch. sc. med.,

28, 1904.
MORAT, J. P., and DOYON, M. Traite de physiologic. I. Secretion interne.

Paris, 1904.

MORAT and DUFOURT. Les nerfs glyco-secreteurs. A. d. P., i8g4.
MOREAU, C. Contr. a 1'etude de la thyroi'dectomie. Acad. med. Belg., 1890.

- De 1'opotherapie ovarienne dans la maladie de Basedow. These Paris,

1899.

MOREL, L. E. L'adrenaline. Progres med.,, Nos. 31 and 32, pp. 65 and 81,
1903.

- Les parathyro'ides dans 1'osteogenese. C. r. S. B., 67, p. 780, igog.
MORESCO. L'opoterapia soprarenale. Gazz. degli osped., No. 98, igo3.
MORI, A. Sull' uso terapeutico del succo renale per iniezioni. Clin. Med.

Ital., i8gS.

MORISON, B. G. Suprarenal haemorrhage in an infant. Lancet, 1908.
MORKOTUN. Uber einen phosphorhaltigen Eiweiszkorper in der Schilddrtise

im Zusammenhange mit der Frage tiber die Funktion derselben.

Petersb. m. W., 1895.

MORLAT, A. Infantilisme et insuffisance surrenale. These de Paris, 74 pp.>
Ref. J. d. P. P., 6, p. 166, 1904.

542 LITERATURE

MORRIS, H. Primary tumours of the suprarenal .gland and their removal
by operation. Brit. Med. Journ., November, 1899.

MOSCHINI, A. Sulle alterazioni delle capsule surrenali nella morte da
scqttatura. Gaz. med. Lombard., 1905.

- Studio sulla capsula soprarenale. Atti Fondaz. Cagnola, Milano, vol. 21,

176 pp., 7 tav.
MOSKOWICZ. Zur Technik der Operationen an der Hypophyse. W. k. W.,

1907.
MOSSE, M. Beitrag zur Lehre von der Autointoxikation beim Morbus

Addisonii. F. M., 15, p. 21, 1897.
Uber Leberzellenveranderungen nephrektomierter und hungernder Tiere,

ein Beitrag zur Lehre von der Azidose. Z. k. M., 60, p. 373, 1908.

- Zwei Falle von Morbus Basedowii. Reichs-Medizinal-Anz., No. 18,

1905.

MOSSE. Etat actuel de 1'opotherapie. VI. C. m. frangaise, Montpellier,
1898.

- Note sur deux cas d'acromegalie. C. r. S. B., p. 686, 1895.

MOSSE, P., and OULIE. Influence de 1'ovariotomie double et de 1'ingestion

d'ovaires sur quelques elements de la secretion urinaire chez la

chienne. C. r. S. B., 51, p. 447, 1899.
MOSSELMAN and RUBAY. Cryptorchidie et Spermatogenese chez le cheval.

Ann. de med. veter. Bruxelles, 1902.

Mosso. Le leggi della fatica. Atti della R. Acad. dei Lincei, 1888.
MOTT and HALLIBURTON. Physiological action of choline. J. o. P., 24, ix,

1899.
The suprarenal capsules in cases of nervous and other diseases. J. o. P.,

34, iii, 1906.
MOURET, J. Contribution a 1'etude des cellules glandulaires (Pancreas).

J. A. P., 1895-

- Lesion du pancreas produites par 1'injection d'huile dans le canal de

Wirsung. C. r. S. B., pp. 132 and 23, 1895.

- Sclerose de greffes du pancreas chez le chien. Ibid., p. 221.
MOUSSET. Note sur 1'adrenaline. C. r. S. B., 54, 36, p. 1471, 1903.

- Les principes actifs des capsules surrenales, leur emploi en therapeu-

tique. Paris, 1903.

MOUSSU. Recherches sur les fonctions thyroidienne et parathyroidienne.
Paris, 1887.

- Effets de la thyroidectomie chez nos animaux domestiques. C. r. S. B.,

p. 271, 1892.

- Sur la fonction thyroidienne. Ibid., p. 972, 1892; pp. 280 and 394, 1893.

- Fonction parathyroidienne. Ibid., 1897-98.

- De la medication parathyr. C. r. S. B., 51, p. 242, 1899.

- Influence de 1'alimentation thyroidienne sur la croissance reguliere.

Ibid., p. 241.

MOUSSU and LE PLAY. Recherches experimentales relatives a 1'exstirpation
et a la destruction des capsules surrenales. Ibid., 66, p. 36, 1909.

- Essais de greffes de capsules surrenales sur la rate. Ibid., p. 83,

16 Janvier, 1909.

MOXTER. Beitr. zur pathol. Anat. der Akromegalie. Char. Ann., 24, 1894.

MOYER, FLEISHER, S., and LOEB, L. The influence of the addition of
adrenalin to solutions of sodium chloride upon the production of
urine ascites and intestinal fluid. J. E. M., n, pp. 470-479 and
480-488.

MUDGE, G. P. On intravascular coagulation in albinos and pigmental
animals and on the behaviour of nucleo-proteids of testes in the pro-
duction of intravascular coagulation. P. R. S., Ser. B., 79, p. 103,
1907.

MUHLMANN, M. Zur Histologie der Nebenniere. V. A., 146, 1896.

- Zur Physiologic der Nebenniere. D. m. W., 1896.

MULLER, B. Uber die Verwendung der Nebennierenpraparate. W. klin.-
ther. W., 1904.

- Uber eine kiinstliche Blutleere. M. m. W., 1904.

— Zur Anwendung des Suprarenins und Adrenalins bei Blutungen.

W. k. R., 1904.

MULLER, JOHANNES. Lehrbuch der Physiologic. I, Koblenz, 1844.
MULLER, F. Ein Beitrag zur Kenntnis der Gefaszmuskulatur. A. A.,
Suppl., p. 41 1, 1906.

LITERATURE 543

MtiLLER, H. F. tiber einen bisher nicht beachteten Formbestandteil des

Blutes. C. a. P., /, p. 929, 1896.
MULLER, L. R. Beitrage zur Histologie der normalen und der erkrankten

Schilddriise. Zieglers Beitr., 19, 1896.
MULLER, \V. Beitr. z. Lehre von der Addisonschen Krankheit. Diss.,

Gottingen, 1900.

- Das Verhalten der Langerhansschen Inseln beim Diabetes mellitus.

Diss., Berlin, 1905.

- Uber die Beeinflussung der Menstruation durch zerebrale Herder-

krankungen. N. C., p. 790, 1905.
MULLER. Uber Ent\vicklung und Bau der Hypophysis cerebri und des Proc.

infundibuli. Jena. Zeitschr. f. Nat., 6, 1871.
MUNZER, A. Die Hypophyse. Sammelref. B. k. W., 1910.
MuLON, P. Note sur la constitution du corps cellulaire des cellules dites

spongieuses des capsules surrenales chez le cobaye et le chien.

C. r. S. B., 1310, 1902.

— Excretion des capsules surrenales du cobaye dans les vaissaux sanguins.

Ibid., 54, p. 1540, 1902.

— Reaction de Vulpian au niveau des corps surrenaux des plagiostomes.
^ Ibid., 55, p. 1156, 1903. r

— Sur une reaction de 1'adrenaline in vitro son application a Tetude des

surrenales. Ibid., 56, p. 115, 1904.

— Specificite de la reaction chromaffine glandes adrenalogenes. Ibid.,
^ 56, p. 113, 1904.^

— Graisse internucleaire dans les surrenales des mammiferes. C. r. A.,

129, 1904.

— Les glandes hypertensives ou organes chromaffines. A. gen. de med.,

No. 52, 1904.

— Sur la couche germinative de la corticale des surrenales chez le cobaye.

C. r. S. B., 57, p. 592, 1905.

— Evolution de la corticale surrenale du cobaye avec 1'age de I'animal.

Ibid., 57, p. 337, 1905.

— Sur la reaction osmique de la medullaire des surrenales. Ibid., p. 757.

- Sur le pigment des capsules surrenales (cobaye). Bibliogr. Anat., xiv,

pp. 177-182, 1905; ibid., pp. 223-234, 1905.

- Parallele entre le corps jaune et la cortico-surrenale chez le cobaye.

C. r. S. B., 6i3 p. 292, 1906.

- Sur certaines cellules des corps jaunes chez le cobaye. Ibid., p. 615,

1906.

- Importance fonctionelle du pigment dans la surrenale. C. r. S. B., 62,

p. 905, 1907.

- A propos de la fonction des corps jaunes chez le cobaye. Ibid., 64,

p. 265, 1908.

— Cristaux de pigment dans les surrenales. Bibliogr. Anat., xvi, F. 4,

1907.
MUNK, F. Kommen doppeltbrechende Substanzen (Myelin) bei der fettigen

Degeneration vor ? Diss., Berlin, 1908.
MUNK, H. Untersuchungen Uber die Schilddriise. Ber. d. preusz. Akad.,

40, 1887.

- Weitere Untersuchungen liber die Schilddriise. Ibid., 1888.

- Zur Lehre von der Schilddriise. V. A., 150, 1897; and Ibid., 154, 1898.
MUNSCH. L'injection intraveineuse d'adrenaline comme moyen de traitement

de la mort apparente. Semaine med., 18 mars, 1903.
MUREL. Case of Addison's disease treated unsuccessfully with extract of

suprarenal capsules. Lancet, 1896.

MURET. De 1'organotherapie. Rev. med. Suisse Rom., 12, 1896.
MURRAY, C. R. Myxcrdema, its treatment. Brit. Med. Journ., 1883.

- Remarks on the treatment of myxoedema with thyroid juice. Ibid., 1892.
— • The signs of early disease of the thyroid gland. Ibid., November 25,

1909.
MYERS, W. A preliminary note on the antidotal properties of normal tissue

emulsions with respect to cobra poison. Path. Trans., 49, p. 368, 1898.
MYRTLE, A. S. Adrenalin in neurotic heart. Brit. Med. Journ., April, 1904.

NABARRO, D. N. The proteids of suprarenal capsules. J. o. P., 17, 1895.
NAGEL. tiber die Struktur der Nebennieren. A. A. P., 366 ff., 1836.

544 LITERATURE

NAGEL, \V. Die weiblichen Geschlechtsorgane. Hdb. d. Anatomic, vii,

1896.

NAGY, L. V. tiber die chromaffinen Organe. Orvosi Hetilap, p. 452, 1905.
NAKAHARA. tiber Veranderungen des Nebennierenmarks nach Nephro- und

Nephrektomien. V. A., 196, pp. 68-73, iQog.
NAPIER. Note on administration of animal extracts during the menopause.

Brit. Gyn. Journ., 46.

NAPP. tiber den Fettgehalt der Nebenniere. V. A., 182, p. 314, 1895.
NARBOUTE. L'hypophyse cerebrale et sa signification pour 1'organisme. St.

Petersbourg, 1903.

NAUNYN. Diabetes mellitus. Nothnagels Hdb., 7, 1898, 2 Aufl., 1906.
NAZZARI. Contributo allo studio anatomo-patologico delle cisti dell' ipbfisi

cerebrale e dell' infantilismo. II Policlinico, 1906.
NEBOUX. Contr. a 1'etude des he'morrhagies surren. d. les infect, et intox.

These Paris, 1905.

NEFEDIEFF. Serum nephrotoxique. Ann. de I'inst. Pasteur, p. 17, 1901.
NELSON, L. tiber das Thymamin : ein Protamin aus der Thymusdriise.

A. P. P., 59-
NERKING, J. Narkose und Lezithin. M. m. \Y., 1908.

— Beitrage zur Kenntnis des Knochenmarkes. B. Z., 10, p. 167, 1908.

— Zur Verteilung des Lezithins im tierischen Organismus. Ibid., p. 193,

1908.
NESS, R., and BARCLAY. Case of probable Addison's disease associated with

leucoderma and tuberculosis. Glasgow Journ., October, 1900.
NETTER, A. Le chlorure de calcium dans la tetanie, les spasmes de la glotte,

la laryngite striduleuse, les convulsions. Revue neur. d. mal.

d'enfants, p. 187, 1907.
NETTER, E. Die Behandlung der Rhachitis mit Nebennierensubstanz. J. K.,

p. 600, 1900; ibid., 52, p. 601.
NEU, M. Experimentelles zur Anwendung des Suprarenins in der Geburt-

shilfe. Gynak. Rundsch., p. 507, 1907.

- Verwendbarkeit des Suprarenins in der geburtshilflichen Therapie. Th.

G., 1907.

- Adrenalin bei Osteomalakie. C. G., 31, 38, 1907.

- Untersuchungen liber die Bedeutung des Suprarenins fur die Geburt-

shilfe. A. G., 85, pp. 617-711, 1908.
NEUBAUER, E. 1st der Unterschied im Verhalten der Glykogenbildung aus

Lavulose bzw. Dextrose beim Diabetes fur diesen charakteristisch ?

A. P. P., 61, 1909.
NEUBAUER, O., and LANGSTEIX, L. Uber die chemische und biologische

Bedeutung der Osmiumschwarzung. V. d. N. A., Karlsbad, 1902.
NEUBERG. Zur chemischen Kenntnis der Melanome. V. A., 192, p. 514,

1908.

- Enzymatische Umwandlung von Adrenalin. B. Z., 8, p. 383, 1908.
NEUBERT, W. Uber Glykogenbefunde in der Hypophyse und im Zentral-

nervensystem. Zieglers Beitr., 45, igog.
NEUGEBAUER, F. Eine Gefahr des Adrenalins. C. Ch., p. 1417, 1903.

- Hermaphrodismus beim Menschen. Leipzig, 1908.

NEUHAUSER. Liber die Fortentwicklung jugendlicher in die Niere im-

plantierer Nebennieren. D. m. W., igog.
NEUJEAN, V. Contr. a 1'etude exp. de 1'adrenaline. Arch. int. de pharma-

codyn., 13, p. 45, igo4.
NEUMANN, H. tiber den mongoloiden Typus der Idiqtie. B. k. W., i8gg.

- Heilung eines Falles von Addisonscher Krankheit. D. m. W., 1894.

- tiber das Zusammentreffen von Graviditat u. Diabetes mellitus. Z. k.

M., 69, 1909.
NEUMANN, M. Zur Kenntnis der Zirbeldriisengeschwulste. Monatschr. f.

Psych., 9, 1901.
NEUMANN, P. Ein neuer Fall von Teratom der Zirbeldriise. Di§s.,

Konigsb., 1900.
NEUMANN and VASS. Uber den Einfluss der Ovariumpraparate auf den

Stoffwechsel. M. G. G., 15.
NEURATH, R. Die vorzeitige Geschlechtsentwicklung. Erg. d. inn. Med. u.

Kinderheilk., 4, ii, 46, igog.

- Die vorzeitige Geschlechtsentwicklung (Menstruatio praecox). W. m.

W., 1909.

LITERATURE 545

NEUSSER. Die Pellagra in Osterreich und Rumiinien. Wien, 1887.

- Die Erkrankungen cler Nebennieren. Nothnagels Handb., 18, 1899.
NEUSSER, v., and WIESEL. Die Erkrankungen der Nebennieren. \\"ien,

IQIO.
NICCOLLINI, C. Sulla citotossica renali. Boll, dclla R. Accad. di Geneva,

xvii, No. 6.
NICHOLSON, B. ST. Abnormal position of suprarenal gland. Brit. Med.

Journ., 1894.
NlCOLAIDE and MELLNISSOS. Untersuchungen liber einige intra- und cxtranu-

cleare Gebilde im Pankreas der Saugetiere auf ihre Beziehung zu der

Sekretion. A. A. P., i8go.
NICOLAS, A. Contribution a 1'etude des cellules glandulaires. Les elements

des canicules du rein primitif chez Ics mammiferes. I. M., viii,

1891.

- Le protoplasma des elements des glandes albumineuses. A. d. P., 1892.

- Glande et glandules thyroides (parathyroides) chez les cheiropteres.

Bull. d. seances de la Soc. d. Scienc. de Nancy, Mai, 1803.

- Reclierches sur vesicules a, epithelium cilie annexees aux derives

branchiaux. Bibl. anat. Nancy, 1896.

- Nouvelles rect. sur les glandules parathyroides. Ibid., 1897.
NICOLAS, J., and BONNAMOUR, S. Karyokinese dans la surrenale du lapin

rabique. C. r. S. B., pp. 213-214, 1905.

NICOLAS and CADE. Un cas de Maladie d'Addison traite par extrait sur-
renale. Province med., 1899.

NICOLAS, J.j and DUMOULIN, F. Influence de la Splenectomie sur la secre-
tion urinaire chez le chicn. G. d. P. P., 5, p. 589, 1903.

NlEDEN. Fall von Tumor (Hydrops cisticus) glandular pinealis. C. f.
Nervenh., ii, 1899.

NlEMANN, A. Die Beeinflussung der Darmresorption durch den Abflusz des
Pankreassaftes nebst anatomischen Untersuchungen tiber die Histo-
logie des Pankreas nach Unterbindung seiner Giinge beim Hunde.
7.. e. P., v, p. 466, 1909.

NlKOLAjEW, W. Uber den Einflusz cler Jodeiweiszverbindungen auf die
Pulsfrequenz. A. P. P., 53, p. 447, 1905.

NlOSI, F. Die Mesenterialzysten embryonalen Ursprungs nebst einigen
Bemerkungen zur Entwicklungsgeschichte der Nebennieren-Rinden-
substanz, sowie zur Frage des Chorion-epithefioms. V. A., 190, p. 217,
1907.

NlSHl, N. Uber Glykogenbildung in der Leberpankreas diabetischer Schild-
kroten. A. P. P., 62, p. 170, 1910.

- Uber den Mechanismus der Blutzuckerregulation. Ibid., 61, p. 186, 1909.
NISKOUBINA, N. Sur la structure du corps jaune pendant et apres la gesta-
tion. C. r. S. B., 65, p. 767, 1908.

— Recherches experimentales sur la fonction du corps jaune pendant la

gestation. Ibid., p. 769.
NOBECOURT, P., and TIXIER, LEON. La pression arterielle dans la scarlatine

de 1'enfant. J. d. P. P., p. 484, 1908.
NOELLNER, F. Die Anatomic des Splanchnicus und der Nierennerven beim

Hunde. Eckhards Beitr. z. A. u. P., iv, 1869.
NoiR, J. L'opotherapie capsulaire, nouvel hemostatique ; 1'adrenaline.

Progr. med., 1902.
NOORDEN, C. v. Handb. d. Pathologic d. Stoffwechsels. 2 Aufl., Berlin,

1907.
Die Fettsucht, II. Aufl., Wien, 1910.

- Die Zuckerkrankheit, 4. Aufl., 1907; and 5 Aufl., 1910.

- Die Bleichsucht. Nothnagels Handbuch. VIII, 1901.

NOTHAFFT. Ein Fall von artefiziellem akuten thyreogenen Morbus Base-
dowii, zugleich ein Beitrag zur Fragc der Schilddriisenfunktion und
zur Frage der Atiologie des Morbus Basedowii. C. i. M., No. 15, 1898.

NOTHNAGEL. Experim. Unters. Uber die Addisonsche Krankhcit. Z. k. M.,
i, p. 77, 1879.

— Zur Pathologic des Morbus Addison. Ibid., 9, p. 195, 1885.

- Geschwulst der Vierhugel. W. m. Blatt., 1888.

— Morbus Addisonii. Allg. W. med. Zeit., 1890.

NOTKIN. Beitrag zur Schilddriisenphysiologie. \\". m. W., 1896; and V. A.,
144, Suppl.

35

546 LITERATURE

ij I. Amygdala pharingee et hypophyse. Soc. med. chir. di Bologna,

15 fevrier, iQoS.

NoviKOFF, M. Uber die Wirkung des Schilddriisenextraktes und einiger
anderer Organstoffe auf Ciliaten. Arch. f. Protistenkunde, u, p. 309.
NURNBERG, A. Zur Kenntnis des Jodothyrins: H. B., 10, p. 125, 1907.

- Zur Kenntnis des Jodthyreoglobulins. Ibid., 16, p. 87, 1909.
NUSSBAUM, M. Zur Differenzierung des Geschlechts im Tierreich. (Von

der Bedeutung der Hodenzwischensubstanz, p. 85.) A. m. A., 18, 1880.

- Untersuchung des Hodensekretes auf die Entwicklung der Brunstorgane

der Landfrosche. Sitzber. d. niederrh. Ges. f. Nat. u. Heilk., 23
Oktober, 1904; and 22 Mai, 1906.

- Uber den Einflusz der Jahreszeit, des Alters und der Ernahrung auf die

Form der Hoden und Hodenzellen der Batrachier. A. m. A., 68, p. i,
1906.

- Uber die Beziehungen der Keimdriisen zu den sekundaren Geschlechts-

charakteren. P. A., 129, p. no, 1909.

Innere Sekretion und Nerveneinflusz. Merkel-Bonnet, Ergebn., 15,
1905.

OBERNDORFER, P. Keimversprengung von Nebennieren in die Leber.

C. a. P., 11, 1900.
OBERNDORFER, S. Lymphcysten der Nebenniere. Zieglers Beitr. , 29, p. 516,

1901.
OBERNDORFER. Uber Untersuchungen an Nebennieren. V. 13. d. p. G.,

p. 273, 1908.
OBERNDORFFER, E. Uber den Stoffwechsel bei Akromegalie. Z. k. M., 65,

1908.
OBREGIA, PARHON and FLORIAN. Note sur un cas de myxoedeme infantile

avec qq. considerations sur la pathogenic de myxoedeme. J. de

Neurol., 1905.

OCANA, GOMEZ. Siehe Gomez Ocana.
OCEANU, P., and BABES, A. Les effets physiologiques 1'ovariotomie chez la

chevre. C. r. A., 140, p. 173, 16 Janvier.
OESTREICH, R. Operative Heilung eines Falles v. Morbus Addisonii.

Z. k. M., 31, 1896.
OESTREICH and SLAVYK. Riesenwuchs u. Zirbeldriisengeschwulst. V. A.,

157, p. 475, 1899.
OGLE, C. Sarcoma of the pineal body. Transact, of the Path. Soc. of

Lond., 50, 1899.

OHLEMANN, M. Zur Basedowschen Krankheit. M. m. W., 1908.
OHLMACHER, J. C. The relation of the islands of Langerhans to disease

of the liver. Transact. Chicago Path. Soc., 83, 1904. Ref. B. C., ii.
OHNACKER, H. Uber Glykosurie bei Erkrankungen des Zentralnerven-

systems. Diss., Kiel, 1905.
OIDTMANN, D. Die anorganischen Bestandteile der Leber, Milz und der

meisten anderen tierischen Driisen. Preisschr. Wiirzburg, 1858.
OKERBLOM, J. Zur Frage iiber das krystallinische Fibrin. Z. p. Ch., 28,

p. 60, 1899. Diss., Petersburg, 1901.
OKOUNEFF, B. Quelques remarques concernant certaines actions indirectes

de 1'adrenaline et sur 1'idiosyncrasie pour 1'adrenaline. Arch. int.

Lar., xxii, i, p. 80, 1906.
OLIVER, G. The action of animal extracts on the peripheral vessels. J. o. P.,

21, 1897.
OLIVER, G., and SCHAEFER. The physiological effects of extracts of the

suprarenal capsules. J. o. P, 18, p. 231, 1895; ibid., 16 and 17;

Proc. Phys. Soc., 1894.
— On the physiological action of extracts of pituitary body and certain

other glandular organs. J. o. P., 18, p. 277, 1895; Proc. Phys. Soc.,

March 10, 1894.
OMELCZENKO, TH. Uber zweierlei Spermatozoen bei Menschen und Tieren.

Russky Wratsch, No. 48, 1908.
OXODY, A. D. Entwicklung des sympathischen Nervensystems. A. m. A.,

26, 1886.
OPIE, E. L. Histology of the islands of Langerhans of the pancreas. Johns

Hopkins Hosp. Bull., 2, No. 119, 1900.
_ On the relation of chronic interstitial pancreatitis to the islands of

Langerhans and to diabetes mellitus. J. E. M., 5, p. 397, 1901.

LITERATURE 547

OPIE, E. L. The relation of diabetes mellitus to lesions of the pancreas.

Hyaline degenerations of the islands of Langerhans. Ibid., p. 527.
OPPEL, A. Lehrbuch der vergleich. mikr. Anat. der Wirbeltiere. Jena.

— Verdauungsapparat. Merkel-Bonnets Ergeb., Q, 1899.
OPPENHEIM. Lehrbuch der Nervenkrankheiten. Berlin, 5 Aufl., 1908.
OPPENHEIM, R. Role des capsules surrenales dans la resistance a quelques

infections experimentales. C. r. S. B., 53, p. 314, 1901.

- Role des capsules surrenales dans la resistance a la toxinfection diph-

terique. Ibid., 53, p. 316.

- Les capsules surrenales, leurs fonctions antitoxique. These de Paris,

1 902.

OPPENHEIMER, R., and LOEPER. Lesions des capsules surrenales dans
quelques infections experimentales. C. r. S. B., 53, p. 318, 1901.

- Lesions des capsules surrenales dans quelques maladies infectieuses

aigues. Ibid., 53, p. 765, IQOI.

— Lesions des capsules surrenales dans quelques infections experimentales

aigues. A. m. e., 13, pp. 332, 683, 1901.

- Lesions des glandes surrenales dans quelques intoxications experim.

Ibid., 1902.

- Insuffisance surrenale chronique experimentale par injections intra-

capsulaires des poisons du bacille tuberculeux humain. Ibid., 55, ii,
p. 330, 1903.

- L'insuffisance surrenale experimentale par lesions directes des capsules.
^ Ibid., p. 332.^

- Syndrome surrenal chronique experimental. A. gen. de med., i, p. 1281,

..

- La medication surrenale. Actual, med. Paris, 1903.

OPPENHEIMER, C. Die Fermente. Leipzig, 1900; and 2 Aufl., 1903.
OPPENHEIMER, E. H. Beitr. zur Verwendung d. Nebennierenpraparate.

D. m. W., 1904.
ORD, \V. W. On myxoedema, a term proposed, &c. Medico-Chirurg. Trans.

61, 1878.

- Some cases of sporadic cretinism. Lancet, 1893.

ORGLER, A. Zur Physiologic der Nebennieren. Diss., Berlin, 1898.

- Uber den Fettgehalt normaler u. in regressive!' Metamorphose befind-

licher Thymusdrusen. V. A., 167, 1902.

- tiber Beziehungen zwischen chemischem und morphologischem Yer-

halten pathologischer Nieren. V. d. p. G., 6, 1903.

- Uber das Vorkommen eines protagonartigen Korpers in den Neben-

nieren. Salkowskis Festschr., p. 285. Berlin, 1904.

- Uber den Einfluss von Schilddriisendarreichung auf den Stickstoffwechel

von Kindern. Z. e. P., 5, p. i, 1908.
ORLOWSKI. Atheromatose exper. par 1'injection d'adrenaline, &c. Przeglad

lek., No. 15, 1906; Ref. J. d. P. P., p. 558, 1906.
ORNSTEIN, SARAH. La suppieance des capsules surrenales au point de vue

de leur richesse en adrenaline. These de Geneve, 1906.
ORRU, E. Sviluppo d'isolotti del Langerhans nel Gongylus ocellatus. Monit.

zool. italiano, anno 2, 119, 1900.

- Sulle sviluppo dell' ipofisi. I. M., 17, 1900.

ORTNER. Zur angeborenen regelwirdrigen Enge des Aortensystems.

W. k. W., 1891.
OSAWA, G. Beitrage zur Lehre von den Eingeweiden von Hatteria punctata.

A. m. A., 49, pp. 113-226, 1897; and ibid., 51, p. 981, 1900.
OSBORNE, O. T. Graves's thyroid disease. Med. News., 77, 1900.
OSBORNE, W. A., and VINCENT, S. The physiolog. effects of extracts of

nervous tissues. J. o. P., 25, 1899-1900; and Brit. Med. Journ., 1900.
OSER. Erkrankungen des Pankreas. Nothnagels Handb., 18, 1898.
OSLER, W. Addison's disease treated with extract of suprarenal capsules.

Dublin J. M. Sc., p. 102, 1896.

- Case of Addison's disease. Johns Hopkins Hosp. Bull., November-

December, 1897.

The principles and practice of med. London, 1901.

OSWALD, A. Uber den Jodgehalt der Schilddrusen. Z. ph. Ch., 23, 265,
1897.

- Die Eiweisskorper der Schilddriise. Z. ph. Ch., 27, 1899.

— Uber die chemische Beschaffenheit und die Funktion der Schilddriise.

Habil.-Schrift, Strassburg, 1900.
_ Der Morbus Basedowii im Lichte neuerer experimenteller und klinischer

Forschung. W. k. W., 1900.

LITERATURE

OSWALD, A. Was wisscn wir liber die Chemie und Physiologic der Schild-
driise ? P. A., 97, IQOO.

- Zur Kenntnis des Thyroglobulins. Z. ph. Ch^.., 32, IQOI.

- Die Chemie und Physiologie des Kropfes. V. A., 169, pp. 444-479, 1902.

- Weiteres uber Thyreoglobulin. H. B., 2, 545.

- Die Schilddrjjse und ihr wirksames Prinzip. B. C., i, p. 249, 1903.

- Neue Beitrage zur Kenntnis der Bindung des Jods im Jodthyreoglobulin

nebst einigen Bemerkungen Uber Thyreoglobulin. A. P. P., 60, p. 115,
1909.

- Zur Klarung der Jqdothyrin-Frage. P. A., 129, p. 103, 1909.

OTT, J. The parathyroid glandules from a physiolog. and path, standpoint.

Philad., 1909.
OTT, J., and SCOTT, J. C. The action of glandular extracts upon the con-

tractions of the uterus. J. E. M., xi, 2, p. 326.
OYA. Vortr. auf dem jap. gynak. Kongr. in Osaka, April, 1903. Zit nach

Sata.

PACKARD, FR. A., and STEEL, J. DUTTOX. A case of sarcoma of the lung,
with symptoms of Addison's disease from involvement of the supra-
renal capsules. Amer. Med. News, September n, 1897.

PADOA, G. Le capsule surrenali in alcune infezioni e intossicazioni bat-
teriche sperimentali. Riv. crit. di Clin. Med., vii, 1907; Bph. C., ii,
p. 618.

PAECHTXER. Kastration u. Stoffwechsel. Verh. d. Berl. phys. Ges., 1906.

PAL, J. Beitr. z. Kenntn. der Pankreasfunktion. W. k. W., 1891.

- Uber die Hemmungsnerven des Darmes. Ibid., 1893.
Nebennierencxstirpation bei Hunden. W. k. W., 1894.

- Physostigmin, ein Gegengift des Curare. C. P., 1900.

- Uber den motor. Einfluss d. Splanchnicus auf den Diinndarm. A. V.,

5, 1900.

- Uber d. Beziehungen zwisch. Zirkulation, Mobilitat u. Tonus d. Darmes.

\V. m. P.. 1901.

- Uber das Vorkommen mydriatisch wirkender Substanzen im Harne.

D. m. W., 1907.

- Uber die Gefasswirkung des Hypophysenextraktes. W. m. W., i9oq;

and C. P., 23, 1909.

PALADIXO. Gli effetti della tiroidectomia. Ace. Medico chirurg. di Napoli,
1894.

- Della caducita del parenchimo ovarico. Giorn. Int. scienz. med. Napoli,

1881.
PALTAUF, A. Uber intralaryngeale Schilddriisentumoren. W. k. W., 1891.

- Der Zwergwuchs in gerichtlicher und anatomischer Beziehung. Wien,

PALTAUK, R. Uber Geschwiilste der Glandula carotica nebst einem Beitrage
zur Histologie und Entwicklungsgeschichte derselben. Zieglers
Beitr., n, 1892.

- Diskussion zum Vortrag Erdheim. W. k. W., 1906.

PAXELLA, A. Azione anticurarica del principio attivo delle capsule surrenali.
Atti della Soc. Toscano di Sc. Nat., Bd. 22, 1906.

- Action anticurarique du princip actif de la capsule surrenale. A. i. B.,

47, p. 17, 1907-

- Azione del principio attivo surrenale sul cuore isolate di mammueri.

Soc. Toscana di Sc. Nat. Pisa, 1907.

- Action da principe actif surrenal sur le cceur isole. A. i. B., 49, p. 321,

1908.

- Action du principe actif surrenal sur la fatigue musculaire. A. i. B.,

48, 1908.

PAXKO\V. Was lehren uns die Nachbeobachtungen von Reimplantation der
Ovarien beim Menschen. C. G., S. 1040, 1908.

- Uber die Reimplantation der Ovarien beim Menschen. B. G. G., 12,

1908.
PANTALEOXE. Contribute sperimentale all' inesto tiroideo. Ref. in C. Ch.,

p. 101, 1907.
PAXTANETTI, O. Saggio di ricerche sull' affatticamento muscolare. II Poli-

clinico, 1893.

- Sur la fatigue musculaire dans certains etats pathologiques. A. i. B.r

22, 1895-

LITERATURE 549

PANZER. Uber das sogennante Protagon der Niere. Z. ph. Ch., 48,, p. 519,
1906.

- Doppelbrechende Substanzen aus pathologischen Organen. Ibid., 54,

p. 239, 1907.

PARHON, C. Pathogenie et traitement de 1'acromegalie. Revista medicalc,
^ No. 2_, 1905.

- Considerations sur le role des alterations endocrines dans la pathogenic

de la generescence. Congr. de Dijon, aout, 1908.

PARHON and CAZACOU. Sur un nouveau cas de throphoedeme chronique.
Nouv. Iconogr. de la Salpetriere. decembre, 1907.

PARHON, DUTRIMESCO and NISSIPESCO. Recherches sur la teneur en cal-
cium des centres nerveux des animaux thyreoparthyreodisectomises.
C. r. S. B., 66, p. 792, 1909.

PARHON and GOLDSTEIN. Sur 1'existence d'un antagonisme entre le fontoinnt-
ment de 1'ovaire et celui du corps thyroi'de. C. r. S. B., 28 fevrier,
1903; Arch. gen. de med., 1905.

- Les secretions internes. Paris, 1909. Zusammenfass. d. ruman.

Literatur.
PARHON and MIHAELESCO. Sur un cas d'infantilisme dysthyroiden et dysor-

bitique. Journ. de Neurol., 1908.
PARHON, C., and PAPINIAN, J. Nota relativa la actinuea corpului tiroid, si

ovarului in asimilarea si desasimilarea calcelui. Romania medicala,

1904; Nos. n, 12, 1905.
PARHON, C., and URECHIE, C. Die Rolle der Schilddriise in der Behandlung

des Ekzems. Spitalul, No. 7, 1908.

- Note sur les effets de 1'opothe'rapie hypophysaire dans un cas de syndrome

de Parkinson. Soc. de Neurol., 7 novembre, 1907.
PARHON, C., and ZALPLASTA, J. Sur un cas de gigantisme precoce avec poly-

sarcie excessive. Nouv. Icon, de la Salp., pp. 91, 97, Janvier, fevrier,

1907.
PART, G. A. Azione locale dell' adrenalina sulle pareti dei vasi ed azione

delle minime dosi di adrenalina sulla pressione del sangue. Arch, di

Farm, sper., iv, april, 1905.

— Action locale de Padrenaline sur les parois des vaisseaux et action des

doses minimes d'adrenaline sur la pression du sang. A. i. B., 46,
p. 209, 1906.

— t)ber den Einfluss der Schilddriise auf den zeitlichen Ablauf der Zer-

setzungen. B. Z., xiii, 1908.

PARISOT, M. Influence de 1'injection du sue pancreatique dans la veine porte
sur la disparition du glycogene du foie. C. r. S. B., 56, p. 720, 6 mai,
1904.

— Hyperglycemie et glycosurie par injection de sue pancreatique dans le

systeme veineux. Ibid., 58, i, p. 64, 1906.

— L'injection du secretine dans la veine porte ne produit pas du sucre dans

le sang de la veine sushepatique. Ibid., p. 66.

— Atherome experimental par injections repetees de chlorure de baryum.

Soc. de med. de Nancy, n mars, 1908; Rev. med de 1'Est, 15 juillet,
1908.

— Action de 1'extrait de thymus sur la pression arterielle. C. r. S. B., 64,

p. 749, 1908.

— Action de 1'extrait d'hypophyse dans la maladie de Basedow. IXe

Congr. franc, de Medecin, 14-16 octobre, 1907.

— Pression arterielle et glande a secretion interne. Paris, 1908.

— Hypertension arterielle, hypertrophie cardiaque hyperplasies hypo-

physaire et surrenale. Arch, des malad. du cceur, p. 426, juillet, 1908.

— Le role de la choline dans les effets cardiovasculaires produits par les

secretions internes. C. r. S. B., 67, p. 749, 1909.
PARISOT and HARTER. Lesions des capsules surrenales consecutives a des

alterations experimentales du rein et du foie. C. r. S. B., 63, p. 821,

1907.
PARISOT and LUCIEN, M. Etude physiologique et anatomique des capsules

surrenales chez les tuberculeux. Ibid., 63, p. 525, 1907.

- Etude physiologique du thymus dans 1'athrepsie. C. r. S. B., 64, p. 747,

1908.
PARODI, U. Dell' innesto della capsula surrenale fetale. Sperimentale, 58,

p. 47, 1904.
PARONA. Acromegalie. Riv. crit. di clin. med., 1901.

550 LITERATURE

PASSLER, H. Beitr. z. Pathologic der Basedowschen Krankheit.

M. G. M. C., 1903.
PATOX, NOEL, L. The influence of adrenalin and thyroid extract on the

metabolism in diabetes mellitus. Scot. Med. and Surg. Journ.,

n, p. 6, IQOS.

- On the nature of adrenalin-glycosuria. J. o. P., 29, p. 286, 1903.

The relationship of the thymus to the sexual organs. Ibid., 32, p. 59,

1904.
PATON, N., and GOODALL, A. Contribution to the physiology of the thymus.

Ibid., p. 49, 1904.
PATTA, A. Contribute critico sperimentale alia studio dell' azione degli

estratti di organi sulla funzione circolatoria. Arch, di Farm., vi,

1907; and A. i. B., 48, 1908.

- Osservazioni intorno alle iniezioni ipodermiche ed intramuscolari di

adrenalina. Arch, di Farm., iv, Nos. 7-8, 1905; and A. i. B., 46,
p. 463, 1906.

PAULESCO, N. C. Recherches sur la physiologic de Phypophyse du cerveau.
L'hypophysectomie et ses effets. J. d. P. P., 9, p. 441, 1907.

- L'hypophyse du cerveau. Paris, 1908.

PAULY, H. Zur Kenntnis des Adrenalins. B. d. ch. G., 36, 1903; and 37,
p. 1388, 1904.

- Bemerkungen zu der Abhandlung des Herrn Bb'ttcher : Eine neue

Synthese des Suprarenins usw. Ibid., 42, p. 484, Februar, 1909.
PAVY. Carbohydrate Metabolisme und Diabetes. London, 1905.
PAWLIK, K. Kasuistischer Beitrag zur Diagnose und Therapie der Ge-

schwiilste der Nierengegend. A. k. Ch.. 53, p. 530, 1896.
PAWLOW. Folgen der Unterbinduns; des Pankreasganges beim Kaninchen.

P. A., 16, 1878.

- Die Arbeit der Verdauungsdriisen. Wiesbaden, 1898.

PAYR, E. Transplantation von Schilddriisengewebe in die Milz. A. Ch., 80.

1906.
PEARCE, R. M. An experim. study of nephrotoxines. Univ. Penns. Med.

Bull., 16, p. 217, 1903.
The development of the islands of Langerhans in the human embryo.

A. J. A., 2, 445.
The relation of lesions of the adrenal gland to chronic nephritis and to

arteriosclerosis: an anatomical study. J. E. M., 10, 6, p. 735, 1909.
PEARCE, R. M., and BALDAUF, L. K. A note on the production of experi-
mental vascular lesions in the rabbit by single injections of adrenalin.

Albany Med. An., xxviii, p. 51, i Januar}r, 1907; Amer. Journ. of

Med, Sci. 132, p. 737, November, 1906.

- Experimental myocarditis ; a study of histological changes following

intravenous injections of adrenalin. Ref, Schmidts Jahrb., Ibid.,

pp. 42, 62 and 67.
PEARCE and JACKSON, H. C. Experimental liver necrosis. J. E. M., 9,

p. 534, 1907.
PFARCE and STAXTOX, E. M. Experimental arteriosclerosis. Ibid. 8, p. 74,

1906.
PECHKRANZ. Zur Kasuistik der Hypophysentumoren. N. Z., 18, pp. 203 and

254, 1899.
PEHAM, H. Aus akzessorischen Nebennierenanlagen entstandene Ovarial-

tumoren. M. G. G., 10, pp. 685-694, 1899.

- Uber Fiitterungen mit Ovarialsubst. z. Beeinflussung d. Geschlechts-

bildung. M. G. G., 25, 1907.
PEIPER. Experimentelle Studien liber die Folgen der Ausrottung des Plexus

coeliacus. Z. k. M., 17, p. 498, 1890.
PEISER, J. Uber die Beeinflussung der Schilddriise durch Zufuhr von

Schildriisensubstanz. Z. e. P., p. 515, 1906.
PEL. Acromegalie partielle avec infantilisme. Nouv. Icon, de la Salp.,

1906.
PELIKAN. Gerichtlich-medizinische Untersuchungen liber das Skopzentum

in Russland. Ubersetzt von N. Ivanoff. Giessen, 1876.
PELLACANI, P. Intorno agli effeti tossici delle diluzione acquose degli organi

freschi introdotte nell' organismo di alcuni animali. Arch, per 1.

scienze med., 2, p. i, 1879.

- Sull' azione tossica delle diluzione acquose degli organi freschi. Rivista

sperim. di Frenetira e di Med. leg., vi, fasc. i e, 2, p. 169, 1880.

LITERATURE 551

PELLIGRINO, M. Studio sugli estratti surrenali. Congr. di med. intern.,
1903.

- Sopra una particolare disposizione della sostanza midollarc nella capsula

surrenale. Bol. d. Soc. di Natural, in Napoli. Ser. i, vol. 18, 1904.

- Contribute allo studio della morfologia dell' organo parasimpatico dello

Zuckerkandl. Monit. zool. Ital., xvii, No. 8, pp. 254-264, 1906.
— La storia e la bibliografia delle capsule surrenali. II Tommasi3 1906.

- La Patagenesi delle Surrenopatie. Ibid., No. 22, 1906.

- A proposito di capsule surrenali. Ibid., No. 26, 1906.

- Le surrenopatie spurie. Contribute critico e clinico. Ibid., 1906.

- La capsule surrenale del bue. Ibid., i, No. 35, No. 36, 1906.

- La glicosuria adrenalinica, contribute sperimentale alia sua patogenesi.

Ibid., iiij Nos. 14-15, 1908.
PEMBERTONj R., and SEVEET, J. E. The inhibition of pancreatic activity by

extracts of suprarenal and pituitary bodies. Arch, of Intern. Med., i,

p. 628, July, 1908.
PEXDE. L'alterazioni delle capsule surrenali in seguito alia resezione del

plessi celiaco e dello splancnico. Policlinico, 1903.

- Contr. alia fisiopatol. d. pancreas con spec, riguardo agli isolotti di

Langerhans. Policlinico, 12, 1905.

- Le moclificazione del pancreas dopo Pocclusione dei canali pancreatici.

Ric. Lab. Anat. Roma, 1907.

- Utenore contr. alia questione dei rapporti fra pancreas e diabete. I!

Tommasi, 1907.
PENZA, A. Osservazioni sulla distribuzione dei vasi sanguigni e nervi del

pancreas. Boll, della Soc. medico-chirurg. di Pavia. 24 giugno, 1904.
PEPERE, A. Sulla penetrazione delle capsule surrenali accessorie dei paren-

chimi degli organi addominali. Monit. zool. Ital., 24, pp. 261-273,

1903.

- Schwangerschaftseklampsie und Parathyroidkorpeninsufficienz. V. d.

Ital. path. G. in Rom, 1905: Ref. C. a. P., 17, p. 313, 1906.

- Della cosidetta sostanza colloide paratiroidea. Clinica Moderna, 13,

fasc. 16.

- Le ghiandole paratiroidea. Ricerche anatomico e sperimentale. Torino,

1906.

- Di un sistema paratiroides assessoria (timica) costante in alcuni mammi-

fere. Giorn.

- Sur les modifications de structure du tissu parathyroidien. A. m. e.,

20, 1908.

- Real. Accad. medica di Torino, 1907, Nos. 7-8, 1909.

PEPPER, W. A study of congenital sarcoma of the liver and suprarenal, with

report of a case. A. J. M. Sc., March, 1901.
PEREMESCHKO. liber den Bau des Hirnanhangs. V. A., 38.
PERRIN, M., and JEANDELIZE, P. Sur la posologie des produits opotherapeu-

tiques. IXe Cong, frang. de Med., Paris, 1907.

- Moindre resistance des lapins thyroidectomises a 1'intoxication par le

chlorure mercurique. C. r. S. B., 67, pp. 849 and 851, 1909.
PERSHING. A case of acromegaly, &c. Journ. of Nerv. and Ment. Dis., 21,

1894.
PETERS, C. Zur Anwendung des Adrenalins und ahnlicher Nebennieren-

praparate in der Gynakologie. Der Frauenarzt, No. 12, 1904.
PETERSEN. Anatomische Studie iiber die Glandulae parathyroideae des

Menschen. V. A., 174, p. 413, 1903-
PETITJEAN. Action de quelques medicaments vasomoteurs sur la circulation

pulmonaire. J. d. P. P., 10, p. 412, 1908.
PETREN. Uber das gleichzeitige Vorkommen von Akromegalie. V. A., 190,

p. i, 1907.
PETRONE and BAGALA. Le modificazioni della milza e del timo in alcune

anemic sperimentali. La Pediatria, p. 505, 1903.
PETTIT, A. Sur les capsules surrenales de Pormthorynchus paradoxus. Bull.

Soc. Zool., 25 decembre, 1894.

- Sur les capsules surrenales et la circulation porte surrenale des Reptiles.

Ibid., 10 decembre, 1895.

- Remarques anatomiques et physiologiques sur les capsules surrenales

des Teleosteens et des Dipnoiques. Bull. d. Mus., No. i, 1896.

Sur les capsules surrenales et la circulation porte surrenales des

Oiseaux. Ibid., No. 3, 1896.

552 LITERATURE

PETTIT, A. De Faction de quelques substances toxiques sur la glande
surrenale. Ibid., No. 4, 1896.

- Sur le mode de fonctionnement de la glande surrenale. C. r. S. B.,

1896.

- Recherches sur les capsules surrenales. Journ. de Tanat. et de la phys.

Par. Annee 32, pp. 301-362 and 369-419; and These de Paris, 1896.

- Modifications structurales des glandes surrenales developpees chez des

nouveau-nes son 1'influence des maladies de la mere. Cinquantenaire

de la Soc. de Biol., p. 516, Paris, 1899.
PEUKER. Uber einen neuen Fall v. kongen. Defekt d. Schilddriise. Z. H.,

20, 1899.
PEXA, VACLAV. O purodo tetanic detske. (Uber Atiologie der Tetanie bei

Kindern.) Sbornik lekarsky, x, H. 4, 1909.
PFAUXDLER, M. Zur Anatomic der Xebennieren. S. W. A., 101, p. 518,

1892.

PEEIFFER, W. M. Uber Addisonsche Krankheit. Diss., Freiburg i. P., 1896.
PFEIFFER, H., and MAYER, O. Uber funktionstiichtige Einheilung v. trans-

plantiert. Epithelkorperchen. W. k. W., 1907.

- Exper. Beitr. z. Kenntnis d. Epithelkorperchenfunktion. M. G. M. C.,

18, 1907.
PFEIFFER, TH., and SCHOLZ, W. Stoffwechsel bei Paralysis agitans und im

Senium. Einfluss der Schilddriisentabletten. D. A. k. M., 63, 369,

1899.
PFORRIXGER. Zur Entstehung des Hautpigments bei Morbus Addison.

C. a. P., n, i, 1900.
PFLUGER, E. Uber die das Geschlecht bestimmenden Ursachen und die

Geschlechtsverhaltnisse des Frosches. P. A., 29, 1882.

- Die teleologische Mechanik der lebendigen Natur. Ibid., 15, Bonn,

1877.

- Uber die Eierstocke der Saugetiere und des Menschen. Leipzig, 1863.

- Uber die Bedeutung u. Ursache d. Menstruation. Unters. a. d. phys.

Labor., Bonn, 1865.

- Le glycogene. Dictionn. de physiol. (Ch. Richet.), Paris, 1905.

- Das Glykogen und seine Beziehungen zur Zuckerkrankheit. 2 Aufl.,

Bonn, 1906.

- Ob die Totalexstirpation des Pankreas mit Notwendigkeit Diabetes

bedingt. P. A., 106, 1905.

- Ein Beitrag zur Frage nach dem Ursprung des _im Pankreasdiabetes

ausgeschiedenen Zuckers. Ibid., 108, H. 3-5, Mai, 1905.

- Das Fett wird als Quelle des Zuckers sichergestellt. Ibid., 108, H. 8-9.

- Prof. Minkowskis Abwehr gegen meine ihn treffende Kritik. Eine

Antwqrt. Ibid., no, H. 1-2.

- Uber die durch chirurgische Operationen angeblich erzeugten Gly-

kosurien. Nachtrag zu meiner zweiten Antwort an O. Minkowski.
Ibid., in, 1906.

- Ob der Zucker im Harn durch Garung mit Sicherheit nachgewiesen

werden kann. (Eine Antwort an E. Salkowski.) P. A., in.

- Untersuchungen iiber den Pankreasdiabetes. Ibid., 118, 1907.

- Uber den Einfluss einseitiger Ernahrung oder Nahrungsmangels auf den

Glykqgengehalt des tierischen Korpers. Ibid., 119, H. 3-4, 1907.
— Uber die Natur der Krafte, durch welche das Duodenum den Kohle-
hydratstoffwechsel beeinflusst. Ibid., 119, H. 5, 1907.

- Bemerkungen zu Rud. Ehrmanns Exstirpationen des Duodenums. Ibid.,

119, H. 5, 1907.

- Unter gewissen Lebensbedingungen nimmt die im Tierkorper enthaltene

Menge des Glykogens trotz vollkommener, iiber Monate sich aus-
dehnender Entziehung der Nahrung fortwahrend erheblich zu. Ibid.,

120, H. 6-9, 1907.

- Uber den Duoclenaldiabetes der Warmbluter. Ibid., 122 and 267, 1908.

- Durch neue Experimente gestiitzte Bemerkungen zu den jiingsten

Arbeiten iiber den Duodenaldiabetes des Hundes. P. A., 123, p. 323,
1908.

- Uber die durch Resektion des Duodenums bedingten Glykosurien. Ibid.,

124, H. 1-2, 1908.

- Die Aufklarung, welche Errico de Renzi und Enrico Reale soeben

(August, 1908) iiber ihre den Duodenaldiabetes betreffenden Versuche
gegeben haben. Ibid., 124, H. 11-12, 1908.

LITERATURE 553

PFLUGER, E. Uber Parabiose und Pankreasdiabetes. Ibid., 124, H. 11-12,
1908.

- Experimentelle Untersuchung iiber den Darmdiabetes. Ibid., 128, H. 3,

IQOQ.
—Ob d. Entwickl. d. sekund. Geschlechtscharakt. v. Nervensystem abhangt.

P. A., 116, 1907.

PHILIPEAUX. Note sur 1'exstirpation des capsules surrenales chez les rats
albinos. (Mus rattus.) C. r. A., 43, pp. 904 and 1155, 10 novembre
and 22 decembre, 1856.

- Ablation successive des capsules surrenales, de la rate et des corps

thyroides sur des animaux qui survivent a Toperation. Ibid., 44,

p. 396, 23 fevrier, 1857.
PHILIPS. Addison's disease with simple atrophy of the adrenals. J. E. M.,

4, p. 581, 1899.
PHILOCHE. Action comparee de 1'amylase et du sue pancreatique sur le

glycogene et 1'amidon. C. r. S. B., 57, i, p. 263, 1905.
Pic and BOXXAMOUR. Contribution a 1'etude du determinisme de Tatherome

aortique experimental. Ibid., 57, ii, p. 219, 1905; J. d. P. P., p. 460,

1906.
PICK, E. P., and PINELES, F. Uber die Beziehungen der Schilddriise zum

Gefasssystem. V. 25; C. M., p. 360, 1908.

- Uber die Beziehungen der Schilddriise zur physiologischen Wirkung

des Adrenalins. B. Z., 12, pp. 473-484, 1908.

- Unters. lib. d. physiologisch wirksame Substanz d. Schilddriise. Z. e. P.,

7, 1999.
PICK, F. Uber Beeinflussung d. ausstrom. Blutmenge durch d. Gefassweite

andernde Mittel. A. e. P., 42, 1899.
PICK, L. Die Marchandschen Nebennieren und ihre Neoplasmen nebst

Untersuchungen iiber glykogenreiche Eierstockgeschwiilste. A. G., 64,

pp. 670-835, u. Festschr. f. L. Landau; B. G. G., pp. 434-603, 1901.
Tetanic und Graviditiit. C. G., p. 1312, 1902.

- Uber Umbildungen am Genitale bei Zwittern. A. G., 76, p. 191, 1905.
PICKART, M. Die Beeinflussung des Stoffwechsels bei Morbus Addisonii

durch Nebennierensubstanz. B. k. W., 1898.
PlERSOL. Uber die Entwicklung der embryonalen Schlundspalten und ihrer

Derivate bei Saugetieren. Z. w. Z., 47.
PILLIET, A. H. Tuberculose d'une capsule surrenale sans melanodermie.

Bull, de la Soc. anat., 65, 4, octobre-novembre, 1890.

- Debris Wolffien surrenal de l'epidid}"me chez le nouveau-ne. Bull. Soc.

anat., 65, p. 471, 1890.

- Recherches sur 1'adenome des capsules surrenales. Ibid., 66, avril, 1891.

- Capsule surrenale dans le plexus solaire. Ibid., 66, pp. 267-268, 1891.

- Capsule surrenale situee sous la capsule fibreuse du rein droit. Ibid.,

68, 1893-

- Etude htstologique sur les alterations seniles de la rate, du corps

thyroide et des capsules surrenales. A. m. e., 5, 1893.

- Pigmentation et hemorrhagies experimentales des capsules surrenales.

C. r. S. B., pp. 97-99, ^94-

- Etude experimentale sur les lesions des capsules surrenales dans

quelques empoisonnements. A. d. P., 27, 1895.
PILLIET, A. H., and VEAU, V. Capsule surrenale aberrante du ligament

large. C. r. S. B., pp. 64-68, 1897.
PIXELES, F. Die Beziehungen der Akromegalie zum Myxodem und zu

anderen Blutdriisenerkrankungen. Volkmanns Samml., N. F., 242,

1899.

- Uber die Beziehungen der Akromegalie zum Diabetes mellitus. Jahrb.

Wien. Krankenanst., 1899.

- Uber Thyreoaplasie (kongenitales Myxodem) u. infantiles Myxodem.

W. k. W., 1902.

- Zur Physiologic und Pathologic der Schilddriise. Ibid., 1904.

- Klinische und experimentelle Beitrage zur Physiologic der Schilddriise

und der Epithelkorperchen. M. G. M. C., 14, 1904.

Uber die Funktion der Epithelkorperchen. S. A. W., 113, 1904; and
117, 1908.

- Zur Pathogenese der Tetanic. D. A. k. M., 85, 1906.
Tetaniestar - - Zuckerstar -- Altersstar. W. k. \V., 1906.

- Zur Pathogenese der Kindertetanie. Jahrb. f. Kinderkh., 66, 1907.

554 LITERATURE

Pl.XKLES, F. Behandlung der Tetanic mit Epithelkorperpraparaten. Arb.
neurol. Inst., 1907.

- Uber parathyreogenen Laryngospasmus. W. k. \Y., 1908.

PIRCHE. Influence de la castration sur le squelette. These Lyon, 1902.
PIRONE, R. Contribution a 1'etude des tumeurs renales d'origine surrenale

hypernephromes). Arch, de scienc. biol., 10, No. i, 1903.
Nouvelle contribution a 1'etude des tumeurs des reins d'origine surrenale

(hypernephromes). A. m. e., 1903.

- Sulla fina struttura e sui fenomeni di secrezione delT ipofisi. A. d. F.,

,2, 1905-

- L hypophyse dans la rage. A. m. e., p. 688, septembre, 1906.
PIRRONE, D. Contr. sper. allo studio della funzione dell' ipofisi. Rif. med.,

19, 1903.
PISENTI. Sulla interpret, da darsi ad alcune particolarita istol. d. gland.

pituitaria. Gazz. d. Osp., 16, 1895.
PISENTI and VIOLA. Beitrag zur normalen und pathologischen Histologic

der Hypophysis, etc. C. m. W., 28, 1890.

PiscHINGER, D. Beitrag zur Kenntnis des Pankreas. Diss., Miinchen.
Pi SUNER and TURRO. Sur 1'inconstance de la glycosurie apres 1'exstirpation

totale de Pancreas. C. r. S. B. , 66, 1909.
PITINI, A. Influenza dell' adrenalina sulla secrezione biliare. A. int.

Pharmac., 16, 1906.
Ricerche farmacologiche sugli amminochetoni. Nota II. Arch, di

Farmac., 12, 1907.

PITTARD. La castration chez 1'homme. C. r. A., 1903.
PLAUT, H. W., and STEELE, P. Treatment of serous effusions by injection

of adrenalin chloride. Brit. Med. Journ., July 15, 1905.
PLATO, J. Die interstitiellen Zellen der Hoden und ihre physiologische

Bedeutung. A. m. A., 48, 1896.

- Zur Kenntnis der Anatomic und Physiologic an Geschlechtsorganen.

Ibid., 50, 1897.
PLAY, L., and CORPECHOT. Action des Nephrolysines. C. r. S. B., p. 207,

1904.
PLOSS, H. Das Weib in Natur- und Volkerkunde. Herausg. von Bartels.

6 Aufl., 1899.
PLUMIER, L. Action de 1'adrenaline sur la circulation cardiopulmonaire.

J. d. P. P., 6, pp. 655-670, 1904.
PLECNIK, O. Zur Histologie der Nebenniere des Menschen. A. m. A., 60,

p. 4M, 1 902.
POCHON. Beitrage zur Kenntnis der Langerhansschen Inseln des Pankreas.

A. wiss. u.'prakt. Tierrheilk., 34, p. 581, Oktober, 1908; Bph. C., iii,

No. 1719.
POEHL. Einwirkung des Spermins auf den Stoffumsatz bei Autointoxika-

tionen. Z. k. M., 26, 1894.

- Verwendung physiologischer Katalysatoren als Heilmittel. D. m. W.,

1903.
POEHL, A., TARCHANOFF and WACHS. Rationnelle Organotherapie. Ubersetzt

aus dem Russischen. Petersburg, 1905.
POLL, H. Uber das Schicksal der verpflanzten Nebenniere. C. P., 1898.

- Veranderungen der Nebenniere bei Transplantation. A. m. E., 54,

1899 ; Diss., 1900.

- Die Anlage der Zwischenniere bei den Haifischen. Ibid., 62, pp. 138-

174, 1903.

- Nebenniere, Enzyklopadie der mikroskopischen Technik (herausgegeben

von Ehrlich, Krause, Mosse, Rosin, Weigcrt), 2, pp. 920-925, 1903.

- Die Anlage der Zwischenniere bei der europaischen Sumpfschildkrote

(Emys europaea) nebst allgemeinen Bemerkungen iiber die Stammes-
und Entwicklungsgeschichte des Interrenalsystems der Wirbeltiere.
I. M., 21, pp. 195-291, 1904-

- Allgemeines zur Entwicklungsgeschichte der Zwischenniere. A. A., 24,

1904.

- Die yergleichende Entwicklungsgeschichte der Nebenniercnsysteme der

Wirbeltiere. O. Hertwigs Handb. d. vergl. u. exp. Entwicklungs-
gesch., iii, i, pp. 442-618, 1006.

- Die Biologie der Nebennierensysteme. Zusammenfassender Bericht

B. k. W., 648, 1886, 1973; 1909.

LITERATURE 555

POLL, H. Zur Lehre von der Nebennierentransplantation. A. A. P., 1906;
M. K., 1905.

- Gibt es Nebennieren bei Wirbellosen ? G. d. naturf. Fr., Berlin, igo8;

S. pr. A. W., 36 and 88Q, 1909.
POLL, H., and SOMMER, A. Uber phaochrome Zellen irn Zcntralnerven-

system. V. Physiol. Ges. Berlin, p. 77, Jg., 1902-1903.
POLLAK, L. Demonstration eines Falles von Morbus Addisonii. W. k. W.,

1909.

- Experimentelle Studien Uber Adrenalindiabetes. A. P. P., 61, p. 149,

1909.

Kritisches und Experimcntelles zur Klassifikation der Glykosurien.
Ibid., 61, p. 157.

- Untersuchungen bei Morbus Addisonii. W. m. W., 1910.

POLLAK, O. Kritisch-experimentelle Studien zur Klinik der puerperalen

Eklampsie. Wicn, 1904.
POLTE. Paranephrin, ein neues Nebennierenpraparat. Arch. Augenh., 51,

p. 54, 1904.
POXCET. Influence de la castration sur le develop, du squelette. Congr.

Ass. franc.., Havre, 1877.
PONFICK. Myxodem und Hypophysis. Z. k. M., 35 and 38, 1899.

- Uber die Beziehungen zivischen Myxodem und Akromegalie. C. a. P.,

1899.

- Zur Lehre vom Myxodem. Verb. d. p. G., 1899.

POXTOPPIDAX. Ein Fall von Tumor der ZirbeldrUse. N. C., p. 553, 1885.
POOL. Tetany parathyreopriva. Ann. of Surg., October, 1907.
POPIELSKI, L. Uber das peripherisch reflektorische Nervencentrum d. Pan-
kreas. P. A., 86, 1901.

- Die Sekretionstatigkeit der Bauchspeicheldriise unter dem Einfluss von

Salzsaure und Darmextrakt (des sog. Sekretins). P. A., 120, p. 451,
1907.

- tiber den Charakter der Sekretionstatigkeit des Pankreas unter dem

Einfluss von Salzsaure und Darmextrat. Ibid., 121, H. 5-6, 1908.
— Uber die Wirkungsweise des Chlorbaryum, Adrenalin und Pepton Witte
auf den peripherischen, vasomotorischen Apparat. A. P. P., Suppl.,
pp. 434-442, 1908.

- Uber eine neue blutdrucksteigernde Substanz des Organismus auf Grund

von Untersuchungen von Extrakten von Glandula Thymus. Speichel-
driisen, Schilddriisen, des Pankreas und Gehirns. C. P., 23, p. 137,
1909.

- Uber die physiologischen und chemischen Eigenschaften des Peptons

Witte. P. "A., 126, H. 9-10, 1909.

- Uber die physiologische Wirkung von Extrakten aus samtlichen Teilen

des Verdauungskanales (Magen, Dick- und Dunndarm) sowie des

Gehirns, Pankreas und Blutes und Uber die chemischen Eigenschaften

der darin wirkenden Korper. Ibid., 128, H. 4-5, 1909.
POPIELSKI, L., and PANEK, K. Chemische Untersuchung Uber das Vaso-

dilatin, den wirksamen Korper der Extrakte aus samtlichen Teilen des

Verdauungskanales, dem Gehirn, Pankreas und Pepton Witte. P. A.,

128, 1909.
POPPER, R. Uber die Wirkungen des Thymusextraktes. S. W. A., 114,

1905 ; ibid., 1 15, 1906.
POPPER. Das Verhaltnis des Diabetes zu Pankreasleiden und Fettsucht.

Ost. Z. f. prakt. Heilk., No. n, 1868.
PORCHER. Sur la physiologic de la mamelle. Journ. de 1'ec. vet. de Lyon,

15 septembre, 1905.
FORGES, M. Exp. Beitr. z. Wirkung u. Nachwirkung v. SchilddrUsengift.

B. k. W., 1900.
PORGES, O. Wirkung der Nebenniere auf den Blutzucker. Ibid., p. 2817,

1908.
— Diskussionsbemerk. zu. Pollak. " Ein Fall von Morbus Addisonii."

W. k. W., 1909.

- Uber Hypoglycamie bei Morbus Addisonii sowie bei nebennierenlosen

Hunden. Z. k. M., 69, p. 341, 1909-
POROSZ, M. Das Tonogen suprarenale sec. Richter, Adstringens und

Anastheticum. Monatsschr. f. Dermat., 39, 1904.
PORTIS, M. Experimental study of the thyrotoxic serum. Journ. of Infect.

Dis., i, p. 127.

556 LITERATURE

POSCHARISKI, J. F. Uber Hypernephrome. Wratschcb. Gaz., N-. 41, 1904.
POSNER, C. Die norm. u. path. Physiol. d. Prostata. Cong. int. d'urologie., i,

1908.
POSPELOW, J., and GAUTIER-DUFOYER, E. W. Zur Kasuistik und Patho-

genese des Melasma suprarenale. (Morbus Addisonii.) Arch. f.

Derm. u. Syph., 66, 3, p. 355, 1903.
POSPISCHIL. Uber Diphtherietherapie. Versuch einer Behandlung der

schwersten Falle mit Adrenalin-Kochsalzinjektionen. W. k. W., 1908.
POSSEK, R. Lassen sich Linsentriibungen organtherapeutisch beeinflussen ?

W. k. W., 1909.
POSSELT. Bericht Uber fiinf zur Obduktion gelangte Falle von Morbus

Addisonii. Ibid., pp. 630, 652, 672, 714, 1894.

- Morbus Addisonii. Ibid., pp. 17 and 24, 1897.

POTSEK. Schilddriise und Auge. Klin. Monatsbl. f. Augenhk., Beilageheft,

1907.

POTTIEN. Beitrage zur Addisonschen Krankheit. Diss., Gottingen, 1889.
POWER, D'ARCY. Symmetrical tubercular disease of the suprarenal capsules.
Path. Trans., xi, p. 300, 1890.

- Case of haemorrhages into the suprarenal capsule of both sides. Lancet,

April 5, 1890.
PRANDI, T. Syndrome myasthenique post-typhoidique. Gaz. degli osped.,

28, 1907.
PREGL, F. Zwei weit. ergograph. Vers. ub. d. Wirk. orchitischen Extraktes.

P. A., 62, 1896.
PRENANT, A. Etude sur la structure du tube seminifere des Mammiferes.

These de Nancy, 1887.

- Contribution a 1'etude du developpement organique et histologique du

thymus, de la glande thyroide et de la glande carotidienne. La
Cellule, 10, i, 1900.

- Sur le developpement des glandes accessories de la glande thyroide, etc.

An. An., xii, 1896.

- Rectification au sujet de la commun. de M. Maurer : Die Schlundspalten-

derivate von Echiona. Ibid., xvi, 1899.

- De la valeur morphologique du corps jaune son action physiologique et

therapeutique possible. R. gen. d. sc., 1898.

PRESBEANU, N. De 1'hypophyse dans I'acromegalie. These de Paris, 1909.
PREVOST, J. L., and MIONI, J. Convulsions de la thyroide par courants

alternatifs apres exstirpation. C. r. S. B., 57, p. 69, 1905.
PRIBRAM, H. Beitr. z. Kenntn. d. Schicksals d. Cholesterins u. d. Chlosterin-

ester. B. Z., i, 1906.
PRIBRAM, E., and PORGES. Uber den Einfluss verschiedenartiger Diat-

formen auf den Grundumsatz bei Morbus Basedowii. W. k. W., 1908.
PRIEUR, G. Le tabac et 1'appareil vasculaire. These de Paris, 1905.
PROCA, G. Insuffisance thyroidienen et bacillus mucinogenes de 1'eau.

C. r. S. B., 60, p. 989.
PROTOPOPOFF. Action de 1'adrenaline sur la circulation intracranienne

(russisch), Ref. J. d. P. P., 6, p. 1122, 1904; and 7, p. 145, 1905.
PROUCHINSKY, J. Uber den Einfluss von Adrenalin auf das Zirkulations-

system. (finn.). Ibid., 6, p. 1121, 1904; and W. k. W., 1904.
PROUST, R. La chirurgie de 1'hypophyse. Journ. de chir., 1908.
PRUNEAU. Note sur la secretion interne du testicule. Rec. de Med.

veterinaire, 1900.
PRYM. Milz und Pankreas. II. Teil. Versuche mit Infusen beider Organe.

P. A., 107.

PUECH. Des Ovaires et leur anomalies. Paris, Levy.
PUPPEL, E. Behandlung der Osteomalakie mit Nebennierenpraparaten.

C. G., 1907.
PURTSCHER, D. Uber Starbildung und Kropf operation. Cbl. f. Augenh. ,

1909.
PUTNAM. Case of myxcedema and acromegaly, treated by sheeps' thyroids.

A. J. M. S., June, 1893.

The clinical aspects of the internal secretions. Ibid., 1898.
PUGLIESE. Zur Lehre v. d. Schilddriise v. H. Munk. V. A., 150, 1897.
- Wirkung v. Thyreoideapraparaten nach Exstirpation d. Schilddriise.

P. A., 72, 1898.
PUGNAT, CH. A. Recherches sur 1'histologie du pancreas des oiseaux.

J. A. P., 33, P. 268.

LITERATURE 557

PUGXAT, CH. A. Xote sur la structure histologique du pancreas des oiseaux
C. r. S. B., 48, p. 1071.

QUADRI, G. Un caso di albuminuria delle gravido curato con la para-

tiroidina. Gaz. Osp. e cliniche, No. 116, 1908.

QUEXU and LEJARS. Etude sur la systeme circulatoire. Paris, 1894.
QUERVAIN DE. Uber Yeranderungen des Zentralnervensystems bei exp.

Cachexia thyreopriva der Tiere. V. A., 133, 1893.
QUEST, ROBERT. Uber den Einfluss der Ernahrung auf die Erregbarkeit des

Nervensystems im Sauglingsalter. \V. k. W., igo6.

- Uber die Bedeutung der Nebennieren in der Pathologic und Therapie

der Rachitis. Z. e. P., 5, p. 43.
QuiNCKE, H. Uber Athyreosis im Kindesalter. D. m. W., 1900.

RABAUD, E. Foetus humain paracephalien hemiacephale. J. A. P., 39, 1903.
RABL, C. Theorie des Mesoderms. Morph. Jahrb., 19, pp. 85-144, 1893.

- Uber die Entwicklung des Urogenitalsystems der Selachier. Ibid., 24,

p. 756, 1896.

— Zur Bildungsgeschichte des Halses. P. m. \\ ., 1886.
RABL, H. Die Entwicklung und Struktur der Xebennieren bei den Vogeln.

A. m. A., 38, pp. 492-523, 1891.

RABL-RUCKHARD. Des gegenseitige Verhaltnis der Chorda, Hypophysis, etc.

Morph. Jahrb., 6, 1880; and A. A., 1883.

RADASCH, H. E. Ectopia of the adrenal. A. J. AI. S., 127, p. 286, 1902.
RADZIEJEWSKI, B. Uber den augenblicklichen Stand unserer Kenntnis von

den Nebennieren und ihren Funktionen. B. k. W., 1898.
RAUBER, H. Zur feineren Struktur der Nebennieren. piss., Berlin. 1881.
RAIXIERI. Le capsule surrenali in rapporto alia ovariectomia, all' ovaro-

isterectomia e all' isterectomia. Folia gynecologica, i, fasc. 2, 1908;

B. k. \V., 1909.

RAMOND and HULOT. Degeneresc. experim. du foie et des reins. C. rr»S. B.,

1901.
RAU, \Y. Uber die Abstammung von Nierensarkomen aus versprengten

Nebennierenteilen. Diss., Bonn, 1896.
RANGE. Contr. a 1'etude pathogenique du syndrome de Basedowii. These

de Paris, 1899.

RAXKIN, G. Myxcedema. Practitioner, Ixxxii, 2, p. 204, 1909.
RAXZI and TAXDLER. Demonstration. W. k. W., 1909.
RAXZY. Intoxication thyreoidienne. These de Lyon, 1898.
RAPAPORT. Exp. Unters. iiber Glykolyse. Z. k. M., 57, p. 208.
RATH. Ein Beitrag zur Kasuistik der Hypophysentumoren. Diss., Got-

tingen, iSSS.

- Zur Symptomenlehre der Geschwulste der Hypophysis cerebri. Grafes

Arch., 34.
RATHKE. Uber die Entstehung der Glandula pituitaria. Aliillers Arch. f.

A. u. P., 1838.
RAUTENBERG. Experimentell erzeugte, mit Arteriosklerose verbundene

chronische Albuminurien. V. d. N. u. A., Salzburg; and D. m. W.,

1909.
RAVAXO. Uber die Frage nach der Tiitigkeit des Eierstockes in der Schwan-

gerschaft. A. G., 83, p. 587, 1907.
RAVEN, H. M. Adrenalin in Addison's disease. Brit. Med. Journ., January^

1904.

RAVER. Die Nebennieren und der Alorbus Addisonii. Berlin, 1883.
RAYMOND. De la pigmentation dans Ta maladie d'Addison. A. d. 3., 1892.

- Alorbus Addisonii mit Integritat der Nebennieren. Soc. med. des hop.,

Marz, 1892.
RAYMOND and LEJOXXE, P. Deux cas de myasthene bulbospinale. Soc. de

Neur. , 5 avril, 1906.
REBEXDI, ST. Eierstock, Corpus luteum und Langerhanssche Zellinseln.

C. G., 41, p. 1332.

RECKE, F. M. Vergleichende experimentelle Untersuchungen lokalan-

asthesierender Mittel. Diss., Leipzig, 1903.

RECKLIXGHAUSEN v. Uber die Akromegalie. V. A., up, p. 36, 1890.
REGAUD, CL. Glandules a secretion interne juxta-epididymaires chez le

lapin. C. r. S. B ., 1899.

LITERATURE

REGAUD, CL. Etude sur la structure des tubes seminiferes et sur la sper-
matogenese chez les Mammiferes. A. d'Anat. micr., iv, fasc. 2, 3, 1901.

REGAUD and BLANC. Action des rayons X sur les diverses generations de la
lignee spermatique. C. r. S. B., 58, ii, p. 163, 1905.

- Action teratogene des rayons X sur les cellules seminales. Ibid., p. 390.
REGAUD and DUBREUIL. Action des rayons de Roentgen sur le testicule

du lapin. I. Conservation de la puissance virile et sterilisation.
C. r. S. B., 63, p. 647, 1907.

- Variations macrosc. de la glande interstitielle de 1'ovaire chez la lapine.

Ibid., p. 780.

- Glande interstitielle de 1'ovaire et rut chez la lapine. Ibid., 64, p. 217,

1908.

- Gravidite et glande interstitielle de 1'ovaire chez la lapine. Ibid., p. 396.

- A propos des corps jaunes de la lapine : ils n'ont avec le rut .relation.

Ibid., p. 442.

- L'ovulation de lapine n'est pas spontanee. Ibid., p. 552.

- Observations nouvelles relatives a 1'independance des corps jaunes et

du rut chez lapine. Ibid., 64, p. 602, 1908.

- Karyokineses des cellules luteinique dans les corps jaunes en regression

chez la lapine. Ibid., p. 858.

- Parallelisme des variations macroscopiques et microscopiques de la

glande interstitielle dans Povaire de la lapine. Ibid., p. 901.

- Perturbation dans le developpement des ceufs fecondes par des sperma-

tozoides roentgenises chez le lapin. Ibid., p. 1014.

- Sur les relations fonctionnelles des corps jaunes avec 1'uterus non-

gravide. Ibid., 66, p. 257, 1909.

- Acceleration du rut par la cohabitation. Ibid., p. 139.

- Variations de volume de 1'uterus par rapport a 1'etat des ovaires. Ibid.,

P. 299.

- Etats de 1'uterus aux diverses phases de la periode pregravidique. Ibid.,

P- 4i3-

- Nouvelles recherches sur les modifications de la glande interstitielle de

1'ovaire consecutives a Tisolement et la cohabitation avec le male.
Ibid., 67, p. 348, 1909.

- Existe-t-il des relations entre les phenomenes du rut et la presence de

corps jaunes ovariens chez la lapine. Ibid., p. 176.

- Effets de la rupture artificielle follicales de 1'ovaire au point de vue

de la formation des corps jaunes chez la lapine. Ibid., 67, p. 166,

1909.
REGAUD, CL., and POLICARD. Etude comparative du testicule du pore normal

impubere et ectopique au point de vue des cellules interstitielles.

C. r. S. B., avril, 1901.
REGERAT. These de Paris, 1903.

REHN. Die chirurg. Behandl. d. Morbus Basedow. M. G. M. C., 7, 1900.
REICHE. Primares Trachealkarzinom. Metastase in der linken Nebenniere.

Melasma suprarenale. C. a. P., 4, p. i, 1893.
REICHER, K. Beziehungen zwischcn Adrenalsystem und Niere. B. k. W.,

1908.

REIKHTMANN. These de St. Petersbourg, 1902.
REIL. Nebenniere. Berl. tierarztl. Woch, 28, 1902.
REINHOLD. Fall von Tumor der Zirbeldruse. Diss., Leipzig, 1886.
REIMANN, G. Melanotisches Karzinom der Nebennieren bei einem Saugling.

P. m. W.j 1902.

REINBACH. Zur Chemie des Kolloids der Kropfe. C. Ch., No. 21, 1898.
REINHARDT. Adrenalin und osteomalakie. C. G., p. 1613, 1907.
REINKE. liber Krystalloidbildungen in den interstitiellen Zellen des

menschlichen Hodens. A. m. A., 42, 1896.
REINL. Die Wellenbewegung der Lebensprozesse des Wiebes. Volkmanns

Samml., 243, 1900.
REITMANN. Beitr. z. Pathologic d. menschl. Bauchspeicheldriise. Z. H.,

26, 1905.
RENAUT. Sur les organes lympho-glandulaires et le pancreas des vertebres.

C. r. A., 89.

- Essai d'une nomenclature methodique des glandes. A. d. P., iSSi.

- Observation pour servir a 1'histoire de la maladie d'Addison et des

tuberculoses locales. Ibid.

LITERATURE 559

RENAUT. Pouvoir secretoire et signification glandulaire des epitheliums des

tubes contournes du rein et valeur therapeutique de leur produits.

Bull. gen. de Therap., 147, p. 3.

— • Opotherapie renale dans Palbuminurie. Sem. med., p. 418, 1903.
RENDU. Note sur deux cas de maladie d'Addison avec autopsie. Bull. Soc.

med des hopitaux, 24 fevrier, 1899.
RENNER. Neue Symptome der Addisonschen Krankheit. Ver. Bl. f. Pfalzer

Arzte, xii, 3, p. 53, Marz, 1896.
RENON, L. Action de 1'opotherapie associee sur le syndrome de Basedo^v.

Acad. de med., 5 mai, 10,08.

- Les syndromes polyglandulaires et 1'opotherapie associee. Journ. des

prat., 1908.
RENON, L., and AZAM. Maladie de Basedow traitee par 1'opotherapie hypo-

physaire. Soc. med. d. hopit., 24 mai, 1907.
RENON, L., and DELILLE, A. Sur quelques effets opotherapeutiques de

1'hypophyse. Soc. de therapeutique, 22 Janvier, 1907; Bull. gen. de

Therap., 153, p. 178.

- De 1'utilite d'associer les medications opotherapeutiques. Ibid., 12 juin,

„ 1907-

- Sur les effets des extraits d'hypophyse, de thyroide, de surrenale,

d'ovaire, emploj'es en injections intraperitoneales. C. r. S. B., 64,
p. 1037, and 65, p. 499, 1908.

— L'insuffisance hypophysaire et la myocardite. IXe Congr. frang. de

Med., 1907.

Insuffisance thyro-ovarienne et hyperactivite hypophysaire (troubles
acromegaliques) medication par 1'opotherapie thyro-ovarienne; aug-
mentation de 1'acromegalie par la medication hypophysaire. Soc.
med des hop., 19 juin, 1908.

- Syndrome polyglandulaire par hyperactivite hypophysaire (gigantisme

avec tumeur de Thypophyse et par insuffisance-thyro-ovarienne). Soc.
med. d. hop., 4 decembre, 1908.

- La medication hypophysaire dans les cardiopathies. Soc. d. Therap.,

9 decembre, 1908.

- L'opotherapie indirecte. C. r. S. B., 16 Janvier, 1909.

RENON, L., DELILLE, A., and MONIER-VINARD, R. Syndrome polyglandulaire

par dyshypophysie et par insuffisance thyro-testiculaire. Soc. med. des

hopit., 5 fevrier, 1909.
RENZI DE. Action nephrotoxique et hemolyt. du rein. Sem med., p. 351,

1904.
RENZI, E. DE, and BOERI, G. Ricerche sperimentali sull' asportazione di

alcuni organi abdominali e sulla suppressione della loro circolazione.

Gazz. d. Osped., 1903.

- Ancora sull' asportazione di alcuni organi abdominali e sulla soppres-

sione completa della loro circolazione. Nuova riv. clin.-terap., vii,
2, 1904.

- Sull' azione nefrotossica ed emolitica del reni. Ibid., 1905.

RENZI DE and REALE. Uber den Diabetes mellitus nach Exstirpation des

Pankreas. B. k. W., 1892; and Nuov. riv. clin.-terap. August, 1908.
RENNIE, J. Uber die physiologische Bedeutung der Langerhansschen Inseln

im Pankreas. C. P., 18; and Quart. J. Micr. Sc., 48, 1904.
RENNIE, J., and FRASER. The islets of Langerhans in relation to diabetes.

J. B. Ch., 2, 1907.

RESTELLI. De thymo. Ticini Regis, 1845.

REVELLI, C. Perche si nasce maschi o femmine. Torino, 1899.
REVERDIN, J. and A. Note sur 22 operations du goitre. Rev med. Suisse

rom., 1883.

- Contribution a 1'etude du myxocdema. II. Congr. Chir. Franc.. 1886.
REYNIER and PAULESCO. Glandes thyroides. Journ. de med. int., 1899.
RHEINBOLDT, M. Zur Fettsuchtsbehandlung mit Schilddruse. B. k. W.,

1906.
RIBADEAU, DUMAS, and PATER. La syphilis congen. des caps, surrenales.

A. m. e., 21, 1909.
RlBBERT. Uber die Regeneration des Schilddriisengewebes. V. A., Bd. 117,

1889.

— Uber kompens. Hypertrophie der Geschlechtsdriisen. V. A., 120, 1890.

— Uber Veranderung transplantierten Gewebes. E. M., 6, p. 131, 1897.

560 LITERATURE

RlBBERT. Uber Transplantation von Ovaricn, Hodcn und Mamma. Ibid.,

7, 1898.
RlCHON, L., and JEANDELIZE, P. Influence de la thyroidectomie sur la

castration chez la lapinc. Effets dc la thyroidectomie sur la lapine

adulte. C. r. S. B., 56, p. 19, 1904.
Tyroidectomie et accidents aigus au cours du gestation. Ibid., p. 22

- Castration pratiquee chez le lapin jeune. Etat du squelette chez 1'adulte.

Examen radiographique. Ibid., 57, i, p. 555, 1905.

- Insuffisance thyroidienne experimentale fruste. Ibid., p. 728, 1905.
RICHTER, M. Uber plotizliche Todesfalle im Kindesalter. V. d. N. A., p.

290, 1902.

RICHTER, P. FK. Eiweisszerfall nach Schilddriisenfiitterung. C. i. M., 65,
1896.

- Fieber und Zuckerausscheidung. B. k. \Y.. 1003.

- Experimentelles u'ber Nieremvassersucht. Ibid., 1905.

RlCKER, G. Beitrage zur Lehre von den Geschwiilsten in der Niere.
C. a. P., 8, 1897.

- Zur Histologie der in der Nebenniere gelegenen Nebennierenteile.

Diss., Jena, 1896.

Thymus. In L. O., i, p. 462, 1896.
RIEDER^ K. Undurchliissigkeit der Froschhaut fur Adrenalin. A. P. P.,

60, 1909.
RIEDL, F. Erfolgreiche Anwendung gefasscnveiternder Einspritzungen.

W. k. W., 1907.

RlEGER. Die Kastration in rechtl., sozial. und vitaler Hinsicht. Jena, 1900.
RlEHL, G. Zur Pathologic des Morbus Addispnii. Z. k. M., 10, p. 521, 1886.

- Mycosis fungoides und Morbus Addisonii. Ibid., No. 5, 1895.
RlELANDER. Das Paroophoron. Diss., Marburg, 1904.

RlESS, L. Die Addisonsche Krankheit. D. K., iii, pp. 227-260, 1903.
RlXGER, A., and PHEAR, A. G. A case of Addison's disease treated with

suprarenal extract. Transact, of the Clin. Soc. Lqnd., 29, 1890.
RlSEL. Spasmophilie und Kalzium. Arch. f. Kinderheilkunde, xviii, Nos.

3 and 4.
RITCHIE. The specificity and potency of adrenalytic and thymolytic sera.

Journ. of Pathol. and Bact., 12, p. 140, 1908.
RlTTER, C. Die Eimvirkung des Adrenalins auf die Lymphgefasse. M. K.,

1906.
RITZMANN, H. Uber den Mechanismus der Adrenalinglykosurie. M. m. W.,

1909; A. P. P., 61, p. 231, 1909.
RlVA-ROCCI. Le sostanze ipertens. del secrete renale. Gazz. mecl. Torino,

Nos. 19-23, 1898.
RIVAS MATEOS, CALLEJA, M. and C., FOLCH, R. Contribucion al estudio de

la estructura de las capsules suprarenals. Bolet. d. soc. espan. d.

hist, nat., iv, pp. 262-264, 1904.
RIVIERE, C. Hemorrhage of adrenals. Pathol. Transact., London, vol. 53,

1902.

ROAF and NIERENSTEIN. The physiol. action of the extract of the hypo-
bronchial gland, of purpura labillus. J. o. P., 36, p. 5, 1907.

- Adrenaline et purpurine. (Reply to M. R. Dubois.) C. r. S. B., 63,

P- 773) JQ07-

ROBERTSON. The parathyroid glands. Scot. Med. and Surg. Journ., 1897.
RODE, F. Das Adrenalin in der Rhino-Laryngologie. W. k. R., 1902.
R6MER, P. Spezifische Organtherapie des beginnenden Altersstars.

D. m. W., No. 7, 1909.
ROMER, R. Adrenaline als haemostaticum. Tijdschr. v. Geneesk., 44, V.-H.

i, 1904.
RORIG, A. Uber die Wirkung der Kastration von Cervus (cariacus) mexi-

canus auf die Schadelbildung. A. E.-M., viii, 633, 1899.
Welche Beziehungen bestehen zwischen den Reprpduktipnsorganen der

Cerviden und der Geweihbildung derselben. Ibid., viii, p. 382, 1899.

- Uber Geweihbildung und Geweihentwicklung. Ibid., x, pp. 525, 618; xi,

65, 225, 1900-1901.

ROSSLE. Uber Hypertrophie und Organkorrelation. M. m. W., 1907.
ROSSLE, R. Die Leber beim Diabetes. V. d. p. G., n, 1907.

- Beitrage zur Pathologic der Nebennieren. M. m. W., No. 26, 1910.
ROGER, H. Lesions des caps, surrenale dans 1'infection pneumo-bacillaire.

C. r. S. B., p. 52, 1894.

LITERATURE 561

ROGER, H. Physiologie norm, et path, du foie. Encycl. sclent. Paris.
ROGKR and GARNIER. Des lesions d. 1. glande thyr. dans 1'intox. phosphoric.

C. r. S. B., IQOO.
ROGER, H., and JOSUE, O. Action du foie sur les extraits intestinaux.

Ibid., 60, p. 580.

- Action de 1'extrait d'intestin. sur la pression arterielle. Ibid., 60, p. 371.
ROGOWITSCH. Zur Physiologie der Schilddruse. C. m. W., No. 36, 1886.

— Sur les effets de 1'ablation du corps thyroide chez les animaux. A. d. P.,

1888.
Veranderungen der Hypophysis nach Entfernung der Schilddruse.

Ziegl. Beitr., 4, 1889.

ROKITANSKY. Handbuch der path. Anat., 1861.
ROLLESTON, H. D. Note on the anatomy of the suprarenal bodies. J. o. A.

a. P., 26, 1892.

The Goulstonian lectures on the suprarenal bodies. Brit. Med. Journ.,
pp. 629, 745, 687.

- Some problems in connection with the suprarenals. Lancet, 1907.
ROLLESTON and MARKS. Primary malignant disease of the suprarenals.

A. J. M. S., 1898.

ROLLY. Uber die Neubildung von Glykogen bei glykogenfreien und auf
Karenz gesetzten Kaninchen. D. A. k. M., 83, 1-2.

ROLOFF. Ein Fall von Morbus Addisonii mit Atrophie der Nebennieren.
Ziegl. Beitr., 9.

ROMBERG, V. Lehrbuch der Krankheiten des Herzens und der Blutgefasse.
Stuttg., 1906.

ROMITTI, G. Atti della Soc. Tosc. di Sc. nat., vol. viii, 1892.

RONA, D. Beitrage zur Frage der syphilitischen und tuberkulosen Degenera-
tion der Nebennieren. Ung. med. Presse, 1899.

ROOS, E. Uber Schilddriisentherapie und Jodothyrin. Habil.-Schrift,
Leipzig, 1897.

- Uber die Wirkung des Jodothyrin. Z. ph. Ch., 22, 16, 1896.

- Unters. iiber d. Schilddruse. Ibid., 28, 1898.

- Klinische Erfahrungen mit Jodothyrin. M. m. W., 1902.

ROSE, E. Der Kropftod und die Radikalkur der Kropfe. A. k. Ch., 22,

1878.
ROSENBERG, A. Nebennierenextrakt in der Rhino-Laryngologie. B. k. W.,

1902.

- Urticaria nach endonasaler Anwendung von Nebennierenextrakt.

B. k. W., 1903.

ROSENBERG, S. Ub. d. Einfluss d. Pankreas auf d. Resorption d. Nahrung.
P. A., 70-

- Pankreas und Diabetes. B. C., i, p. 777, 1903.

- Zur Frage des Duodenaldiabetes. P. A., 121, p. 358, 1908.

— Weitere Untersuchungen zur Frage des Duodenaldiabetes. Ibid., p. 209.

- Innere Sekretion. Pankreas und Glykolyse. Handb. d. Bioch., iii, 1909.
ROSENFELD, G. Uber Antithyreoidinserum. Allg. med. Zentralz., 1903.

- Uber die Fettleibigkeit des Mannes und der Frau. M. K., 1907.
ROSENHAUPT. Beitr. zur Klinik der Tumoren usw. B. k. W., 1903.
ROSENHEIM, O. Choline in cerebro-spinal fluid. J. o. P., 35, p. 465, 1907.
ROSENHEIM, O., and TEBB, CHRISTINE. On a new physical phenomenon

observed in connection with the optical activity of so-called " pro-
tagon." Ibid., 37, pp. 348-354-

- On the lipoids of the adrenals. Ibid., 38, 1909.
The lipoids of the brain. Ibid., 38, 1909.

— On the so-called " protagon." Quart. Journ. of Exp. Phys., i, 1908.
ROSENSTEIN, E. Beitrage zur Pathologic der Nebennieren. Arb. aus d.

path.-anat. Inst. in Posen. Herausg. v. Lubarsch, 1901-1902.
ROSENSTIRN. Die Harnbestandteile bei Morbus Addisonii. V. A., 56, pp.

27-37, 1872.
ROSITSKY, V. Uber den Jodgehalt von Schilddriisen in Steiermark.

W. k. W., 1897.
ROSSA, E. Uber akzessorisches Nebennierengewebe im Ligamentum latum

und seine Beziehungen zu den Cysten und Tumoren des Ligaments.

A. G., 56, 1898.
ROSSI, G. Di alcune proprieta microchimiche delle isole di Langerhans.

II Monit. Zool. Italiana. Firenzi, 205.

36

562 LITERATURE

ROSSI, G. Sullo sviluppo delT ipofisi, etc. Accad. rned. Perugia, 1899; and
Lo Sperim., 1900.

- Sulla struttura della ipofisi e sulla esistenza di una ghiandola infundi-

bulaire nei mammiferi. Monit. Zool., 15, 1904.
ROSSMEISL, JOSEF. Untersuchungen uber die Milch kastrierter Kiihe. B. Z.,

21, p. 164.
ROUFFART and DELPORT. Etude d'une serie de malformations congemtales

des organes genitaux de la femme. Ann. de la Soc. beige de chir.,

2-3, 1910.

ROTH, P. Ein Fall von Morbus Addisonii. Diss., Wiirzburg, 1888.
ROTHBERGER, I., and WINTERBERG, H. Uber Vergiftungserscheinungen bei

Hunden mit Eckscher Fistel. Z. e. P., i, 1905.
ROUD, A. Contribution a Tetude du developpement de la capsule surrenale

de la souris. Bull, de la soc. vaudoise des sciences naturelles, 38,

Lausanne, 1903.
ROUQUES. Substance thermogenes extraites des tissus animaux sains et

fievres par auto-intoxication. These de Paris, 1893.

ROUTIER. Annales des maladies des organes genito-urinaires, xix, 1901.
ROUX, J. Sclerodermie et corps pituitaire. Rev. neurol., pp. 721-723, 1902.
ROUXEAU. Note sur 65 operations de thyroidectomie^ chez le lapin. C. r.

S. B., p. 638, 1895.

- De Pinfluence de 1'ablation du corps thyroide sur le developpement en

poids des glandes parathyroidiennes. Ibid., 1896.

- Resultats d. 1'exstirpation isolees d. glandules parathyroides. Ibid.,

p. 16, 1897.

- La bronchopneumonie consecutive a la thyroidectomie chez le lapin.

Ibid., 27 juillet, 1897.

- Relation des cent-trois operations de thyroidectomie. A. d. P., p. 136,

1897-
RUDERT. Wirkung des Adrenalins auf den intraocularen Druck. Z. f.

Augenh., 21, 1909.
RUBINATO. Osserv. sul rapporto fra diabete ed isole di Langerhans. Soc.

Med. Chir. di Bologna, 1908.
RUBENSTEIN. Uber die Verhaltnisse des Uterus nach Exstirpation beider

Ovarien und nach ihrer Transplantation an eine Stelle der Bauch-

hohle. Petersb. m. W., 1899.
RUBNER, M. Die Gesetze des Energieverbrauchs. Leipzig, 1902.

- Das Wachstumsproblem und die Lebensdauer des Menschen vom

energetischen Standpunkte aus betrachtet. A. H., 66, p. 127, 1908.
RUCKERT, A. t)ber die Emwirkung von Oidium lactis und Vibrio cholerae

auf Cholin-chlorid. Arch, de Pharmac., p. 676, 1908.
RUDINGER, CARL. Zur Atiologie und Pathogenese der Tetanic. Z. e. P.,

5, 1908.

- Uber Eiweissumsatz bei Morbus Basedowii. W. -k. W., 1908.

- Physiologic und Pathologic der Epithelkorperchen. Erg. d. inn. Med.

u. Kind., ii, 1909.
RUDINGER, C., and JONAS. Uber d. Verhaltnis d. Tetanic z. Dilatatio

ventriculi. 1904.

RUHRAEH, J. The relation of the thymus gland to marasmus. Lancet, 1903.
RUMMO and FERRANINI. Geroderma genitodistrofico. Rif. med., 1897.
RUSSEL, A. E. Cysts of the pineal body. Trans. Path. Soc. Lond., 50,

1888.
RUYTER, DE. Kongenitale Geschwulst d. Leber und der Nebennieren.

A. k. Ch., 40, 1890.
RYNBERK, G. v. Sulla funzipne endocrina del pancreas nei vertebrati e

sugli elementi morfologici che partecipano ad essa. Arch, di Fisiol.,

4, 497, 1907.

- A proposito di una rivista smtetica sugli elementi istologici che com-

ponio la funzione interna del pancreas. Arch, di Farm., vii, H. 3.

- Ancora la secrezione interna del pancreas. II Tomassi, 1909.
RZF.NTKOWSKI, v. Atheromatosis aortae bei Kaninchen nach intravenb'sen

Adrenalininjektion. B. k. W., 1904.

SABOLOTNOW, P. Zur Lehre von den Nierengeschwiilsten suprarenalen

Ursprungs. Ziegl. B., 41, 1907.
SABRAZES, J., and BONNES, J. Examen du sang dans 1'acromegalie.

C. r. S. B., 57, 1905.

LITERATURE 563

SABRAZES, J., and HUSNOT, P. Hypertrophie avec adenomes enkystes mul-
tiples des surrenales chez les vieillards. C. .r. S. B., 61, p. 445, igo6.

Tissu interstitiel, macrophages et cellules a 1'engrais des capsules sur-
renales chez 1'homme et les animaux. Gaz. hebd. de Bordeaux, 1907.

Tissu interstitiel des glandes surrenales. Folia hsematol., iv, 10,07.

- Nevromes et fibromes des surrenales. A. m. e., 20, 1908.

SACAZE. Syphilis avec syndrome Addisonien. Gaz. des hop., p. 58, 1895.
SACCHI. Di un caso di gigantismo infantile con Tumore del testicolo. Riv.

sper. di freniatria, 21, p. 149, 1895.

SACHS, H. Die Cytotoxine des Blutserums. B. C., i, 1903.
SACERDOTE. A proposite d. Marassini : " Sopra una particolarita, etc." Riv

d. Fisic. Sc. Nat. Pavia, 9, 1908.
SACERDOTTI, C. Sui nervi della tiroide. Ace. d. Torino, 29, 1893.

- Uber die Nerven der Schilddriise. I. M., n, 1894.

SAINTON, P. Les troubles psychiques dans les alterations des glandes a
secretion interne. L'Encephale, Nos. 3 and 4, 1906.

- Pathogenic et traitement du goitre exophtalmique. IXe Congr. franc

m., 1907.
SAINTON, P., and FERNET, JEAN. Corps thyroi'de et glande mammaire.

Progr. med., 1908.
SAINTON, P., and FERRAND, J. L'adipose douloureux ou maladie de Dercum.

Gaz. des hop., p. 957, 1903.
SAINTON, P., and PISANTE. Goitre exopht. traite par le serum de mouton

ethyroide. Revue Neurol., p. 1109, 1904.
SAINTON, P., and RATHERY, F. Myxaedeme et tumeur de 1'hypophyse. Soc.

med. hop., 1908.
ST. REMY. Contribution a 1'histologie de 1'hypophyse. C. r. A., 1892; and

A. B., 12, 1892.
— • Sur la signification morph. de la poche pharyngienne de Seessel.

C. r. S. B., 1895.
SAIZ, G. Beitrag zum Vorkommen u. zur Behandlung der Tetanic.

W. k. W., 1908.
SAJOUS, DE. The internal secretions and the principles of medicine. I,

Philadelphia, 1903.

— Physiological action and uses of adrenal extractives. Med. Rec. New

York, 70, p. 800, 1906.

- Les secretions internes, 1'appareil hypophyseo-surrenal, son role a 1'etat

normal et a 1'etat pathologique. IXe Congr. frang. de med. Paris,

1907; Gaz. des. hop., 1908.
SAKORRAPHOS, M. Examen du sang dans Pacromegalie. C. r. S. B., 57, p.

831, 1905.
SALECKER. Verwendung v. Nebennierensubstanzen z. brtlichen Analge-

sierung. D. militararztliche Z., p. 1904.
SALMON. L'hypophyse et la pathogenic de la maladie de Basedow. Rev.

de med., 1905.

- Sur 1'origine du sommeil. Ibid., 26, p. 368, 1906.

SALOMON. Gaswechsel bei Morbus Basedow u. Akromegalie. L. O., 5,

1900; B. k. W., 1904.
SALTYKOW. Atherosklerose bei Kaninchen nach wiederholten Staphylokken-

injektionen. Ziegiers Beitrage, 43, p. 147, 1908.

- Uber experimentelle Arteriosklerose. V. d. D. p. G. , 1908; C. a. P.,

19, 1908.

- Experimentelle Forschung in der Lehre der Arteriosklerose. C. f.

Stoffw., iii, 1908.
SALVIOLI. Du mode d'agir de 1'extrait des capsules surrenales sur le tissu

musculaire lisse. A. i. B., 37.
SALVIOLI and CARRARO. Sulla fisiologia dell' ipfisio. Arch, scienze med.,

31, 1907; and A. i. B., 49, 1908.
SALVIOLI and PEZZOLINI. Sur les differents modes d'agir des extraits medul-

laire et cortical des capsules surrenales. A. i. B., 37, p. 380.

— Contr. a 1'etude de la fonction des capsules surrenales. Ibid., 37, p. 390.
SALZER, H. Zur Entwicklung d. hypophyse bei Saugern. A. m. A., 51,

1898.

- Zur Frage der Schilddriisentransplantation. A. k. Ch., 89; W. k. "\V.,

1909.

SAMBERGER, F. Uber die Wirkung wiederholter Injectionen von Nebcn-
nierenextrakt. W. k. Rundschau, p. 577, 1902.

564 LITERATURE

SAMUEL. Uber Gewebssafttherapie und innere Sekretion. D. m. W., 1909.
SANCTIS DE, S. Gli infantilisme. Riv. Sperim. di Fren., 31, 1905.
SANDES. The corpus luteum of Dasyurus viverrinus. Zit nach Sobotta.
SANDMEYER. Die Folgen der partiellen Pankreasexstirpation beim Hunde

Z. B., 31, 1894.
SANDSTROM, J. Uber eine neue Driise beim Menschen und bei verschiedenen

Saugetieren. Ref. in Hofmann-Schwalbes Jahresb., ix, i Abt. ;

Schmidts Jahrb., 1880.
SANO, T. Uber die Entgiftung v. Strychnin u. Kokain d. d. Ruckenmark.

P. A., 120, 1907.

SANQUIRICO. Sur 1'exstirpation du corps thyroide. A. i. B., 9, 1888.
SANQUERICO and ORECCHIA. Accad. d. Fisiol. d. Siena, 6, 1887 and 1893.
SANSOM. Addison's disease treated by suprarenal extract. Brit. Med.

Journ., November 16, 1895.
SANTI RINDONE LO RE. Sulla estirpazione delle capsule surrenali. Rif.

med., 1895.
SANTIDE. Parathyroidgeschwulst. Laryng. Ges., London, 1899; Int. Cbl.

f. Laryng. ^ 1900.
SARTIRANA. Neuer Beitrag zur Kenntnis der zytotoxischen Sera. C. f. B.,

36, 37, 1904.
SATA. Uber die VVirkung und die Spezifitat der Zytotoxine im Organismus.

Zieglers Beitr., 36 and 39, 1906.
SATRE, A. Insuffisance hypophysaire traite avec succes par 1'opotherapie.

Dauphine medical, 1907.
SAUERBECK, E. Die Langerhansschen Inseln des Pankreas und ihre Bezie-

hung zum Diabetes mellitus. V. A., 177, Suppl. u. L. O., 8, p. 473,

1902.
— Zur Frage des Pankreaszytolysins. Kritische Bemerkung. C. f. B.,

34, 1905-

- Neue Exper. z. Frage n. d. Bedeutung d. Langerhansschen Inseln.

V. d. p. G. , 1904.

SAUR£, L. Physiologic du Pancreas. Arch. gen. de med., p. 25, 1908.
SAVAGNONE, E. Contr. alia conosc. della fine struttura dell' ipofisio. Riv.

ital. di Neuropath., In Patalog. , i, 1909.
SAVARI, M. Ub. d. giftigen Bestandteil des Hams bei Eklampsie. H. B.,

n, 1907.
SAVIOTTI, G. Untersuchungen iiber den feineren Bau des Pankreas.

A. m. A., 5, 1869.
SAWELIEW, S. Uber die Wirkung der Adrenalininjektionen auf das Blut

und iiber Adrenalinimmunitat. Diss., St. Petersburg.
SCAFFIDI, V. Feinerer Bau und Funktion der Hypophysis des Menschen.

A. m. A., 64, 1904.
SCIALLERO. L'organoterapia testiculare et 1'orchipina. Rif. med., Jg. 21,

No. s-
SCHABAD. Uber Diabetes pancreaticus. Diss., Moskau, 1895. Ref. V. H.,

ii, 1895.

SCHADE, H. Diabetes und Katalyse. M. m. W., 1907.
SCHAEFER, E. A. On internal secretion. Brit. Med. Asso. Lancet, ii, p.

320, 1895; Brit. Med. Journ., ii, 1895.

- On certain practical applications of extract of suprarenal medulla.

Brit. Med. Journ., 1901, April 27, 1901.

- Schafer's Text-book of Physiology, i, 1898; ii, 1900.

- Les vaisseaux coronaires ont-ils des nerfs vasomoteur ? A. d. sc. biol.,

n, Suppl. Festschrift fur Pawlow, p. 251, 1904.

- On the present condition of our knowledge regarding the functions of

the suprarenal capsules. Brit. Med. Journ. ; Lancet, i, 1908.

- Functions of the pituitary b,ody. P. R. S., Si, p. 550, October, 1909.
SCHAEFER and HERRING. The action of pituitary extracts upon the kidney.

P. R. S., 77, p. 571, 1906; Phil. Trans, of the Royal Soc. of London,

ser. B, 199, 1907.
SCHAEFER and MOORE. On the contractility and innervation of the spleen.

J. o. P., 20, 1906.
SCHAEFER and SCHARLIEB. Chloroform poisoning. Trans. Roy. Soc. of

Edinb., 41, 1904.
SCHAEFER and VINCENT. On the action of the pituitary extract injected

intravenously. J. o. P., 24, xix, 1899; and ibid., 25, p. 87, 1899.

LITERATURE 565

SCHAEFFER, G. La physiologic de 1'appareil thyro-parathyroidien d'apres les

travaux recents. Biol. med., ann. 4, pp. 1-34.
SCHAFFLE, KARL. Notes on family goitre. J. A. M. A., lii, p. 212, January

16, 1909.
SCHAFFER, J. Uber das Vorkommen eosophincr Zellen in der menschlichcn

Thymus. C. m. Y\T.S 1891.

- Uber den feineren Bau der Thymus. S. \V. A., 102, 1893.
SCHAFFER, J., and RABL, H. Das thyreothymische System des Maulwurfs

und der Spitzmaus. I. u. II. Th., S. W. A., 118, IQOQ.

SCHAPER, A. Beitrage zur Histologie der Glandula carotica. A. m. A., 40,
pp. 287-319, 1892.

- Uber die sogenannten Epithelkb'rperchen. A. m. A., 46, 1895.

- Einige Bemerkungen iiber das Wesen und die mqrphologische Stellung

der Glandula coccygea (Glomus coccygeum.). An. An., 25, 1904.
SCHATILOFF, P. Die Nierensekretion im Lichte der Adrenalinwirkung.

A. A. P., 1908.
SCHEEL, OLAF. Uber Nebennieren. Sekretkb'rnchen-Odem-Gewicht. V. A.,

192, 1908.

- Erwiderung auf E. O. Hultgrens Bemerkungen. V. A., 194, p. 566.
SCHEIDEMANDEL, E. Uber die durch Adrenalininjektionen zu erze^ugenden

Aortenverkalkungen der Kanninchen. V. A., 181, p. 363, 1905.

SCJJENK, F. Giftwirkung des menschlichen Plazentasaftes bei Kaninchen.
C. G., 1909.

SCHEULT, R. A case of Addison's disease in a negress. Lancet, ii, 1907.

SCHIEFFERDECKER, P. Uber das Verhalten des Bindegewebes bei der Hyper-
trophie und Atrophie der Muskeln und iiber die Schliisse, welche man
aus diesem Verhalten iiber die Symbiose verschiedener Korpergewebe
machen kann. S. d. niederrhein. Ges. f. Natur- u. Heilk., pp. 75-91,
26 Oktober, 1903.

— Nerven- und Muskelfibrillen, das Neuron und der Zusammenhang der

Neuronen. Ibid., pp. 85-93, Bonn, 1904.

— Uber die Neuronen und die innere Sekretion. Ibid., pp. 46-54. 23

Oktober, 1905.

- Uber Symbiose. Ibid., pp. 44-54, 13 Juni, 1904.

- Indikationen und Kontraindikationen des Radfahrens. Leipzig, IQOI.
— - Neuronen und Neuronenbahnen. Leipzig, Barth, 1906.

SCHIEFFERDECKER and SCHULTZE. Beitrag zur Kenntnis der Myotonia con-
genita, der Tetanic mit myotonischen Symptomen, der Paralyse
agitans und einiger anderer Muskelkrankheiten, zur Kenntnis der
aktiven Hypertrophie und des normalen Muskelbaues. D. Z. N., 25,

27, 345, 1903-

SCHIFF, A. Beeinflussung des Stoffwechsels durch Hypophysis- und Thy-
reoideapraparate. Z. k. M., 32, Suppl., pp. 284-290, 1897; W. k. W.,

1897.

SCHIFF, M. Unters. iiber d. Zuckerbildung in d. Leber. Wiirzburg, 1859.
Zur Physiologic des Pankreas. A. f. Heilk., 271, 1862.

- Sopra 1'estirpazione delle capsule soprarenali. L'imparziale, pp. 234-

237, 1863; Union medicale, p. 347, 1863.

— Bericht iiber eine Versuchsreihe betr. die Wirkungen d. Exstirpation der

Schilddriise. A. P. P., 18, 1884; and Rev. med. de la Suisse Rom.,
Nos. 2 and 8, 1884.

— Gesam. Beitr. z. Physiologic. 3 Bande. Lausanne, 1894.
SCHILLING, F. Morbus Addisonii und Organotherapie. M. m. W., 1897.
SCHIPEROWITSCH, W. Zur Atiologie und Therapie des Morbus Addisonii.

(Russisch.) Wochenschr. prakt. Med., No. 13, 1895.

SCHIROKOGOROFF. Die skleroitische Erkrankung der Arterien nach Adre-
nalininjektionen. V. A., IQI, p. 482, 1908.

- Sur action phagocytaire des capsules surrenales. C. r. S. B., 65, p. 300.

17 octobre, 1908; Wratsch. Gaz., No. 44, 1908; Fol. haem, iii.

SCHLAGENHAUFER and v. WAGNER. Beitrage zur Atiologie und zur Patho-
logic des endemischen Krentinismus. Leipzig-Wien, 1910.

SCHLAYER. Zur Frage der drucksteigernden Substanzen im Blute bei
chronischer Nephritis. D. m. W., 1907; and M. w. M., 1908.

SCHLAYER and HEDINGER. Exper. Studien Uber toxische Nephritis. D. A.
k. M., 90, 1907.

SCHLECHT, H. Einfache Methode zur Priifung der Pankreasfunktion.
M. m. W., 1908.

566 LITERATURE

SCHLESINGER, H. Therapeutische Erfahrungen bei Behandlung schwerer
innerer Blutungen mit Nebennierenextrakt. W. k. W., 1904.

SCHLESINGER, W. Uber den Ursprung des diastatischen Fermentes im Blute
und iiber Beziehungen zum Diabetes mellitus. D. m. W., igoS.

SCHLOFFER. Erfolgreiche Operation eines Hypophysentumors auf nasalem
Wege. W. k. W., p. 621, 1907.

- Berichtigung zu dem Artikel " Erfolgreiche Operation." W. k. W.,

No. 22, 1907.

- Weiterer Bericht iiber den Fall von operiertem Hypophysentumor.

W. k. W., 1907.

- Zur Frage der Operation der Hypophysis. Bruns. Beitr. z. k. Ch., 50.
SCHMALTZ. Zur Kasuistik des Morbus Addisunii. D. m. W., 1890.
SCHMID, E. Der Sekretionsvorgang in der Schilddriise. A. m. A., 47, 1896.
SCHMID, J. Beeinflussung von Druck und Stromvolumen in der Pfprtader

durch die Atmung und durch experimentelle Eingriffe. P. A., 126,
1909.

SCHMIDT, E. Beziehung der Langerhansschen Insel des Pankreas zum
Diabetes mellitus. M. m. W., 1902.

- liber Cholin, Neurin and verwandte Verbindungen. Lieb. Ann., 337.
SCHMIDT, M. W. Uber Pseudo-Hermaphroditismus bei Rana temp.

A. m. A., 72, 1908.

SCHMIEDEN. Erfolgreiche Einheilung exstirpierter Nebennieren b. Kanin-
chen. P. A., 90, 1902.

- Erfolgreiche experimentelle Verlagerung von Nebennierengewebe.

Z. Ch., 70, 1903.

Si'HMIERGELD, A. Lesions des glandes a secretion interne dans deux cas
d'alcoolisme chronique. A. m. e., 21, 1909.

- Les glandes a secretion interne dans la paralyse generale. L'Encephale,

ii, 1907.

SCHMORL., G. Patholog.-anat. Untersuchungen Uber puerperale Eklampsie.
Leipzig, 1893.

- Zur Kenntnis der akzessorischen Nebennieren. Zieglers Beitr., 9, 1891.
SCHNAUDIGL, O. Das Suprareninum. Opht. KL, No. 13, 1903.
SCHXEIDEMUHL. Vergl. anat. Unters iib. d. Ban der Cowperschen Driisen.

D. Z. f. Tierm. u. vergl. Path., vi.
SCHNITZLER and EWALD. Uber das Vorkommen von Thyreoidin in der

Hypophyse. W. k. W., 1896.

SCHON, N. Zwei Falle von Infantilismus. Moskau, 1898; Ref. N. C., 1899.
SCHONBORN, S. Zur Wirkung der Thyreoideastoffe. A. P. P., 60, 1909.
SCHONDORFF, B. Uber den Einfluss der Schilddriise auf den Stoffwechsel.

P. A., 67, 395, 1897.

- Ausscheidung von Zucker im Harn von gesunden Menschen. Ibid., 121,

1908.
SCHONE. Transplantation von Geschwiilsten und normalen Geweben.

B. z. k. Ch., 61.

SCHONEMANN. Hypophysis und Thyreoidea. V. A., 129, 1892.
SCHOLZ, W. Untersuchungen iiber den Kretinismus. Zusarnmenf. Arbeit,
Berlin, 1906.

- Uber den Stoffwechsel der Kretinen. Z. e. P., 2, 1905.

- Schilddriisenbehandlung und Stoffwechsel bei Morbus Basedowii.

C. i. M., 1895.

SCHOLZ, W., and ZINGERLE, H. Beitr. z. path. Anatomic der Kretinengehirne.

Z. H., 1906.
SCHRANK, F. Experimentelle Beitrage zur Wirkung der Jodpraparate auf

die Adrenalin-Arterionekrose. Z. k. M., 64, p. 471, 1908.
Uber die Wirkung des Spermins bei Adrenalin-Arterionekrose. Ibid.,

64, 1907.

- Zur antagon. Wirkung des Adrenalins und Chlorkalciums. Ibid., 67,

1909.
SCHRAUBE, K. Die Beziehungen der Thymusdriise zum Morbus Basedowii.

Diss., Miinchen, 1908.
SCHREIBER, L. Beitrage zur Kenntnis der Entwicklung und des Baues

der Glandulae parathyreoideae (Epithelkorperchen des Menschen).

A. m. A., 52, 1908.
SCHRYVER, S. D. Autolysis, the influence of the thyroid. J. o. P., 32,

P- 159-
SCHUBIGKR-HARTMANN, F. Adrenalin. Schw. Korr.-BL, 1902.

LITERATURE 567

SCHUCKLXC;. Hautverfiirbung nach Injektion von Nebennierenextrakt.

M. m. W.j 1903.
SCHULLER, A. Keimdriisen u. Nervensystem. Arb. a. d. Neurolog. Inst.

Wien, 1007.

- liber Infantilismus. W. m. W., 1907.

- Die Schadelbasis im Rontgenbild. Fortschr. a. d. Geb. d. Rontgenstr.

Erganzungsbd. n.
SCHULLER. Antithyreoidinserum Moebus bei 5 Fallen von Morbus Base-

dowii. D. m. Z., 1905.
SCHUTZE, A. Beitrage zur Kenntnis der zellenlosenden Sera. D. m. W.,

1900.

- Antinebennierenserum. Z. k. M., 12, 1908.

SCHULTZ, P., and ZUELZER, G. Totalexstirpation des Pankreas beim Hunde.

C. P., 19.

SCHULTZ, W. H. Der Einfluss der Instillation von Adrenalin in Augen von

Saugetieren. C. f. P., 22, p. 713, 1908.
SCHULTZE, F. tiber Melanoplakie der Mundschleimhaut und die Diagnose

auf Morbus Addisonii. D. m. W., 1898.
SCHULTZE, O. Zur Frage von den geschlechsbildenden Ursachen. A. m. A.,

63, p. 97, 1904.
SCHULTZE, W. Die Bedeutung der Langerhansschen Inseln im Pankreas.

Ibid., 56, 491.

Fall von Akromelagie. D. m. W., 1904.
SCHULZ, O. tiber die Lebenswichtigkeit der Schilddriise und des Schild-

dnisenapparates. D. m. W., 1900.
Neure und neueste Schilddriisenforschung. Festschr. f. J. Rosental.

Leipzig, 1906.

SCHULZ, R. Tumor der Zirbeldriise. N. C.., iv, 1886.
SCHUMACHER, S. v. tiber das Glomus coccygeum und die Glomeruli

caudales der Saugetiere. A. m. A., 71, pp. 58-115, 1907.
SCHUR, H., and WIESEL, J. tiber eine der Adrenalin wirkung analoge

Wirkung des Blutserums von Nephritikern auf das Froschauge.

W. k. W., Nos. 23 and 27, 1907.

- Beitrage zur Physiologie und Pathologic des chromaffinen Gewebes.

V. d. p. G. Dresden, n ; and W. k. W., No. 40, 1907.

- tiber das Verhalten des chromaffinen Gewebes bei der Narkose.

W. k. W., 1908.

- Zur Frage d. drucksteigernden Subst. im Blute bei chron. Nephritis.

D. m. W., 1907.

SCHWARZ. Alcune considerazioni a proposito delle consequenze della com-

pleta tireoidectomia. Lo Sperimentale, 1891.
Tumeur de la capsule surrenale droite ; neprectomie. Bull, et Mem. de

la Soc. Chir., p. 764, 1893.
SCHWARZ, C. Beitrag zur Wirkung des Cholins auf die Pankreassekretion.

C. P., 23, No. 16, 1909.
SCHWARZ, C., and LEDERER, R. tiber das Vorkommen von Cholin in der

Thymus, in der Milz und in den Lymphdriisen. P. A., 124, 1908.
SCHWARZ, O. tiber einige Anfallserscheinungen nach Exstirpation beider

Nebennieren. W. k. W., 1909.
SCHWARZWALD, R. T. tiber das Verhalten des chromaffinen Gewebes beim

Menschen unter dem Einfluss der Narkose. V. 13, p. G., p. 268, 1909.
SCHWONER. Uber hereditare Akromegalie. Z. k. M., 32, Suppl.-Heft.
ScmvYZER, F. Zur Atiologie des Morbus Addisonii. New York m. M.T

x, 1898.

SciAMANNAj C. Patologia et Terapia del Gran simpatico. Milano, 1894.
SCOTT-MACFIE, J. W. Action of tissue extracts on protoplasm. J. o. P.,

30, 1905.
SCOTT- AVARTHIN, A. Accessory adrenal body in the broad ligament (adrenal

of Marchand). Amer. Journ. of Obstet., vol. 42, 1900.
SEBASTIANI, V. Contribute alia studio del potere tossico ed emolitico del

sieri di sangue nei basedowiani e nuove vedute a proposito della

sieroterapie di questi ulcimi. Riy. crit. di clin. med., ix, p. 22.
SEDGWICK, A. Development of the kidney in relation with the Wolffian

body in the chick. Quart. Journ. Micr. Soc., 22, pp. 146 and 372, 1880.
SEEGEN. Der Diabetes mellitus. Berlin, 1875; 3 Aufl., 1893.

- Die Zuckerbildung im Tierkorper. Berlin, 1900.
SEELIG. Beitrag zum Diabetes pancreaticus. B. k. W., 1892.

568 LITERATURE

SEEMANN, CHAVE. Uber eine neue Methode der Transplantation des Schild-

driisengewebes. Z. Ch., 96, 1908.

SEEMANN, J. Die blutbildenden Organe. E. P., 3, I. Abt., p. 45.
SEESSEL. Zur Entwicklungsgeschichte des Vorderarms. A. A., 1877.
SEHRT, E. Zur Fermentwirkung des Mumienmuskels. B. k. W., 1904.
SEIDELL, A. The determination of iodine in thyroid. J. Am. Chem. Soc.,

31, p. 1326, 1900.
SEITZ. Die Follikelatresie wahrend der Schwangerschaft, insbesondere die

Hypertrophie und Hyperplasie der Theca-interna-Zellen (Theca-

Luteinzellen) und ihre Beziehung zur Corpus luteum-Bildung. A. G.,

77, 203, 1905.

- Eklampsie und Parathyroidea. A. G., 89, 1909.

SELLEI, J. Tonogen in der Urologie. Orvos. Lapja, p. 895, 1904.
SELIGSOHN. De pigmentis pathologicis ac morbo Addisonnii, adjecta chemia
glandularum suprarenalium. Diss., Berlin, 1858; and V. A., 18,

P- 355-
SELKE. tJber ein epitheliales Papillom des Gehirns. Diss., Konigsberg,

1891.
SELHEIM, H. Zur Lehre von den sekundaren Geschlechtscharakteren.

B. G. G., i, 1898.

- Kastration und Knochenwachstum. Ibid., ii, 1899.

- Kastration und sekundare Geschlechtscharaktere. Ibid., v, p. 409, 1901.
SEMON, R. Die indifferente Anlage der Keimdriisen beim Hiihnchen und

ihre Differenzierung zum Hoden. Habilitationsschrift, Jena, 1887.

- t)ber die morphologische Bedeutung der Urniere in ihrem Verhaltnisse

zur Vorniere und Nebenniere und iiber ihre Verbindung mit dem
Genitalsystem. A. A., 1890.

- Studien iiber den Bauplan des Urogenitalsystems; dargelegt an der

Entwicklung dieses Organsystems bei Ichthyosis glutinosus. Jena,
Zeitschr. f. Nat., 19, 1891.

- Das Exkretionssystem der Myxinoiden in seiner Bedeutung fur die

morphologische Auffassung des Urogenitalsystems der Wirbeltiere.
Fests. Gegenbaur, 3, 1896.

SEMPER, C. Das Urogenitalsystem der Plagiostomen und seine Bedeutung
fur das der iibrigen Wirbeltiere. Arb. a. d. zool.-zoot. Inst.
Wtirzburg, 2, pp. i95-5OQj 1875.

- Stammesverwandtschaft d. Wirbeltiere u. d. Wirbellosen. Ibid., 2,

1875-
SENATOR, H. Osteomalacie und Organtherapie. B. k. W., 1897.

— Untersuchung des Stoffwechsels bei einem mit Nebennierensubstanz

behandelten Falle von Addisonscher Krankheit. Charite-Ann., 22,

p. 235, 1897.

SERGENT, E. L'insuffisance surrenale aigue. P. m., 1902 and 1903.
SERGENT, E., and BERNARD, L. Note pour servir a 1'etude de la pathol.

des caps, surren. C. r. S. B., 1898.

- Sur un syndrome clinique non Addisonien a evolution aigue, a 1'insuf-

fisance capsulaire. A gen. ined., nouv. ser., ii, 1899.

- L'insuffisance surrenale. Encycl. scient. Paris, 1902.

- Les Surrenalites chroniques d'origine infectieuse et 1'insuffisance sur-

renale lente. A gen. de med., i, No. i, p. 14, 1904.

- Le Diagnostic du syndrome d'lnsufKsance surrenale pure. Soc. d.

hopit., 1904.
SERRALACH and PARES. Quelques donnees sur la physiologic de la prostate

et du testicule. C. r. S. B., 63, p. 790, 1907.
SEZARY. Les glandes surrenales des tuberculeux. C. r. S. B., 65, p. 603,

12 decembre, 1908.

- Structure metatypique de la corticale des surrenales. Ibid., 65, p. 430.
SHATTOCK, C. G. Ovarian Teratomata. Lancet, February 15, 1908.

- Cretinism in calves. J. o. P., 29, 1903.

SHATTOCK, C. G., and SELIGMANN, C. G. Some experiments made to test
the action of extract of adrenal cortex. P. R. S., So, pp. 473-477.
1908.

— Verschluss d. Vasa deferentia. Ibid., 72, Februar, 1904.

- Example of incomplete glandular hermaphroditism in domestic fowl.

Ibid., 1907.
SHAW, H. BATTY. Organotherapy. London, 1905.

— Autointoxication. Goulstonian Lect. Lancet, i, 1906.

LITERATURE 569

SHIMA, R. Uber die Erweiterung der Pupille bei Adrenalineintraufelugen
in ihrer Abhangigkeit vom Zentralnervensystem. P. A., 126 and 127,
1 909.

- Zur Frage der nach Adrenalinwirkung auftretenden Veranderungen des

Zentralnervensystems. N. C., 1908; and Arb. a. d. neurol. Inst. Wien,

1908.
SHIOTA, H. Uber das Schicksal und die Funktion der transplantierten

Nebennieren. P. A., 128, 1909.
SHORT-RENDLE, A. Blood-pressure and pigmentation in Addison's disease.

Lancet, 1506.

SlCARD. Surrenalite hemorrhagique. Sem. med., 1904.

SICK, K. Flimmerepithelcysten in der Nebennierenkapsel. V. A., 172, 1903.
SIEGEL. Abkuhlung als Krankheitsursache. D. m. W., 1908; Z. e. P., 5,

1908.
SIEGERT. Zur Pathologic der infantilen Myxidiotie, des sporadischen Kretin-

ismus oder infantilen Myxodems der Autoren. Jahrb. f. Kinderh.,

1901.
SIKEMEIER, W. Adrenalin und Cocain-Adrenalinanasthesie. A. k. Ch., 78,

1905.
SILVESTRI, E. L'opoterapia renale e la teoria delle nefrolisine. II Poli-

clinico, 9, 53, 1904.
SILVESTRINI, E., and TOSATTI, C. Degli effetti della capsulectomia in cavie

e coniglie gravide. Soc. med. chir., Modena, 7 dicembre, 1908;

Pathologica, 1909.
SILVESTRINI, R. Sull' azione dell' estratto acquoso del lobo posteriori dell'

ipofisi sulla pressione sanguinea e sul cuore. Riv. crit. di clin.

med., No. 28, 1905.
SILVESTRINI, R., and BADUEL, A. Recherches pour preciser quelle est la

partie active du lobe posterieur de 1'hypophyse. Nouv. Icon, de la

Salp., 13, 1900.
SILVESTRINI, R., and DADDI, G. Ricerche istologiche in un caso di morbo

di Addison. Settimana med., lii, 1898.
SIMMONDS, M. Uber kompensatorische Hypertrophie der Nebenniere.

V. A., 153, 1898; and M. m. W., 1898.

- tiber Nebennierenblutungen. V. A., 170, pp. 242-256, 1902.

- Uber Nebennierenschrumpfungen bei Morbus Addisonii. Ibid., 172,

1903.

Weitere Beobacht. lib. kompensator. Hypertrophie der Nebenniere.
C. a. P., 13, 1902.

- Uber Bronzediabetes und Pigmentzirrhose. B. k. W., 1909.

- liber die Einwirkung von Rontgenstrahlen auf die Hoden. Fortschr.

a. d. G. d. Rontgenstr., 14, 1909-10.
SIMON, CH. Thyroide laterale et glandule thyroide chez les mammiferes.

These de Nancy, 1896.

SIMON, J. A physiological essay on the thymus gland. London, 1845.
SIMONOWITSCH. Contr. a 1'etude de Faction et d'empoi' d'adrenaline.

These de St. Petersb., 1903; Ref. J. d. P. P., 6, p. 564, 1904.
SINGER, H. Die Nebennieren und ihr wirksames Prinzip. Th. M., 1902.
SlNIBALDI. Arch, d'anat. patholog. e sc. affin., fasc. ii, 1906.
SINN. Der Einfluss exper. Pankreasgangunteroind. auf d. Nahrungsresorp-

tion. Diss., Marburg, 1907.
SLXNHUBER, F. Beziehung der Thymus zum Kalkstoffwechsel. Z. k. M.,

54, 1904-
SlPPEL. Ein typisches Krankheitsbild von protrahiertem Chloroformtod.

A. G., 88, 1998.
SKROBANSKY, K. Uber Immunisierung von Tieren mit Ovarien einer

anderen Tierspezies. Russ. Zeitschr. f. Geb. u. Gyn., Januar, 1904.

- Diskuss. zu Fraenkels Vortrag. C. G., 1904; and M. m. W., 1903.
SLADE, J. G. The physiological action of muscle extract. J. o. P., 35,

1907.
SLATINEANO. Recherches sur le serum thyreotoxique. C. r. S. B., 57, ii,

p. 76, 1905.
SMALLWOODj W. M. Adrenal tumours in the kidney of the frog. An. An.,

26, 1905.
SMIRNOFF, A. Struktur d. Nervenzellen im Sympathicus d. Amphib.

A. m. A., 35, 1890.
SMITH, T. A case of " Thymic Death." Lancet, 1908.

57° LITERATURE

SOBOTTA. Tiber die Bildung des Corpus luteum bei der Maus. A. m. A., 47.

- tiber die Entstehung d. Corpus luteum d. Saugetiere. An. Hefte, n,

IQOI.
SOCA. Sur un cas de sommeil prolonge pendant sept mois par tumeur de

1'hypophyse. Nouy. Icon, de la Salpetriere, 13, p. 101, 1900.
SODDU, L. Intorno agli effetti della estirpazione delle capsule surrenali

nel cane. Sperimentale, 52; Ref. C. i. M., 20, i8gg.
SOEDERLUND, G., and BACKMA.X.X, A. Studien iiber die Thymusinvolution.

Die Altersveranderungen der Thymusdriise beim Kaninchen. A. m. A.,

73, 1909.
SOKOLOFF, B. Uber die Bauchspeicheldriise in verschiedenen Phasen ihrer

Tiitigkeit. Diss., St. Petersburg, 1883.

- Einfluss der Ovarialexstirpation auf Strukturveranderungen d. Uterus.

A. G., 51.
SOLDI, T. Casi di osteomalacia guariti colla terapia adrenalinica. Patho-

logica, 1908.

SOLGER. Nebenniere. In Zuelzers Handb., 1894.
SOLI, U. Les testicules chez les animaux ayant subi 1'ablation de thymus.

P. m., 1907.

- Comment se comportent les testicules chez les animaux prives de thymus.

A. i. B., 47, 1907.

- Influenza del timo sullo sviluppo scelettico. Soc. ital. di Patol. Modena,.

1909.

SOLLIER and CHARTTER. L/opotherapie ovarienne et hypophysaires dans cer-
tains troubles mentaux. Congr. de Dijon, aout, 1908.

SOLLMANN, T. The comparative physiologic activity of some commercial
suprarenal preparations. A. J. M. S., 47, pp. 792-793, 1906.

SOMMER, A., and FLORCKEN, H. Uber die Funktion der Thymus. Sitzungs-
ber. d. phys. med. Ges. z. Wiirzburg, H. 3-4, 1908.

SOUZA-LEITE. De Pacromegalie. These de Paris, 1890.

SOULIE, A. Sur les premiers stades du developpement de la capsule sur-
renale chez quclques mammiferes. C. r. de 1'Assoc. des Anatomistes,
IVe session. Montpellier, 1902.

- Recherches sur le developpement des capsules surrenales chez les verte-

bres superieurs. Journ. de 1'anat. et phys. These de Paris, 1903.

- Sur le developpement de la substance medullaire de la capsule surrenale

chez quelques mammiferes. C. r. de 1'Assoc. des Annt., 5 sess., p. 63,

Liege, 1903.
SOULIE and VERDUN, P. Sur les premiers stades du developp. de la thyroide,

C. r. S. B., 1897; and J. A. P., 33, 1897.

SOUPAULT. Maladie de Basedow. Bull, de la Soc. d'Anat., p. 592, 1897.
SOUQUES and MOREL. Traitement de I'hemoptysie par Tadrenaline. Soc.

des hop., 1902.
SriLLMAN, L., and HOCHE, L. Maladie d'Addison a denouement rapide.

A. gen. de med., ii, p. 2369, 1903.
SriNA, A. Experimentelle Untersuchungen iiber den Einfluss von Riicken-

marksdurchtrennungen auf den Kreislauf des Gehirns. W. k. W.,

1897-

- Beitr. zur Lehre von der Erektion und Ejakulation. ^ . m. Bl., 1897.

- Exp. Beitr. z. Kenntn. der Hyperamie des Gehirns. Ibid., 1898.

- Exp. Unters. iiber die Bildung d. Liquor cerebrospinaiis. P. A., 76 and

80, 1899-1900.

SPINEANU. These de Boucarest, 1899; zit. nch Vitzou.
SPITTA, W. Uber Morphiumdiabetes. Z. e. P., 5, p. 94, 1908.
SPITZER. Die zuckerzerstbrende Kraft des Blutes und der Gewcbe. P. A.,

60, 1896.
SRDINKO, O. Uber Bau und Entwicklung der Nebennieren des Frosches

(bohmisch). Sitzungsb. d. bohm. Kaiser-Franz-Joseph-Akad. in Prag,

2 Kl., No. 12, 1898.

- Beitrage zur Kenntnis iiber die Fntwicklung der Nebennieren bei den

Amphibien (bohmisch). Ibid., No. 32, 1900.

- Bau und Entwicklung der Nebennieren bei Anuren. An. An., 18, pp.

500-508, 1900.

- Beitrage zur Kenntnis der Nebenniere der Knochenfische. Uber Bau

und Entwicklung der Stanniusschen Kb'rperchcn der Lopobranchier.
A. m. A., 66, pp. 773-802, 1903.

LITERATURE 571

SRDINKO, O. Beitrag zur vergleichendt n Anatomic und Embryologie der
Nebenniere, 1903.

- tiber die Blutzirkulation in der Nebenniere der Wirbeltiere. I-IV.

Sitzungsb. der bohmischen Kaiser - Franz - Joseph - Akad. Prag
(bohmisch), Nos. 12, 16, 28, 1905.

- TJber die Kreislaufbahnen in der Nebenniere des Menschen und deren

Beziehungen zu gewissen Affektionen dieser Driise. Ibid., 1905; Ref.
Schmidts Jahrb., 291, p. 33.

— Beitrag zur Sinusoidenfrage (bohmisch), 1905.

- Eine sichere Methode zur Differenzierung der Rinclen- und Markelemente

in de.r Nebenniere, besonders bei Saugetieren und Menschen. An. An.,
26, 1905.

- tJber d. Entwicklung d. Nebenniere bei d. Lophobronchien (bohmisch).

1907.
SSAWELJEW. Uber den Einfluss der subkutanen Adrenalininjektion auf das

Blut und liber Adrenalinimmunitat. Ref. B. C.. iii, No. 326, 1904.
SSOBOLEW, L. W. Zur normalen und pathologischen Morphologic der

inneren Sekretion der Bauchspeicheldriise. V. A., 168; Diss, St.

Petersburg, 1901.

— Uber die Struktur der Bauchspeicheldriise. C. a. P., 16, 1902.

- Uber die Struma der Langerhansschen Inseln. V. A., 177, Suppl., 1904.

- Zur Lehre liber die Entwicklung von Paraphysis und Epiphysis bei den

Schlangen. A. m. A., 70, p. 318, 1907.
STABEL, H. Vers. m. Thryrojodin u. Thyraden an thyreoidektom. Hunden.

B. k. W., 1897.

STACHINI. Rivista sperimentale di Freniatria, 29; and Rev. Neur. , 1903.
SXADELMANN. Uber das Vorkommen von Gallensauren, Hippursaure und

Benzoesaure in den Nebennieren. Z. p. Ch., i8,_p. 380, 1893.

- Zur Lehre von der Akromegalie. Z. k. M., 55, 1904.

STAMATIADE, A. Beitrage zum Studium der Lasionen der Nebennieren bei
verschiedenen Krankheiten. Diss., Bukarest, 1907; Ref. C. i. M.,
p. 764, 1907.

STANGL, E. Zur Histologie des Pankreas. W. k. W., 1901; V. 6 d. p. G.,
1902.

— Tumor der chromaffinen Nebenorgane d. Symphaticus (Zuckerandl).

W. k. W., 1902.

- Zur Pathologic der Nebenorgane des Symphaticus. V. G. d. N. A.

Karlsbad, 1902.
STARGART. Nekrosen nach Suprarenininjektionen. Klin. Monatsbl. f.

Augenh., 1906.
STARLING, E. H. On the mode of action of lymphagogues. J. o. P., 17,

1894.

- On the physiological factors involved in causation of dropsy. Lancet,

1894.

The chemical correlation of the functions of the body. Lancet, August,
1905.

- Die chemische Koordination der Koipertatigkeiten. V. d. N. A., Stutt-

gart, 1906.

- Physiology of digestion. London, 1906.

STARLING and LANE CLAYTON. Hormon der Brustdrlise. P. R. S., 77, 1905.
STATE. La forme douloureuse de I'acromegalie. These de Paris, 1900.
STATKEWITSCH. Uber Veranderungen des Muskel- und Drlisengewebes sowie

der Herzganglien beim Hungern. A. P. P., 33, 1894.
STAUBER, A. Uber das embryonale Auftreten diastatischer Fermente. P. A.,

114, p. 619.
STAUBLI. Zur Pathologie und Therapie des Diabetes mellitus. D. A. k. M.,

03, 1908.
STECKSEN, A. Befund von Adenomknotchen an Nebennieren und von akzes-

sorischen Nebennieren bei Erwachsenen. Arb. a. d. path. Inst.,

Tubingen, iii, 1901.
STEFANI, A. Azione del vago sugli scambi e sulla temperatura interna.

A. d. F., 1908.

STEFFECK. Menstruation und Ovulation. Jahresb. f. Geb. u. Gyn., 9, 1905.
STEGMANN. Die Behandlung der Struma mit Rontgenstrahlen. M. m. W.,

1905.
STEIN. Zur Kenntnis des Morbus Basedowii. Ibid., 1905.

572 LITERATURE

STEINACH, E. Z. vergl. Physiol. d. mannl. Geschlechtsorgane. P. A., 56,

1894.
STEINACH, E., and KAHN, R. W. Echte Kontraktilitat und motorische Inner-

vation der Blutkapillaren. P. A., 97, p. 105, 1903.
STEINLEIN, M. Uber den Einfluss d. Schilddrusenverlustes auf die Heilung

von Knochenbriichen. A. k. Ch., 60, 1896.

STEINSCHNEIDER. Adrenalin bei Gebarmutterblutungen. M. m. W.. 1905.
STEPANOFF. Le corps thyroide et les defenses naturelles. C. r. S. B., 66,

1909.
STERN. Innere Sekretion der Niere. Trav. de labor, de phys. de Geneve,

1901-1902.

STERNBERG. Akromegalie. Nothnagels Handb., 7, 1897.
STERRI. Intorno alia struttura dell' ipofisi nei vertebrati. Padova, 1904.
STIEDA. Untersuchungen iiber die Entwicklung der Gl. thymus, Thyreoidea

u. Carotica. Leipzig, 1881.

- Uber das Verhalten der Hypophyse des Kaninchens nach Entfernung der

Schilddriise. Zieglers Beitr., 7, 1890.
STILLING, H. Zur Anatomie der Nebennieren. V. A., 109, pp. 324-346, 1887.

- Uber die kompensatorische Hypertrophie der Nebennieren V. A., 118,

1889.

- Note sur 1'hypertrophie compensatrice des capsules surrenales. Rev.

med., T. 9, pp. 459-461, 1888.

- Quelques experiences nouvelles sur la maladie d'Addison. Ibid., 10,

1890.

- Du ganglion intercarotidien. Recueil inaugural. Lausanne, 1892.

- Zur Anatomie der Nebenniere. II. Mitt. A. m. A., 52, pp. 176-195, 1898.

- Die chromophilen Zellen und Korperchen des Symphaticus. An. An.,

53, 1899-
Einige Fragen als Antwort auf die Erwiderung von A. Kohn. A. m. A.,

53, 1899-

- Die Entwicklung transplantierter Gewebsteile. V. d. p. G. , 1903.

- Uber das Ergebnis der Transplantation von Nebennierengeweben.

Zieglers Beitr., 37, pp. 480-484, 1905.

- Versuche iiber Transplantation. III. Mitt. Uber den Bau und die

Transplantation des Epoophoron. Zieglers Beitr., 43, p. 26^5, 1908.
STINA, NADEJDA. Des fonctions de la thyreoide. Lausanne, 1900.
STOHR, PH. Lehrbuch der Histologie. Jena, 9 Aufl., 1901.

- Uber die Thymus. S. d. phil. Ges. Wurzburg, 8 Juni, 1905.

- Uber die Natur der Thymuselemente. An. Hefte, 95, 1906.
STOLTZNER. Behandlung der Rachitis mit Nebennierensubstanz. J. K., 51,

1900.

- Histologische Untersuchung der Knochen von 9 mit Nebennierensubstanz

behandelten rachitischen Kindern. Ibid., 53, iii, 5 and 6, 1901.

- Pathologic und Therapie der Rachitis. Berlin, 1904.

- Die Kindertetanie eine Calciumvergiftung. J. K., 63, p. 661, 1906.

- Nebennieren und Rachitis. M. K., 1908.

- Menstruatio praecox. M. K., 1908.

STOLTZNER and SALGE. Vorkommen von eigentiimlichen Krystallen in den
Knochen von mit Nebennierensubstanz behandelten rachitischen Kin-
dern. B. k. W., 1900.

STOERK, O. tiber Protagon. W. k. W., 1906; and S. W. A., 115, 1906.

- Ub. Chromreaktion v. Gl. coccygea u. Bezieh. z. N. sympathicus.

A. m. A., 69, 1907.

- Beitrage zur normalen Histologie der Nebennierenrinde. I. Gibt es eine

Lumenbildung an den Rindenzellenverbanden. B. k. W., No. 16,
1908.

- II. Uber adenomartige Bildungen in der Nebennierenrinde. Ibid., No.

19, 1908.

- Zur Histogenese der Grawitzschen Nierengeschwiilste. Zieglers Beitr..

43, 1908.

STOERK, O., and HABERER, H. v. Beitrag zur Morphologic des Nebennieren-
markes. A. m. A., 72, pp. 481-496, 1908.

- Uber das anatomische Verhalten intrarenal eingepflanzten Nebennieren-

gewebes. A. k. Ch., 87, 4, 1908.

STOKLASA, J. Alkoholgarung im Tierorganismus. P. A., 101 ; dort zahlr.
Arb. v. Stoklasa und seinen Schiilern.

LITERATURE 573

STOLZ. Uber Adrenalin und Alkylaminoacetobrenzkatechin. B. d. ch. G.,
37, 1904.

— Synthese der wirksamen Substanz der Nebennieren, synthetisches Supra-

renin. V. d. N. A. Stuttgart, 1906; Pharm. Zeitg., No. 80, 1906.
STOOKEY, L. B., and VERA-GARDNER. On the pharmacology of the iodides.
Proc. Soc. exper. Biol. Med., 5, pp. 122-123.

— Relation of the thyroids to autolysis. Ibid., 5, p. 120.
STOOKEY, L. B. On the physiology of the thyroids. Ibid., 5, p. 121.
STRADIOTTI, G. Di un tentative di cura del Morbo Flajani-Basedow mediante

un siero tireotossico. Riv. crit. clin. med., No. 7, 1907.

— Paraganglioprecipitine e siero ipotensivo. Ace. med. fis. fiorent., 1905.
STRASSMANN. Beitrag zur Lehre von der Ovulation, Menstruation und

Kastration. A. G., 52, 134.

- Handb. d. Geburtsh. v. Winckel, i, 1903.

STRAUB, H. Akuter Morbus Addisonii nach doppelseitiger Nebennieren-

thrombose. D. A. k. M., 97, H. i and 2.
STRAUB, W. Mechanismus der Adrenalinwirkung und die mogliche Be-

deutung der Substanz fiir den Kreislauf. M. m. W., 1907.

- Uber den Mechanismus der Adrenalinglykosurie. M. m. W., 1909.
STRAUSS, H. Neurogene und thyreogene Glykosurie. D. m. W., 1897.

- Die chronischen Nierenentziindungen. Berlin, 1902.

- Untersuchungen tiber den Wassergehalt des Blutes bei Herz- and Nieren-

wassersucht. Z. k. M., 60, 1906.
STRAUSSLER. Zur Symptomatologie u. Anatomie d. Hypophysengangs-

geschwiilste. Arb. d. psych. Klinik, Prag, 1907.
STREHL and WEISS. Beitrage zur Physiologic der Nebennierc. P. A., 86,

p. 107, 1901.
STRICKER, S. Handbuch der Lehre von den Geweben. Leipzig, 1871.

- Vorlesungen liber allgemeine und experimentelle Pathologic. Wien,

1883-
STRICKER, S., and SPINA, A. Untersuchungen liber die mechanischen

Leistungen der acinosen Driisen. S. W. A., 80, 1879.
STRUMPELL v. Akromegalie und Diabetes. D. Z. N., n, 1897.
STUDNICKA, F. K. Die Parietalorgane. Lehrb. d. vergl. Anat., Jena, 1905.
STUTZ, L. Uber den Einfluss von Korperarbeit und Uberwarmung auf die

Zuckerassimilationsgrenze eines gesunden Menschen. Diss., Jena,

1908.
STUVE. Unters. uber den respiratorischen GasAvechsel bei Schilddriisen-

fiitterung. Frankfurt a. M., 1896.
STUMME, E. Ein Fall von Basedow mit Tuberkulose einer Glandula para-

thyreoidea. Z. Ch., 90, p. 265, 1907.

- Akromegalie und Hypophyse. A. k. Ch., 87, 1908.

STURLI. Gefassveranderungen n. Injektionen von Methylaminobrenzkate-

chin. M. m. W., 1905.

STURSBERG. Ein Beitrag zur Addisonischen Krankheit. M. m. W., 1907.
STYBR, J. Deux cas de carcinome primitif des glandes surrenales non-suivis

de la maladie d'Addison. Arch. Bohem. de Med., iv, p. 100, 1890.
SUDECK, P. Uber die Strukter der Nierenadenome. V. A., 133, pp. 405-

449, 1893.

- Zur Lehre von den aberrierten Nebennierengeschwiilsten. Ibid., 136,

1894.
SULTAN, G. Beitrage zur Involution der Thymus. V. A., 144, 1896.

- Zur Histologie der transplantierten Schilddriise. C. a. P., 9, 18

- Beitrag zur Kenntnis der Schilddriisenfunktion. A. k. Ch., 63.
SUNNER, A. Sur 1'action inhibitoire du sang uremique sur la secretion

urinaire. C. r. S. B., Bd., 58, p. 775.

— • Sur le pouvoir antitoxique des reins. J. d. P. P., vii, p. 935, 1905.
SUPINO. Sur la physio-pathologie des capsules surrenales. A. i. B., 18,

1893-

- Sulla fisio-patologia delle capsule surrenali. Rif. Med., Settembre, 1892.
SURY, K. v. Uber die fragl. Bez. der sogenannten Mors thymica zu den

plotzlichen Todesfallen im Kindesalter. Viertelj. f. ger. Med.,

36, 1908.
SUTHERLAND. The differential diagnosis of Mongolism and Cretinism.

Lancet, 1900.
SUZUKI. Chromaffiner Tumor des Nebennierenmarkes. B. k. W., 1908.

574 LITERATURE

• SVEHLA, K. Exp. Unters. iib. d. Einwirk. des Thymussaftes a. d. Kreislauf.
W. m. Bl., 1896.

- Experimentelle Beitrage zur Kenntnis der inneren Sekretion der Thy-

mus, der Schilddriise und der Nebennieren von Embryonen und

Kindern. A. e. P., 43, IQOO.
SYMINGTON, J. tiber Thyreoidea, Gl. parathyreoideae und Thymus beirn

Faultier. A. A. Suppl., 1897
SzUREK, ST. Die Lehre von Alexander Poehl und die mit seinen Praparaten

erzielten Erfolge. W. k. W., 10,08.
SZYMONOWICZ, L. Uber die Erscheinungen nach der Nebennierenexstirpation

bei Hunden und liber die Wirkung der Nebennierenextrakte. Anz. d.

Krak. Akad., 1895.

- Die Nebennieren vom Standpunkte der Morphologic und Physiologic

(polnisch). Krakau, 1895.

- Die Funktion der Nebenniere. P. A., 64, pp. 97-164, 1896.

TADDEI, D. Contr. allo studio del cosidetto ipernefroma del rene. Rif.

med., IQOQ.
TAKAMINE, J. The isolation of the active principle of the suprarenal gland.

J. o. "P., 27, p. xxix, 1901; A. J. P., 73, 1901.
TALBOT, E. Cases of haemorrhages into the suprarenal capsules. St. Barth.

Hosp. Rep., 1900.

TAMBACH. Zur Chemie des Jods in der Schilddruse. Z. B., 36, 549, 1898.
TAMBRONI and LAMBRANZI. Una varieta di mixoedema frusto. Riv. di pat.

nerv., 1899.
TAMBURINI, C. Beitrag zur Pathogenese der Akromegalie. C. f. Nervenh.

u. Psych., 1894.

- Contribute allo pathogenesi dell' acromegalia. Riv. sperim. di fren.,

vol. xx, 1894.
TANDLER, J. Untersuchungen an Skopzen. W. k. W., 1908.

- Uber den Einfluss der innersekretorischen Anteile der Geschlechtsdriisen

auf die aussere Erscheinung des Menschen. W. k. W., 1910.

- Einfluss der Geschlechtsdriisen auf die Geweihbildung bei Renntieren.

Anz. d Wien, Akad., 1910.

TANDLER, J., and GROSZ, S. Einfluss der Kastration auf den Orgnisnius.
W. k. W., 1907-

- I. Mitteilung : Beschreibung eines Eunuchenskelett. A. E. M., 27, 1909.

- II. Mitteilung : Die Skopzen. Ibid., 30, 1910.

- III. Mitteilung: Die Eunuchoide. Ibid., 29, 1910.

TANTUURI. Osteomalakie, geheilt mit den Adrenalineinspritzungen. C. G.,

1907.
TARABINI, L., and MASSAGLIA, A. La paratiroidina Vassale contro il tremore

senile. Gaz. Osp. e clin., No. 149, 1908.
TARAMASIO, P. Etude toxicologique de 1'adrenalin. Rev. med. Suisse rom.,

22, 1902.
TARANTINI. Contribute allo studio delle alterazioni aortiche prodotte del la

paraganglina. II policlinico, 13, p. 321, Luglio, 1906.
TARCHANOW. Uber einige physiologische Wirkungen des Adrenalins auf

Tiere. Russki Wratsch, No. 47, 1902; Ref. B. C., i, p. 369, iQ°3-
TARGETT, J. H. Accessory adrenal bodies in the broad ligaments. Trans.

Obst. Soc., 39, 1898.
TARGHETTA. Etude sur le thymus. A. i. B., 30, 1898-99; These de Paris,

1902.
TARUFFI, C. Sulla struttura delle capsule soprarenali. Boll. d. scienc. med.

Bologna, 1866.

- Delia Microsomia. Riv. clin. di Bologna, 1878.

- Hermaphroditismus und Zeugungsfahigkeit. Ubersetzt von Teuscher.

Berlin, 1903.

TARULLI. Sur les effets de 1'exstirpation du Thymus. A. i: B., 37.
TARULLI, L., and LOMONACO, D. Ricerche sper. sul timo. Boll, della R.

Accad. Med. di Roma, p. 311, 1898.
TASSINI, R. Effetti terapeutici della paraganglina Vassale. Gazz. Osp. e

Clin., 1908.

TAURET, C. Sur 1'ergotinine. Journ. de Pharm. et de chim., Bd. 24, p. 307.
TAUSZK and VAS. Beitr. z. Stoffwechsel bei Akromegalie. Pest, med.-chir.

Presse, 1899.
TEBB, CH. The cholesterins of the brain. J. o. P., 34, 1906.

LITERATURE 575

TEDESCHI, B. Contr. a la pathogenic du goitre exophtalmique. Rev.
Neur., p. 683, 1902.

- Ancora sulla Patogenesi del gozzo esoftalmico. Autoref. B. C., i, p. 631,

1903.
TEISSIER, J. A propos 1'hypertension arterielle. S. m., 1904.

— • Arteriosclerose et atheromasie. Paris, 1908.
TEISSIER and FRAENKEL. Effets phys. des inj. souscont. d'extrait renal.

A. d. P., 1898.
TEISSIER and THAON, L. La pression arterielle dans la scarlatine de Padulte.

J. d. P. P., 15 mai, 1908, p. 481.
TEISSIER and THEVENOT. Antagonisme de la choline et de 1'adren. C. r.

S. B., 64, p. 425.
TESCIONE. Modific. istolog. della gland, tiroide in seguito all' ablazione dell'

ovaie. Arch. ital. d. Ginec., 1907.
THAON, P. Note sur la secretion de 1'hypophyse et ses vaisseaux evacuatcurs.

C. r. S. B., 62, avril, 1907.
— Toxicite des extraits de prostate ; leur action sur la compression

arterielle et de rythme cardiaque. C. r. S. B., 63, p. in, 1907.

- Contribution a Petude des glandes a secretion interne : L'hypophyse a

1'etat normal et dans les maladies. These de Paris, 1907.
THEOARI, A., and BABES, A. Uber ein gastrotoxisches Serum, mit eineni

Studium des Chemismus des Magens und der von diesem Gastrotoxin

veranlassten histologischen Veranderungen. C. f. B., 38, H. 6; 39,

H. i and 2.

THEVENOT. Atherom aortique experimentale. Paris, 1907.
THIBIERGE. Maladie d'Addiscn chez un negre arabe. Gaz. cles Hopit., 1899.

- Radiographie dans un cas d'infantilisme myxosdemateux. Ibid., 10

fevrier, 1899.
THIELE-NEHRING. Untersuch. des respir. Gaswechsels unter dem Einfluss

von Thyreoideapraparaten. Z. k. M., 30, 1896.
THIEMICH. Anatomische Untersuchungen der Glandulae parathyreoideae bei

der Tetanie der Kinder. Monatsschr. f. Kinderhk., 5, p. 165, 1906.

- Entwicklung eklamptischer Sauglinge in der spateren Kindheit. J. B.,

1906.
THIENGER. Einige Beobachtugen iiber Moebius' Thyreoidin. M. m. W.,

1905.
THIES. Der Gebrauch des Adrenalins zur Unterstiitzung der Lokalan-

asthesie. Diss., Leipzig, 1903.

- Wird die Giftigkeit des Cocains durch Kombination mit Adrenalin

herabgesetzt ? Z. Ch., 74, p. 434, 1904.
THIROLOIX. Diabete pancreatique. Bull, de la Soc. anat., 62, 1891.

- Fonction des capsules surrenales. Soc. anat., p. 207, 1892; C. a. P.,

5, p. 87.

- Precede d'ablation sur le chien des capsules surrenales, ectopie de ces

organes. Mercredi medic., p. 557, 1892.
Donnees exp. p. servir a eclairer la pathogenic du Diabete sucre. Gaz.

Hop., 1894.
THOINOT and DIAMARE. Etude sur le pancreas diabetique. A. m. e., 19,

1907.
THOM. Unters. iiber d. norm. u. patholog. Hypophysis cerebri. A. m. A.,

57, 1901.
THOMPSON. Die physiologische Wirkung der Protamine und ihrer Spal-

tungsprodukte. Z. ph. Ch., 29, 1900.
THOMPSON, G. Atrophy of the parathyroid glandules in primary infantile

atrophy. A. J. M. S., October, 1907.
THOMPSON and HARRIS. Path, histology of the parathyroid glands, &c.

Journ. of Med. Res., Boston, 1908.

- A study of Addison's disease and of the adrenals. Ibid., October, 1893.
THOMPSON and JOHNSON. Note on the effect of pituitary feeding. J. o. P.,

33, iQOS-
THOMPSON and LEIGHTON. The results of chronic parathyroiditis in the

dog. Ibid., 1008.
THOREL. Zur Frage der Erweichungescysten in den Geschwiilsten der

Nebenniere. Festschr. d. Niirnberger arztl. Vereins, 1902.
THUMIN, L. Geschlechtscharaktere und Nebenniere in Korrelation.

B. k. W., 1909.
— • Beziehungen zwischen Hypophysis und Eierstocken. Ibid., 1909.

576 LITERATURE

TIBERTI, N.. -^yber die Sekretionserscheinungen in den Nebennieren der
Amphibien. Zieglers Beitr. , 36, p. 161, 1904.

- Intorno alia estirpazione totale del duodeno. Lo Sperimentale, 62, 479,

1908.

- Intprno-al modo di comportarsi dell' isola del Langerhans in seguito alia

ligatura del condottp pancreatico. A. i. B., 51, 1908.

- Intorno alia rigeneraziqne del pancreas. Arch. d. Fisiol., 5, 1908.

- Ulteriori ricerche sperim. int. all' isole di Langerhans. Sperim., 62,

1908.
TIBERTI, N., and FRANCHETTI, A. Sugli effetti della estirpazione parziale e

totale del pancreas ne cani. Sperimentale, 62, Si-iiS, 1908.
TIGERSTEDT, R., and BERGMANN. Niere und Kreislauf. S. A., 8, 1898.
TILLE. L'opotherapie ovarienne dans la maladie de Basedow. These de

Paris, 1899.
TILNEY, F. Un cas de myasthenie grave pseudoparalytique avec adenome

du corps pituitaire. Neurograph. New York, vol. i, March 20, 1907.
TlMOFEEW, S. Zur Frage von der Pathogenese der nephritischen Odeme.

A. P. P., 60, 1909.
TITO. Morbo maculoso Werlhof curato con injez. ipoderm. d'adrenalina.

Gazz. d. Osped., 1904.
TIZZONI. Physiologie et pathologic des capsules surrenales. A. i. B., 5,

1884.

- Ric. sper. int. alia fisiopat. di corpo tiroide. Gazz. d'Osped., 1885.

- Sur physiologic pathologiques des corps surrenales. C. r. A., p. 832,

1886.

- Ablations des capsules surrenales chez le chien. A. i. B., 10, pp. 372-

378, 1888.

- tjber die Wirkungen der Exstirpation der Nebennieren auf Kaninchen.

Zieglers Beitr., 5, pp. 3-100, 1889.
TizzONI and CENTANNI. Sugli effetti remoti della tiroidectomia nel cane.

Arch, scienc. med., 14, 1890.

TODARO. Sur 1'epiphyse et 1'hypophyse des Ascidiae. Arch, de Biol., 1881.
TOGAMI. Experimentelle Untersuchung liber den Einfluss einiger Nahrungs-

und Genussmittel auf die Pankreassekretion. Z. physik.-diat. Th.,

xii, p. 403, 1908.
TOMASZEWSKI and WlLENKO. Beitrag zur Kenntnis der antagonistischen

Wirkungen des Arenalins und der Lymphagoga. B. k. W., 1908.
TOPOLANSKI. Zur Frage des chromaffinen Systems. W. k. W., 1907.
TORETTA. Les glandules parathyroidiennes chez les mammiferes. Ann.

malad. de 1'oreille. Ref. C. Ch., 1902.
TOROPOFF, D. J. tiber die pathologisch-anatomischen Veranderungen des

Gefasssystems bei intravenpser Injektion von Adrenalin. Diss.,

Petersburg, 1907; Bph. C., iii.
TORRI. L'ipofisi nelle infezioni. Pisa, 1904.
TORRINI, U. L. Ricerche sperimentali sulla modificazipni istologiche delle

ghiandole surrenali in seguito ad alcuni interventi operatorii sul rene.

Lo Sperim., 63, pp. 79-98, 1909.
TOUJAN, G. S. P. Recherches experimentales sur 1'adrenaline. Son dosage,

sa formation, son origine, sa destruction. These de Toulouse, 1905.
TOURNADE. Etudes sur les modifications du testicule consecutives a 1'inter-

ruption du canal deferent. These de Lyon, 1903-04.
TOURNEUX, F. L'organe de Rosenmueller (Epoophore) et le parovarium

(Paroophore) chez les mammiferes. J. A. P., 24, 1886.

- Hermaphroditisme de la glande genitale chez la taupe femelle adulte et

localization des cellules interstitielles. Ass. des Anat., VI session.

Toulouse, 1904.
TOURNEUX, F., and HERRMANN. Sur 1'evolut. histologique du thymus.

C. r. S. B., 1887.
TOURNEUX and SOULIE. Sur les premiers devel. d. 1. pituitaire ch. 1'homme.

Ibid., 1898.
TOURNEUX, F., and VERDUN, P. Sur le developp. de la thyr., du thym. et

de gl. parathyr. J. A. P., p. 305, 1897.
TRACHTENBERG. Uber experimentelle heteroplastische Knorpelbildung in der

Aorta bei Tieren. Charkower med. Journ., No. 5, 1906; Ref. Bph.

C., ii.
TRAINA. Ric. sperim. sul sistema nervoso degli animali tireoprivi. Poli-

clinico, 1898.

LITERATURE 577

TRAINA. Sulle modificazioni delle paratiroidi del cane in diversi stati

morbosi sperimentali. Lo Speriment., H. 1-2, igoS.
TRAMONTI, E. Contr. clinique a 1'etude de 1'acromegalie. II Policlinico,

IQO6.

TRANCHINI. Ricambio materiale in Acromegalia. Boll, scienc. med.,

Bologna, 1905.

TRANJEN. Das Altern als abwendbare Krankheit. Halle a. S., 1908.
TRAUTMANN, A. Anatomic und Histologie der Hypophysis cerebri. A. m. A.,

74, 1909.
TREBITZSCH, H. tiber eine ungewohnliche Form der Hautpigmentierung

beim Morbus Addisonii. Z. k. M., 32, Suppl.-H., p. 163, 1897.
TREUPEL. Stoffwechselversuche bei Myxtidem. M. m. VV., p. 885.
TREROTOLI, A. Sull' azione deiP estratto acquoso del lobo posteriore dell'

ipofisi nei cardiaci e nei ncfritici. Riv. crit. clin. med., 8, 1907.
TREWITHICK, E. G. Addison's disease; treatment with suprarenal extract.

Lancet, 1900.
TRIEPCKE, O. Uber Blutcysten in Nebennierenstrumen. Diss., Greifswald,

1901.
TRINCI, GiULIO. Cellule cromaffine e " Mastzellen " nella regione cardiaca

dei mammiferi. R. Accad. delle Scienze dell' Istituto di Bologna, 26

maggio, 1907.
TRIVAS. L'adrenaline en otorhinolaryngologie. These de Bordeaux, 1892;

C. r. S. B., 1903.
TROUSSEAU. Maladie d'Addison. Bull, de 1'acad. de med., seance du 26

aout, 1855.
TSCHASSOWNIKOFF, J. Ub. d. histol. Veranderg. d. Bauchspeicheldriise nach

Unterbindung des Ausfiihrungsganges. A. m. A., 67, 1906.
TSCHEBOKSAROFF. Sur les nerfs secreteurs des surrenales. Russki Wratsch.,

viii, 873. 27 juin, 1909; Ref. J. d. P. P., n, p. 962.

TSCHERNIACHOVSKI, E. Gibt es einen Duodenaldiabetes ? Z. B., 53, 1907.
TSCHERWENTZOFF. Des alterations des capsules surrenales dans la peste

bubonique. Arch, de Scienc. biol., 12, St. Petersbourg, 1906.
TSCHIRKOFF. Blutveranderungen bei der Addisonschen Krankheit. Z. k. M.,

19, 1891.
TSCHUEWSKY, J. A. Uber den Blutstrom in der Schilddruse. P. A., 97,

1903.
TSUBOI, H. Experimentelle Studie u'ber die Uramie. M. med. Fak. Tokio,

vii, 1907.

TUFFIER. Le capsule adipeux du rein. Revue de Chirurgie, 1890.
TUFFIER and LEJARS. Les veines de la capsule adipeux du rein. A. d. P.,

1892.
TUNICLIFFE. Uber die Wirkung des Piperidins auf den Kreislauf. C. P.,

10, p. 777, 1896.
TURNER, F. CH. Spindle cell sarcoma of pineal body containing glandular

and carcinomatous structures. Transact, of the Path. Society of

London, 36, p. 27, 1885.

— A case of Addison's disease in which the blood-pressure was taken two

days before death. Lancet, June 10, 1899.
TURRO, R., and SUNER, A. Inkonstantes Auftreten von Glykosurie nach

Totalexstirpation des Pankreas. C. f. Phys. d. Stoffw., 1909.
- Der Mechanismus der natiirlichen Immunitat. C. f. B., 39.

UHTHOFF. Ein Beitrag zu den Sehstorungen bei Zwergwuchs und Riesen-
wuchs, respektive Akromegalie. B. k. W., 1897.

ULRICH, A. Anatomische Untersuchungen iiber ganz und partiell verlagerte
und akzessorische Nebennieren und iiber die Frage der von den Neben-
nieren ausgehenden Geschwiilste. Ziegl. Beitr., 18, Diss., Zurich,

1895.
UMBER, F. Uber die wirksamen Substanzen der Nebennieren. Th. G.,

August, 1902.
UNDERBILL, F. P. Certain aspects of experimental diabetes. J. B. Ch., i,

p. 113.
UNDERBILL and CLOSSON, O. E. The mechanism of salt glycosuria.

A. J. P., 15, 1906.

— Adrenalin glycosuria and the influence of adrenalin upon nitrogenous

metabolism. Ibid., 17, 1907.

37

578 LITERATURE

UNDERBILL and CLOSSON, O. E. The influence of subcutaneous injections
of dextrose upon nitrogenous metabolism. J. B. Ch., ii, 10,06.

UNDERBILL and HILDITSCH, \\7. W. Certain aspects of carbohydrate meta-
bolism in relation of the complete removal of the thyroids and partial
parathyroidectomy. A. J. P. October 25, IQOQ.

UNDERBILL and KLEINER. Further experiments on the mechanism of salt
glycosuria. J. B. Ch., iv, p. 395, 1908.

UNDERBILL and SAIKI, T. The influence of complete thyroidectomy and thy-
roid feeding upon certain phases of intermediary metabolism. Ibid.,
v, p. 225, October, 1908.

URECHIA, C. J. Action de 1'extrait hypophysaire en injections intra-
peritoneales. C. r. S. B., 65, p. 278, 1908.

USPENSKI. Organotherapie. St. Petersburg, 1896 (Russisch).

VABLEN, E. Pankreas und intermediarer Stoffwechsel. C. P., 22, No. 7,
1908.

- Uber die Einwirkung bisher unbekannter Bestandteile des Pankreas auf

den Zuckerabbau. I. Mitt. Z. ph. Ch., 50, p. 194, 1909.
YALENTI, A. Del ricambio materiale nello gravidanza e nell' allattamento.

Arch. Farmacol., vii, H. 8 and 9.
VALENTI, G. Sulla sviluppo delle capsule surrenale nel polio ed in accuni

mammiferi. Atti d. Soc. Tosc. x, Pisa, 1889; and Accad. med. chir.

di Perugia, 1894.

— Sulla origine e sul significato dell' ipofisi. Ibid., 1895.

— Sopra la piega faringea. Monit. zool. Ital., 9, 1898.

VALENTIN, F. Der Einfluss letaler Verbrennungen auf das histologische Bild

der Schilddrtise. V. A., 191, p. 42.
LA VALETTE, A. v. ST. GEORGE. Zwitterbildung beim Wassermolch.

A. m. A., 45, 1895.
VALUDE and DuCLOS. Effets de 1'adrenaline en instillations longtemps pro-

longees. Ann. Ocul., Paris, 138, p. 115, 1907.
VAMOSSY, Z. V., and VAS, B. Experimentelle Untersuchungen u'ber die

Wirkung des Jodothyrins. M. m. W., 1897.
VANNI, E., and MANZINI. Sulla parte che spessa al rene nella patog. dell'

uremia. Gazz. degli Osped., 16 dicembre, 1893.
VANORI, L. Sugli effetti dell' estirpaz. del pancreas. A. ital. clin. med.,

33, 1894.
VAQUEZ, H. Hypertension arterielle et ses consequences au cours de Tintoxi-

cation saturnine aigue de Peclampsie et de 1'uremie. Sem. med., 1904.
VAQUEZ and AUBERTIN. Cceur de Traube et hyperplasie medullaire des

surrenales. C. r. S. B., 62, 967, 1907.
VARALDO, F. Capsule surrenali aberrenti nell' ovajo. Arch, d'ostetr. e

ginec., xi, 1905.
VARIOT and BEZANCON. Independance de la spermatogenese et de la secretion

testiculaire proprement dite. Bullet, de la Soc. d'Anthropologie de

Paris, ser. 4, T. iii, 1892.

- Influence de la secretion testiculaire sur le developpement organique.

Independance de cette fonction et de la spermatogenese dans certains

cas. Gaz. med., 1892.
VAS. Uber das Chromatin in den sympathischen Ganglienzellen. A. m. A.,

40.
VASSALE, G. Ricerche niicroscopiche e sperimentali sull' alterazioni del

pancreas consecutive alia legatura del dutto di Wirsung. Reggio

Emilia, 1889-1891.

- Ulterior! esper. int. alia gland, tiroide. Riv. sper. fren., 1892.
Tetanie provoquee par 1'allaitement chez une chienne partiellement para-

thyreoidectomisee. A. i. B., 30, p. 49, 1897.

- Funzione paratiroidea e funzione tiroidea. Riv. sperim. di fren., 27,

1901.

- L'hypophyse dans le myxcedeme et dans 1'acromegalie. Ibid., 38, 1902.

- Physiopathologie de 1'appareil des capsules surrenales. A. i. B., 43,

p. 256, 1905.

- Le traitement de 1'eclampsie gravidique par la parathyroidine et con-

siderations sur la physiopathologie des glandes parathyroi'des. A. i. B.,
43, p. 256, 1905.

Srhwangerschaftseklampsie und Insuffizienz der Parathyr.oiddriise.
M. m. W., 1906.

LITERATURE 579

VASSALE and DONAGGIE. Les alterations de la moelle epin. chez les chiens

operes d'exstirp. des gl. parathyroidiennes. A. i. B., 27, 1897.
VASSALE, G., and GENERAL:. Sur les effets de 1'exstirpation des glandes

^ parathyroides. A. i. B., 25, p. 459; 26, p. 61, 1896; and 33, 1906.

Sopra le ghiandoli paratiroidee dell' uomo. Rif. med., 2, p. 631, 1897.

- Ulterior! ricerche intorno alle ghiandole paratiroidee. Ibid., 3, p. 77,

1897.

- Intorno agli effetti dell' estirpazione delle ghiandole paratiroidee. Ibid.,

i, p. 800, 1897.

- L'alimentazione tiroidea contro gli effetti dell' estirpazione delle ghiandole

paratiroidee. Ibid., 2, p. 235, 1897.
VASSALE and ROSSI. Sur la spleno-thyroidectomie chez le chien. A. i. B.,

21, 1893.
VASSALE and SACCHI. Sur la destruction de la glande pituitaire. Ibid., 1893.

- Sulla distruzione della glandola pituitaria. Riv. sperm, di fren., 18,

1892 ; and 20, 1894.
VASSALE, G., and ZANFROGNINI. Sur 1'exportation de la substance medullaire

des capsules surrenales. A. i. B., 38, p. 175, 1902; and Rif. med., 1902.
VECCHI, DE. liber experimentelle Tuberkulose der Nebennieren. C. a. P.,

12, 1901.

- Wirkung einiger Organextrakte bei den akuten Infektionsprozessen.

C. f. B., 35, pp. 577 and 708.

\ EDOVA, DALLA. Per la funzione dell' ipofisi. Bull. Ace. med. Roma, 29,
1903 and 1904.

- Ein Fall von Hypernephrom der Leber. V. A., 177, 1904.

VEIEL, TH. Pruritus cutaneus bei Erkrankung der Niere und Nebenniere.

A. Derm. Syph., So, 1906.

VEIT, D. Verschleppung der Chorionzotten. Wiesbaden, 1905.
VELDE, VAN DE. Uber den Zusammenhang zwischen Ovarialfunktion,

Wellenbewegung und Menstrualblutung. Jena, 1905.
VELICH, A. Uber die Einwirkung des Nebennierensaftes auf den Blut-

kreislauf. W. m. Bl., Nos. 15-21, 1896; and Allg. W. m. Ztg., 1897.

— tJber die Folgen der einseitigen Exstirpation der Nebenniere. W. k. R.,

1897-

- Vergleichende Untersuchungen iiber die Einwirkung des Pipendins und

des Nebennierenextraktes auf den Kreislauf. W. k. R., 1898.

- tJber die Einwirkung der ortlichen Applikation des Nebennierenextrakts

auf die Blutgefasse der Haut des Menschen. W. m. BL, 1897.

- Beitrag zum Experimentalstudium von Nebennieren. V. A., 184, 1906.
VELITS, D. v. tiber Adrenalinwirkung bei Osteomalakie. C. G., 31, 29,

p. 929, 1907.
VELLESEN. Morbus Basedowii mit bes. Berticksichtigung der Pathogenese.

Z. k. M., 1899.
VERDUN. Sur les glandes satellites de la thyroi'de dans les mammiferes.

These, Toulouse, 1897.

- Derives branchiaux chez les vertebres superieurs. Toulouse, 1898.
VEREBELY, J. v. Beitr. zur Schilddrusenzirkulation. M. G. M. C., 17, 1907.

- Beitr. zur Pathologic der branchialen Epithelkorperchen. V. A., 187, 192.
VERNON. Intercellular Enzymes. London, 1908.

VERSTRAETEN. L'acromegalie. Rev. d. med., pp. 377 and 493, 1889.
VERTRA and ANGIOLELLA. Manicomio moderno. Nos. i and 2, 1899.
VERWORN. Allgemeine Physiologic. 4 Aufl., Jena, 1903.

— Zur Analyse der dyspnoischen Vagusreizung. A. P., p. 65, 1903.
VIALLETON. Anat. des caps, surrenales. Montpellier med., 1898.
VlCOLlNl. Cura del prolasso rettale con la paraganglina. Gaz. d. Osped.,

1906.
VIDAL and BOIDIN. Adenomes des capsules surrenales avec atRerome

generalise et hypertension arterielle. Soc. med. des hopit., seance du

21 juillet, 1905; Sem. med., p. 356, 1905.
VIDAL, ROY and FROIN. Un cas d'acromegalie sans hypertrophie, £c. Rev.

de Med., 1906.
VIDAL and SUTIER. Atrophie congenitale complete des testicules. Absence

d'infantilisme et de feminisme. Bull, de la Soc. med. des hopitaux,

20 mai, 1902.
VIGLIANI, R. Contr. allo studio delle funzione del pancreas. Lo Sperim.,

1905.

580 LITERATURE

VIGOUREUX and DELMAS. Infantilisme. Bull, de la Soc. anat., p. 686, 1906.
VlGNES. L 'Adrenaline en ophtalmologie. Presse med., 10 mai, 1902.
VILLEMIN. Sur la regeneration de la glande seminale apres destruction par
les rayons X. C. r. S. B., p. 1077, 1905.

- Sur le role du corps jaune ovarien chez la femme et la lapine. Ibid.,

64, P- 363, 1908.

- Sur les rapports du corps jaune avec la menstruation et le rut. Ibid.,

P- 444-
L'ovulation est-elle spontanee chez la lapine? Ibid., p. 662.

- Le corps jaune considere comme glande a secretion interne de 1'ovaire.

These de Lyon, 28 Janvier, 1908.
VINCENT, S. The suprarenal capsules in the lower vertebrates. Proc. of

the Birmingham Nat. Hist, and Phil. Soc., vol. 10, pp. 1-26, 1896.
The physiology of the suprarenal bodies. Birmingham Med. Rev., 1896.
The suprarenal gland. Brit. Med. Journ., 1896.

- Contribution to the comparative anatomy and histology of the suprarenal

capsules. The suprarenal bodies in the fishes and their relation to the
so-called head-kidney. Trans. Zool. Soc., vol. 14, part 3, pp. 44-84,
1895. Published 1897.

The comparative physiology of the suprarenal capsules. P. R. S., 61,
pp. 64-77, 1897.

- On the general effects of the extracts of the suprarenal capsules. J. o. P.,

22, pp. 111-120, 1897.

The effects of subcutaneous injections of extracts of suprarenal capsules.
J. o. P., 21, 1897.

- On the morphology and physiology of the suprarenal capsules in fishes.

An. An., 13, pp. 39-48, 1897.
— The effects of extirpation of the suprarenal bodies of the eel. P. R. S.,

62, 1898.

The nature of the suprarenal bodies of the eel and the effect of its
removal. J. o. P., 22, p. 48, 1898.

- On the suprarenal and the lymphatic tissue of Teleostean fishes. An.

An., 14, pp. 151-152, 1898.
The comparative histology of the suprarenal gland. I. M., 15, 1898.

- Addison's disease and the functions of the suprarenal capsules. Birming-

ham Med. Rev., 1898.

- Further observations upon the comparative physiology of the suprarenal

capsules. P. R. S., 64, 1899.

The carotid gland of mammalia and its relation to the suprarenal cap-
sule, with some remarks upon internal secretion and the phylogeny
of the latter organ. An. An., 18, pp. 69-76, 1900.

- A discussion of some points in connection with the suprarenal glands,

cortical and medullary. J. A. P., 38, pp. 34-48, 1903.

- On the results of extirpation of the thymus gland. J. o. P., 30, 1904.

- Internal secretion and the ductless gland. Lancet, I, 348, p. 1198, 1906.
The ductless glands. Science Progress, No. n, January, 1909.

- Innere Sekretion u. Driisen ohne Ausfiihrungsgang. Zusammenfass.

Ref., E. P., ix, 1910.

VINCENT, S., and CRAMER, W. The nature of the physiologically active
substances in extracts of nervous tissues and blood, with some remarks
on the methods of testing for choline. J. o. P., 30, pp. 143-154, 1904.

VINCENT, S., and HARRISON. Spleen and lymphatic glands. J. o. A. and

P., 31, 1887-
VINCENT, S., and JOLLY, W. A. Function of thyroid and parathyroid glands.

Ibid., 32.
VINCENT, S., and SHEEN. The effects of intravascular injections of extracts

of animal tissues. Ibid., 29, 1903.
VINCENT, S., and THOMPSON, F. D. On the relation between the islets of

Langerhans and the zymogenous tubules of the pancreas. I. M., 24,

1907.
VIRCHOW, R. Die Bronzekrankheit in Canstatts Jahresber., 1856-1858.

- Zur Chemie der Nebennieren. V. A., 12, 1857.

- Gesammelte Abhandlungen zur wissenschaftlichen Medizin, p. 747, 1862.

- Die krankhaften Geschwiilste, 3 Bde., Berlin, 1867.

- Fb'tale Rachitis, Kretinismus und Zwergwuchs. V. A., 94, 1883.

- Zur Frage der Kropfkachexie. Ibid., 144, 1896.

LITERATURE 581

VISENTINI, A. Zur Frage der Duodenalglykosurie. M. K., 1908.

- Sulla questione dell glicosuria duodenale. II Morgagni, No. 8, 1908.

- Uber das Verhalten des Pankreas nach Unterbindung und Durch-

schneidung seiner Ausfiihrungsgange. A. A. P., 1908. Suppl.

- Uber die anatomische und funktionelle Wiederherstellung der unter-

bundenen und durchschnittenen Pankreasausfuhrungsgange. V. A.,

195, 1909.
VITRY, G., and GlRAND, G. Lesions histologiques du corps thyroide des

tuberculeux, leur rapports avec la teneur en iode. C. r. S. B., 65,

pp. 404-406, 1908.
VlTZOU. Recherches exper. sur la secretion interne des reins. J. d. P. P.,

1901.

VlVIER. Sur Tinfantilisme. These Paris, 1897.
VOENA, G. Azione sulle capsule suprarenali di alcune particolari spstanze

introdotte nell' organismo con injezioni ipodermiche. Bibliogr.

ItaL, ii, 92; Ref. V. H., ii, 1893.
VOGT. Uber Mongoloidentypus der Idiotic. Jahresvers. d. d. Ver. f. Psych.

in Miinchen, 1906.

VOIGT, B. Uber Anwendung und Wirkung des Adrenalins. M. m. W., 1904.
VOINOV. Role probable de la glande interstitielle. C. r. S. B., 57, p. 414,
, 1905-

- Glande interstitielle et spermatoxines. Ibid., p. 688.

VOIT, FR. Stoffwechseluntersuchungen am Hund mit frischer Schilddriise

und Jodothyrin. Z. B., 35, 1897.
VOLLBRACHTj F. Ein Fall von Morbus Addisonii nach vorausgegangener

Purpura haemorrhagica mit einer Stoffwechseluntersuchung.

W. k. W., 1899.
VOLLBRACHT and PANZER, TH. Aufklarung zu voriger Mitteilung. Ibid.,

No. 34.
Vos, J. DE, and KOCHMANN. De la rapidite avec laquelle la principe actif

des caps, sun-en, disparait du sang. A. intern. Pharmacod., 14, p. 81,

1905.
VOSBURGH and RICHARD. An experimental study of the sugar content and

extravascular coagulation of the blood after administration of

adrenalin. A. J. P., 9, 1903.

VULPIAN. Note sur quelques reactions propre a la substance des capsules
^ surrenales. C. r. A., xliii, pp. 663-665, Paris, 29 septembre, 1856.

- Note sur quelques reactions propres au tissu des capsules surrenales

chez les reptiles. Ibid., p. 223, 1856.

- Lecons sur 1'appareil vasomoteur. T. ii, p. 38, 1875.

VULPIAN, A., and CLOEZ, S. Note sur Fexistence des acides hippuriques et
choleriques dans les capsules surrenales des animaux herbivores.
C. r. A., xlv, 7 septembre, 1857.

WAGNER v. JAUREGG, J. Uber die Folgen des Exstirpation der Schild-
driise. W. m. Bl., No. 25, p. 771, 1884.

— Weitere Versuche Uber Exstirpation der Schilddriise. Ibid., No. 30,

. P- 93i.

- Uber endemischen und sporadischen Kretinismus und dessen Behand-

lung. W. k. W., 1900.

- Behandlung des endemischen Kretinismus mit Schilddriisensubstanz.

Ibid., 1904.

- Uber marinen Kretinismus. Ibid., 1906.

— Zweiter Bericht iiber die Behandlung des endemischen Kretinismus mit

Schilddriisensubstanz. Ibid., p. 33, 1907.
WAHNCAU. Zur Kasuistik des Morbus Addisonii und der akzessorischen

Nebennieren. Jb. der Hamb. Staatskrank., Jg., i, p. 158, 1889.
WALBAUM. Unters. iiber die Epithelkorperchen beim Kaninchen. M. G.

M. C., 12, 1903.
WALDEYER, W. Die Ruckbildung der Thymus. Ber. d. preuss. Akad., 1890.

— Die Entwicklung der Carcinome. V. A., 55, 1872.

- Uber Bindegewebszellen. A. m. A., n, 1875.

WALLART, J. Chem. Unters. iiber den Luteingehalt des gelben Korpers
wahrend der Graviditat. B. G. G., xiv, No. i.

- Untersuchungen xiber die interstitielle Eierstockdriise beim Menschen.

A. G., 81, 271.

582 LITERATURE

WALLART, J. tiber das Verhalten der interstitiellen Eierstockdriise bei

Osteomalakie. Z. G. G., Ixi, p. 581.
WALLMANN, H. tiber das akzidentelle Vorkommen physiologischer Gewebe.

Zeitschr. d. Ges. Arzte, Wien, 1859.

WALTER and DIXON. Pharmacology, Adrenalinwirkung, p. 425, 1906.
WARDA. tiber Akromegalie. D. Z. N., 19, p. 358, 1901.
WARRINGTON, W. B. Exophthalmic Goitre. Liverpool Med. Chir. Journ.,

1908.
WASSERTRILLING. Die funktionelle u. klinische Bedeutung der Epithel-

korperchen. W. m. W., p. 1439, 1908.
WATERMAN, N. Einige Bemerkungen zur Frage : Arteriosklerose nach

Adrenalininjektionen. V. A., 191^ pp. 202-208, 1908.

- tiber den Nachweis von Nebennierenprodukten im Blut und Harn.

P. A., 128, 1909.

- tiber einige Versuche mit Rechtssuprarenin. Z. ph. Ch., 63, p. 290,

1909.

WATERMAN, N., and BODDAERT, R. J. tiber den Nachweis von Nebennieren-
produkten im Blut und Harn. D. m. W., 18 Juni, 1908.
WATERMAN, N., and SMIT, H. J. Nebenniere und Sympathicus. P. A.,

124, p. 198, 1908.
WATSON, CH. Influence of a meat diet on the thyroid and parathyroids.

J. o. P., 32, 1905.
The influence of meat diet on the thyroid gland in the second generation

of meat-fed rats. J. o. P., 34, 1906.
WERSILOFF. Ein Fall von Akromegalie. Ges. d. Neurol. u. Irrenarzte zu

Moskau., 6 Oktober, 1900; Ref. N. C., 21, p. 35, 1902.
WEBER, F. P. Symmetrical adenomata or nodular hyperplasia of the

suprarenal glands and extreme sclerosis of the aorta and coronary

arteries. Transact, of Path. Soc., 57, p. 3, London, 1906.
WEBER, H. tiber Anasthesie durch Adrenalin. V. 21, C. M., 1904.
WEBER, L. tiber die Behandlung des M. Addisonii mit Tuberkulin.

B. k. W., 1891.
WEBER, M. tiber einen Fall von Hermaphroditismus bei Fringrilla coelebs.

Zool. Anz., 13, p. 508, 1890.
WEBSTER, W. Choline in animal tissues and fluids. Biochem. Journ., iv,

Nos. 3 and 4, 1909.
WEICHARDT. Zur placentaren Theorie der Eklampsieatiologie. A. G., 87,

1909.

WEICHSELBAUM. Diskussion z. Vortr. Erdheims. W. k. W., 1906.
WEICHSELBAUM and KYRLE. tiber das Verhalten d. Langerhansschen Inseln

d. menschlichen Pankreas im fotalen und postfotalen Leben.

A. m. A., 74, 1909.

WEICHSELBAUM and STANGL. Z. Kennt. d. feineren Veranderungen des Pan-
kreas bei Diabetes mellitus. W. k. W., 1901.
— Weitere histolog. Unters. . . . Ibid., 1902.
WEIGANDT, W. Der heutige Stand der Lehre vom Kretinismus. Halle,

1903-4.
WEIGERT, C. Zur Lehre von den Tumoren der Hirnanhange. V. A., 65,

p. 212, 1875.

- Hemicephalie und Aplasie der Nebennieren. Ibid., 100, pp. 176-179,

1885.

- Nachtrag zur Mitteilung. . . . Ibid., 103, p. 204, 1886.
WEIL, M. tiber Adrenalin bei Asthma. D. m. W., 1903.

WEIL, E., and BOYE. Action differente des lobes hypophysaire sur la coagu-
lation du sang chez Thomme et le lapin. C. r. S. B., 67, pp. 192 and
428, 1909.

WEIL, E., and MOURIQUAND, G. Ichthyose et corps thyroide. Press, med.,
1909.

WEILAND. tiber d. Einfl. ermiid. Muskelarb. auf d. Blutzuckergehalt.
D. A. k. M., 92, 1908.

WEILER, J. Die Bildungsanomalien der Nebenniere und deren pathologische
Bedeutung. Diss. , Kiel, 1885.

WEINTRAUD. Pankreasdiabetes der Vogel. A. P. P., 34, 1894.

WEISS, B. Zur Kenntnis der von versprengten Nebennierenkeimen ausge-
henden Geschwiilste. Zieglers Beitrage, 24, pp. 34-55, 1898.

WEISS, F. tiber den Jodgehalt von Schilddriisen in Schlesien. M. m. W.,
1897.

LITERATURE 583

WEISS, N. Zur Pathologic und pathologischen Anatomie der Tetanie.
W. m. W., p. 683, 1883.

- Uber Tetanie. Volkmanns Samml. klin. Vortr. , 7. Serie, No. 189,

p. 1696, 1880.
WEISS, O., and HARRIS, J. Die Zerstorung des Adrenalins im lebenden

Tier. P. A., 103, p. 510.
WEISSMANN and REISMANN. Die Veriinderg. d. weibl. Sexualorg. n. Exstir-

pation d. Geschlechtsdriisen. Jahresb. f. Geb. u. Gyn., 6, 1890.
WELDON, W. F. R. On the head kidney of Bdellostoma with a suggestion

as to the origin of the suprarenal bodies. Quart. Journ. Micr. Soc.,

24, pp. 171-183, 1884.

- On the suprarenal bodies of vertebrates. Ibid., 25, pp. 137-150, 1885.
WELECKI. Bull, intern. Acad. Cracovie, p. 768, 1907.

WELLS, H. G., and BENSON, R. L. Studies on calcification and ossification.

J. o. M., Res. xvii, p. 15, 1907.
WELSH, R. On the parathyroid glands of the cat. J. o. P. B., 5, p. 202,

1898.

- Concerning the parathyroid glands. J. o. A. a. P., 32 (12), 1898.

- Influence de 1'extrait de rate sur la digestion pancreatique. A. i. Ph., vii,

p. 247, 1908.

WENDEL. Zur Chirurgie der Nebennierengeschwulste. A. k. Ch., 73, 1904.
WENCKEBACH, K. F. Zur Entwicklungsgeschichte der Knochenfische

A. m. A., 28, 1886.
WERNECKE, TH. K. Zur Wirkung des Thyreotoxin auf das Auge. Klin.

Monatstbl. f. Augenhk., 1908.

WERSILOFF. Ein Fall von Akromegalie. Ref. N. C., 1902.
AVERTHEIMER, E. De Faction sur le lait du sue pancreatique secrete sans

Pinfluence de la pilocarpine. C. r. S. B., 64, H. 10, 1908.
WERTHEIMER and BATTEZ. Sur le mecanisme de la piqure diabetique. Ibid.,

Bd. 66, p. 1059, 1909.
WERTHEIMER and DUBOIS. Des effets antagpnistes de Fatropin et de la

physostigmine sur la secretion pancreatique. C. r. S. B., 56, p. 195,

1904.
WERTHEIMER and LEPAGE. Sur 1'association reflexe du pancreas avec 1'intes-

tion grele et sur les proprietes reflexes des ganglions du sympathique.

Ibid.. 51, p. 1 146, 1899.

- De Faction du chloral sur la secretion pancreatique. Ibid., 52, p. 668,

1900.

WTESSELY, K. Zur Wirkung des Adrenalins auf Pupille und Augendruck.
Vortr. in der Berl. ophth. Ges., 1903; and Zeitschr. f. Aug., 13, 1905.

- Zur Wirkung des Adrenalins auf das enukleierte Froschauge und die

isolierte Warmbluteriris. D. m. W., 1909.
WESTENHOEFFER. Ein bemerkenswerter Fall von rapid verlaufener Addi-

sonscher Krankheit. Militararztl. Ztschr. , No. 2, 1901.
WESTPHAL. Wcitere Beitrage zur Lehre von der Tetanie. B. k. W. , 1901.
\\"F,YMEERSCH, A. Lesions du thjmus obtenues ;i la suite d'injections d'un

serum tlrymotoxique. Bull. d. 1. soc. de sc. mod. et nat., Bruxelles,

p. 206, 1908.
WHIJHE, J. W. VAN. Uber die Mesodermsegmente des Rumpfes und die

Entwicklung des Exkretionssystems bei den Selachiern. A. m. A., 33,

pp. 461-516, 1889.
WTHITE, C. P. On the so-called fatty degeneration of the adrenals. J. o.

P. B., 1908.

WHITE, W. H. On Addison's disease. Practitioner, 82, 1909.
WHITEHEAD, R. H. The histogenesis of the adrenal in the pig. A. J. A., 2,

1903.
WHITNEY, J. Uber die Gesetze der Zuckerausscheidung beim Diabetes

mellitus. Z. k. M., 65, p. 476, 1908.
WIEDERSHEIM, R. Lehrbuch der vergleichenden Anatomie der Wirbeltiere

•auf Grundlage der Entwicklungsgeschichte. 2. Aufl. Jena, 1886.
WIEDERSHEIM, B. Beitrage zur Entwicklungsgeschichte des Urogenital-

apparates Krokodile und Schildkroten. A. m. A., 36, 1890; An. An.,

5, 1890.
WlECHOWSKI, W. Uber exper. Beeinfl. d. Kontraktionszust. d. Gefasse im

Schadelinnern. A. P. P., 52, 1905.
WlEFEL, A. Uber Adenome der Nieren. Diss., Bonn, 1883.

584 LITERATURE

WIENER, H. tiber den Thyreoglobulingehalt der Schilddriise nach experi-

mentellen EingrifFen. A. P. P., 61, 1909.
WlESEL, J. Akzessorische Nebennieren im Bereiche des Nebenhodens.

W. k. W., 1898.

- tiber akzessorische Nebennieren am Nebenhoden beim Menschen und

iiber Kompensationshypertrophie dieser Organe bei der Ratte.
S. W. A., 108, 1899.

- tiber Kompensationshypertrophie der akzessorischen Nebennieren bei

der Ratte. C. P., 12, pp. 780-783, 1899.

- tiber die Entwicklung der Nebenniere des Schweines, insbesondere der

Marksubstanz. Anat. Het'te, xvi, H. i, pp. 117-150, 1900

- Zur Entwicklung der menschlichen Nebenniere. C. P., 15, pp. 614-615,

1902.

- Beitrage zur Anatomie und Entwicklung der menschlichen Nebenniere.

Anat. Hefte, 63, xix, 3, pp. 481-522, 1902.

- Chromaffine Zellen in Gefasswanden. C. P., 16, 1903.

- Zur pathologischen Anatomie der Addisonschen Krankheit. Zeitschr. f.

Heilk., 24, pp. 257-281, 1903.

- Zur Pathologic des chromaffinen Systems. V. A., 176, pp. 103-114, 1904.

- Bemerkungen zu der Arbeit von Dr. Iv. Karakascheff. Beitrage zur

pathologischen Anatomie der Nebennieren. Zieglers Beitr., 37, p. 169,
1904.

- Bemerkungen zu der Arbeit H. Kiisters " Uber Gliome der Nebennieren."

V. A., 180, p. 553, 1905.

- Uber Befunde am chromaffinen System bei Hitzschlag. Ibid., 183, p.

163, 1906.

— Uber Erkrankungen der Koronararterien im Verlaufe akuter Infektions-

kranheiten. W. k. W., 1906.

- Chromaffmes Gewebe im Herzen. W. k. W., 1906.

— Renale Herzhypertrophie und chromafFmes System. Mitt. d. Ges. f. inn.

Med., Wien, 1907.

- Der heutige Stand d. Lehre v. d. Arteriosklerose. Wien, 1909.
WIGGERS, C. J. Of the action of adrenalin on the cerebral vessels. A. J. P.,

14, 1905.
The innervation of coronary vessels. Ibid., 24, 1909.

WlJHE, W. VAN. tiber die Mesodermsegmente des Rumpfes und die Ent-
wicklung des Exkretionssystems bei Selachiern. A. m. A.j 33, 1889.

WILCOX, R. W. Thymic opotherapy. Bost. Med. and Surg. Journ., August
13, 1908.

WlLDT, A. Beitrag zur mikroskopischen Anatomie der Speicheldriisen.
Diss., Bonn, 1894.

WILENKO, G. G. Zur Kenntnis der Glutarsiiurewirkung auf den Phloridzin-
diabetes. D. m. W., 1908.

WiLKS, S. Addison's disease and leucoderma. Lancet, July 28, 1900.

WlLLRICH, E. Sklerodermie in Verbindung mit Morbus Addisonii. Diss.,
Gottingen, 1892.

WlNDAUS. Die Entgiftung der Saponine durch Cholesterin. B. d. ch. G.,
32, 1909.

WINTER, tiber Wirkungen des Nebennierenextrakts auf das durch grosse
Chloroformdosen vergiftete Saugetierherz. W. k. W., 1905.

WINTERNITZ, N. C. Tuberculosis of the parthyroid gland. Bull. Johns
Hopkins Hosp., 20, 1909.

WTIRTH, KARL. Tetanie bei Phosphorvergiftung. W. k. W., 1908.

WlTHINGTON, CH. F. Addison's disease with and without adrenal tuber-
culosis. Amer. Med. News, September 24, 1904.

WITZEL, O. Die Technik der Pankreasexstirpation beim Hunde. P. A.,
1 06.

WOLFLER, A. tiber die Entwicklung und den Bau der Schilddriise mit
Riicksicht auf die Entwicklung der Kropfe. Berlin, 1880.

- tiber die Entwicklung und den Bau des Kropfes. A. k. Ch., 29.

— Die chirurgische Behandlung des Kropfes. Berlin, 1887; and III. Teil,

1891.
WOLF. Zur Histologie der Hypophysis des normalen und pathologischen

Gehirns. V. p.-m. G. Wiirzburg, N. F., 31, p. 233, 1898.
WOLOWNIK, B. Experimentelle Untersuchungen iiber das Adrenalin. V. A.,

180, p. 225, 1905.

LITERATURE 585

WOOLEY. Adrenal tumours. Amer. Journ. Med. Scienc., 125, p. 33, 1903.
WORMSER, E. Experimentelle Beitrage zur Schilddrusenfrage. P. A., 67,
505, 1897.

- Adrenalincocain in der Geburtshilfe. Schw. Korr.-BL, No. 23, 1904.
WRAY. Treatment of post-operative shock by pituitary extract. Brit. Med.

Journ., 1905.
WRIGHT and JOSLIX. Degeneration of the islands of Langerhans in

diabetes mellitus. J. Med. Research 6, 1901.
WURMBRAND, GF. Histol. Unters. an drei oper. Fallen v. Akromegalie mit

Hypophysentumor. Ziegl. B., 47, 1909.

WURTZ. Maladie d'Addison. Manuel de med. de Bebove et Achard.
WYBAUW. Contribution a 1'etude des capsules surrenales dans les maladies.

infectieuses experimentales. Bruxelles, 1897.
\Vvss, R. v. Beitr. z. Entwickl. d. Skeletts von Kretinen. Diss., Bern 1899.

YANASE, J. Uber Epithelkorperbefunde bei galvanischer Ubererregbarkeit
der Kinder. W. k. W., 39, 1907; J. K., 67, Erganzungsh. , pp. 57-122.

YATES, J. L. Notes on the experimental production of specific cytolysins for
the adrenal, thyroid and parathyroid glands of dogs. Univ. Penns.,
Med. Bull., 16, 1903.

YONK\VAY and OERTEL. Bemerk. z. Pathologie der Zuckerharnruhr. V. A.,.

i/i, P- 547-
YOUNG, F. A., and LEHMANN, J. E. Internal secretion of the suprarenals.

Experiments with the blood-stream from the suprarenal glands of the

dog. J. o. P., 37, 1908.
YUKAWA. Klinisch experimentelle Untersuchungen der Adrenalinwirkung

auf die Magendrvisen. A. V., xiv, 166, 1908.

ZAHRADNICKY, F. Medullare Anasthesie kombiniert mit Adrenalin und
Suprarenin. Lekarske rozhledy, xiii, i, 1905; Ref. Schmidts Jahrb.,.
289, p. 163, 1905.

ZAK, E. Uber Hypophysistumoren. W. k. R., p. 165, 1904.
— - Glykosurie bei Yeratzung des Duodenums. W. k. W., 1908.
— Zur Kenntnis der Adrenalinmydriasis. V. 25, C. M., 1908.

- Exp. u. klin. Beobacht. liber Storungen sympathischer Innervationen

und intestinale Glykosurie. P. A., 132, 1910.
ZAMBONI. Sugli effetti della resezione dei nervi del pancreas. Rif. med.,

1905.
ZANDER, R. Uber funktionelle und genetische Beziehungen der Nebennieren

zu den anderen Organen, speziell zum Gehirn. Zieglers Beitr., 7>

pp. 489-535, 1890.

- Uber die Lage der Dimensionen des Chiasma opt. D. m. W., 1897.
ZANDY. Peritonitisartiger Symptomenkomplex im Endstadium der Addison-

schen Krankheit. Z. k. M., 38, 1899.
ZANETTI, G. Sur les paralysies des nouveaux-nes et sur la myotonie

generalisee d'Oppenheim. Clinica Moderna, 1906.
ZANFROGNINI, A. Insufricenza paratiroidea e gravidanza. Boll. Ace. Med.

di Genova, 1905.

- Eclampsia e anomalia paratiroidea congenita. Istituto ostetr. Genova,

1905.

- La paratiroidina Vassale nel trattamento dell' eclampsia puerperale.

Clinica Ostetrica, anno 7, fasc., 9, 1905.

- Eine neue kolorimetrische Methode zur Adrtnalinbestimmung.

D. m. W., 1909.
ZAPPERT. Histologische Nervenbefunde eines ii Jahre alten Kindes mit

tetanischen Kriimpfen. W. k. W., 1898.
ZEIGAN. Untersuch. u'ber subdurale Injektion von Adrenalin und Kokain.

Th. M., 1904.
7.KSAS, D. G. Uber d. physiol. Zusammenhang z\v. Milz u. Schilddriise.

A. k. Ch., 31.
ZlEGLER, K. Uber die Wirkung intravenoser Adrenalininjektionen auf das

Gefasssystem und ihrc Bcziehung zur Arteriosklcrose. Zieglers Beitr.,

38, i, 1905.

ZIEHEN. Fall von Gigantismus. Ges. d. Char.-Arzte, 28 Juni, KjoO.
ZlELIXSKA, M. Beitrage zur Kenntnis der normalen und strumosen Schild-
driise des Menschcn und des Hundes. V. A., 136, 1894.

38

586 LITERATURE

ZIETZSCHMANX, OTTO. Ein Beitrag zum Studium der Folgen der Schild-
driisenexstirpation. Thyreoidektomie bei Ziegen. M. G. M. C., IQ,
1908.

ZllNO. Giorn. intern, di scienz med., 3, 1880.

ZINNER. A case of tumour of the pineal gland. The Alienist and Neuro-
logist, xiii, 4, p. 470j 1892.

ZIMMERMANN, W. Uber die Karotisdriise von Rana esculenta. Diss. ,
Berlin, 1887.

ZIVIERI, A. Sulla presenza di colina e potassio nel liquido cefalorachideo
e nel sangue in alcune malattie mentali. Riv. it. di Neurop., Psich.
ed Elettroterap., i, 1908.

ZOLLNER. Tumor der Schadelbasis, ausgehend v. d. Hypophyse. A. Psych.,
44, 1908.

ZOTH, O. Zwei ergographische Versuchsreihen liber die Wirkung orchi-
tischen Extraktes. P. A., 62, 1896.

— Neue Versuche (Hantelversuche) liber d. Wirkung orchitisch. Extraktes.

Ibid., 69, 1898.
ZSCHECH, B. Versuche iiber die Entstehung von Hautalterationen und Gly-

kosurie bei der subkutanen Anwendung der Nebennierenpraparate.

Diss, Mai, 1994.
ZUCKERKANDL, E. Uber Nebenorgane des Sympathicus im Retroperitoneal-

raum des Menschen. An. An., Ergazungsh. zu Bd. 19, pp. 95-107,

1901.

- Die Entwicklung der Schilddriise u. Thymus bei der Ratte. Anat. Hefte,

66, 1902.

- Uber akzessorische Nebennieren bei Torpedo marmorat. An. Hefte, 31,

H. i, pp. 219-232, 1906.
ZUELZER, G. Zur Frage des Nebennierendiabetes. B. k. W., 1901.

- Untersuchungen iiber den experimentellen Diabetes. V. 24, C. i. M.,

1907.

- Uber Versuche einer spezirlschen Fermenttherapie des Diabetes. Z. e. P.,

v, 1908.

ZUELZER, G., DOHRN, M., and MAYER, A. Neuere Untersuchungen iiber den
experimentellen Diabetes. D. m. W., 1908.

— Spezifische Anregung der Darmperistaltik durch intravenose Injektion

des Peristaltik-Hormons. B. k. W., 1908.

ZUNTZ, L. Uber den Einfluss der Ovarien auf den Stoffwechsel. I. Men-
struation und Stoffwechsel. A. G., 78, 1906.

- Einfluss der Kastration auf den respiratorischen Stoffwechsel. Z. Ch.,

95, 1908.

— Weibliche Geschlechtsorgane. Handb. d. Bioch., iii, 1909.

ZUNZ, E. A propos du mode d'action de la secretine pancreatique. A. i. P.,

viii, 1909.
ZUNZ and MEYER. Sur les effets de ligature des canaux pancreat. chez le

chien. Bull. Ac. med., Bruxelles, 1905.

lohn Bale, Sons and Danielsson, Ltd., 83-91, Great Titchfield Street, W.

INDEX.

ABORTION following injection of
adrenalin, 207

Accessory hypophysis, 314
- organs, compensatory hyper-
trophy, 19

Aceto-acetic acid, 419, 420

Acetone bodies, normal formation, 419
in urine, increase of, see
Ketonuria.

— , hot, used in distillation of pigs'
suprarenals, 290, 291

Acetonitril, subcutaneous injection,
resistance to, increased by blood
from subjects with Graves's
disease, 109

increased by oral ad-
ministration of thyroid extract,
108, 109

Achondroplasia, 78

Acidosis, 419

Acromegaly, clinical appearances of,

— , exophthalmos in, 331

— , glandular hyper-function in, 17

— , hypophysal tumour in, 332, 333

— , metabolic changes in, 332

— , pathologico - anatomical findings

in, 332

— , sexual derangement in, 331
— , symptoms in, gigantism similar

to, 343

— , therapeutics of, 347
— 3 tumours of hypophysis associated

with, 306
Addison's disease, 126

— , adrenalin contents of supra-
renal capsules in, 250
— 3 asthenia in, 164
— , clinical signs absent, with
destruction of suprarenal cap-
sules, 162

— , with healthy suprarenals,
159, 1 60

— j emaciation in, 164
— , " experimental," 157
— , fatality of, 126
— , nervous or sympathetic theory

of, 160
— , normal processes becoming

hypoplastic in, 17
— j pigmentation in, 164, 165, 168
— — , symptoms, 126, 163-165
— , symptom-complex of, 267
— , treatment by suprarenal ex-
tract, 168

39

Addison's disease, typical findings in,

ISO

Adiposis dolorosa, 74
Adrenal cells, measure of adrenal
contents, 247

organs, Selachian, extracts ob-
tained from, 247

system, 129, 130, 131

— , condition in renal diseases, 262

— , connected with nervous system,
160, 162

— , development, 132

— , distribution over body wide,
264, 265

— , effect of extirpation of supra-
renal capsules on, 267

— , functions, defined, 264

— , nature, defined, 264

— , secretory process, how con-
trolled, 261

— — — , morphology, 266

, total suppression impossible,

267
tissue, chrome-brown, activity of,

251

Adrenalin, 177

— , action of, altered by increase of
doses of ergot, 231

— large doses on dogs, 236

- — — •, limited, by internal secretory

activity of pancreas, 226
— , modification by thyroid appar-
atus, 226

, by body temperature, 226

— , peculiarities in, 230, 231
— • • — , relation to internal secretory

activity of pancreas, 220
— , site, 227, 228

— , specific, different from blanch-
ing process, 206
— , tables showing, 222-225
— , action on blood-pressure, 213

— , altered by administration of
ergot, 231, 232

- on blood-supply to kidney, 212

- on bronchial muscles, 208

- on composition of blood, 214

- on digestive tract, 203, 204

— on embryonal heart, 202, 203

- on eye, 209

- on gastric secretion, 212

- on genital organs, 206

- on hair muscles, 208

- on heart after removal from
living body, 201

588

INTERNAL SECRETION

.Adrenalin action, experiments to de-
termine nature, 202

- neutralized by apocodein, 203

- on heart of cold and warm
blooded animals compared, 202

- on lachrymal glands, 212

- on lymphatics of peritoneum,

213

- on metabolism, 214, 215

- on muscles, 228, 229

- on organs innervated by sym-
pathetic system, 189

- on pancreas, 212

- on pigment cells and granules
of frog, 214

- on pregnant uterus, altered by
ergot, 232

- on pupil, 230

- on respiration, 235

- on salivary glands, 211

- on submaxillary glands, 211

- on sweat-glands, 214

- on sympathetic and autonomous
nervous system compared, 230,

231

- contrasted, 231

- on urinary bladder, 205

- on uterus, 200, 207

- as quantitative test, 207
, therapeutic, 207

— , amount in suprarenal capsules,

182, 248, 249

— • — , modification by path-
ological conditions, 249
— , antagonism of cholin to, 276, 278
— , by-effects of, 234-236
causing abortion, 207

mydriasis in Graves's disease,

21 I

— , cells producing, 253
— , chemical tests for, in liquids and
secretions, 180, 181

- — • — , colorimetric methods,
181, 182

- contents in cats and rabbits
compared, 251

- of dog, 254

- of suprarenals in Addison's
disease, 250

— , conversion of tyrosin into, 180

— , destruction of, factors in, 256, 257

— , diabetes, 220

--, disassimilatory hormone, 206
-, disassociation of auricular and

ventricular beats under, 203
, drugs antagonistic to, in action,

200
, effects after thyroidectomy and

thyroparathyroidectomy, 54, 55
— , modified by previous adminis-
tration of curarin, 196, 197

- determined by Meyer's method,
1 99

- on arteries, 198

- on coronary vessels of heart,
186

Adrenalin, effects on heart, how and
when determined, 200

- on nerve-endings, 197, 198

- on pigment in Addison's disease,.
165

- on pulmonary circulation, 185

- vessels negative, 197

- on thyroid gland, 28
— , excretion of, 256

- of lymph from thoracic duct
promoted by, 213

—, formation of, relation to chemical

processes of muscles, 296
— , function of, 266

— , connected with sympathetic

system^ 266, 267
Adrenalin-glycosuria, 215, 259, 429

- accompanied by hyperglycsemia,.
216

— , effect of subcutaneous injection

of chyle on, 431
— , experimental, and puncture of

fourth ventricle, 219
— , inhibition of, 220, 221

— , by fever, 221 (footnote)
— , by hirudin, 221
— , by lymphagoga, 221
— , by pancreatic extract, 429
— , by pilocarpin, 226
— , mechanism of, 217, 218
Adrenalin in blood, 250, 251
— , disappearance, 256-258
— , persisting after cessation of.

specific action, 258
— , ultimate fate of, 255
— , see also Adrenalaemia
in collapse, 188, 189
in heart failure, iS'S, 189

- following diphtheria, 189
— , increases secretion of bile, 212

— , inhibitory influence on activity of

pancreas, 221, 226

— , injection of, contraction of blood-
vessels following, 196

followed by glycosuria after
parathvroidectomy, 68
— , not followed by glycosuria in

thyroidectomized animals, 68
— , intravenous injection, antidote to
poisoning by chloral, 201

- causing dilatation of cerebral
vessels, 185

- in urine, method of testing for, 182
— , isolation methods, 177, 178
— , matrix of, 180

mydriasis, inhibition of, 220
— , neutralization of strychnine by,.

295

— , organic composition, 179, 180
— , physiological activity, 183

effects on sympathetic system,
196
poisoning, symptoms of various

animals dying from, 238
— , portion of blood-vessels acted on

by, 187
— , precursors of, 296, 297

INDEX

589

Adrenalin, production of anirmia by,
187

of hyperaemia by, 187
raises heat-tone, 226
— , reaction of suprarenal capsules to,

212

— , resuscitating effect on heart, 201
-, rise in blood-pressure due to, 183,

184

— , secretion of, process, 253
— , stimulation of myoneural sympa-
thetic terminals by, 230
- sympathetic nerves by, under
normal conditions and after
large doses of ergot, 232, 233
— , subcutaneous injection followed

by hyperglycaemia, 217
—3 synthetic, 178, 179
— , toxic action, 236-246, 259
— , on dogs, 240

— , inflammatory and degenera-
tive, 239

— • — , intravenously, 236, 239
— , on rabbits, 239, 240

, subcutaneously, 237, 239

— , on various animals, 236, 237
— , on vascular system, 240-246
— , toxo-chemical action, 244
— , toxic dose, 236

-, transfusion, continuous, perma-
nent increase of blood-pressure
under, 259
— , tyrosin and, 165
— , tests for, 297
— , therapeutic applications, 188
— , time of formation, 251
— , vasoconstriction due to, 184
— , vasodilator properties of, 198

and apocodein, action on muscles

compared, 228
and muscarin, action compared,

258, 259

and sympathetic system, 219
as diurecic, 212
as secretory process of adrenal

system, 246

— , see also Phloriz'm and adrenalin
Adrenalinaemia and Graves's disease,

264

— , mydriasis as test for, 262, 263
— , pathological human, 262
— , physiological, 254-260

— , transient, 255
Alanin, 298

Albumin, decomposition of, 13
— , metabolism of, 267, 386

— , after extirpation of supra-

renals, 154
Albuminoids in suprarenal capsules,

275

Albuminuria in tetany of animals, 43
Ammonia poisoning, experimental
production, by formation of
Eck's fistula, 10
Amniota, suprarenals of, 129
Amphibia, organs representing supra-
renal capsules in, 129

Amphibia, suprarenal bodies in,

development, 133
Amphioxus, absence of structure

similar to suprarenal tissue in,

129
Anaemia following exhibition of

adrenalin, 187
Animals, cold and warm-blooded,

action of adrenalin on hearts of

compared, 202
— , endemic cretinism in, 83
— , extirpation of hypophysis in, 334
— , goitre in, experimental production,

82

---, natural development, 82
— , suprarenal-less, metabolism of

carbohydrates in, 154, 155
— , thyroidectomized, changes in, 62-

7i

— , various, histology of suprarenal
cortical granules in, 285

Anisotropic substances, 289

Antibodies, formation not provoked by
hormones, 16

Antigens, hormones and, 16

Antitoxic action of suprarenal cap-
sules, 293, 294
activity of thyroid glands, 108

Antlers as secondary sexual charac-
ters, 360, 365

Aorta, atheromatous degeneration fol-
lowing thyroidectomy, 63
— , toxic action of adrenalin on, 241

Apathy following suprarenal suppres-
sion, 156

Apes, acute tetany in, 41

— , parathyroid glands in, 36

Apocodein, 197

and adrenalin, action on muscles

compared, 228

neutralizes action of adrenalin on
heart, 203

— • paralysing effect on nerve endings,
197

Arhythmia, production of by large
doses of adrenalin and extract of
chromaffine bodies, 236

Arteries, changes due to toxic action
of adrenalin on, 241, 242, 243

— , effect of adrenalin on, 198

• — , when isolated from bodv.

198

— , isolated, suspension in Ringer's
solution, 198, 199

— , muscles of, effect of adrenalin on,

200
— , sympathetic innervation, 200

— , treatment with adrenalin, 199, 200;
see also Meyers method,

Arteriosclerosis due to adrenalin, 245,.
246

— , hypertension in, 262

Artery, pulmonary, toxic action of
adrenalin on, 243

Athyrosis and dwarfism, 80
and endemic cretinism, 80

— in man, 71

590

INTERNAL SECRETION

Athyrosis, operative, changes follow-

ing* ?i , 72

Asthenia in Addison's disease, 164
— following suprarenal suppression

156

Asthma thymicum, 122
Atropine, paralysis of vagal nerve

endings by, 200
and pilocarpine, action compared,

Auto-intoxication in pancreatic dia-

betes, theory of, 423
Auto-nephrotoxins, formation of, 443

BARIUM chloride, action of, altered by

increase in doses of ergot, 231
Basophile cells, 308
Batrachians, suprarenal capsules in,

299

Benzoic acid, affinity for glycocoll, 9
Bile, secretion, increased by adrena-
lin, 212

Biology, problems of, solved by
doctrine of internal secretions, 23
Birds, acute tetany in, 41, 42
— , castration in, results of, 378
— , heart of, action of adrenalin on,

202
— , perversion of sex characteristics

in, 365, 366

— , portal system of suprarenals pre-
sent in, 300
— , suprarenal capsules in, 128, 130,

133, 299., 300

— , thyroid apparatus in, 36
Bladder, urinary effect of pituitary
extract on, 326

action of adrenalin on, 205
— , experiments to determine, 205
— , innervation of, differences in mam-
mals, 205, 206

— , experiments to deter-
mine, 205
Blood, action of thymus extract on,

121

--, adrenalin in, 250, 251
--, disappearance, 256-258
— , remaining after cessation of

specific action, 258
— , ultimate fate of, 255
— , see also Adrcnalscniia
— , alkalinity of, disappearance of

adrenalin under, 256
— , changes in, following extirpation

of suprarenals, 157, 158
— , following thyroidectomy, 66
— , cholesterinester in, source of, 292
— , circulation of, and humoral path-
ology, 2

in suprarenals of mammals,
300, 301
— , pulmonary, effects of adrenalin

on, 185
— , composition of, action of adrenalin

on, 214
— j effect of castration on, 388

Blood formation, influence of thyroid
gland on, 37

— , sugar-contents of, on what de-
pendent, 428

--, toxicitv after extirpation of supra-
renals, 156

Blood-letting in tetany, 56

Blood-pressure, action of adrenalin
on, 213

— , altered by previous adminis-
tration of ergot, 231, 232
of methylaminoketone on, 213

— , condition of, after extirpation of
suprarenal capsules, 147, 148

— , effect of intravenous injection of
organic extracts on, 21, 22

of pituitary extract on, 323
- of renal extract on, 442, 443

— , fall of, induced by cholin, 276, 277

— , increase induced by suprarenal
extract, how abolished, 157

— , intracranial conditions governing,

329

— , permanent increase following con-
tinuous transfusion of adrenalin,
259

— , rise in, due to adrenalin, 183, 184

Blood-serum, mydriatic, 262

Blood-supply to kidney, action of
adrenalin on, 212

Blood-vessels, contraction, drugs in-
ducing, 200

— , contraction following injection of
adrenalin, 196

— , dilatation, drugs inducing, 200

— , effect of pituitary extract on, 326

— , portion of, acted on by adrenalin,
187

— , pulmonary, effect of adrenalin on,
negative, 197

— , toxic action of adrenalin on, 240

Boiling, activity of thymus extract
not affected by, 121

Bones, changes in, in acromegaly, 333

— , growth of, effect of pituitary ex-
tract on, 328

— , influence of generative glands
on, 382

Brain, blood-vessels of, dilated by
adrenalin, 185

— , fourth ventricle, puncture of, and
experimental adrenalin-glycos-
uria, 219

of pigs, lipoid substances in,
290, 291

— , relationship of tetany to, 60, 61
-, weight of, in gigantism, 342

Bronchi, muscles of, action of adrena-
lin on, 208

CACHEXIA, chronic, following thyroid-
ectomy, 63

— , following total thyroidectomv, 71,
72, 73

— , strumipriva and Graves's disease,
symptoms common to, Q9

INDEX

591

Cachexia strumipriva, treatment by

thyroid extract, 87
thyropriva, symptoms compared
with those of Graves's disease, 94,

95

— , see also Myxcedema, post-

operative
Ca-ions, n
Calcium metabolism in relation to

parathyroid glands, 57
salts, treatment by, of tetany, 58,

59

Capons, characteristics of, 378
Carbohydrates, metabolism, action of

adrenalin on, 215
—, after extirpation of suprarenal

capsules, 154, 155

— 3 central point respecting, 427
- — , in Graves's disease, 99

— , in suprarenal-less animals, 154,

155

— , influence of thyroid apparatus
on, controlled by pancreas, 430

--- , in thyroidless animals, 67, 68
Carbonic acid, affinity for urea, Q
-- , effect on respiratory centre, 15
Carnauba-acid-cholesterinester, 292
Carotid organ (gland), 302

— -- , origin, theories respecting,

303
Castration, effects of, 17

— • — -, on composition of blood, 388

— , on thyroid gland, 344

— , hypertrophy of hypophysis after,

-—, in relation to thymus gland, 116

— , obesity after, 386

— , results of, 366

— , in animals, 379

— , in birds, 378

— , on generative glands, 376-382

— , in man, 378, 380

— , weight of suprarenals increased

after, 269
Cat, acute tetany in, 39, 40

— , adrenalin contents in, 251

— , effect of iodothyrin on circulatory

apparatus in, 90

— , parathyroid glands in, 35

— , suprarenal capsules in, experi-

mental extirpation, 141
Cell-altruism, 5
Cell-complex of ovary, 399
Cell formation of hypophysis, 308
Cells of generation, 359, 362

— , somatic, 359, 362
Cerebellum, relationship of tetany to,

60, 6 1
Cervida?, secondary sex character-

istics in, 360, 365
Children, hypothyrosis in, 76, 77
Chloral, poisoning by, adrenalin anti-

dote to, 201
Chlorinester, crystallizing, from hot

acetone used to distil pigs' supra-

renals, 292

Chloroform anaesthesia, sudden death

at commencement of, in status

lymphaticus, 123
Chlorosis, relationship to ovarian

function, 388
Cholesterin palmitate and stearate in

suprarenals, 288
Cholesterinesters, 287, 288
— , colour reactions, 289

in blood, source of, 292
— , permanent emulsions of double

refractive globules yielded by,

288
Cholin, antagonism to adrenalin, 276,

278

— , constitutional formula, 277
— , distribution throughout body, 278
— , in combination with leci-
thin, 278
— , effects of, 324
— , fall of blood-pressure induced by,

276, 277

in suprarenal capsules, 275, 276
— , method of extraction, 275,

276

— , origin of, 278

— , physiological activity, 278, 279
Chromaffine bodies, 304
— - — , extract of, action on dogs, 236

cells, 132, 133
— - — , derivation, 264

— — , staining of, 247, 248

system, effect on metabolism, 70

— — , hypoplasia of, 158

— , effect, 123

— , in sudden death in status
thymicolymphaticus, 158
- - tissue, 6
— - — , free grafting of, 173

— , extracapsular, extracts from,
action, 247

— — , hyperplasia, in true contracted

kidney, 263 (footnote)
— , in suprarenal medulla, hyper-
plasia, 262

Chromates, treatment of myelin forms
of suprarenal cortex with, 289

Chrome-brown cells, attached to gan-
glia of nervous system, 265

Chromophile cells of hypophysis, 308.

3ii

Chrysotoxin, action of, 198
Chyle, flow of, how increased, 444
— , subcutaneous injection, effect on

adrenalin-glycosuria, 431
Circulatory system, effect of pituitary

extract on, 323

— — , physiological effects of thyroid

extracts on, 89, 90
Coccygeal gland, 304

, human, primal origin, 305

Collapse, adrenalin injection in, 188,

189
Colloid in parathyroid glands, 33

- substance of the hypophysis, 312
Coma, diabetic, cause of, 41.9, 420

592

INTERNAL SECRETION

Conarium, see Pineal body

Corpus luteum, function of, 400, 402,

407
— - — , hypothesis, 404

, menstruation originating in,

406

verum, cells of, similarity of
cells of suprarenal cortex to, 269
Crabs, parasites causing neuter charac-
teristics in, 367
Cretinism, endemic, 79
— • — , and athyrosis, So
— , clinical signs, 79
— , deaf-mutism in, 79
— , geographical distribution, 79

— , same as that of endemic
goitre, 8 1
— , in animals, 83
— , metabolism in, 89
— , treatment by thyroid extract,

87 .

Cryptorchidism, suppression of sper-

matogenesis, 393

— , unilateral, 393-394

Curarin, effects of adrenalin, modified
by previous administration of,
196, 197

Cyanophile cells, 308

Cytotoxins, specific, attempted de-
struction of suprarenal capsules
by, 144

DEAF-MUTISM in endemic cretinism, 79
Decomposition, products of, effects of

over-irritation by, 15
— , formation in intestinal canal, 7
Dercum's disease, sec Adi-posis dolorosa
Diabetes, changes in pancreas in, 432
— , clinical, and experimental pan-
creatic, analogy between, 431, 432
— , duodenal, 422
— , pancreatic, 220

and auto-intoxication, 423
— , experimental in animals of
different species, 414

-, in dog, 414
— , failure of organo-therapy in,

423, 424

— , glycosuria in, factors in-
fluencing, 416, 417
— , metabolism in, 415
— , mydriasis characteristic of,

production, 431

—, nervous origin, theorv of, 422
— , permanent factors originating,

432

— , theories respecting, 420-432
— , see also Adrenalin-diabetes
Diet, effect on glycosuria in pan-
creatic diabetes, 416
Digestive tract, action of adrenalin

on, 203, 204

Dimorphism, sexual, 361
Diphtheria, heart failure following
adrenalin administration in, 189
Diseases, reflex manifestation of, 2
Diuresis due to pituitary extract, 327

Diuretic action of thyroid extract, 91

— , adrenalin as, 212

Dog, acute tetany in, 39, 40

— , adrenalin contents of, 254

• — , effects of large doses of adrenalin
and extract of chromamne bodies
on, 236

— , effects of ligature of excretory
ducts of pancreas on, 430

— j effect of thyroidin on, 92

— , emaciation in, following extirpa-
tion of pancreas, 420

— , extirpation of hypophysis in, 319,
320

— , parathyroid glands in, 35
— , supernumerary, 35

— , production of pancreatic diabetes
in, 414

— , suprarenal capsules in, experi-
mental removal, 141

— , thymus gland in, 113

— — - — , extirpation, results, 114, 117

- implantation into, 119, 120
— , thyroidectomized, changes in, 65

— , staggering gait of, 61
— , toxic action of adrenalin on, 240
Ductless glands, functions of, early
discoveries, 3

— • — , importance of, 17
Duodenum, see Diabetes, duodenal
Dwarfism, 78

— , athyrosis and, So

Dystrophia adiposogcnitalis, 17, 345

ECK's fistula, formation of, leading to

ammonia poisoning, 10
Eels surviving removal of suprarenal

capsules, 153
Eggs, fertilization of, 356
Electric current, thymus gland and

reaction of motor apparatus to,

1 20

Emaciation in Addison's disease, 164
following extirpation of pancreas,

420
— - following extirpation of supra-

renals, 154

— , following thyroidectomy, 66
Embryo, development of hypophysis

in, 313

Enzymes, organic substances formed
by, in process of decomposition
of sugar, 426

P^osinophile cells of hypophysis, 308

Epilepsy, colloid in hypophysis, as
cause of, 305

Epinephrectomy, sec Suprarenal cap-
sides extirpation

Epinephrin, 178
-, toxic dose, 236

Epiphysis, see Pineal body

Epoophoron, 410

Ergot, administration of, increase in,
alters action of adrenalin, 231

— , alters action of adrenalin on preg-
nant uterus, 232

INDEX

593

Ergot, effect of adrenalin on blood-
pressure, altered bv, 231, 232
- , inhibitory action of, site of dis-
cussed, 233, 234
— , poisoning by, acute, 232
— , stimulation of sympathetic nerves
by adrenalin after large doses of,
^32, 233
Ergotoxin, effect on sympathetic

system, 196

Excretion, distinction from secretion, 3
Excretory organs, expulsion of toxic

substances by, 8

Exophthalmos in acromegaly, 331
— in Graves's disease, 96, 97
Extremities, upper, effect of mountain

climbing on, 14

Eunuchs, characteristics of, 378
Eye, action of adrenalin on, 209
— , diseases of, in acromegaly, 331
— , symptoms following intravenous
injection of thyroid juice, 92

FASTING, prolonged, followed by gly-
cosuria, 216

Fat, absorption after ligature of ex-
cretory ducts of pancreas, 437

- ceases after total extirpation
of pancreas, 437

distribution in suprarenal cap-
sules, 285

granules in epithelial cells of para-
thyroid glands, 32, 33

— , labile, in spongiocytes, 282

Fatigue, muscular, suprarenal cap-
sules in relation to, 295

Fats, metabolism of, effect of thyroid-
ectomy on, 71

Females, incidence of Graves's disease
among, 102

Femininity, 362

Ferments in suprarenal capsules, 275

Ferret, motor and inhibitory inner-
vation of bladder in, derivation,
205 _

Fever, inhibiting adrenalin glyco-
suria, 221 (footnote)

Fish, cortex and medulla of supra-
renal capsules distinct bodies in,
130

— , embryology of pineal body in, 351

— , heart of, action of adrenalin on,
202

— , interrenal body in experimental
extirpation, 150, 152

— , suprarenal capsules in, extirpation
not fatal, 152, 153

— , thyroid apparatus in, 36

Fistula, pancreatic, 437, 438

Flesh-free diet in Graves's disease, 107

Foetus, extract of, effect on mammary
gland, 373

— , sexually differential tissues in, 361

Fowls, extirpation of thynuis in, 1 14,
1 16

Frog, extirpation of hypophysis in,
' 316

Frog, extirpation of thymus in, results,

115

— , pigment cells and granules of,
action of adrenalin on, 214

— , suprarenal capsule in, experi-
mental extirpation, 140, 141

Frog's eye, isolated, action of adrena-
lin on, 209, 210

Function, suspension of, effects, 10

Functional equilibrium, disturbances
of, explanation, 2

GANGLION" cells, particular, affected by

nicotine, 194
Gastric and intestinal mucosa, internal

secretion, 438
secretion, action of adrenalin on,

212

Generation, cells of, 359, 362
— , organs of, female, physiological

association of thyroid gland with,

37

Generative glands, developmental
history of, 358

—3 effect of Rontgen rays on, 396

— , extract of, 389-391

— , hormone in, sexually un-
differentiated activity of, 382-389

— , influence upon growth of
skeleton, 382

— , internal secretory tissue, ele-
ments of, 391-410

— , relationship to ostcomalacia,

387

— , results of castration, 370-382
Genitals, defective, in gigantism, 342,

344
(external), action of adrenalin on,

206
— , female, tumours of, derived from

Marchand's accessory supra-

renals, 270
— , internal secretory tissue, elements

of, 410-412
— , hypoplasia of, 340, 349

(internal), action of adrenalin on,

206

Genito-vesicular reflex, 390
Gigantism, infantile type, 344
— , pathogenesis of, 343
— , relationship to hypophysis, 341
— , sex incidence of, 342
— , symptoms in acromegaly similar

to, 343

— , weight of brain in, 342
Glandulae pinealis, see Pineal body
Glandular secretions, classification, 8
— , deficiency or superfluity effects,

3
Globules, double refractive bodies

showing, 288

— , colour reactions, 289
Glycogen, accumulation in liver, 427,

428
— , content of leucocytes, increase in,

cause, 418

594

INTERNAL SECRETION

Glycogen, conversion into grape-
sugar, 428
— , deposition in liver after extirpation

of pancreas, how effected, 430
— , formation in liver, 216

in liver, reduced after extirpation

of pancreas, 418
in muscles, diminishing after

extirpation of pancreas, 418
Glycogenesis, 4

Glycogoll, affinity of benzoic acid for, 9
Glycolytic ferment in muscles, 426

— , 'theory of, 424, 425
Glycosuria, absent after adrenalin
injection in thyroidectomized
animals, 68

- after partial extirpation of
pancreas, 415

— , alimentary, in Graves's disease, QQ
— , factors originating, 432

following administration of
adrenalin, sec Adrcnalin-glyco-
sitria

following inhibition of internal
secretion of pancreas, 428
ligature of thoracic duct, 431
prolonged fasting, 216
total extirpation of pancreas,

.413
— in acromegaly, 332

in pancreatic diabetes, factors in-
fluencing, 416, 417

— , immediate cause of, 418
— , marked after adrenalin injection

following parathyroidectomy, 68
— , production following phlorizin in

suprarenal-less animals, 155
— , site of origin, 207
— , slight, follows extirpation of

larger portions of pancreas, 416
— , test for, 2Qy
Glycuronic acid, affinity for mercap-

turic acid, 9

Goat, parathyroid glands in, 35
— , tetany in, 41
— , thyroidectomized, administration

of thyroid extracts to, 86
— , changes in, 64, 65
Goitre, cardiac symptoms, 103
— , causal agent unknown, 82
— , endemic, etiology, Si, 82

—i geographical distribution of
endemic cretinism same as that
of, 8 1

— , extirpation, preservation of para-
thyroid glands during, 44
— , geological distribution, 81
— , hyperplastic, reduction of amount

of iodine-thyroglobulin in, 30
in animals, 82
in Gravest disease, 95
— , relation of iodine in thyroid gland

to, 29, 30, 31
— , removal, thyroidectomy must be

partial in, 73
— , simple, 102

Goitre, simple, functional aspect not
identical with hyperthyroidism,
103

— , soil in relation to, Si
— , transmission by drinking water, Si
Goitre-heart, 19
Graafian follicles, bursting of, 406

— . function of, 401
Grape-sugar, conversion of glycogen

into, 428
— , intravenous injection, effect on

islands of Langerhans, 435
Graves's disease, 93

— , alimentary glycosuria in, 99

and cachexia strumipriva, sym-
ptoms common to, 99
— associated with adrenalaemia,

264

— , blood from, increases resist-
ance to acetonitril, subcutaneously
injected, 109
— , due to flooding of organism

with thyroid substances, 102
— , etiological connection with thy-
roid gland, 100, 101
— , exophthalmos in, 96, 97
— , flesli-free diet in, 107
— , glandular hyperf unction in, 17
-, goitre in, 95
— , hypertrophy of heart in, 96

of thymus in, 96
— , incidence among females, 102
— , metabolism in, greatly in-
creased, 98

— , mydriasis produced by adrena-
lin in, 211

- myxocdema and, difference be-
tween, 99

— , reduction of amount of iodine-
thyroglobulin in, 30
— , symptoms and organic changes
in, 95-98

compared with those of
cachexia thyropriva, 94, 95

- in relation to those of experi-
mental hyperthyroidization, 103

- resembling those of found
in other diseases, 99

— , treatment by adrenalin causing
mydriasis, 211

by serum-therapy, 100
by thyrotoxic immune serum,
101
— - — , operative, 100

by organo-therapy, 100
by X-ray, 100

— , vasomotor excitability in, 97
Guinea-pig, suprarenal capsules in,
exceptional weight of explained,
269

- experimental removal, 141,
M4

— , thymus gland in, 113

extirpation, results, 116
Gynaecomastia, 372

H.EMOLYSINS, action of, iS

INDEX

595

Hair-muscles of different animals,
action of adrenalin on, com-
pared, 208

Heart, action of adrenalin on, experi-
ments to determine nature, 202

— — • — , neutralized by apocodein,

203
after removal from living body,

action of adrenalin on, 201
— , coronary vessels of, effect of

adrenalin on, 186
- — , effect of adrenalin on, how and

when determined, 200

— — of pituitary extract on, 323-325
— , embryonal, action of adrenalin on,

203
— - failure, adrenalin in, iSS, 189

following diphtheria, adrenalin

in, 189

— , hypertrophy accompanying hyper-
trophy of thymuSj 19
— , in Graves's disease, 96
— , resuscitating effect of adrenalin

on, 201
— , toxic action of adrenalin on, 240;

see also Goitre-heart
Heart-beats, auricular and ventricular,

disassociation under adrenalin,

203
Heart-muscle, chemical changes in,

nature, 14

Heart-puncture, 221 (footnote), 226
Heart-symptoms of goitre, 103
Heat-tone raised by adrenalin, 226
Hens, extirpation of hypophysis in,

316

— , thyroidectomizecl, changes in, 64
Hermaphroditism, 357, 362
— , glandular, 363
Hippuric acid, where formed in body.,

9

Hirudin, suppression of adrenalin-
glycosuria by, 221

Homoeopathy, isopathy, a branch of, 2

Hormone, 5, 6

— , definition of, 5

— , dissimilatory, action of thyroid
gland secretion as, 109, no

• — • - — , adrenalin as, 266

— , genital, relationship of Leydig's
cells to, 398

— • in generative glands, activity of,
382-389

— , mammary, origin of, 374-376

— , pancreatic, 431

— , action of, 429, 430
— , isolation, so far, impossible,
430

Hormones, activity of, 12
and antigens, 16

— j chemistrv of, 16

— , classification, 13

— , dissimilatory, 13, 109, 266

— , distinction from nutrient secre-
tions, 13

— , formation of antibodies not pro-
voked by, 16

Hormones, inhibitory, 14

— , negative properties, 16
-, origin of, 15

— , pancreatic, 423, 424

— , production of, 8

Hydrogen ethyl sulphates, toxic
bodies with affinity for, 9

Hyperaclrenalinism, experimental, 261

Hyperremia> following exhibition of
adrenalin, 187

Hyperglycsemia accompanying adrena-
lin-glycosuria, 216

— • following subcutaneous injection

of adrenalin, 217

— , immediate cause of glycosuria in

pancreatic diabetes, 418

— • in suprarenal-less dogs, 155

— , phenomena accompanying, 418

— , source of, 419
Hypernephroma, extracts of, 251

— , renal, 270
Hyperparathyroidism, diseases follow-

ing, 46

Hyperpituitarism, 335, 337, 345
Hyperthyroidism, experimental, 92

— , following administration of thy-

roid extracts, 90

— , functional aspect of simple goitre

not identical with, 103

— , human, following administration

of thyroid extracts, 92, 93

— , true, conditions classed under, 93
Hyperthyroidization, experimental,

symptoms in relation to those or

Graves's disease, 103
Hyperthyrosis in man, 71
Hypoparathvroidism, diseases follow-

ing, 46
Hypophysectomy, experimental, 315-

Hypophysis, accessory, 314

— , anatomy of, 306-308

— , chemistry of, 322

— , change in function, no

— , death following removal of, 319-

321

— , development of, history, 313

— , diseases of, 330-348

— , effects of, 326

on blood-pressure after stimu-
lation of, 329

— , embryonal, development of, 313

— 3 enlargement, following thyroid-

ectomy, 63, 66

— , experimental extirpation of, 315-

3 '9, 334

- stimulation of, 328-330

— , function of, 306

— , determined by experiment, 18

- theory of, 305, 309, 348-50

— , histology of, 308

— , hyperf unction of, 338

— , hypertrophy of, 335

— following extirpation of thy-
roid, 19

— , influence of pregnancy on, 307,

309, 310

596

INTERNAL SECRETION

Hypophysis, nervous portion of struc-
ture of, 310

— , physiology of, 315-321
— , relationship to gigantism, 341

to sexual glands, 339-341
— • to suprarenals, 339

to thymus, 339

to thyroid gland, 338
— , sarcoma of, 334
— , secretion of, histology of, 311
— , sources ot origin, 315
— , tumour of, extirpation of, in man,

330
— , in acromegaly, 306, 332, 333

— — , obesity associated with, 345-347
— , weight of, 307

— , see also Pituitary extract
Hypothyrosis, metabolic changes in,

88'

in children, 76, 77
Humoral pathology, 2
— - — and circulation of blood, 2

INDICAN reaction in urine after re-
moval of suprarenal capsules,

Infantilism, 77

— , dystrophic, 77

— , following thyroidectomy, 64

— , myxcedematous, 77

Infants, laryngeal spasm of, 122

— tetany in, 45

Infective diseases, mortality from,
great among subjects of status
thymicolymphaticus, 124
Internal secretion, definition and

limitation of term, 5
— , doctrine of, date of origin, 4

— , when first formulated, 3
Interrenal body in fish, experimental

extirpation, 150
bodies, accessory, 131, 134

— • — , compensatory hypertrophy of

portions of, 268

in fish, experimental extirpa-
tion, fatal, 152

— structures, accessory, 268

— , connection of suprarenal
capsules with, 268
systems, 129-131, 267-270
— , development, 131, 132
— , functional significance of free
portions, 268

, function of theory as to, 292-

294

tissue, importance of to life, 302
Interrenals, accessory, in white rats,

155
Intestinal canal, formation of products

of decomposition in, 7
mucosa, secretion, mechanism of,

440
— • tract, atrophy present in senile

degeneration, absent in myx-

(jedema, 76
Intestines, action of adrenalin on,

determined by experiment, 204

Intracranial blood-pressure, conditions
governing, 329

Invertebrates, adrenal system in, 135

— , suprarenal systems in, tables illus-
trating, 135-137

Invertin, action of, inhibited by levu-
lose, 419

Iodine, distribution in human organs,

30
in thyroid gland, 29, 30, 106

— , relation to goitre, 29, 30, 31

lodine-thyroglobulin, 30

— , reduced in hyperplastic and ex-
ophthalmic goitre, 30

lodization, process of, in thyroid
gland, 105

lodothyrin, 30

— - , administration of, after thyroid
suppression, 87

— , effects on circulatory apparatus,
in animals, 90

— , function, 37

lodothyro-globulin, effects on circu-
latory apparatus, 89

Ions, function of, 1 1

Islands of Langerhans, see Latigcr-
hans, islands of

Isopathy, branch of homoeopathy, 2

— , defined, 2

JECORIN, 286

KETONURIA, experimental, difficult to
obtain, 420

— , symptoms of diabetes, 419

Kidney, blood-supply to, action of
adrenalin on, 212

— , contracted, true hyperplasia of,
chromaffine tissue in, 263

— , disease of blood from subjects of,
containing lymphagogue sub-
stance, 444

disease, condition of adrenal
system in, 262

— , effects of pituitary extract on, 325,

. 3^7
— , internal secretion, 440

— , effect of renal extract on,
442
— , parenchyma of, reduction of,

effects, 444, 445

— , transplantation of suprarenal cap-
sules in, 170, 171, 172

LACHRYMAL glands, action of adrenalin

on, 212

Lactic acid and respiratory centre, 15
Langerhans, islands of, concerned in
internal secretory function of
pancreas, 436, 437
— , effect of injection of phlorizin
and adrenalin on, 435

- of intravenous injection of
grape-sugar on, 435
— , function, 433, 434
Lecithin, cholin combined with, in
body, 278

INDEX

597

Lecithin, function of, 289

— , pure, hardly obtainable, 290

in suprarenal capsules, 280
Lecithin-carbohydrate, 286
Leucocytes, glycogen content, cause of

increase, 418
Levulose, administration of, effect,

430
— , experimental results, 417, 418,

419

— , inhibits action of invertin, 419
" Leydig's between-cells/' 392
Leydig cells, 394

— , relationship to genital hormone,

398
Lipoid granules in cells of suprarenal

cortex, 272
substances, 21

in suprarenal capsules, 292,

293

Lipoids, suprarenal, 279, 287
Liver, accumulation of glycogen in,

427, 428
- — , deposition of glycogen in, after

extirpation of pancreas, how

effected, 430
— , effect on destruction of adrenalin,

257
— , formation of glycogen in, 216

- of sugar in, inhibited by pan-
creas, 430

— , how controlled, 428, 429
urea by, antitoxic function, 9
— , glycogen in, reduced after extir-
pation of pancreas, 418
Lutein cells, origin of, 401

tabloids, therapeutic use of, 405
Lymph, excretion from thoracic duct,

promoted by adrenalin, 213
glands, cells of thymus gland not

identical with those of, 112
Lymph-vessels, passage of thyroid

secretion into, 28
Lymphagoga, suppression of adrenalin-

glycosuria by, 221
Lymphagogues, 443, 444
— , blood from subject of kidney dis-
ease acting as, 444
Lymphatic ducts, ligature of, 221
Lymphatics, peritoneal, action of
adrenalin on, 213

MAMMALS, blood-circulation in supra-
renals of, 300, 301

— , cortex and medulla of suprarenal
capsules amalgamated in, 130

— , innervation of bladder, differences
in, 205, 206

— , suprarenal bodies in, develop-
ment, 133

Mammary glands, 355, 360

— , development of, 372, 375

Marchand's accessory suprarenals,
tumours of female genitals
derived from, 270

" Masculinity,-'' 362

Menstruation, connection of ovulation

with, 403, 406

— , disordered, in acromegaly, 331, 337
— , origin of, 406
— , relationship of ovarv to, 381
Mental changes following thyroid-

ectomy, 65
Mercapturic acid, affinity of gly-

curonic acid for, 9

Metabolic changes in hypothyrosis, SS
— , how influenced by thyroid
extract, 88
Metabolism, action of adrenalin on,

214, 215
— , effects of pituitary extract on, 327

— , thyroid extract on, 91
— , end-products of, function, 15
in endemic cretinism, 89
in Graves's disease greatly in-
creased, 98
in myxcedema, 88, 89
in pancreatic diabetes, 415
— , processes of, changes following

thyroidectomy, 67
— , glands accelerating, 70

- retarding, 70

Methylaminoketone, action on blood-
pressure, 213
Meyer's method, effects of adrenalin

determined by, 199
Mice, parathyroid tetany in, 41
Milk diet in acute tetany, 107
— , secretion of, 372, 375
Mongolism, diagnosis from sporadic

myxcedema, 78
Monoamidomonophosphatide cephalin,

292
Mors thymia, sec Status thymico-

lyin'phaticiis, sudden death in
Mountain climbing, effect on upper

extremities, 14

Muscarin and adrenalin, action com-
pared, 258, 259

Muscles, action of adrenalin on, 228,
229

and apocodein on, com-
pared, 228
-3 chemical processes, relation of

formation of adrenalin to, 296
— , effect of pituitary extract on, 320
— , glycogen in, disappearing after

extirpation of pancreas, 418
-3 glycolytic ferment in, 426
— , involuntary nerve supply to, 191
, toxicity of, following extirpation

of suprarenals, 156
— 3 unstriated, action of adrenalin on,

229
— , and sympathetic nervous

system, 229

— , vascular, see Arteries, muscles of

Muscular exertion, effect on glyco-

suria in pajicreatic diabetes, 417

weakness following suprarenal

suppression, 156

598

INTERNAL SECRETION

Myasthenia gravis pseudoparalytica,

cause of, 46, 47
Mydriasis, characteristic of pancreatic

diabetes, production of, 431
due to adrenalin in Graves's dis-
ease, 211
due to blood-serum from chronic

nephrosis, 262
due to pituitrin, 322
following suppression of sympa-
thetic function, 210, 211
following treatment by thyroid

extract, 211
of frog's eye, due to adrenalin,

209, 210
produced by adrenalin in Graves's

disease, 211
— , production of, 297
— , test for adrenalremiu by, 262, 263
— , see also Adrenalin mydriasis ;

Pupil, dilatation of
Myelin, 283

— , double refractive substances in
suprarenal cortex resembling,
284
forms, double refractive bodies

showing, 288

Myoneural junction, 229, 233, 234
Myotonia congenita, cause of, 46

periodica, cause of, 46
Myxcedema, abortive, 74
— , appearances in, 72
— , atrophy of intestinal tract present

in, 76
• — , congenital, 76

following thyroidcctomy, 66
— j infantile, 70
— , metabolism in, 88, 89
— , normal processes becoming hypo-
plastic in, 17
— , post-operative, 38, 71
— , sporadic, diagnosis from mon-

golism, 78
— , treatment by thyroid extract, 87,

107

— and Graves's disease, differences
between, 99

NECK, organs of, development, 33
Nephrectomy, experimental, 441, 442
Nephritis, chronic, hypertension in,

262

— , toxic, experimental results, 417
NephroblaptinSj 443, 444
Nephrosis, chronic, blood serum from,

causing mydriasis, 262
Nerve cells in hypophysis, 310
Nerve-endings, effect of apocodein

on, 197
— , sympathetic, as site of action of

adrenalin, 228

— , effect of adrenalin on, 197
— , myoneural, stimulation by

adrenalin, 230

— , vagal, paralysis by atropine, 200
Nerve-fibres, efferent, supplying vege-
tative organs, 190

Nerve-roots, spinal anterior, function,

190
Nerves, autonomous, table showing,

192

— , resection, experimental, to dis-
cover seat of tetany, 59, 60
— , sympathetic and autonomous,,
effects of stimulation on, com-
parative table showing, 222-225
— , stimulation by adrenalin, under
normal conditions and after
larger doses of ergot, 232, 233
— , table showing, 193
Nervous centre, impressions conveyed

from periphery to, effect of, i
excitement, effect on thyroid gland,,

28

origin of pancreatic diabetes, 422
system, autonomous, 191
— , definition, 191
— , differentiation from sym-
pathetic, 194, 195
— , adrenal system connected with,.

160, 162
— , central, regulation of organic

function bv, i

— , centres of, in relation to forma-
tion of sugar, 428, 429
— , cerebrospinal, 190
— , classification, 190, 191
— , effect of extirpation of thymus

on, 1 20

--, ganglia of, chrome-brown cells-
attached to, 265

— j sympathetic and autonomous,
action of adrenalin on, com-
pared, 230, 231
— , adrenalin and, 219
- and autonomous, action of
adrenalin on, contrasted, 231

— , effect of adrenalin on organs
controlled by, 189

- on dilatation of pupils..
210
— , function, 191

— • of adrenalin connected!
with, 266, 267

— — , hyperinflation of, 218

— , physiological effects of
adrenalin on, 196

— , unstriated muscles and, 229.

— , vasodilator function, 198
— , vegetative, 190-196

— , effects of nicotine confined
to, 195

— , effect of internal secretory
organs on, 70

— , effect of toxic substances on,
105

— — , irritability of, no
Neural theory of correlation of

organs, 2
Neurin, constitutional formula of, 276

(footnote)
— gold, 276, 277
N euro-hypophysis, histology of, 310

INDEX

599

New-born infants, pineal gland in,

, Sexually differentiated tissues
in, 361

Nicotine, action of, altered by increase
in doses of ergot, 231

_ effects confined to vegetative ner-
vous system, IQ5

_, particular ganglion cells affected

by, 1 94 ,

Nitrogen, excretion after reduction ot

renal parenchyma, 445
? metabolism of, in Graves s disease,

99

Nutrient secretions and hormones, dis-
tinction between, 13

OBESITY associated with hypophysal
changes, 345

— , origin of types ot, 3^5

3 reduction by thyroid extracts, 91

Organic extracts, intravenous injec-
tion, effect on blood-pressure,

21, 22

3 physiological action, 21, 22

— . — , toxic action, 21
Organotherapy, 20

after experimental extirpation ot

suprarenal capsules, 165-168

t failure in pancreatic diabetes, 423,

424
— , forerunners ot, 2

— in Graves's disease, 100
— , uses of, ii

Organs of body, chemical correlation,

j experimental extirpation, ad-
vantages, 18
— — , by-effects, 19

} internal secretory, 6

} partial destruction, 19

— — , potential energy, 10
Ossification, effect of extirpation of

thymus on, 117, n8
? influence of generative glands in,

382
— , retardation of, following thyroid-

ectomy, 63
Osteomalacia, relationship to genital

glands, 387

Ovarian extract, effects of, 380
Ovaries, relationship of, to chlorosis,

388

— , transplantation of, 380
Ovary, influence of X-rays on, 403
— , internal secretion of, 398-406
— , interstitial tissue of, 399, 4°2
— , relationship to menstruation, 381
Ovotestis, 363
Ovulation, connection of menstruation

with, 403, 406
Ovum, nidation of, 408
Oxidation, increased, following extir-
pation of pancreas, 420
Oxybutyric acid, 419, 420

PANCREAS, action of adrenalin on, 212

Pancreas, agency in influence of thy-
roid apparatus on carbohydrate
metabolism, 4.1°
— , changes in, in diabetes, 432

effects on metabolism, 70
— , excretory ducts, experimental liga-
ture, results, 436

— , absorption of fat after,

— , external secretion, mechanism ot,

extirpation, deposition of glycogen

in liver after, how effected, 430
__ __5 experimental, change in meta-
bolism following, 420
. ? increased oxidation follow-
ing, 420

. — , emaciation following, 420

_ , partial, not followed by gly-

cosuria, 4^5

of large portions followed by

slight glycosuria, 416
— , total, followed by cessation of
fat absorption, 437

. — } followed by glycosuria, 413 ;

see also Diabetes (pancreatic)

. _3 reduction of glycogen in

liver under, 4l&
-, function of, inhibitory, 2 1 1

? in relation to decomposition ot

sugar, 426
-, internal secretion of, 412

— , inhibition followed by gly-
cosuria, 428

- of formation of sugar

in liver by, 430

- secretory activity of, action ot
adrenalin and, 220

— , inhibited by adrenalin,

221, 226

, limiting action of adrena-
lin, 226

. — , elements of, 432-438

, function, 18, 421, 423

_ — , acini and islands of

Langerhans concerned in, 43^,

437

— , transplantation experimental, 422
and metabolism of sugar, 424, 425
and thyroid gland, relationship

between, 60,, 70
— , see also Hormones, pancreatic ;

Langerhans^ islands of
Pancreatic extract, inhibition of

adrenalin glycosuria by, 429
Paralysis agitans, cause of, 46
Parathyroid extract, 49

— , physiological activity, 49, 5p
— - — , treatment by, of post-operative

tetany, 49

glands, accessory, 31
— , anatomy, 31

, colloid in, 33

. — . — , comparative anatomy, 34

— , development, 34
-, effect on metabolism, 70

6oo

INTERNAL SECRETION

Parathyroid glands, extirpation, re-
sults, 38
— , fat granules in epithelial cells,

32, 33
— , function, 55

— , determination of, 18
— , functional derangement,

diseases, following, 46
—5 glycogen in, 33
— , histology, 3-
— , preservation, at extirpation of

goitre, 4.4

— . — , in relation to calcium meta-

bolism, 58

— , secretory function, 32
— , supernumerary, 35
— . — , transplantation, 48

- and thyroid gland, relationship
between, 51-55; see also under
Thyroid gland
Parathyroidectomy, effects of, 53, 54,

55, 84
— , experimental, results, 41

— , tetany following, 55

with remnant of thyroid tissue left,

result, 106

Parietal eye in saurians, 351
Parkinson's disease, see Paralysis

agitans
Penis, retractor muscle in rat, nervous

network, 228, 229
Periphery, impressions conveyed from,

to nervous centre, effect of, i
Peritoneum, lymphatics of, action of

adrenalin on, 213
Phenylalanin, 297
Phlorizin, action on suprarenal-less

dogs, 155
and adrenalin, injection, effect on

islands of Langerhans, 435
Phosphates in urine after removal of

suprarenal capsules, 154
Phosphorus, excretion of, due to

pituitary extract, 327
Phrenosin, 288

Pigeons, effects of ligature of ex-
cretory ducts of pancreas on, 436
Pigment cells and granules of frog,

action of adrenalin on, 214
Pigmentation, anomalies of, following

extirpation of suprarenals, 157
— , disordered, in Addison's disease,

164, 165, 168
— • , effect of adrenalin on,

165

Pigs, brain of, lipoid substances in,
291

— , suprarenals of, lipoid substances
in, 290, 291

— j thyroidectomized, changes in, 64

Pilocarpin, adrenalin-glycosuria in-
hibited bv, 226

— effect on thyroid gland, 28

and atropine, action compared, 195
Pineal body, anatomy of, 351

— , clinical signs of diseases of,
354

Pineal body, embryology of, 351

— , histology of, 351
- in newborn infants, 351

— , pathological anatomy of, 353
Pituitary body, see Hypophysis

extract, action of, altered by in-
crease in doses of ergot, 231

— , cardiac effects of, 323-325

— , characteristics of, 349

— , effect on circulatory system.,

323

- on metabolism, 327

— , hypotensive action of, 324, 325

in acromegaly, 347
, physiological activity of, 323
— , toxicity of, 322
— , vasoconstrictor action of, 321,

324
- gland, see Hypophysis

Pituitrin, mydriasis due to, 322

Placenta, extract of, effect on mam-
mary gland, 374

— , internal secretion, of, 411

Pneumothorax following experimental
extirpation of thymus, 117, 119

Poisons, inorganic, resistance to, small
after thyroidectomy, 108

Polyuria after extirpation of supra-
renals, 154

— following reduction of renal paren-
chyma, 445

Portal system of suprarenals 298, 299

- in birds, 300

- in reptiles, 299

Potential energy of organs of body,
1 1

Precocity, sexual, 370

Pregnancy, enlargement of hypo-
physis during, 340

— , increase of weight of hypophysis
in, 307, 309, 3io

- of suprarenal capsules dur-
ing, 269

— , interstitial ovarian tissue de-
veloped during, 400
— , mammary growth during, 372, 375
— , mydriatic blood serum in urine of,

262

Progeria, 75

Prostate, effect of castration upon, 377
— , hypertrophy of, cause of, 377
— , internal secretion of, 410
Protagon, 286, 287
— - not a chemical entity, 290
Proto-adrenalin, see Adrenalin, pre-
cursors of

Pseudo-hermaphroditism, 358, 362
— , hypertrophy of suprarenals in, 269
Puberty, precocious, connection of
hypertrophy of suprarenals with,
270

— , sexual development at, 369
Pulse, effect of pituitary extract on,

323-325

Pupil, action of adrenalin on, 230
— , dilatation of, effect of sympathetic

system on, 210

INDEX

601

Pupil, dilatation under adrenalin, 209;

see also Mydriasis
. Of frog's eye (isolated), action ot

adrenalin on, 209, 210

— , of various drugs on,

210
Pvlorus, action of adrenalin on, 204

RABBIT, acute tetany in, 40

, adrenalin contents in, 251

^ effects of ligature of excretory

ducts of pancreas on, 436
— , extirpation of hypophysis in, 3*7
— , gestation in, 404
— , parathyroid glands in, 35
— , suprarenal capsules, amorphous

masses in, 284
. in, experimental removal,

139, Ui

— , thymus gland in, 113

— — , extirpation, results, 114, 115,

116

— , toxic action of adrenalin on, 239,
240, 245

Rats, effect ot suppression of supra-
renals on, 155

, retractor muscle in penis of, ner-
vous network, 228, 229

, suprarenal extract from, toxicity,

, survival after extirpation of both

suprarenals, 143
— , tetany in, 41, 43
— , white, accessory interrenals in,

155

Reflex manifestation of diseases, 2
Renal extracts, administration, effects

of, 44i ,

- and internal secretion or

kidneys, 442
— , effect on blood-pressure, 442,

443

Renin, production ot, 442
Reptiles, embryology of pineal body

in,. 35i

— , suprarenal bodies in, 128, 130, 133
Respiration, action of adrenalin on,

235
Respiratory centre, effect of carbonic

acid on, 15

— , lactic acid and, 15
Ringer's solution, suspension of

isolated arteries in, 198, 199
Rb'ntgen rays, action of, on spermatic

cells, 397
— , elective destruction of tissue

foundations by, 19

1 influence on ovary, 403

-, treatment by, of Graves's

disease, 100
Rutting and menstruation, 403

SALIVARY glands, action of adrenalin

on, 211
Salt, metabolism of, 267

, increased by adrenalin, 215

— — , effect of thyroidectomy on, 71
Secretin, discovery of, 439

Secretin, formation of, 5
— , function of, 439
— , nature of, 439

Secretion, distinction from excretion, 3
Secretory organs, internal, 6

— tissue elements of generative

glands, 391-41°

Selachians, suprarenal capsules in, 299.
Senile degeneration, 75

and thyroid gland, 75
? atrophy of intestinal tract pre-
sent in, 76

Sera, cytotoxic action of, 19
Sertoli's cells, 394
Serum (immune) in tetany, 56

therapy in Graves's disease, 101 ^
— , thyrotoxic immune, in Graves's

disease, 101

Sex, determination of, 356
Sexual characteristics, 355

— , development of, 358
— , secondary, 359

— dimorphism, 361

— derangement in acromegaly, 331
glands, activity of, connection with.

suprarenals, 269

— , changes in, in gigantism, 342
— , relationship to hypophysis, 33Q-

341
— , secretion of, changes following

suppression, how explained, 2

— organs, changes following thyroid

suppression, how effected, 110
— , removal, changes following,

how once explained, 3
precocity, 370
stigmata, 362, 364
Shark, interrenal body of, 151
Sheep, parathyroid glands in, 35
— , thyroidectomized, changes in, 64
Skeleton, influence of generative

glands on growth of, 382-384
Soil in relation to goitre, 81
Somatic cells, 359, 362
Spasm, laryngeal, of infants, 122
Species, characteristics of, 360
Spermatogenesis, suppression of in

cryptorchidism, 393
Spermatozoa, varieties of, 356
" Spermin," 389
Sphingomyelin, 288, 292
Spinal cord, relationship of tetany to,

60
Spleen, action of adrenalin on,

altered by increase in doses of

ergot, 232

— , enlargement, following thyroid-
ectomy, 67
— , implantation with thyroid tissue,

results, 86
— into which thyroid had been

implanted, extirpation, effects,

85

— , transplantation of suprarenal cap-
sules into, 170

Spongiocytes, 282

— , labile fat in, 282

<602

INTERNAL SECRETION

Staining methods for granules of

suprarenal cortex, 274
Stannius, corpuscle of, 129, 152
.Status thymicolymphaticus, 122

— , enlargement of thymus in, 122,

i?3
— , mortality from infective diseases

great among subjects of, 124
— , sudden death in, 122, 123

— • — • at commencement of
chloroform anaesthesia in, 123

- in, with hypoplasia of
chromaffine system, 158
— • — , symptoms, 122
Stigmata, sexual, 362, 364
.Stomach, action of adrenalin on, 204
.Struma suprarenalis, 270
Strychnine, neutralization by adrena-
lin, 293
Submaxillary glands, action of

adrenalin on, 21 1
Succus entericus, 439
.Sugar-contents of blood, on what

dependent, 428
Sugar, decomposition of, function of

pancreas in relation to, 427
— , formation in liver, how controlled,
428

— , inhibited by pancreas, 430
— , nervous centres in relation to,

428, 429
— , metabolism of, in relation to

pancreas, 424, 425'
— , oxidation of, 426
Supernumerary ribs and vertebrae, 361
Suprarenal capsules, accessory, 134,

139, M3
— , compensatory hypertrophy

after removal of suprarenals, 268
— , compensatory power of, 140,

146
— , connection of interrcnal

structures with, 268
— , tumours of female genitals

proceeding from, 270
— , active substance in chemistry,

177, 178; see also Adrenalin
— , adrenalin contents in Addison's

disease, 250
— , adrenalin in, how to ascertain

amount, 182
— 3 albuminoids of, 275
— , amount of substance necessary

for life, 146
- and activity of sexual glands,

connection between, 269
— , antitoxic action, 293, 294
— , attempted destruction by specific

cytotoxins, 144

— , blood circulation of, in mam-
mals, 300, 301

— , chemistry of (excluding adrena-
lin), 274-292
— , cholesterin, palmitate and

stearate in, 288
— j cholin in, 275

Suprarenal capsules, chrome-brown
cells of, granules in, 252

— colour of, 133
— , comparative morphology and

embryology, 127
— , connection with precocious

puberty, 270
— , cortex of, 128, 131

— , cells of lipoid granules, 272
— , method of examining,

274

— , pigment in, 274

— • • — , essential to life, 268, 269

— , experimental extirpation,
146-150

— , histology, 270-274
— , hypertrophy, connection with
tumours, 270

— , granular, comparative his-
tology, 285

— - — , granules in, 280
— • - — • — , double refractive, 283

- chemistry, 286, 287

— . — • — , resembling myelin,

284

— , staining of, 284

— , histology, 285

— • — - — , micro-chemical relation-
ships, 280
— - - — , importance of, 148, 150

- and medulla, amalgamated
in mammals, 130

, methods of staining gran-
ules, 274

— — , myelin - forms, treatment
with chromates, 289

— • — , similarity of cells to those
of corpus luteum verum, 269

— — , destruction without clinical

signs of Addison's disease, 162

— , development, 133

— , disease of, see Addison's dis-
ease

— , effect of injected toxic sub-
stances on, 250

— , extirpation, anomalies of pig-
mentation following, 157

— • — , changes in blood, 157, 158

— — - — , effect on adrenal system,

267

— 3 experimental extirpation, 138
— • of one after another,

finally fatal, 141, 142, 145

— — — of both, survival after,
146

— , condition of blood-pre-

sure after, 147, 148

— - — — of one, not fatal, 141,
144, 145

- of both at once, rapidly
fatal, 138, 140, 141, 145

— of one, followed by, Com-
pensatory hypertrophy in other,

139, MS

— • — • — , not followed by death in
rat, 143

INDEX

603

Suprarenal capsules, experimental ex-
tirpation, death following, 142

. - — , followed by toxicity of

blood, 156

— -. — . — — , followed by toxicity of
muscles and viscera, 156

— - — , organotherapy after, 165-

168

— , symptoms, 153-158

, fat-contents, distribution, 285

— . — , ferments in, 275

— , functions of, historical account
of discoveries, 124-127

— , in relation to muscular
fatigue, 295
— , suppression chronic, 159

— , due to haemorrhage into
organ, 159

— , symptom - com-
plex, 159

— • in man, 158
— , symptoms, 153-158
— , hypersecretion, experimental,

260; see also Hy-peradrenalism
— , hypertrophy in pseudo-herma-

phroditism, 269
— , hypofunction, 261
— , hypoplastic infantilism of, 158
in adder, 298
in Batrachians, 299
in birds, 299, 300

, indispensable to life, 17

in fish, extirpation not fatal,
152, 153

, innervation, physiology of, 260

in Selachians, 299
— — , lecithin in, 286

—3 lipoids in, 279, 287, 292, 293

, medulla of, 128, 131

— , experimental extirpation,
146-150

— , hyperplasia of chromaffine
tissue, 262
— , quantitative value, 265

— , over-estimated, 265
— , secretory processes, morph-
ology, 252
— , total aplasia of, 158

, not homogeneous organs, 127

of pigs, distillation with hot
acetone, 290, 291

— , lipoid substances in, 290,
291

of rabbits, amorphous masses

in, 284

— , physiology of, 134, 138
— • — , portal system, 298, 299
— in birds, 300

in reptiles, 299
— , primary disease, rare, 159

, reaction to adrenalin, 212

— • — , reduction in size of, 158

— , relationship to hypophysis, 339

, secretory process of, 251

, sound, but with clinical signs

of Addison's disease, 159, 160

40

Suprarenal capsules, stimulation, ex-
perimental, 260
-3 substitution, 165
, transplantation, 168
— , functional capacity. 171
— , histological observations,
169

— , regression and proliferation
of tissue following, 170, 171
— , site of, 170, 171, 172
— , successful, 170

— , conditions for, 173
— , tuberculosis of both, typical
feature of Addison's disease, 159.
— , vascularization of, 298
— , weight of, increased after cas-
tration, 269

— , increase during pregnancy,.
269

in different animals, 269
extract, blood-pressure increased
bv, how abolished, 157

in Addison's disease, 168
— , physiological action of, 173,.

174
— , specific action centred in

adrenal body, 247
— , toxic action, 175, 176
— , watery, intravenous injection,

177; see also Adrenalin
— organs, accessory, 131, see also-

Intcrrctial bodies, accessory
systems in invertebrates, tables

illustrating, 135-13?
Suprarenin, 178
— , d, toxic dose, 237
— , 1, toxic dose, 237
— , synthetic racemic, 179
Sugar in urine, see Glycosnria
Surgery, operative, knowledge as to-
internal secretions obtained
through, 17
Sweat glands, action of adrenalin on,

214
— , innervation of, 191, 195

TACHYCARDIA, following administration

of thyroid extracts, 90
Temperature, bodily, modified bv

action of adrenalin, 226
Testicle, cryptorchidic, 393
— , development of, 366, 369, 371
— , secretory elements of, 392
— , watery extract, 21
Testicular extract, effects of, 389

— , injection of, effect, 4
Tetania parathyropriva, 38, 39, 47
Tetany, acute, experimental, 37, 39, 40-

— , milk diet in, 107

— , secondary symptoms following,

43

— , tuberculosis and, 46
— , chronic, experimental production,

43

— , experimental, albuminuria accom-
panying, 43

604

INTERNAL SECRETION

Tetany, following" extirpation of thy-
roid gland, 38

parathyroidectomy, 55

— , human, 44

— , infantile, 45

, causative factor, 120

— , localization of seat of, experi-
ments for, 5Q
— , undetermined, 61

— , post-operative, 44

, treatment by parathyroid ex-
tract, 49, 50

— , puerperal, 44, 45

— , relationship to brain and cere-
bellum, 60, 61

- to spinal cord, 60

— , symptoms of, latent, 45
— , toxin of, 55, 56

— , nature of, 56

— , point of attack, 50
— , treatment by blood-letting", 56
— — • bv calcium salts, 58, 59

- by immune serum, 56

by thyroid extract, 50, 51
Thomsen's disease, see Myotonia con-

genita
Thoracic duct, excretion of lymph

from, promoted by adrenalin,

213
, ligature causing glycosuria,

43i
Thvmus extract, action of, 121

on blood, 121
— , depressant, 121
— , toxic, 121
— , activity not affected by boiling,

121

gland, no
— , anatomy, in
— , cells of, not identical with those

of lymph glands, 112
— , development, 34. ru
— , enlargement in status thymico-

lymphaticus, 122, 123
— , extirpation, effect on nervous
system, 120
— , experimental, 115

• — , effect on ossification, 117,

118

— , followed by pneumo-
thorax, 117

— , hypertrophy in Graves's dis-
ease, 96

— ,' accompanying cardiac hyper-
trophv, 19
— , implantation, experimental,

119, 120

— , normal weight in man, 113
— , involution, 112
— , persistent and enlarged, follow-
ing thvroidectomy, 65
— , physiology, 113
— , reaction of motor apparatus to

electric current, 120
— , relation of castration to, 116
— , relationship to hypophysis, 339

Thymus extract, secretion, action as
disassimilatory hormone, 109,
1 10
— , size in dog, guinea-pig, and

rabbit, 113
Thyroglobin, 29
Thyroglobulin, 28, 31
Thyroid apparatus, 26

— , influence on metabolism of
carbohydrates controlled by pan-
creas, 430
— - — j modification of action of

adrenalin by, 226
extract, administration after sup-
pression of thyroid function, 86
in cachexia strumipriva, 87
in endemic cretinism, 87
— , followed by hyperthyroid-
ism, 90, 92, 93

- by tachycardia, 90
in myxoedema, 87
— , oral, resistance to sub-
cutaneous injection of acetonitril,
increased by, 108, 109
— , physiological effects, 89-92

, antitoxic theory, 104, 105

— , diuretic action, 91
— , effect on metabolism, 91
— , favourable influence on tuber-
culous processes experimentally
produced, 108

in myxoedema, 107
— , neutralizing activity, 108, 109
— , physiological effects on circu-
latory system, 89, 90
— , reduction of obesity by, 91
— , treatment by, mydriasis follow-
ing, 211

— gland, administration, effect on

metabolic changes in hypothy-
rosis, 88

, anatomy, 26

— , antitoxic activity, 108
- autotransplantation, 73

, chemistry of, 29

— , colloid of, 27, 28
— , comparative anatomy, 34-36
— , development, 34
, diseases of, cause of pathologi-
cal conditions following, 107
— , effect of adrenalin on, 28
of castration on, 344
on metabolism, 70
of nervous excitement on, 28
— of pilocarpin on, 28

— — , etiological connection with

Graves's disease, 100, 101

— , extirpation, followed by hyper-
trophy of pituitary gland, 19

— 3 function, secretory, negative,
104

— , positive, 104

, suppression, 105

— , histology, 26, 27

— , influence on blood-formation,
37

INDEX

605

Thyroid gland, iodization process in,

105

— , iodine in, 29, 105
, ligature of vessels leading

away from, result, 106

— — , parenchyma of, 27

— , physiological association with
female organs of generation, 37

-, physiology, 62

, theories as to, 36, 37

, relationship to hypophysis, 338

, secretion, passage into lymph

vessels, 28

, secretory processes, 27

— , storage in, 28

— , substitution of, treatment by,

83

— , suppression, changes in sexual
organs, how effected, no

, transplantation, 84

, experimental, 47, 83, 84

— , processes following healing
in, 85

— and pancreas, relationship be-
tween, 69, 70

and parathyroid glands, rela-
tionship between, 51-55

- experimental evi-
dence, 52, 53
• and senile degeneration, 75

— glands, accessory, 62, 63
insufficiency in youth, 76
— , partial, 107

juice, intravenous injections, eye-
symptoms following, 92

— preparations, treatment by, of

tetany, 50, 5 1

substances, Graves's disease due to
flooding of organism with, 102

— tissue, implantation into spleen,

results, 86
Thyroidectomy, effects of, 53, 54

adrenalin after, 54
— , experimental, 62, 63

— , changes following, 62-71

— , resistance to inorganic poisons,

small after, 108

, results, 63

— , partial, 42

1 necessity for, in removal of

goitre, 73
— , results, 37-40
— , symptoms following, how aborted,

84

— , total, cachexia following, 72, 73
Thyroidin, 30
— , effect on dogs, 0,2
Thyroparathyroidectomy, effects of

adrenalin after, 54
— , results of, 68
Thvroplasia, 76
Thyrotoxalbumin, formation of, 105,

107
Tissue-formation, elective destruction

by Rontgen rays, IQ
Tortoise, parathyroid bodies in, 36

Toxic substances, effect on vegetative

nervous system, 195
— , chemical neutralization, 9

, expulsion by excretory organs,

8
— , injection, effect on suprarenal

capsules, 250

Toxins, chemical affinity for sub-
stances occurring in body, 9
— , method of production, 105
— , see also Tetany, toxin of
Transplantation of glands, results of,

379

— of organs, n, 20

- of body, see also Spleen, Thy-
roid, Parathyroid glands

Tritons, experimental removal of
suprarenal capsules in, 141

Trypsin ferment, 439

Tryptophan, 296

Tuberculosis and acute tetany, 46

— , experimentally produced, effect of

thyroid extracts on, 108
of both suprarenal capsules, typical
feature of Addison'b disease, 159

Tumours, coexistence with hyper-
trophy of suprarenal cortex, 270

Turtle, heart of, action of adrenalin
on, 202

Tyrosin and adrenalin, 165

— , conversion into adrenalin, 180

UREA, affinity of carbamic acid for, 9
— , formation by liver, 9
Ureters, ligature of, experimental, 441
Urine, acetone bodies in, increase of,

see Ketonuria
—, adrenalin in, method of testing

for, 182
— , examination after removal of

suprarenal capsules, 154
of pregnancy, mydriatic substances

in, 262

— , sugar in, see Glycosuria
Urohypertensin, 256
Uterus, action of adrenalin on, 206

— , altered by increase of doses

of ergot, 232

— , effect of pituitary extract on, 326
— , internal secretion of, 411
— , muscles of, action of adrenalin on,

206, 207
— , pregnant, action of adrenalin on,

altered by ergot, 232

VAGI, stimulation of, effect on blood-
pressure, 329

Vagus nerve, assimilatory activity, 14
Vas deferens, ligature of, effects of,

3Q3, 395 .
Vaso-constriction due to adrenalin,

184

- to pituitary extract, 321, 324
Vaso-dilator effect of adrenalin, 198
Vasomotor excitability in Graves's

disease, 97

6o6

INTERNAL SECRETION

Vegetative organs, innervation of,
table showing, IQO, 192, 193, 194

Vertebrates, embryology of pineal
body in, 351

— lower than Batrachians, two
systems of bodies replacing
suprarenals in, 129

Viscera, toxicity of, produced by ex-
tirpation of suprarenals, 156

Vision, disturbances of, in acromegaly,
33i, 337

WATER (drinking), transmission of

goitre by, 81

Women, castration of, results of, 380
— , sexual characteristics of, 355

X-RAYS, see Rontgen rays

YOUTH, thyroid insufficiency in, 76

ZONA glomerulosa, 270

reticularis, 274
— spongiosa, 282, 283