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THE ENDOCRINE ORGANS

WORKS BY THE SAME AUTHOR

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/
THE ENDOCRINE ORGANS

AN INTRODUCTION TO THE STUDY OF
INTERNAL SECRETION

BY

SIR EDWARD A. . SGHAFER, LL.D., D.Sc., M.D., F.R.S.

PROFESSOR OF PHYSIOLOGY IN EDINBURGH UNIVERSITY

WITH NUMEROUS ILLUSTRATIONS

LONGMANS, GREEN, AND CO.

39 PATERNOSTER ROW, LONDON

FOURTH AVENUE & 30TH STREET, NEW YORK

BOMBAY, CALCUTTA, AND MADRAS

1916

All Rights Reserved

5 o 3

PREFACE

THIS book is founded upon a course of lectures (Lane Medical Lectures)
delivered at Stanford University, California, in the summer of 1913.
The lectures were issued in the following year amongst the publications of
the University, but in an abbreviated form and without illustrations. It
also happened that the proofs, which had been sent for correction, failed
to reach me ; so that the work as it appeared contained an unusual number
of incidental errors. On these and other grounds, I have thought it
desirable, with the concurrence of the University authorities, to publish
the substance of the lectures in a revised form with the addition of the
tracings and photographs which were used to illustrate them : thus both
enabling the subject to be brought up to date and affording the oppor-
tunity of presenting it to a wider audience.

The time at my disposal for the lectures precluded anything more than
a passing mention of some of the many workers who have contributed to
our knowledge of this, the newest, development of physiology ; and in
republishing, it has not been deemed desirable unduly to extend the
references to literature, seeing that they are already to be found in such
standard works as Biedl's Inn ere Sekretion, in which the bibliography
occupies more than 250 large octavo pages, and Swale Vincent's Internal
Secretions and the Ductless Glands, where they run to over 2000 titles.
Since the appearance of those works much new matter has been added ;
and more than one long list of literature has appeared in monographs deal-
ing with special internally secreting organs. It is to publications of a
comprehensive character such as these that the scientific worker will turn
for detailed information. The aim of this little book is less ambitious : it
is designed to supply a concise account of our present knowledge for the
benefit of students and practitioners who may be desirous of obtaining
more information regarding the internal secretions than is afforded by the
ordinary text-books of physiology, but have not the time or opportunity
to peruse extensive monographs or consult original articles.

For a concise history of the subject, as well as a critical examination of
the main facts on which the doctrine of internal secretion is based, the
small but masterly compendium Les secretions internes, by E. Gley, cannot
be too warmly recommended.

CONTENTS

HAUE

PREFACE . .... . v

CHAPTER I
GENERAL CONSIDERATIONS

Internal secretions and the organs which furnish them . 1

The nature of the active principles of the internal secretions . 4

Groupings of the chief endocrine glands ... .7

Methods of determining the functions of the endocrine organs 8

CHAPTER II
THE THYROID AND PARATHYROIDS

Structure and development of the thyroid . . 12

Structure and development of the parathyroids 16

CHAPTER III
THE THYROID AND PARATHYROIDS (continued]

Effects of removal of the parathyroids . 22

Effects of parathyroid extract ... 26

The mode of action and the nature of the parathyroid autacoid . 27

CHAPTER IV

THE THYROID AND PARATHYROIDS (continued)
Effects of removal and of atrophic degeneration of the thyroid : hypothyroidism . 29

CHAPTER V
THE THYROID AND PARATHYROIDS (continued)

Effects of increase of thyroid secretion : hyperthyroidism 35

Clinical evidence relating to hyperthyroidism . 36

CHAPTER VI
THE THYROID AND PARATHYROIDS (continued)

The nature of the autacoid substances produced by the thyroid 40

Interaction of the thyroid with other organs . . 41

Influence of the nervous system on thyroid secretion . 44

viii The Endocrine Organs

CHAPTER VII
THE THYMUS GLAND

PAGE

Structure and development of the thymus 45

Functions of the thymus 47

CHAPTER VIII
THE SUPRARENAL CAPSULES

Morphology . . 50

Structure of the cortex . .51

Functions of the cortex . 52

Structure of the medulla 54

Vessels and nerves of the suprarenal . 55

CHAPTER IX
THE SUPRARENAL CAPSULES (continued)

Effects of suprarenal removal . 56

The nature of the autacoid furni,shed by the medulla . 58

Effects of administration of suprarenal extracts 58

CHAPTER X
THE SUPRARENAL CAPSULES (continued)

Evidences of the passage of adrenalin into the blood . 68

Influence of nerves upon the secretion . ... 69

Relations of the suprarenals with other endocrine organs and secreting glands 70

CHAPTER XI
THE PITUITARY BODY

Structure of the pituitary 74

CHAPTER XII
THE PITUITARY BODY (continued)

The active principles of the pituitary . 84

Effects of extracts of the posterior lobe . 84

.Effects on metabolism and in disease . . . D6

Are the various effects obtained from extracts of the posterior lobe due to only one

or to more than one autacoid 1 96

CHAPTER XIII
THE PITUITARY BODY (continued)

Effects of complete removal . 100

Effects of partial removal and injury . 102

Effects of grafting and feeding with pituitary . 104

CHAPTER XIV

THE PITUITARY BODY (continued)
Clinical evidence KM!

Contents ix

CHAPTER XV
THE PITUITARY BODY (continued)

I'AOK

Relations of the pituitary with other endocrine organs . . . 115

CHAPTER XVI
THE PINEAL GLAND

Structure of the pineal ..... 118

Effects of injecting extracts of pineal . . . . . . .120

Effects of extirpation. Relations of the pineal witli the sexual glands . 120

CHAPTER XVII

THE INTERNAL SECRETIONS OF THE ALIMENTARY MUCOUS
MEMBRANE AND OF THE PANCREAS

Secretines ..... .... 124

The internal secretion of the pancreas ... . 125

The islets of Langerhans ... . 125

Effects of removal of pancreas. Diabetes . . . 127

Nature of the pancreatic autacoid . . . . . . .128

Relation of internal secretion of pancreas with other endocrine organs . . 130

CHAPTER XVIII

THE INTERNAL SECRETIONS OF THE GENERATIVE ORGANS

IN THE MALE

The interstitial cells of the testicle . . . 132

Effects of castration ..... .133

The nature and source of the testicular autacoid . .135

Effects of extracts of testicle ..... 136

CHAPTER XIX

THE INTERNAL SECRETIONS OF THE GENERATIVE ORGANS

IN THE FEMALE

The interstitial cells of the ovary . . 137

The corpora lutea .... 138

Effects of removing and reimplanting ovaries . 139

CHAPTER XX

THE INTERNAL SECRETIONS OF THE GENERATIVE ORGANS

IN THE FEMALE (continued)

Effects of ovarian extracts (hilum ovarii, Graafian follicles, corpora lutea) . . 141

Metabolic effects produced by corpus luteurn . . . 145

Internal secretion of uterus . 148

Internal secretion of mammary gland . 150

Internal secretion of placenta . 150

INDEX .... 151

THE ENDOCRINE ORGANS

AN INTRODUCTION TO THE STUDY
OF INTERNAL SECRETION

CHAPTER I
GENERAL CONSIDERATIONS

INTERNAL SECRETIONS AND THE ORGANS WHICH FURNISH THEM

MATERIAL which is passed into the blood or lymph from any tissue or
organ of the body forms its internal secretion, and organs which are not
known to possess any other function than that of passing such material
into the blood or lymph are internally secreting or endocrine organs.1
This term is not usually extended to organs like the lymphatic glands,
of which the material production is of a morphological character, although
until recently all such organs used to be included along with the true endo-
crine glands, the functions of which were at that time unknown, in the
general expression of ductless glands. Under this last term were comprised
not only the organs to which we now commonly ascribe internally secreting
functions, such as the thyroid, parathyroids, the suprarenal capsules or
adrenals, the pituitary body or hypophysis cerebri, and the pineal gland
or epiphysis cerebri, but also the thymus gland, the tonsils, lymph-glands
and lymph-follicles, and the spleen ; with these the bone-marrow is associated.
Regarding the thymus gland, although some evidence has been adduced
that it may yield an internal secretion to the blood which exercises a
specific action upon growth and development, and especially the matura-
tion of the generative organs, it appears both developmentally and
structurally to resemble the tonsils, which are generally allowed to be
structures of a lymphatic nature, and like the tonsils most of its cells
are lymphocytic in character. The spleen has been described as furnish-
ing an internal secretion which activates the proteolytic ferment of the
pancreatic juice; and the contractions of plain muscular tissue, especially
that of the intestines, have been supposed to be stimulated by another
substance formed in the organ. But the proof of the existence of such
internally secreting functions in connexion with most of these lymphoid
structures is so inferior to that which we possess regarding the thyroid,

1 From evSov, within, and Kpivca, to separate.

2 The Endocrine Organs

parathyroids, adrenals, and pituitary, and even the pineal gland, that we
may, at least provisionally, exclude them from the class of bodies which
secrete active chemical agents into the blood for the purpose of influencing
other organs. It is to this latter class that I intend to restrict my remarks,
and it is to them and them alone that the term endocrine will be applied
in these pages.

It follows from what has just been said that by the expression en-
docrine organ we imply an organ which is known to form some specific
chemical substance within its cells, and to pass this directly or indirectly
into the blood stream.1 The substance thus formed is the active material
of the secretion, just as ptyalin is the active agent of the salivary secretion.
But while in the case of such glands as the salivary their secretion is con-
ducted by a duct to the exterior, in the case of the endocrine glands the
secreted material remains within the body and circulates with the blood ;
hence the term internal applied to their secretions.

The expression internal secretion was originally used in a sense somewhat
different from that in which it is now applied, having been employed by Claude
Bernard to describe the grape sugar which, as he showed, is passed from the liver
cells into the blood. It has also been used to designate all materials which are
contributed to the blood by the tissues. In this sense the carbon dioxide and other
products of metabolism which are taken up by the blood in its passage through the
capillaries, or are received by it through the medium of the lymph stream, are
internal secretions, and every tissue is an internally secreting structure. It is,
however, convenient to restrict the term to secretions containing specific organic
substances such as the active chemical agents which are produced by certain
ductless glands, and this is the sense in which the expression will be employed
in this book (see also pp. 5 and 6).

It is well known that the production of specific chemical agents which
are passed into the blood and carried by it to influence distant structures is
not confined to the ductless glands — that an active internal secretion may
be produced by other organs than these. A notable example is met with
in the pancreas, the more obvious function of which is the production and
excretion into the intestine of pancreatic juice; which, by virtue of the
ferments it contains, is the most active agent in the digestion of foodstuffs
within the alimentary canal. It was shown, however, by v. Mering and
Minkowski in 1889, that the pancreas possesses an internal secretory function
which is of even greater importance in the economy than its long-recognised
external secretory activity. For by totally removing the pancreas in
animals, these observers proved that the presence of the gland, and of some
substance yielded by it to the blood, is essential to the proper utilisation of
carbohydrate material in the tissues, so that wThen the pancreas is totally
removed grape sugar is no longer stored in the liver, to be split up little by

1 It must be clearly understood that although this passage of a specific substance into
the blood is an essential part of the doctrine of internal secretion, the definite proof of
such substances in the blood has only been furnished in very few cases.

Internal Secretions and Internally Secreting Organs 3

little by the organism into simple oxidisable substances, but is passed out
at once into the blood and extracted from the blood by the kidneys, pro-
ducing glycosuria. It may be added that our present knowledge of the
causation of diabetes is based mainly on these observations.

Now it is known that the pancreas possesses, besides the secreting
alveoli which form the enlarged and blind terminations of its ducts, a
special kind of secreting cells which are massed together into islets of
irregular shape and variable number and size, having a special kind of
blood supply. These islets, which were first described as a distinct element
of pancreatic tissue by Langerhans, have been originally developed from
and may retain a connexion with the ducts of the organ, in this respect
resembling the ordinary alveoli. But in the course of growth they have
lost all open connexion with the ducts ; their cells have acquired specific
properties ; and their function is without doubt different from the ordinary
cells of the gland. With some show of reason the special internal secreting
function above mentioned has been ascribed to them, and in support of this
it may be stated that in many if not most cases of diabetes these cells are
found to have undergone degeneration. They, in fact, form an organ within
an organ, and collectively may be regarded as belonging to the group of
internally secreting or endocrine glands.

An example of a tissue devoted to the formation of both an external
and an internal secretion is found in the epithelium which lines the
duodenum. The functions of this epithelium which have been longest
known are those of promoting the absorption of digested food materials
and of helping to furnish the secretion known as the intestinal juice. But
in 1902 it was discovered by Bayliss and Starling that if an extract of the
duodenal epithelium is boiled with dilute hydrochloric acid and, after
neutralisation, is injected into the blood stream of an animal, a rapid flow
of pancreatic juice is determined. It had already been known that the
gush of acid gastric juice through the pylorus, or the painting of the mucous
membrane of the duodenum with dilute acid, would determine a flow of
pancreatic juice, but this flow had been supposed to be brought about as
a reflex act by excitation of a local nervous mechanism by the acid. The
observations of Bayliss and Starling rendered it clear, however, that this
is not the correct explanation of the phenomenon ; but that the flow must
rather be regarded as due to the absorption of some internal secretion into
the blood : the material of this internal secretion being produced in an in-
active form by the epithelium cells, and becoming so altered by the dilute
acid as to be converted into an agent which, after absorption into the blood
stream, excites the secreting cells of the pancreas to activity.

To the active substance which is yielded by the epithelium cells of the
duodenal mucosa the name secretine was given by Bayliss and Starling,
whilst they termed pro-secretine the inactive material contained within
the cells before the action of dilute acid upon them. The active material
is obviously of the nature of an internal secretion ; it appears, however,

4 The Endocrine Organs

not to be produced by a special structure, certainly not by a special organ,
but. so far as one can tell, by the ordinary cells which line the rnucosa and
extend into its glands.

A similar but not identical internal secretion was shown by Edkins to
be produced by the cells of the mucous membrane of the pyloric end of
the stomach. When rendered active and absorbed into the blood, this
secretion, which is termed gastrine, stimulates not the cells of the pancreas,
but those of the fundic glands of the stomach itself.

A yet more remarkable example of the coincidence of external and in-
ternal secretory functions in the same organ is supplied by the generative
glands (ovary and testicle). It has been known from time immemorial—
the experiment is repeated daily for commercial purposes in thousands of
animals, and is still practised upon man for domestic reasons in certain
Oriental countries — that the removal of the generative glands in the young-
male animal usually entirely prevents the development of the accessory
generative organs, such as the prostate, and of the features which
characterise the male sex externally. These changes may be prevented by
successfully grafting a testicle in the castrated animal.

Again, removal of the ovaries in the young female exerts a profound
influence over the organism and prevents the development of many female
characteristics. In some cases, even in the adult, removal or atrophy of
the ovaries has been noticed to lead to the development of male characters.
Instances of this have been often recorded in birds. In young mammals
removal of the ovaries is followed by arrest of development of the uterus.
This may be prevented by successfully transplanting the ovaries, or by
grafting an ovary from another animal of the same species into the
peritoneum or elsewhere. It seems clear, therefore, that the result of
removal is due in both male and female to the absence of- the internal
secretion of the generative gland.

THE NATURE OF THE ACTIVE PRINCIPLES CONTAINED IN THE

INTERNAL SECRETIONS

We have compared the active materials of the internal secretions, which
are formed within cells and passed out into the blood, to the active agents
of the ordinary secretions, which are directed on the exterior by means of
a duct. But the comparison cannot be pressed. In the case of the external
secretions, the active agents when present are always of the nature of a
ferment. They belong to the class of bodies which are known as enzymes.
The conditions and modes of action of these bodies are for the most part
familiar to the biologist. They occur not only in secretions, but in the
bioplasm of most if not of all cells ; indeed the chemical activity of the cell
in most cases depends upon its contained enzymes. Although far simpler
in chemical nature than the bioplasm by which they are produced, and in
no sense endowed with life, enzymes are very probably of a protein nature,

Nature of the Active Principles of the Internal Secretions 5

and they are readily destroyed by heat in presence of water. The active
materials of the endocrine organs, on the other hand, are for the most part
not rendered inactive even by prolonged boiling, and are certainly of a
much simpler chemical constitution than enzymes. They are dialysable ;
and although most of them have not yet been isolated in a crystalline form,
due probably to the fact that it is difficult to obtain them free from im-
purities, some of them have been so obtained, and at least one — the active
material of the adrenal medulla — has been prepared synthetically. Many
of them act instantly ; their action, as Starling has pointed out, being similar
to that produced by the active principles of drugs, especially those of organic,
i.e. of vegetable, origin. These also operate by immediate chemical action,
being conveyed to the parts which they influence in solution in the circu-
lating blood. But while some of the materials of the internal secretions
produce their effects upon the tissues immediately, others operate more
slowly, so that the results of their action may only become apparent after
a prolonged period of time. The latter class usually exert their influence
upon the growth and nutrition of special organs or of the body generally ;
they are accordingly termed by Gley morphogenetic.1 None of the sub-
stances we are dealing with are known to cause the production of anti-
bodies when introduced into " foreign " blood. Their action is similar in

c*

all animals, however different from the animal yielding the secretion.

As with drugs, some of the principles yielded by the endocrine organs
act by stimulating or exciting cell-functions : this is notably the case with
the principle obtained by the action of acid on the duodenal epithelium.
Others depress or inhibit those functions : an example of this is met with
in extract of placenta, which when injected into the blood-vessels tends to
prevent the secretion of milk. To such stimulating principles as that con-
tained in the extract of duodenum after treatment with acids the term
hormone (from op/xaa), to stir up) was originally applied by Starling,2 and
the expression has been extended to include the active principles of all
internal secretions. So long as only exciting agents were known, there
could be no objection to this extension of the term, but since agents which
produce depression or cessation of function have been shown also to be
produced in the body — and their number will probably become considerable
as the nature of the internal secretions is more fully examined — it is advis-
able to employ an expression which will discriminate between these and
the stimulating agents. On this account I propose to distinguish the action
of the depressants from that of the excitants by the use of the term chalone
(xaXaw, to make slack). A chalone may therefore be defined as an
endocrine product which inhibits or diminishes activity, as distinguished
from a hormone, which excites to increased activity.3

1 He suggests the name harmozones for them (ap^6£<a, to govern).

! Verhandl. d. Naturforscher-Versammluny, Stuttgart, 1906.

3 The original expression employed by Bayliss and Starling (Journ. Physiol., xxviii.,
1903) in their paper on secretine was chemical messenger. This is more appropriate
as a general term than hormone, because it includes all chemical agents which produce

6 The Endocrine Organs

Starling does not, however, confine the use of the term hormone to
organic principles of an endocrine nature. His definition is much wider.
" By the term ' hormone,' " he says, " I understand any substance normally
produced in the cells of some part of the body and carried by the blood
stream to distant parts, which it affects for the good of the organism as a
whole " (Proc. Roy. Soc. Med., 1914, vol. vii., Therap. and Pharm. Sect., p. 29).
He then proceeds to give as examples of hormones, secretine, adrenalin,
and carbonic acid — the last, which is produced by the tissues in general
and more especially by muscular tissue, stimulating the respiratory centre
to activity. Obviously this definition would include many substances
normally present in the blood, such as water, urea, glucose, and inorganic
salts, which are produced in various parts of the body and affect distant
organs such as the kidneys ; indeed it may be supposed that most circulating
materials will, when we know more about their history, come into the
definition. The expression hormone has not been hitherto employed by
physiologists and clinicians in this extended sense ; the term has usually
been restricted to the active organic principles of the internal secretions.
But it will perhaps be best to employ the term hormone in the sense in
which it was used by its inventor, i.e. to denote any substance in the blood
which excites cells of the body to activity, and to express by a special term
those specific substances which are produced by the organs of internal
secretion for the purpose either of exciting or of restraining the activity
of other organs. Since the most characteristic feature of the action of
these substances is the resemblance to the action of drugs, such as the
vegetable alkaloids, I propose to employ for these specific substances the
general title autacoid substances, or, simply, autacoids (avro?, self, and
a/cos, a medicinal agent or remedy). I would accordingly define an autacoid
as a specific organic substance formed by the cells of one organ, and passed
from them into the circulating fluid to produce effects upon other organs
similar to those produced by drugs. Such effects are either in the direction
of excitation, in which case the endocrine substances producing them are
excitatory autacoids and would come under the expression hormones, or
in the direction of restraint or inhibition, in which case they are restraining
or inhibiting autacoids and would be classed as chalones. The action
of an autacoid may therefore be described as hormonic or chalonic, ac-
cording to the kind of effect it produces.

Some autacoid substances appear to produce opposite results in different parts.
Thus the adrenalin of the suprarenal medulla causes contraction of the plain muscle

an effect at a distance, whether such effect be excitatory or inhibitory. If, in place of
hormone, the expression hermone ('Epjnjs, Mercury) had been selected, the difficulty
which is caused by the use of the term hormone, which implies excitation, for agents
which act in exactly the contrary manner, would not be felt. Biedl uses the expressions
erreyende Hormonen and hemmende Hormonen, i.e. excitants which excite and excitants
which prevent excitation ! It is true that he regards the one class as exciting katabolic
changes and the other as exciting anabolic changes, but this is purely theoretical, and it is,
to say the least, improbable that these agents operate in the manner thus indicated.

Groupings of the Chief Endocrine Glands 7

of the blood-vessels and inhibition of that of the intestines. But in both cases
the action may be regarded as that of a hormone or exciting agent, for both
effects are produced by stimulation of the end substance of the sympathetic nerves.
In extreme dilution (1 to several millions) in mammals, and in a less dilute form
in birds, adrenalin is said to cause inhibition instead of contraction of the muscle
of the blood-vessels. But this again may be produced by excitation of inhibitory
nerve fibres by the more dilute solution, and if so, the action would still be
hormonic. Nevertheless, the possibility of the same autacoid substance acting
under some circumstances as a hormone or excitant, and under other circumstances
as a chalone or depressant, must be borne in mind. This, indeed, serves to illustrate
the drug-like nature of these principles, for such inversion of action under difference
of circumstance is known to occur with some drugs.

Noel Paton (Regulators of -Metabolism, 1913) takes a view of the action of the
principles of the internal secretions different from that usually adopted. He regards
them as playing the same sort of part in the metabolism of the various organs
they influence as Sydney Ringer showed to be the case with the salts of blood in
maintaining the activity of the heart. " A certain minimum amount of each seems
to be essential, and some proportion between the amounts of each must be main-
tained if the metabolism is to continue in its normal course. ... It seems to me that
such a conception is more in accordance with the facts which we possess than that
of a series of hormones or excitors directly calling forth the activity of the various
tissues."

GROUPINGS OF THE CHIEF ENDOCRINE GLANDS

Most of the purely endocrine glands can be grouped under the three
main heads of thyro-parathyroid apparatus, suprarenals, and pituitary,
It is noteworthy with regard to these groups that each of the organs
forming the group is compounded of two distinct but usually closely inter-
grown parts. Thus the thyro-parathyroid group is composed of thyroid
proper and parathyroids ; the suprarenal of cortical and medullary portions ;
the pituitary of epithelial and epithelio-neural parts. And in each case
the functions of the two portions, so far as is known, appear to be in no
way similar, difficult as it is to believe that tissues so closely connected
anatomically should have no sort of functional connexion. The close
anatomical connexion is, however, sometimes absent, as with those para-
thyroids which are altogether detached from the thyroid, and as with the
paired bodies and the interrenal body of Elasmobranch fishes. A close
anatomical relationship without any apparent functional bearing is, how-
ever, not without examples in other organs, e.g. in the frog there exists
a very intimate anatomical connexion of the suprarenal with the kidney,
although there is no particular reason to believe that any special functional
relationship obtains between the two.

It is further noticeable that in each of the above groups one of the two
parts has a more evident, and in a sense a more active, function than the
other. Thus the removal of the parathyroids occasions symptoms which
are far more acute than those produced by the corresponding operation on

8 The Endocrine Organs

the thyroid. And extracts of the medullary substance of the adrenals and
of the posterior or epithelio-neural part of the pituitary have an immediate
and striking effect on various tissues and organs when injected into the
blood-vessels, whilst similar extracts of the cortical substance of the adrenals
or of the anterior or epithelial part of the pituitary are without any
immediate action. There is, however, in the case of the thyroid, direct
experimental as well as clinical evidence, and, in the case of the suprarenal
capsules and pituitary, the testimony of much clinical observation, to furnish
reason for the belief that the parts of these glands which at first sight
appear less active may exercise, if a slower, yet a no less potent influence
upon the organism than the portions the activity of which can be more
immediately demonstrated.

METHODS OF DETERMINING THE FUNCTIONS OF THE ENDOCRINE ORGANS

Two general methods are employed for this purpose, the one being
the observation of the changes which result from partial or complete
surgical removal of the organ in man and animals, or its destruction by
disease ; the other, observation of the changes which result from the ad-
ministration of watery or saline extracts prepared from the organ. As
has been already stated, the active principles of the endocrine glands are
not destroyed by boiling with water or with Ringer's solution, at least for
a short time. Advantage is taken of this to prepare extracts which are
free or almost free from protein or nucleo-protein, since the introduction
of these substances into the blood might tend to mask the effect of the
autacoid which is being tested. Solutions obtained in this way may be
kept, after sterilisation, in hermetically sealed receptacles almost indefinitely.
Preserved in the dry condition the autacoids also appear to undergo no
diminution of their activity. In these particulars animal autacoids re-
semble extracts of plants containing active medicinal principles of an
organic nature, with the action of which, as has already been indicated,
the effects they produce bear a close comparison.

As with drugs, the extracts can be administered by the mouth, or by
subcutaneous, or intramuscular, or intraserous, or intravenous injection. Or
isolated organs and tissues may be perfused with or immersed in the extract
the action of which is to be examined. The intravenous method was first
employed by Oliver and myself to investigate the physiological action of
such extracts in 1894, and led immediately to the discovery of the active
principles of the suprarenal capsules and the pituitary body.

Administration by the Mouth. — This is well known to be effective in
the case of the thyroid, and the fact is taken advantage of in cases of hypo-
thyroidism such as occurs in endemic goitre, cretinism, and myxoedema.
On the other hand, thyroid juice or the substance of the gland given freely
with the food in normal individuals produces symptoms which are inter-
preted as due to excess of the thyroid autacoids in the blood. With smaller

Methods of Determining Functions of Endocrine Organs 9

doses effects are produced upon metabolism, including an increase of N-
secretion and an increase of O2 intake and of CO., output, with reduction
of body fat. Buccal administration of pituitary extracts or pituitary
gland substance is also stated to yield beneficial results in cases of deficiency
of pituitary secretion, although in normal individuals no effect may be
apparent. Similarly, buccal administration of suprarenal extract gives
little, result in normal individuals, but both in Addison's disease and in
certain other affections beneficial effects have been recorded.

Administration by Subcutaneous or Intramuscular Injection. — As
with drugs, the effects of administering the animal autacoids by hypodermic
injection are usually more rapid and more marked than with buccal ad-
ministration, although in some cases the difference is not striking. But
Meltzer and Auer have shown that if extract of the medulla of the supra-
renals, or of the posterior lobe of the pituitary body, are administered by
intramuscular injection — absorption being promoted by gentle massage—
they rapidly cause their characteristic effects. Probably the reason why
these extracts when given by hypodermic injection produce little general
result — although the local effects in causing vasoconstriction may be very
marked — is that the autacoid is rapidly destroyed in the body; so that
when absorbed slowly it is got rid of before any excess is able to accumulate
in the blood. This applies onty to moderate doses and to the immediate
effects. Secondary effects may be seen with large doses, and these may be
of a marked character.

Intravenous Injection. — The immediate effects — if any — of the animal
autacoids are, as with drugs, unfailingly exhibited as the result of the in-
jection into a vein of the extracts containing them. In this manner can be
shown the action of extract of thyroid in causing a marked but evanescent
depression of the blood-pressure : the various effects of extract of suprarenal
medulla ; such as contraction of blood-vessels with raising of blood-pressure,
acceleration of pulse, sometimes preceded or followed by retardation, flow
of saliva, erection of hairs, dilatation of pupil, retraction of third eyelid,
and protrusion of eyeball, contraction of uterus, vas deferens, and seminal
vesicles, inhibition of gastric and intestinal movements and of the bladder :
as well as those produced by extracts of the posterior lobe of the pituitary,
such as contraction of the blood-vessels with slowing of the heart, increase
of secretion from the kidneys, outflow of milk from the mammary gland,
contraction of the uterus, of the intestines, and of plain muscle in general.

A caution must be entered against the too hasty conclusion that a particular
effect obtained in injecting an organ extract is a specific effect due to an autacoid
substance. Especially is this warning necessary in experiments in which the blood-
pressure is employed as the gauge of activity. For there are few organs which
yield extracts that are absolutely inert when tested by intravenous injection. This
applies to many glandular and lymphatic structures, extracts of which generally
cause a rapid fall of blood-pressure, usually speedily recovered from. The depressor
effect is not dependent upon the presence of nucleo-proteins in the extract, as was

10 The Endocrine Organs

at one time supposed, nor upon the presence of choline ; but seems to be caused
by an organic material of a specific nature which varies in different organs, the
extracts producing in each case a specific form of blood-pressure curve.

Extracts of animal tissues — if unboiled — are liable to produce intravascular
clotting. If this is general, instant death is the result ; if localised, it may manifest
itself by serious interference with the functions of the nervous system or of other
organs : and the result of such injection might erroneously be set down to a specific
action of the extract injected, although it would only represent the result of an
accident. A similar caution applies, although in a minor degree and for a different
reason, to effects which may be obtained as the result of buccal and hypodermic
administration of animal-extracts. Such effects may (unless they are otherwise
proved to be specific) be produced by variations in amount of such organic sub-
stances as nucleo-proteins, which, when added to the ordinary diet of animals, are
capable of affecting growth and metabolism.

It is a perfectly legitimate criticism regarding the employment of
extracts of organs, that we are not justified in assuming that because
we obtain evidence of the presence of active substances in such extracts
they are necessarily preformed in the organ, and still less that they are
passed out from it into the blood. In fact, as we have seen, actual chemical
evidence of the presence of such substances in the circulatory fluids is
almost entirely lacking. Nevertheless, the action of extracts of certain of
the ductless glands is quite specific, which is not the case with extracts of
other organs ; and since the active principles contained in such extracts are
always readily soluble in water and diffusible, it is difficult not to believe
that they are formed with the object of producing their specific action after
being passed into the blood, in greater or less quantity according to the
needs of the organism. The criticism that with many such extracts an
amount of material may be necessary to produce a visible effect which is
altogether out of proportion to the size of the endocrine organ the action
of which is being studied, loses force if we remember that these organs
are extraordinarily vascular and probably proportionately active, so that
within a short time a larger amount of active substance may be formed and
passed into the blood than is present at any given moment in the cells of
the organ. Nor need the action, under physiological circumstances, be so
striking as we endeavour to obtain it under conditions of experiment;
indeed it is not improbable that in many cases the functions of the internal
secretions under normal circumstances are rather facilitating than active.

The terms substitution therapy, organotherapy, qpotherapy, and autotherapy are
employed to denote the effects produced by administration of organs and their
extracts — especially the endocrine organs — with the view to combat symptoms
which are believed to be caused by a deficiency in the blood of the autacoids
which are produced by those organs. The fact that such extracts have come
into extensive therapeutic use emphasises the essentially drug-like action of the
active substances they contain. Harrower (Practical Hormone Therapy) has col-
lected a large number of observations bearing upon this subject.

CHAPTER II
THE THYROID AND PARATHYROIDS

THE thyro-parathyroid group of endocrine glands consists (1) of the thyroid
proper, which takes the form of two lobes situated on either side of the
larynx and windpipe, and often united by
an isthmus over the trachea (fig. 1); (2)
of the parathyroids : generally two on
each side — one, the upper (parathyroid IV ),
which is usually in contact with the corre-
sponding lobe of the thyroid near its upper
and dorsal aspect, whilst the other, the
lower (parathyroid III), lies either in con-
tact with the corresponding lobe of the
thyroid near its lower and mesial aspect
or is removed a greater or less distance
from it, sometimes as low down as the
thymus. Both upper and lower para-
thyroids are usually supplied with blood
by branches of the inferior thyroid artery,
with which they are anatomically closely
connected. But there is a good deal of
variation in this, as well as in their posi-
tion relatively to the thyroid and to one
another (Halsted and Evans, Geis). In
many animals (dog, cat, rabbit, monkey)
the upper parathyroid is deeply embedded
in the substance of the thyroid (Kohn), and
it has on that account then been termed
the "internal" parathyroid, the lower being
designated " external." The expressions
parathyroid III and parathyroid IV, which
indicate the source of each gland, are on
the whole the least ambiguous and ought
if possible to be employed.

FIG. 1. — Sketch of a preparation of
human larynx and oesophagus from
the dorsal aspect, showing the thy-
roid and parathyroids.

The thyroid may also contain a portion of tissue resembling thymus
gland, and, like that, containing lymphocytes and corpuscles of Hassall.
Such portion of thymus tissue is developed from the same branchial pouch
(IV) as the upper parathyroid, whereas the main thymus is developed

12

The Endocrine Organs

from pouch III, which gives origin to the lower parathyroid (fig. 2).

Accessory thyroids, usually quite small, occasionally occur in the tissues of
, the neck and in the anterior

mediastinum. Accessory
parathyroids also occur ;
they are common in the
rabbit, and are in this animal
often found to a consider-
able number embedded in
the thymus. This is also
the case with the rat.

In the rat, mouse, and
guinea-pig only the parathy-
roid III is ordinarily present,
and this varies greatly in posi-
tion relatively to the thyroid.
The thyroid is repre-
sented in all Vertebrates.
In Amphioxus and Am-
mocnetes it retains an open

Tfiym. ///

_ Post. branch.
T/tym./V body

I

connexion with the phar-
ynx. Parathyroids do not
occur below Amphibia.1

STRUCTURE AND DEVELOP-
MENT OF THYROID
Structure. — The thyroid
proper is an organ consist-
ing of small closed vesicles
(fig. 3) of varying size and
shape, but for the most
part irregularly spheroidal.
Each vesicle is lined by epi-
thelium, the cells of which
are columnar, cubical, or
flattened in accordance
with the state of distension of the vesicles. There is no definite base-
ment membrane separating the epithelium from the connective tissue
and blood-vessels. The vesicles are generally filled by the so-called
"colloid," a viscid fluid in the fresh organ, which is coagulated into a

1 For the structure and morphology of the thyroid and parathyroids, the paper by the
late Mrs F. D. Thompson in the Phil. Trans, for 1910 may be consulted. The following
works deal with, the whole subject : — Leopold-Levi, Physio-pathologie du corps thyro'ide,
1908; L. Lannoy, Thi/roides, Parathyroides, Thymus, 1914. For the parathyroids, see
D. A. Welsh, Journ. Anat., 1898 ; D. Forsyth, Trans. Path. Sue., 1907 ; and Guleke, Chirurgie
der Nebenschilddrusen, 1913.

r/tyro/cf

FIG. 2.— Diagram to illustrate the origin of the cleft organs
(thyroid, parathyroids, thymus, etc. ) in the mammalian
embryo.

I, II, III IV, branchial pouches; Parathiir.iii, origin of lower
parathyroid from cephalic aspect of third poiu-h ; Parathyr.iv,
origin of upper parathyroid from cephalic aspect of fourth
pouch ; Tliiini.iii,iv, origin of thymus from caudal aspect of
third and fourth pouches (Thym.iv usually forms the part
associated with the thyroid) ; Post.branch.bodi/, post-branchial
body, which forms a separate organ in lower Vertebrata,
but in mammals either disappears or is incorporated with
the thjroid.

•Structure of Thyroid

13

solid substance by fixative reagents. The intervesicular substance is
areolar tissue, containing in parts many small cells. Some of these are

FIG. 3. — Section of thyroid (cat). Magnified 300 diameters.

lymphocytes, whilst others are not unlike those of the parathyroids,
although the identity has not been established. There are also very
numerous blood-vessels, the thyroid being one of the most vascular organs
in the body ; it receives in proportion to its size
more than five times as much blood as the
kidneys. The capillaries form a close network
around each vesicle, giving a characteristic ap-
pearance to an injected specimen (fig. 4) : they
come into immediate contact with the vesicular
epithelium (fig. 5). There are numerous lym-
phatics within the organ, and " colloid " like
that of the vesicles is occasionally seen within
them. The gland receives nerves from the
sympathetic and from the superior and inferior
laryngeal : they are distributed both to the blood-
vessels and to the secreting epithelium.

The vesicles of the thyroid do not always

FIG. 4. — Thyroid of dog in-
jected, low power.

present the appearance above described. Sometimes they are smaller
or irregular, with projections into their cavities, and the lining epi-
thelium cells are pronouncedly columnar. In these circumstances there
is usually little or none of the typical colloid material in the vesicles —
although the appearance of the cells is suggestive of secretory activity.
It may be inferred that the secreted material finds in these cases a

14

The Endocrine Organs

ready exit from the vesicles, and thus fails to accumulate within them ;
it is possible that it may also be different in consistence and quality.
So far as can be ascertained, these differences of appearance are seen in
animals which are otherwise normal. A glandular structure of this type,
but more pronounced, is noticeable in the thyroid in cases of exophthalmic
goitre in man. It is usually there interpreted to indicate the pro-
duction of excess of secretion (hyperthyroidism). The epithelium cells
of the vesicles contain fatty granules which are said to increase in
number with age ; they are most numerous near the free border. The

FIG. 5. — Section of thyroid, human, injected. (Major.) Highly magnified. The close
relation of the capillaries to the vesicles is shown.

colloid is insoluble in alcohol, water, or ether; when coagulated it is
readily stained by eosin, less easily by hasmatoxylin. In fixed sections
it often appears shrunken away from the epithelium. It is believed to
be formed from granules which are produced within the cells, and which
become changed and dissolved on extrusion. Doubtless it contains the
active principles of the secretion, and probably forms a storehouse whence
they can be extracted as required by the organism.

A close relationship exists between the size and structure of the thyroid
and the state of general nutrition of the animal. The effect of variations
of diet upon the thyroid has been studied in rats by Chalmers Watson (see
figs. GA and 6fi), who has shown that all transitions from an active or super-
active organ with highly developed columnar epithelium and irregular

Development of Thyroid

15

Magnified 250

FIG. 6A. — Section of thyroid of wild rat.

diameters. The vesicles are seen to be distended with
colloid and the cells flattened. (Chalmers Watson.)

large vesicles and without any great accumulation of colloid, to a gland

with flattened epithelium
and vesicles greatly dis-
tended by colloid are ex-
hibited under the influence
of different nutritive sub-
stances in the diet : the
former conditions being, in

O "

the rat, typically seen when
the animals have been fed
upon a mixed food such as
bread and milk ; the latter
when the diet has been
composed of lean meat.
Prolonged feeding of rats

o O

with lean meat led eventu-
allv to a shrinking in size

t> O

of the vesicles and of the
whole organ, these changes
being associated with dry-
ness of skin, falling off of
hair, and other evidences
of ill-health ; in carnivora results of this kind were not observed.

Development. — The thy-
roid is originally developed
like an ordinary secreting
gland by a median outgrowth
from the entoderm lining the
floor of the pharynx at a
level between the first and
second branchial pouches
(fig. 2). It appears very early
and grows backwards as a
solid column of cells, bifur-
cating at the upper end of
the trachea into two lateral
portions. The solid column
becomes hollowed out into a
duct (ductus thyreoglossus),
which presently becomes obli-
terated, usually completely ;
its original opening is marked
throughout life by the fora-
men ccecum at the back of

The lateral parts into which the caudal end divides, branch

-.-•

FIG. SB. — Section of thyroid of another wild rat. Magnified
250 diameters. The vesicles contain little or no colloid ;
the epithelial cells are columnar. (Chalmers Watson. )

the

tongue.

16

The Endocrine Organs

again and again to form a system of hollow epithelium-lined tubes, and
later these become cut up into the closed vesicles which are characteristic
of the gland. The thyroid bud is joined by outgrowths from the ventral

FIG. 7. — Section of parathyroid (cat). Magnified 400 diameters. This is a good
illustration of the compact type of gland.

wall of the pharynx on each side behind the fourth branchial pouch (post-
branchial bodies) ; these may be involved in the thyroid, but it is doubtful
if they contribute to the formation of its vesicles.

STRUCTURE AND DEVELOPMENT OF PARATHYROIDS

Structure. — The parathyroids (fig. 1) are four minute organs averaging
6 to 7 mm. in length, 3 to 4 mm. broad, and 1'5 to 2 mm. thick (Welsh).
Each weighs about 0'03 gramme (half a grain). Rarely there are more
than four, sometimes fewer. As already stated, one (the lower) may
occur altogether detached from the thyroid,1 but usually in man both are
closely attached to it. The upper of the parathyroids may be completely
embedded in the substance of the thyroid (fig. 13).

The parathyroids were described by Sandstrom in 1880. Their plwsio-
logical independence and distinction from the thyroid proper was first re-
cognised by Gley in 1891, and confirmed by Vassale and Generali in 1896,
but is not fully accepted by Forsyth, Vincent, and some other authorities.

1 This is constantly the case, as Gley pointed out, in the rabbit, and partly accounts
for the fact that when thyroidectomy is performed in that animal, two parathyroids being
left behind, tetany does not occur until these are removed. Even then tetany sometimes
fails to show itself ; this may perhaps be accounted for by the presence of accessory para-
thyroids in the thymus.

Structure of Parathyroids

17

The parathyroid is composed of epithelium-like cells (figs. 7 to 13), which
either form a compact mass (fig. 7) or are divided up into lobules or

FIG. 8. — Section of parathyroid of dog. Magnified 400 diameters. This shows
a looser arrangement of the trubecula? than the gland represented in fig. 7.
On the right is part of one of the vesicles of the thyroid.

FIG. 9.— Section of parathyroid of man. Magnified 400 diameters. On the left is a strand
of eosinophil cells (e). (Figs. 8 and 9 are from specimens prepared by Dr Kojima.)

trabeculse (fig. 8) by strands of connective tissue. These differences of
structural appearance may sometimes be observed even in different parts
of the same gland. The interstitial connective tissue conveys the vessels,

2

18

The Endocrine Organs

which mainly take the form of sinus-like capillaries. There is a capsule of
areolar tissue sending in processes to join the interstitial tissue of the organ :

. •- —

..

\

FIG. 10. — Section of parathyroid and adjacent thyroid tissue (rat). Magnified 50 diameters.
The vesicles of the thyroid are filled with colloid. The parathyroid is of the reticular
type, consisting of loosely arranged trabeculse.

-'

V •;.':..-

FIG. 11. — The same, from another preparation. The thyroid vesicles are
fempty and their cells columnar.

plain muscle cells have been described in this ; it may also contain fat-cells.
Besides the ordinary or principal cells of the gland — which are small and

Structure of Parathyroids

19

either clear or somewhat granular — others occur which are considerably
larger and contain oxyphil granules, staining with eosin (Welsh) : these only

%:*£!£'•

| -,. ?®S®8&$&

(%.,- v.^«.->- v.
*i - ?.v*/-»^<

• >.

:Jg- «fi4p-

VN.- -

-V-s-i ' ^ -' '• > ' l'^>
m> f\A, "• V. •'•• -«A
\«"' .*!" V

FIG. 12. — Part of a section of thyroid and parathyroid (rat). Magnified 200 diameters.
In this gland the vesicles of the thyroid are distended with colloid ; the parathyroid
is of the reticular type.

FIG. 13. — Section of an internal parathyroid (rat). Magnified 50 diameters. (An internal
parathyroid is rarely to be found in the rat, although common in many animals. )
The vesicles of the thyroid are empty of colloid in this preparation.

appear after the tenth year in man. Probably they represent a functional
stage of the ordinary^cells, since transitional forms occur. Both kinds of cell

20

The Endocrine Organs

call.

contain fatty granules, which increase in number with age ; glycogen has

also been detected both in the cells and in the interstitial spaces of the gland.

Vesicles containing colloid material similar to those of the thyroid, but

usually smaller, are frequently found in the parathyroids. They usually

increase in number with age, and
occasionally the colloid is found be-
tween the cells, not enclosed within
a vesicle. Whether it is of the same
chemical nature as that of the thyroid
is not established, but it is probably
different, as it appears to contain no
iodine. After complete removal of
the thyroid, in the parathyroids
which had been left colloid-contain-
ing vesicles were found by Vincent

conn Clss,

FIG. 14. — Section of parathyroid of cat after
previous removal of thyroid. (Vincent and

Jolly ) Vesicles which contain colloid are and jony in considerable number

developed within the gland. „ . ml .

and ot some size (fig. 14). Ihis

observation has been confirmed by Halpenny and Thompson, who found
that if the animal survives a sufficient time the vesicles become large and
irregular (fig. 15),1 presenting a certain resemblance to those of a thyroid

: •-

";v- - •«• -- —

— c. ves.
-- e. ves.

FIR. 15. — Section of parathyroid of dog, eighty-three days after thyroidectomy.
(Halpenny and Thompson. ) The gland now contains a large number of irregular
vesicles and exhibits signs of hypertrophy and increased activity.

e.vex., epithelium of vesicles; e.interves., epithelium between vesicles; c., colloid; c.ves.,
cavity of vesicle.

in exophthalmic goitre (fig. 26, p. 38). The same observers state that
after removal of all the parathyroids the vesicles of the thyroid tissue

1 It is suggested by Guleke that the authors were here dealing not with a parathyroid
but with an accessory thyroid. The parathyroids usually remain unaltered in myxoedema :
Forsyth has, however, described one case which was an exception to this rule (Trans. Clin.
/Soc., 1907). Biedl has also recorded the development of colloid-containing vesicles in the
parathyroid in a case of atrophy of the thyroid in man.

Development of Parathyroids 21

itself take on a similar appearance, becoming large and irregular (fig. 16).
In this case there is also seen a multiplication of intervesicular cells, which
the authors believe to be of the same nature as the cells of the parathyroids.
The conclusion they arrive at is that the tissues of the two organs are
largely intermixed, at least in birds and mammals. In lower Vertebrates,
however, Mrs Thompson found the two to be completely separate both
developmentally and structurally.

The parathyroids are amongst the most vascular organs in the body.
They are supplied each by a special branch of the inferior thyroid artery

ves.

\-i" .

---c.t.

FIG. 16. — Section of thyroid of dog, thirty-two days after removal of all the para-
thyroids. (Halpenny and Thompson.) The appearance is singularly like that of
the parathyroid shown in fig. 15, and somewhat resembles the thyroid of ex-
ophthalmic goitre (tig. 26).

ves., vesicle ; e.vex., epithelium lining vesicle; e.internes., intervesicular tissue ; c.t., connective tissue.

The sinus-like capillaries come into close relationship with the epithelial
cells of the gland.

The nerves of the parathyroids, like those of the thyroids, pass both
to the vessels and to the secreting cells. Some evidence has been adduced
which seems to show that the cell-activity is controlled by the nervous
system.

Development. — The parathyroids are developed as outgrowths of the
Illrd and IVth visceral pouches on each side (fig. 2), that from the
Illrd pouch giving rise to the upper, and that from the IVth to the lower
parathyroid. From the same pouches the thymus is also derived; occasionally,
as already mentioned, one or more outgrowths from the thymus rudiments
pass into the thyroid. On the other hand, parathyroid and even thyroid
tissue occasionally occurs within the thymus ; in some animals constantly.

CHAPTER III
THE THYROID AND PARATHYROIDS (continued)

EFFECTS OF REMOVAL OF THE PARATHYROIDS

Parathyroidectomy. — If the operation is complete — i.e. if it includes all four
parathyroids — most animals die as the result of the removal ; some within
a few days, others within a few weeks. The most acute symptoms are
exhibited by carnivora such as dogs, cats, foxes, and wolves (Vincent), and
the young of herbivora (v. Eiselsberg, Sutherland Simpson), and are of a
nervous nature. For the first day or two there are no symptoms, other
than some loss of appetite. There then supervenes marked exaltation of
reflexes, which leads to the occurrence from time to time of fibrillar con-
tractions of muscles, and later cramp-like and clonic contractions, with
eventually convulsive fits; these may be of considerable violence and
alternate with intervals of depression. The limbs in progression and the
tail are stiff and exhibit quiverings. The irritability of the peripheral
nerves to both electrical and mechanical stimuli is markedly increased.
The pulse is quickened and the heart-beat becomes greatly exaggerated.
There is profuse salivation. The body temperature may rise two or
three degrees centigrade during the fit. The paroxysms are usually accom-
panied by rapid gasping respirations which may be synchronous with the
heart-beats ; sometimes by vomiting and* diarrhcea. There is considerable
wasting. The hair tends to be shed. In the rat, Erdheim found that the
growing incisors fail to be properly calcified. Deficient calcification of the
teeth has also been found by Fleischmann to occur in children affected by
tetany. Death may occur within a few days, or the affection may last a
long time and spontaneous recovery may occur. The fits are sometimes
frequent, but more often occur at long intervals; the animal, if it fails
to recover from the effects of the removal, usually succumbs during a
convulsion.

In man the contractions of muscles tend rather to take on a tonic
character: this is also observed in rats and puppies. In most animals
they are clonic. The tonic contractions are usually associated with
diminution of respirations and of frequency and force of heart-beats, and
with fall of body temperature : the clonic with increase, as above described.
The meaning of these differences is not clear.

The syndrome is usually spoken of as " tetany " (tetania parathy-
reopriva) ; this is in no way synonymous with " tetanus." It may be acute

22

Effects of Removal of Parathyroids 23

or chronic : in the former clonic, in the latter tonic contractions of the
muscles tend to manifest themselves.

Tetany is without doubt due to deprivation of the parathyroids, for
it will occur when these alone are removed. It varies greatly in severity
and often takes on an intermittent character. The symptoms may
remain latent for a considerable time, and only show themselves as the
result of some unusual condition such as pregnancy. The effect is on
the lower neurones, for according to Horsley it is not arrested by abla-
tion of cerebral cortex. Lanz and Biedl state that it is increased on
the side of the ablation; with cerebellar lesion they find an increase
on the opposite side. According to Mustead, section of dorsal roots does
not affect it. After spinal transection it disappears below the level of
the lesion. Tetany is relieved by injection of parathyroid extract, and in
many cases by administration of thyroid substance : it is uncertain if
this last result is due to included parathyroid. When tetany is produced
by total extirpation of all parathyroid tissues it can apparently only
be cured by a successful graft of a parathyroid from an animal of the
same species. The condition has been found to occur after complete
removal of the thyro-parathyroid apparatus in man, and may be suffi-
ciently serious to threaten life, unless suitable measures are taken to combat
the effects of parathyroid loss.1

In order to prevent the accession of tetany in operations for removal
of thyroid tumours it is usually necessary to leave at least two of the
four parathyroids. In one dog experimented on by Edmunds, he found
that a single parathyroid was sufficient to prevent the onset of tetany
(the three others and both lobes of the thyroid having been removed) : on
extirpation of the remaining parathyroid the animal speedily developed
tetany.

Animals with insufficient amount of parathyroid tissue may not suffer
from tetany under ordinary circumstances, but the symptoms may come on
under special conditions. Thus Vassale observed, in a bitch from which
three of the four parathyroids had been removed, that the animal was
especially subject to fits of tetany during pregnancy 2 and lactation. The
character of the food also influences the onset of the symptoms, flesh
foods being much more apt to bring on the condition than a vegetable or
milk diet.

1 A case in which all possible remedies, and grafts from various animals, including a
monkey, were tried without avail, but which was rapidly and completely cured by the
implantation into the subcutaneous tissue of parathyroids obtained fresh from the dead-
house, is described by W. H. Brown in the Annals of Surgery, vol. liii., 1911. In ex-
periments on animals it has been almost universally found that to ensure the success of a
graft of parathyroid it must be derived from the same animal from which the parathyroids
have been removed (Halsted and others).

2 This is contrary to what might be expected, considering that the mother would have
had the parathyroids of the foetuses to draw upon. It seems, however, to be confirmed by
the results of other experiments on dogs, and also by those of Acller and Thaler upon
partially parathyroidectomised rats. Animals which have suffered complete parathyroidec-
tomy do not become pregnant.

24 The Endocrine Organs

The most satisfactory explanation of the nervous results of the removal
of the parathyroids is the assumption that they yield to the blood a special
autacoid — presumably of a chalonic or restraining nature — which tends to
prevent over-excitation or discharge of nerve-cells. It has been suggested
that the over-excitation, since it occurs most markedly in carnivora, is
induced by products of protein metabolism. Some species exhibit no
symptoms whatever — at least when the operation is performed on the
adult. Horsley stated that this is the case Avith birds and rabbits ; but,
according to Gley, the latter are affected if care is taken to find and remove
all parathyroids. Doyon and Jouty obtained typical tetany in hens which
had been parathyroidectomised. Vincent and Jolly found that rats and
guinea-pigs do not seem to suffer from removal of their parathyroids, but
Christian! and Erdheim both readily obtained tetania parathyreopriva in
rats, although in them it takes much longer to produce a fatal result than
in most animals ; and Pfeiffer and Meyer obtained it in mice. According
to Vincent and Jolly, badgers are totally unaffected by complete removal
of both thyroids and parathyroids.

It is possible that insufficient attention has been paid to age by many
who have experimented on the subject. For it is certain that — with the
exception of puppies, which are less susceptible than adult dogs — young
animals are much more susceptible both to thyroidectomy and to para-
thyroidectomy than adults. This is strikingly exemplified in experiments
by v. Eiselsberg and by Sutherland Simpson on sheep and lambs. They
found, as had been done by others, that sheep show no symptoms what-
ever as the result of complete removal of thyroids and parathyroids,
while lambs exhibit both symptoms of tetany and arrest of development
with supervention of cretinism (fig. 17). Adult goats, on the other hand,
may exhibit well-marked tetania parathyreopriva. In monkeys this
condition has often been missed, but it occurs if the removal of para-
thyroids is complete.

As already mentioned, Halpenny and Thompson describe changes in the
thyroid (of dogs) following parathyroidectomy (fig. 16) which resemble the
changes met with in exophthalmic goitre in man (see p. 37), and are
usually interpreted to mean increased activity of the gland. If this inter-
pretation is correct, we must regard the parathyroids as exercising an
inhibitory influence upon the thyroid, and some at least of the symptoms
of parathyroidectomy as due to the removal of this restraining influence.
Rudinger has upheld the view that there is reciprocal antagonism between
thyroid and parathyroids.

Various clinical symptoms are associated with pathological changes
in the parathyroids, and have been referred (1) to atrophy or diminished
secretion (hypo-parathyroidism), (2) to enlargement or increased activity
(hyper-parathyroidism), (3) to altered secretion (dys-parathyroidism).
To the first condition must be ascribed manifestations resembling those of
tetania parathyreopriva. These occur under various circumstances, e.g.

Effects of Removal of Parathyroids

25

during pregnancy, in the course of infectious diseases, and in new-born
infants. In some such cases degenerative changes or haemorrhages have

o o o

been observed in the parathyroids. But other cases have been recorded
in which changes of a similar character have been found post-mortem in
the parathyroids without symptoms of tetany having been noticed during
life. Various attempts have been made to associate conditions showing
increase of response to reflex or to cortical stimuli, e.g. such as occur in
Thomson's disease and in paralysis agitans, with a condition of chronic
deficiency of parathyroid secretion. It is stated by Berkeley that cases of
paralysis agitans are benefited by administration of parathyroid. The

FIG. 17. — Photograph showing a thyroidectomised cretin lamb about fourteen months old
and a normal sheep of the same age. The thyroids (with the parathyroids) had been
removed from the cretin about twelve months previously. (Sutherland Simpson.)

gland has also been recommended in chorea, epilepsy, and eclampsia. On
the other hand, it has been suggested that pseudoparalytic conditions, such
as those which are found in myotonia paralytica and myastltenia gravis,
are due to chronic increase of the secretion. But the evidence in support
of the view that these affections are related to abnormalities of the para-
thyroids is not at present convincing.

Effects of Parathyroid Removal on Metabolism. — Chronic parathyroid
tetany is always accompanied by rapid diminution in weight and general
emaciation, indicating that the nutrition of the body as a whole is seriously
affected. The emaciation is however due, at least in part, to incidental
circumstances such as loss of appetite and the supervention of diarrhoea.
These conditions may appear, even in the absence of actual tetany, with
insufficiency of parathyroid secretion, such as occurs when the vessels

26 The Endocrine Organs

of the parathyroids are ligatured (Thompson, Leighton and Swarts).
An observation which has frequently been made after parathyroid-
ectomy is the occurrence of changes in the hair and nails, and also in
the growth and structure of the bones and teeth. These changes are, of
course, only seen if the animals survive the operation for some time. As
Erdheim has shown, the calcification of the teeth is delayed and imper-
fect, and they are unusually brittle. In the skeleton the bones remain
smaller than in the controls; also the healing of fractures is delayed.
If these changes are the direct result of the removal of the parathyroids,
there is obviously reason for believing that the parathyroids influence
calcium metabolism in some way which is not understood ; a further founda-
tion for this is met with in the fact that more than one observer has
described an increase of calcium excretion in parathyroidectomised animals.
In connexion, however, with this subject, other facts appear to point in
the opposite direction, since many cases of osteomalacia have been found
to be associated with hyperplasia (adenoma) of one of the parathyroids, and
therefore presumably with a condition of hyperparathyroidism.

MacCallum and Voegtlin found that the effects of parathyroidectomy
could be removed by injection of extract of parathyroid. The extract has
also been used with some success in man by Halsted. Extract of pituitary
is said by Ott to have a similar effect. The same result was obtained by
MacCallum from the administration of calcium salts, both subcutaneously
and by the mouth ; he regards tetany as caused by a diminished calcium
content of the blood. According to Biedl, however, these salts do not
prolong life after the operation ; and in my own experience they may
altogether fail either to prevent or alleviate post-operative tetany. Accord-
ing to Carlson and Jacobson, the action of calcium salts, when it occurs,
is merely like that of other substances which decrease the excitability of
the nervous system.

In man, cataract is often found to be associated with chronic tetany.

PHYSIOLOGICAL EFFECTS OF PARATHYROID EXTRACT

Probably largely owing to the difficulty of obtaining enough material,
very few observations have been made on the physiological effects of
injections of parathyroid extracts. Ott finds that when injected intra-
venously they have an entirely different effect from those of thyroid
(see p. 35). He states that the blood-pressure is first raised, then lowered ;
that the rate of respiration is increased ; that they are diuretic, acting
directly on the renal epithelium, and that in large doses they have the effect
of lowering the body temperature. Also that applied locally the extracts
increase the extent of the contraction both of intestines and uterus, and
dilate the pupil. These statements await confirmation.

Nature of the Parathyroid Autacoid 27

THE MODE OF ACTION AND THE NATURE OF THE PARATHYROID

AUTACOID

The theory that the parathyroids serve the purpose of destroying
poisonous products of metabolism which are elaborated in the main thyroid
— apart from its a priori improbability — has received no support from the
results of experiment. If the removal of the pai'athyroids were to be
explained in this manner, simple parathyroidectomy should produce much
more acute symptoms, than total removal of the whole thyroid and para-
thyroid apparatus, but Biedl states that there is no difference in the acute-
ness of the symptoms. It is, however, possible that, as already stated, the
symptoms of tetany may be produced by the presence in the blood of a
special toxin — for which the term tetany toxin has been proposed — and
that the parathyroids may have the function of destroying or neutralising
such a toxin ; in this case they need possess no power of producing an
internal secretion. It has also been suggested that there may occur in
tetany an accumulation in the blood of toxic intermediate products of
protein metabolism, such as appear when the metabolic functions of the
liver are interfered with, and that the parathyroids produce an autacoid
of hormonic nature which excites some other organ (e.g. the liver) to
complete the metabolism of proteins. But the simplest theory to explain
the phenomena is that already suggested, which assumes the production
of a chalonic autacoid serving to diminish the excitability of nerve-cells.
This hypothetical autacoid — which it must be understood has never been
isolated — may provisionally be termed parathyrine. We shall see that
there is reason to believe that the thyroid produces an autacoid with an
opposite tendency.

The explanation which is often given of parathyroidectomy, as of
extirpation of other endocrine glands, that it produces disturbances of the
chemical correlation between the blood and organs affected, is merely
another way of stating the problem to be explained.

The production of a special autacoid which tends to regulate the deposi-
tion of calcium in the tissues is not proved, and we must bear in mind
that any changes which seriously interfere with general nutrition are
especially liable to affect the process of ossification.

RELATION OF THE PARATHYROIDS WITH OTHER ENDOCRINE ORGANS

Although some authors believe the parathyroids can functionate vi-
cariously for the thyroid, the generally received and most probable opinion
seems to be that they are independent in function, or, if anything, antagon-
istic. They usually show no enlargement in congenital atrophy of the
thyroid, and although certain experiments by Vincent and others have
appeared to indicate that there may be enlargement and colloid formation
after thyroidectomy, it must be borne in mind that it is by no means
difficult for errors to creep in in experiments of this kind.

28 The Endocrine Organs

There seems, however, to be no doubt that cases of tetany benefit by
the administration of thyroid extracts, although the tetany cannot be cured
by such administration. It is unlikely that the effect is due to the minute
proportion of parathyroid substance in these extracts.

Mrs Thompson has described the development of colloid vesicles in the
pars intermedia of the pituitary after parathyroidectomy, and has con-
cluded that this is a vicarious effect — but it must be remembered that
there are great individual variations in the number of such vesicles in the
pituitary, and that some animals exhibit a very large number even normally.
Most other authors have failed to substantiate any change in the pituitary
after parathyroidectomy alone, although there are marked changes after
thyroidectomy.

Very little that is definite has been substantiated regarding the rela-
tions of the parathyroids with the suprarenals, or with the internal secret-
ing functions of the pancreas or the generative glands. It has, how-
ever, been affirmed (Guleke) that removal of the suprarenals prevents the
appearance of tetany after parathyroidectomy, but only when the thyroid
is included in the removal. And, on the other hand, that adrenalin
injection will bring on a fit of tetany in a parathyroidectomised animal.
These effects are produced no doubt through the nervous system, and point
to a certain antagonism between suprarenal and parathyroid.

Gozzi has described degenerative changes in the liver-cells as a result of
parathyroidectomy, but regards them as secondary to the general effects on the
organism as a whole.

CHAPTER IV
THE THYROID AND PARATHYROIDS (continued)

THE EFFECTS OF SURGICAL REMOVAL AND OF ATROPHY OR
DEGENERATION OF THE THYROID: HYPOTHYROIDISM

Thyroidectomy. — Schiff, who . had previously (1856) performed the opera-
tion in various animals with incomplete results, was led in 1884 to again
investigate the effect of thyroidectomy in animals : he was also the first to
attempt to combat the resulting symptoms by implantation of thyroid from an
animal of the same species. SchifFs extirpations probably in most instances,
as the symptoms he records show, included the parathyroids. Gley drew
attention to the importance of leaving at least two of these in order
to study the effects of thyroidectomy alone. Subsequent observations on
the subject are numerous, although some are contradictory. This is due
mainly to the fact that differences are found with animals of different
species, and that age introduces a material factor into the result ; young
animals being much more susceptible to thyroidectomy than adults, as they
are also to parathyroidectoiny.

When positive results are seen in adult animals they take the form of
thickening and dryness of the integument, with a tendency to loss of hair.
Adiposit}" may supervene later, although there is at first usually some
wasting. The muscles lose tone and are weaker than in the normal animal.
Regeneration of tissues is retarded. Anaemia is usually present. The body
temperature is low ; the power of heat regulation by means of the skin is
diminished (Lorraine Smith). The sexual functions are interfered with.
The limit of assimilation of carbohydrates is raised. The nervous system is
markedly affected, dullness and apathy being prominent symptoms. Many
nerve-cells, especially those of the cerebral cortex, exhibit a shrunken
appearance and present a strong contrast with those of the normal animal.
A myxcedematous condition of the integument was described in monkeys
by Horsley, Murray, and Edwards, but others (H. Munk, Kishi, Vincent
and Jolly, Halpenny and Gunn) have not seen this.

Similar symptoms are observed in cases of spontaneous atrophy, or
degeneration of the gland in children (fig. 18, A). There is arrest of growth,
especially of the skeleton, the cartilage bones long remaining incompletely
ossified ; development of the generative organs is much delayed ; the integu-
ment is swollen ; the surface of the skin is dry ; the hair tends to fall out
and becomes thin ; the face is pale and puffy ; the abdomen swollen ; the
nose depressed ; the hands and feet are podgy. The fontanelles of the skull

29

30

The Endocrine Organs

remain open. The muscles are limp and weak. Deaf-mutism is common.

A B

FIG. 18. — Myxcedema of child (A) before and (B) after treatment with thyroid.

(Byrom Bramwell.)

"

The highest functions of the nervous system remain undeveloped, the

child becoming idiotic : this seems to
be due to an arrested development of
cells of the cortex cerebri.

The above combination of symptoms
forms the condition known as cretinism.
This may be either sporadic or endemic.
The former is generally associated with
absence or early atrophy of the thyroid ;
the latter with goitrous degeneration.
Of endemic cretinism, according to
M'Carrison, there are in the Himalayan
valleys two types, the myxredematous
and the nervous : the latter is presum-
ably associated with changes in the
parathyroids ; whilst in the former the
parathyroids are unaltered. This is
the type chiefly met with in Europe
(fig. 19).

The symptoms do not show them-
selves until some little while after
birth, in spite of the absence of a thyroid. The absence appears to be
compensated, for a time at any rate, by autacoids conveyed from the

FIG. 19. — Photograph of a case of endemic
cretinism. (E. Bin-her.) The character-
istic depression of the root of the nose
is well seen.

Effects of Removal or Atrophy of Thyroid

31

mother's thyroid to the child ; before birth through the placenta, after
birth through the milk. When the atrophy is congenital it usually takes
the form of complete lack of development of the thyroid proper — the para-
thyroids are generally present and well developed — the condition of
cretinism and all the above symptoms being well marked.

If in the adult subject either thyroid atrophy occurs or such degenera-
tive changes take place in the gland as materially affect its functions, the
condition known as myxoedema (or myxcedema adultorum to distinguish
it from the corresponding affection of the child) becomes manifested
(fig. 20). This condition, which is much more common in females than in
males, was described by Gull in 1873, and recognised by him to be a

A B

FIG. 20. — Myxcedema of adult (A) before and (B) after treatment with thyroid. (Andersson.)

cretinoid condition of adult life; and subsequently, in 1877, by Ord, who
gave the name to the disease and showed that it is associated with
changes in the thyroid. It is characterised by thickening and swelling of
the integument, which pits on pressure, the pitting disappearing on relax-
ing the pressure ; by the skin becoming dry and the hairs falling out ; by
a low body temperature ; and by mental dullness and general impairment
of sensibility. In cases of myxcedema in the human subject, Brun and Mott
have found general chromatolysis of nerve-cells of subacute character.
Both in spontaneous and in operative myxcedema the metabolic processes
are diminished in activity, so that although less food is taken the body
weight may increase. Regenerative changes also occur more slowly.
There is usually a considerable deposition of fat, especially under the skin.
The activity of the sexual functions is diminished in both sexes. There is
a diminution in the amount of oxygen consumed and in the amount of
nitrogen excreted. There is increased tolerance for sugar, so that a con-

32

The Endocrine Organs

siderably larger amount than usual (as much as 300 grammes) may be
taken without producing glycosuria. Nevertheless, glycosuria occurs
sometimes, but it is not excessive.1

Symptoms similar to those of myxoedema are produced as the result of
surgical removal of the thyroid in man (fig. 21). This was first apparent as
the result of the effects of operation for goitrous tumours (J. L. and A.
Reverdin, Th. Kocher). The Reverdins spoke of the condition as post-
operative myxoedema ; Kocher termed it cachexia strumipriva. It begins
to show itself at a variable period after operation — from a few days to
months or even years — and is moi-e readily produced in young than in

older subj ects. It is sometimes
accompanied by symptoms of
tetany : when present, these
symptoms are presumably re-
ferable to involvement of
parathyroids. According to
Kocher, the patients rarely
survive the complete loss of
the thyroid for more than
seven years. To prevent ulti-
mate -ill-effects at least one-
fourth of the organ must
be left.

The above symptoms,
whether due to congenital
atrophy or to operative re-
moval, can be allayed or en-
tirely removed by successful
implantation of pieces of thy-
roid (Schiff) — an operation which has, however, rarely succeeded in man
— or by administration of thyroid substance or extract either hypoder-
mically (G. Murray) or by the mouth (Mackenzie and Fox). Patients
suffering from the effects of loss of thyroid secretion, whether this take the
form of cretinism, myxcedema, cachexia strumipriva, or endemic goitre,
can be completely restored to health and kept normal for apparently any
length of time by buccal administration of the gland or its extracts
(see figs. 18, 20, 22). If the treatment is intermitted the symptoms almost
at once begin to reappear. The effects are therefore obviously due to
the loss of an autacoid contained in the internal secretion. This autacoid
in some way affects the metabolic processes of the body, either directly or
indirectly promoting the nutrition of the connective tissues and influencing
the functions of the cells of the nervous system, particularly those of the
cerebral cortex.

1 The alterations in metabolism in myxcedema and the effect of thyroid treatment upon
them have been studied in Tigerstedt's laboratory by J. A. Andersson (Hygiea, 1898).

FIG. 21. — A case of post-operative myxoedema (cachexia
strumipriva) in a 26-year-old woman, (v. Brun.)

Effects of Removal or Atrophy of Thyroid

33

Enlargement of the thyroid such as occurs in endemic goitre (fig. 22),
in spite of a great increase in volume of the gland, is commonly attended

A

B

FIG. 22. — A case of endemic goitre (A) before and (B) after treatment
with thyroid, (v. Brun. )

by symptoms of hypothyroidism ; not, as might have been expected, by
those of hyperthyroidism.
But when the enlargement
is the result of malignant
cell-proliferation (carci-
noma or sarcoma), the func-
tions of the organ may still
be carried on. It is indeed
a significant fact in con-
nexion with the genesis of
malignant tumours, that
when in such cases the
whole of the thyroid is
removed by the surgeon,
should there be any meta-
static growths elsewhere,
e.g. in the liver, the usual
symptoms of cachexia
strumipriva do not show
themselves.

The enlargement of the
gland in endemic goitre
generally takes the form
of a diffuse hypertrophy : the follicles enlarge and their epithelium pro-
liferates : new follicles may also become formed. There is nearly always a

3

FIG. 23. — Section of thyroid from a case of endemic goitre.
Magnified 50 diameters. Notice the enormous size of
some of the colloid-filled vesicles.

34 The Endocrine Organs

tendency for colloid to accumulate. This ultimately causes enormous dis-
tension of the vesicles and flattening of their epithelium (fig. 23), which
may eventually undergo almost complete degeneration. A characteristic
degeneration of the arteries of the gland has also been described.

Whilst the above are the usual changes found in endemic goitre, many
exceptions are met with. One would expect the enlarged gland to yield
an excessive amount of secretion to the blood, but this appears not to be the
case, although endemic goitre is occasionally characterised in its early stages
by symptoms suggestive of hypersecretion and resembling some of those
seen in incipient exophthalmic goitre (p. 37). More often these symptoms
of hyperthyroidism are absent : generally from the first and always
eventually, the appearances which show themselves are unquestionably
symptomatic of hypothyroidism. This must mean that even if the
secretion is being produced in abundance it is not of a normal character,
the normal autacoid being either absent or deficient in quality. Perhaps
the enlargement of the gland represents an attempt by nature to compensate
for such deficiency.

CHAPTER V

THE THYROID AND PARATHYROIDS (continued)
EFFECTS OF INCREASE OF THYROID SECRETION : HYPERTHYROIDISM

THE effects of a too great amount of the thyroid autacoids in the circulating
blood can be investigated either by their introduction directly into the
circulation or indirectly by other channels, such as the alimentary canal ;
or by studying the symptoms of affections in which there is reason to
believe that an excess of these autacoids is being secreted by the gland.

EFFECTS OF ADMINISTRATION OF THYROID EXTRACT OR JUICE

The immediate result of intravenous injection (fig. 24) is to produce a
marked but evanescent fall of blood-pressure, which is mainly due to
dilatation of the peripheral vessels. This effect is probably specific,

a
t

FIG. 24. — Effect upon the blood-pressure of injecting thyroid extract intravenously.

ftp., arterial pressure ; a., 'abscissa ; ?., time in one-second intervals. (From the British Medical

Journal, Aug. Id, 1895.)

although somewhat similar results are obtained with extracts of many
other organs (see pp. 9, 10).

The fall of blood-pressure caused by thyroid extract is often preceded
by a slight rise. The fall is just as well marked after administration of
atropine as before : it is therefore not due to vagus action.

35

36 The Endocrine Organs

Asher states that the fall of blood-pressure does not occur in the rabbit. I have,
however, occasionally obtained it in that animal, but usually the fall is absent and
a slight rise alone apparent.

Asher and Flack found that the prior injection of thyroid extract in the rabbit
increases the excitability of the cardiac vagus and of the depressor. I have not
been able to confirm this result either in the rabbit or in the cat or dog, although, in
the last two, if depressor fibres are stimulated at the same time that thyroid extract
is injected into a vein the fall of blood-pressure is greater than with either of these
by itself. This is, however, an effect of summation, as is shown by the circumstance
that in those cases in the rabbit in which a slight rise is produced by thyroid
extract instead of a fall, the combined effect of depressor and thyroid extract is less
than that of the depressor alone.

Given by the mouth in the human subject thyroid extract produces lower-
ing of the bleed-pressure.1 Large doses are followed by tachycardia (rapid
pulse), often with some irregularity ; nervous excitability ; flushing of the
skin, with feeling of heat ; increase of perspiration ; and increase of nitrogen
metabolism. If long continued the fat of the body is diminished and
glycosuria may be caused. Alimentary glycosuria is also more easily
produced than normally. There is considerable wasting, although the
appetite is increased. There are often digestive disturbances. In extreme
cases there may be exophthalmos and other effects referable to cervical
sympathetic excitation, such as dilatation of the pupil and (in animals) re-
traction of the third eyelid ; psychical excitement ; sleeplessness ; tremors
of the limbs ; in short, most of the symptoms of exophthalmic goitre. The
addition to the food of animals of even a small amount of thyroid gland
has the effect of increasing nitrogenous metabolism, as shown by the
increase of nitrogen in the urine. This is accompanied by a corresponding
increase in food consumption. Some of the additional nitrogen thus
ingested is retained in the body, but this is compensated for by increased
fat consumption, so that the difference in growth curve of the thyroid-fed
animals and the controls is but slight. With large doses of thyroid there
soon ensues marked loss of weight, due both to increased nitrogen elimina-
tion and loss of fat. There is also an increased respiratory exchange.

The colloid contents of the thyroid vesicles are augmented by the
ingestion of much thyroid substance.

CLINICAL EVIDENCE

Exophthalmic Goitre. — This affection, first described by Parry (1825)
and connected by him with the thyroid, is also associated with the names
of Graves (1835) and Basedow (1840), both of whom called special attention
to the symptoms. The name exophthalmic goitre expresses its most
prominent signs (fig. 25). The disease is usually accompanied by consider-
able enlargement of the thyroid. According to Moebius and Greenfield

1 In diabetic subjects it is said to cause the opposite result — an effect lasting for several
days.

Clinical Evidence relating to Hyperthyroidism

37

the enlargement is accompanied by hypersecretion which is the direct
cause of the symptoms, this opinion being founded on the facts that, (1) as
has just been mentioned, some of the symptoms of the disease can be
produced by excessive administration of thyroid, and (2) that the symptoms
are for the most part opposite in character to those which are known to
be produced by atrophy or diminution of function of the gland. Thus
there is a rapid and often irregular pulse ; nervous and psychical excitation,
with muscular tremors ; a feeling of warmth in the skin, and throbbing of
cutaneous vessels, often accompanied by profuse sweating ; shallow re-
spiration ; markedly increased metabolism (especially nitrogenous), with
abnormal appetite and loss of body fat ;
a decreased assimilatory power for carbo-
hydrates; an anxious, restless expression;
prominence of the eyeballs ; wide pal-
pebral aperture, often with dilatation
of pupils. The enlargement of the thy-
roid may involve only one lobe. The
enlarged gland pulsates, and gives a
murmur on auscultation.

Exophthalmic goitre is far more
common in the female than in the male
(as 4'6 to 1), a fact which maybe related
to the enlargement of the gland which
usually occurs in the female at puberty
and during pregnancy. It is generally
associated with a persistent thymus,
which has by some authors been credited
with the production of certain of the
symptoms of the disease. About 13'5
per cent, of cases have polyuria without sugar. Only 2 per cent, have"
permanent glycosuria, although alimentary glycosuria is not uncommon.
Albummuria is present in about 11 per cent.

The histological appearances (figs. 26, 27) are conformable with the
theory of a hypersecretion. The gland is greatly enlarged, and the indi-
vidual vesicles are irregular and tend to run together. The interstitial
tissue is increased in amount and assumes a lymphoid appearance, some-
times with characteristic germinal centres. The follicle wall tends to grow
into the interior of the conjoined follicles in the form of projections, thus
increasing the surface for secretion and giving the cavities a still more
irregular aspect. In some parts the follicles are smaller than usual, and
may even disappear. The cells lining the follicles tend to acquire a
columnar form : in later stages they may undergo degeneration and become
set free within the follicles. The contents of the follicles are more fluid
than in the normal thyroid, and in sections show little or no coagulated
colloid.

FIG. 25.- — Case of exophthalmic goitre.
(Byrom Bramwell.)

38 The Endocrine Organs

Direct proof of hypersecretion of the thyroid is thought to be furnished

FIG. 26. — Section of thyroid from a case of exophthalmic goitre. Magnified 75 diameters.

FIG. 27. — Part of the same section, magnified 200 diameters. Notice the irregularity in size
and shape of the vesicles, and the fact that they are mostly empty of coagulated colloid.

by the experiments of Reid Hunt, who found that the blood of a person
afflicted with exophthalmic goitre increases the resistance of mice to the

Clinical Evidence relating to Hyperthyroidism 39

poisonous effects of acetonitrile ; an effect he had previously found to
result from injection of thyroid extract. Some observers have stated that
injection of blood-serum from cases of exophthalmic goitre produces effects
in animals similar to the symptoms of that disease in man. Others, on the
contrary, have obtained different results, and state that, although in dogs
small doses of extract from an exophthalmic goitre may cause increased
rate of heart-beat and some rise of blood-pressure, this is soon followed
by the opposite condition. They therefore hold that the symptoms are
produced not by excess of normal thyroid secretion circulating in the blood,
but as the result of the production of a perverted secretion (dysthyroidism).
This view is not, however, that generally taken, either by physiologists or
clinicians, most of whom are disposed to regard the hypersecretion theory as
more probable. The favourable results which ensue in many cases from
surgical removal of a large portion of the hypertrophied gland or ligature
of some of its vessels point in that direction.

CHAPTER VI
THE THYROID AND PARATHYROIDS (continued)

NATURE OF THE AUTACOID SUBSTANCES PRODUCED BY THE THYROID

THE active principle of the thyroid which is concerned with metabolism
has been usually assumed to be represented by the non-proteid nitrogenous
material known as iodo-thyrin, or by the compound of this with protein
(iodo-thyro-globulin). The former was prepared from thyroid by Baumann
(1895), and found by him to contain a marked amount of iodine (0'3 to
0'9 per mille of dry substance). In confirmation of this assumption, the
experiments of Reid Hunt, Marine, and others show that the production
of the autacoid is promoted by administration of iodides, and that there is
a certain relation between the physiological activity of the gland and its
iodine content. But the fact that even when the desiccated thyroid con-
tains a considerable amount of iodine it is sometimes found to have no
action suggests that Baumann's substance may not be the actual autacoid,
although it may be associated with it. We are, in fact, still in the dark as
to the true nature of this autacoid, and it seems better to express our
ignorance by a term which implies no theory, leaving the question of its
identity with iodo-thyrin or iodo-thyro-globulin open. I propose, therefore,
provisionally to apply the word thyrine to denote the active principle,
whether it be identical with or contained in the iodo-thyrin of Baumann
or not.

As we have already seen, the autacoid of the parathyroid (parathyrine)
is probably of chalonic, i.e. of inhibitory nature, serving to keep in check
the activity of certain tissues, especially of nerve-cells. On the other hand,
the autacoid of the thyroid (thyrine) acts like a hormone in increasing
their excitability. This increase of excitability is especially well marked
in connexion with the sympathetic. The question arises : Is this a direct
effect on the sympathetic system or is it indirect through the adrenals,
which are stimulated to increased secretory activity by excess of thyroid
in the blood ? The answer is not easy. But it may be stated that although
certain symptoms of hyperthyroidism are similar to those produced by
excess of adrenalin in the blood, others are not so. This is the case
with the flushing of the skin, which is due to vascular dilatation ;
whereas adrenalin ordinarily produces vasoconstriction. Further, excess
of adrenalin in the blood leads to glycosuria, which is not as a general
rule seen in exophthalmic goitre, nor is glycosuria a necessary result of

40

Nature of Autacoid Substances produced by Thyroid 41

administration of thyroid. Moreover, it is undoubtedly the case that the
administration of adrenalin exercises a beneficial effect in some cases of
exophthalmic goitre : a fact which would be inexplicable on the theory
that the results of hyperthyroidism are simply due to excitation of the
suprarenals and the production of an excess of adrenalin.

But although many of the effects of thyroid feeding and of hyperthy-
roidism otherwise produced can be explained by the presence of excitatory
or hormonic autacoids, it is not possible to explain the results produced by
thyroid deprivation, or hypothyroidism, upon the body generally, and certain
organs in particular, merely by assuming the absence of these excitatory
substances. For loss of the thyroid is followed by increased growth and
presumably increased activity of certain other organs. This is the case
with the pituitary ; and although it has been suggested that this is an
instance of vicarious increase of size associated with the performance of
similar functions, the similarity of the functions of the two glands is far
from obvious. A more probable explanation is that besides a hormone
which excites some cells, the thyroid secretes an autacoid of chalonic nature
which restrains the activity of others: on removal of the thyroid this
restraint is abolished, and over-activity is the result.

The thyroid autacoids affect the growth of the thymus gland, which
has been found to undergo an increase in size in foetal animals after
thyroid feeding of the pregnant mother (guinea-pigs) ; on the other hand,
the suprarenal capsules (cortex) and the thyroid itself are said to undergo
a diminution in weight under these circumstances. Hoskins, who furnishes
this observation, ascribes the effect upon the growth of the thymus to
stimulation by a hormone furnished by the thyroid; if this is so, the
opposite results on suprarenal and thyroid should be ascribed to an autacoid
of opposite sign. To carry out this line of reasoning to its logical con-
clusion, the diminished growth of the skeleton and of the generative organs
which follow thyroid removal in young animals would be explained by the
absence of a hormone which promotes their development. We must,
however, be on our guard in assuming that every effect obtained is due to
a direct action upon the organ affected (see below).

INTERACTION OF THE THYROID WITH OTHER ORGANS

With the Generative Organs. — The important influence exerted by the
thyroid secretion on nutrition generally is no doubt responsible for the fact
that hardly any organ in the body remains unaffected as a result of its
complete removal or atrophy. But the secreting organs with which it may
be regarded as being more specifically associated are few. Among them
are the generative glands. In the female the thyroid becomes enlarged
at puberty, during the menses, and during pregnancy. In the young
thyroidectomised subject the generative glands are only slowly or im-
perfectly developed, the resulting condition being characteristically one of

42 The Endocrine Organs

sexual infantilism. In the adult animal (dog) Alquier and Theuveny found
diminished activity so far as production of spermatozoa is concerned, but
less distinct evidence of change in the ovary ; although the animals
appeared to come on less completely in heat and to conceive with difficulty.

With the Liver and Pancreas. — Other effects, of a more or less specific
character, are produced upon liver-glycogen. Krause and Cramer find that
in the cat and rat, fed with thyroid, glycogen disappears from the liver ;
but there is no glycosuria, the sugar having been conveyed to the tissues
and oxydised. Parhon has obtained a similar result with the rabbit. The
thyroid therefore produces mobilisation of carbohydrates. Thyroid feeding
also tends, as we have seen, to diminish the limit for the assimilation of
sugar. This may be due either to an increase in the secretion of adrenalin
or to a direct inhibitory effect on the internal secretion of the pancreas.

After thyroidectomy the assimilation limit for sugar is markedly
raised; and according to some observers adrenalin-glycosuria is greatly
diminished or fails to show itself. This statement, however, is contradicted
by Underbill. If the parathyroids are included in the removal, the assimila-
tion limit for sugar is lowered and adrenalin produces a stronger glycosuria
than in the normal animal. The influence of the thyroids and parathyroids
is therefore antagonistic in this as in some other respects. According
to Lorand, if a dog deprived of pancreas and exhibiting glycosuria is
thyroidectomised, the sugar disappears from the urine. Lorand further
states that extirpation of the pancreas has the effect of increasing the
amount of colloid in the thyroid vesicles, and that thyroidectomy causes a
marked increase in the amount of islet tissue in the pancreas. But both
these statements are difficult to accept on account of the differences which
are normally present, both in amount of colloid in the thyroid and in
number of islets in the pancreas. If substantiated, they would show a
direct correlation between the thyroid and the pancreas, the internal
secretion of the thyroid being restrained by that of the pancreas and the
internal secretion of the pancreas by that of the thyroid, so that when
either gland is extirpated, the internal secretion of the other either becomes
more active or increased in amount.

With the Suprarenal Capsules. — There is an indirect way in which the
internal secretion of the pancreas can be influenced by thyroid secretion,
and that is by the effect which this produces upon the action of the
secretion of the suprarenal medulla. This effect appears, as Asher and
Flack have shown, to be in the direction of increase of excitability of those
tissues which are amenable to the action of adrenalin. On the other
hand, when the thyroid is extirpated the activity of the secretion of the
suprarenals is diminished. And the phenomena which are normally pro-
duced by sympathetic stimulation are similarly affected. Further, with
hyperthyrosis, such as occurs in intense thyroid feeding, most of the
symptoms are those of over-excitation of the sympathetic, and are similar
to those caused by adrenalin. There is, moreover, some evidence that the

Interaction of Thyroid with Other Organs 43

amount of adrenalin in the blood is increased in hyperthyroidism. Thus,
Ott and Scott got increase of adrenalin in the blood after intravenous

o

injection of thyroid extract : they obtained, however, a similar result after
injection of other organ extracts. With regard to exophthalmic goitre,
Krause observed dilatation of the pupil of the excised frog's eye when placed
in blood-serum of patients affected by this disease, although blood-serum
of normal individuals does not give this reaction. Krause has further ob-
tained chemical evidence of the presence of excess of adrenalin in blood
after injection into animals of the juice of thyroid gland from cases of
exophthalmic goitre, and its presence has also been demonstrated in such
cases by physiological tests (Fraenkel with the uterus ; Trendelenburg and
Broking with the frog's blood-vessels). It may therefore be assumed that
the secretion of the thyroid in exophthalmic goitre acts as a direct stimulant
to the suprarenal capsules, causing them to yield adrenalin to the blood in
larger quantity ; a result which is also obtained with thyroid feeding.
But the fact that some cases of exophthalmic goitre benefit by the
exhibition of adrenalin is difficult of explanation on this hypothesis, for
this treatment should cause an exacerbation of the symptoms. Moreover,
it must be borne in mind that most of the physiological tests which have
been used for adrenalin would also be given by pituitrine.

Incidentally, it may be mentioned that F. Munk noticed a diminution of lipoids
in the cortex of the suprarenals in animals fed with thyroid gland.

With the Pituitary Body. — As has been pointed out above, a very
striking effect is caused by removal or atrophy of the thyroid upon the
pituitary body: which not only undergoes general enlargement, but also
exhibits well-marked indications of increased secretion. These changes
will be described when the pituitary is dealt with.

What part, if any, concomitant removal of parathyroids may take in
promoting the changes in the pituitary is not certainly known. Accord-
ing to Halpenny and Thompson, some of the alterations which have been
described in the pituitary occur if the parathyroids only are extirpated.
But other observers have failed to find any changes in the pituitary after
parathyroidectomy .

With the Thymus Gland. — Reference has already been made to the
anatomical and developmental relationship between thymus and thyroid,
to the effect of thyroid feeding of a pregnant animal upon the growth
of the thymus of the foetus, and to the supposed effect of the thymus
in assisting to produce the symptoms of exophthalmic goitre : indeed
its removal by operation has been recommended and even practised in
that affection. In view of these circumstances some authorities believe
that there exists a mutual relationship between the two organs, and that
they exercise — by their internal secretions — an excitatory influence upon
one another. In conformity with this it has been stated that increase or
diminution in size of the two organs frequently go hand in hand. But

44 The Endocrine Organs

this can only be early in life, for under normal conditions of growth and
development the thymus is undergoing retrogression whilst the thyroid is
becoming more active in its functions. Moreover, the normal variations in
both organs are so considerable, and at present, in spite of many observa-
tions, so little is accurately known regarding the conditions under which
they occur, that it will be wise to reserve judgment as to their mutual
relations.

INFLUENCE OF THE NERVOUS SYSTEM ON THYROID SECRETION

It was shown by Cyon that vasodilator nerve-fibres pass from the re-
current laryngeal nerves to the thyroid gland. Ossokin showed the gland
to be supplied by both superior and inferior laryngeal, and also by pharyn-
geal branches of the vagus. Vasoconstrictors pass to it by way of the
sympathetic. H. Wiener found extirpation of the inferior cervical ganglion
to be followed by atrophy of the gland and diminution of thyro-globulin
in the thyroid of the same side. Asher believes that the internal secretion
of the thyroid is directly influenced by the nerve-fibres which pass to the
gland by the superior and inferior laryngeal nerves. But he used as a
test of the outpouring of secretion the increase of excitability of certain
nerves (depressor and cardiac vagus), which he states is also produced by
injection of thyroid extract into the blood. This, however, I have not
found to be the case, and therefore, although it is not improbable that
the secretion is under the influence of either the vagus or sympathetic, or
both, further evidence is necessary before we can regard this as a proven
fact. It has been stated that the iodine content of a thyroid lobe is
diminished as the result of excitation of the vagus of the same side, but
this also needs confirmation.

The view which was at one time held that the function of the thyroid
is merely that of a destroyer of toxic substances circulating in the blood is
no longer tenable. The same may be said for an old idea — resuscitated by
Cyon — that the organ serves as a kind of shunt to regulate the flow of blood
in the cranial cavity. This, indeed, has nothing to support it beyond the
extreme vascularity of the gland and its position in close connexion with
the carotids.

CHAPTER VII
THE THYMUS GLAND

THE STRUCTURE AND DEVELOPMENT OF THE THYMUS

RELATIVELY to the rest of the body the thymus is largest at birth, but it
remains well developed during childhood. It is essentially an organ of
early life. After puberty it generally undergoes retrograde changes ; these
consist in diminution in volume of the proper gland substance accompanied

FIG. 28. — Part of lobule of the thymus of a child. Magnified 60 diameters.
c., cortex ; m., medulla ; 6., b., large blood-vessels in connective tissue trabeculee.

by an increase in connective tissue, the whole organ becoming smaller and
often embedded in a mass of fat. Occasionally it remains fully developed ;
such cases are generally associated with an unusual development of lym-
phatic tissue in the body, the condition being termed status lymphaticus.

In its developed condition the thymus consists of two main lobes, one
on each side, the lobes themselves being subdivided into lobules and the
whole strung together in an irregular manner along a strand of connective
tissue which sends offsets into the lobes, subdividing the lobules from one
another and sending partial septa into the individual lobules. The con-

45

46

The Endocrine Organs

nective tissue conveys blood-vessels, lymphatics, and nerves to and from
the organ.

Each lobule is composed of a cortex which is very dark in stained sections

FIG. 29. — Medulla of thymus of child. Magnified 300 diameters. The small
darkly stained cells are lymphocytes. The preparation shows two or three
concentric corpuscles, and blood-vessels.

and a medulla which is lighter (rig. 28). The difference is due to the large
number of lymphoid cells in the cortex, which is densely packed with

them. The medulla is formed of
a cell-reticulum as a basis, in the
meshes of which are a considerable
number of lymphoid cells ; and in
addition the characteristic " concen-
tric corpuscles of Hassal," which
are formed by nests of epithelium
cells surrounding one or more cells
which occupy the centre of the nest
(figs. 29, 30). Some of the concen-
tric corpuscles are compound, having
more than one centre. Occasionally
the medulla is found to contain
small ciliated cavities, and rarely
striated muscle-fibres are seen with-

FIG. 30. — A concentric corpuscle of the thymus
with a part of the adjoining reticulum.
(Hammar. )

c., a ciliated vesicle.

in it.

The thymus is developed in the
embryo from sprouts of the epithelium of the third branchial pouch on
each side (fig. 2). These unite to form a single median column of cells
which becomes hollowed out and tubular, and ultimately branched. Even-
tually lymphoid nodules forming the cortex of the lobules appear in the

Functions of the Thy m us

47

walls of this branching tube (tig. 31), and its epithelium becomes broken

up and modified to form the reticulum and concentric corpuscles of the

medulla. In Petromyzon the thymus retains its

original connexion with the branchial clefts, but

in all other vertebrates this connexion becomes

lost, and in mammals the organ takes up a position

either in the neck or in the anterior mediastinum.

In birds it forms a series of isolated masses

on each side of the neck. Small portions of

thymus tissue are frequently found embedded

in the thyroid, these having developed from the

sprouts of the fourth branchial pouch ; on the

other hand, an accessory thyroid is often met

with in the substance of the thymus.

The thymus is singularly susceptible to the
effects of inanition; even a short period of fasting
produces a considerable diminution in its size.

FUNCTIONS OF THE THYMUS

The functions of the thymus are more obscure
than those of most of the endocrine organs :
indeed there is room for question whether it
should be included amongst these bodies. But

FIG. 31. — Section of developing
thymus. (From Prenant,
Bouin, and Maillard.)

c., cortex; m., medulla. At this
stage the medulla is continuous
throughout the gland.

the mutual relations which appear to be estab-
lished between it and the generative glands in
the male sex perhaps entitle it to occupy a place amongst them.

Injection of extracts of the gland seems to have no specific effect.
The results of feeding with the thymus appear also to be non-specific ;
such as are obtained seem to be dependent upon the large amount of
nuclein it contains. But according to Gudernatsch, tadpoles which are
fed with thymus do not undergo metamorphosis, although they increase
greatly in size: the same observer describes exactly the opposite effect
as the result of thyroid feeding. Noel Paton and Goodall, who removed
the thymus in a number of guinea-pigs, were not able to establish any
relation of the gland to the rate of growth of these animals, which
apparently suffered no deleterious effects from loss of the organ. Other
observers (Basch, Klose and Vogt, Matti), who for the most part employed
kittens and puppies for experiment, have described certain positive results
of thymectomy ; especially softening of the bones with increased excretion
of calcium salts, muscular weakness often with tremors, and diminution
of intelligence. Compensatory increase in amount of the splenic follicles
has been described. The symptoms were not alleviated by grafting or
by feeding with thymus.

Klose and Vogt also obtained an increase in rate of development of both
the testicles and ovaries. As regards the testicles, this result has been

48 The Endocrine Organs

confirmed by Noel Paton, who finds that the converse is also true, viz., that
castration in the guinea-pig is followed by increase in size of the thymus.
In castrated cattle also the thymus is nearly double the size that obtains
in uncastrated beasts (J. Henderson). In all castrated animals the involu-
tion of the gland is retarded.

Noel Paton has also found that removal of both thymus and testicles
has a marked effect in delaying the rate of growth of guinea-pigs, whilst
this result is not obtained by removal of thymus or testicles alone.

In the female no such relationship has been established between the
generative glands and the thymus.

CHAPTER VIII
THE SUPRARENAL CAPSULES

THE suprarenal capsules or adrenals have received special attention, both
from clinicians and physiologists, since Addison (1855) described the
symptoms of the disease which bears his name and which he associated
with degeneration of these organs. Addison's disease is characterised by
great languor and general debility, with weakness and diminution of tone,
not only of the skeletal but of the vascular and visceral musculature,
feeble action of heart, loss of appetite, disturbance of the digestive tract,
severe abdominal pain, and extreme emaciation. Anaemia, which is an
occasional accompaniment of the disease, was regarded by Addison, when
it occurs, as symptomatic ; but it is probably the result not of the destruc-
tion of the capsules, but of the intercurrent affection (generally tuberculosis)
which has produced their destruction. The most striking characteristic of
the disease as described by Addison was undoubtedly the pigmentation
(bronzing) of the skin, which occurs as a diffuse colouration upon the face
and hands and other exposed parts, and is increased in regions where there
is some pigmentation normally present, such as the areolaa of the nipples
and the external genital organs. It is also found on the mucous membrane
of the mouth and on that of the conjunctiva. Sometimes the bronzing
does not occur ; these cases are usually the more acute. The disease is
fatal. Its course may be prolonged, " even to six or ten years. In rare
instances recovery has taken place, and periods of improvement lasting
many months may occur" (Osier). Some cases are markedly benefited
by administration of suprarenal extract per os or hypodermically ; others
not at all.

The cause of the excessive formation of pigment is not understood, but
it has been suggested (by Adami and others) that adrenalin may be derived
from the same source as the melanin of the skin, and that if the formation
of adrenalin is interfered with an excess of melanin is formed and deposited.
Meirowsky states that in portions of skin removed from patients who have
died of Addison's disease an increase of pigment occurs as long as five days
after death if the pieces are kept in a warm, moist chamber, but that this
does not occur in skin from those who have died from other causes.
He suggests that a colourless precursor of the melanin is present in the
skin, and supposes this to become transformed under the influence of light.
Somewhat similar observations have been made by Konigstein, and by
Biedl and Hofstatter, on the skin of dogs deprived of their suprarenal

49 4

50

The Endocrine Organs

apparatus ; but negative results were obtained with rabbits and other
rodents. In epinephrectomised animals pigmentation of the skin is not
seen ; it therefore probably requires a gradual destruction, such as occurs
in chronic disease of the capsules in man, a condition which has not hitherto
been successfully imitated in animals. Some observers have described
obscure pigmentation of the skin and mucous membranes in animals as
the result of removal of the adrenals, or as the effect of removal of one and
injury of the other, but the evidence that the pigmentation was produced
by the operation is inconclusive.

MORPHOLOGY

It is well known that the suprarenals consist of two parts, cortex and

medulla (fig. 32), which,
although anatomically
united in many animals,
are morphologically dis-
tinct and are developed
from different embryonic
formations ; the cortex be-
ing formed from meso-
derm-cells of the genital
ridge, whilst the medulla
is developed from cells
which belong to the same
neuroblast-masses as give
rise to the nerve-cells of
the sympathetic ganglia.
The cells of the medulla
are characterised by the
brown colour which they
strike with chromic acid
and its salts (chromaphil
reaction) (figs. 32, 34)
This reaction is due to the presence of adrenalin (see p. 58).

In fishes these two parts remain separate, but in all higher verte-
brates they are united into one organ, which is generally attached to the
kidney on each side. In birds and reptiles and amphibia the renal and
adrenal tissues interlock. It is only in mammals that the same condition
is found as in man, viz., a central medulla with an enclosing cortex.

Accessory suprarenals are not infrequent. They consist either of
cortical substance alone or of medullary substance alone, or of the two
combined. They occur most commonly between the kidneys and along the
lower part of the abdominal aorta as far as its bifurcation. In the male
rat such an accessory gland is almost constantly seen close to the epidi-
dymis. They are relatively longer and more frequent in the new-born

FIG. 32. — Section of suprarenal, low power.
c., cortex; »«., medulla.

Structure of Suprarenal Capsules 51

animal than in the adult, in which they may be missed altogether. The
possibility of their presence must, however, be borne in mind when con-
sidering the results of the extirpation of the adrenals in animals.

Those accessory glands which have a structure and derivation similar
to the medulla of the suprarenal capsules also contain cells which are
coloured brown by chromic acid. Such bodies have been termed para-
ganglia by Kohn, chromaphil bodies by Vincent, chromajj/ine bodies by
most other authors.

The carotid gland is of this nature. The coccygeal gland is different.
It contains no chromaphil cells and appears to represent an arteriovenous
anastomosis which is met with in certain lower mammals. Paraganglia in-
variably occur in close morphological and developmental connexion with
sympathetic nerves and ganglia (Stilling).

Chromaphil cells have been found in almost all vertebrates, even in
Petromyzon. They have also been described in the epithelium cells of the
mantle of a gasteropod (Purpura lapillus} by Roaf. In Annelids they
occur, according to Sommet and Pol, in some of the nerve-cells of the
segmental ganglia. This is well seen in the leech, the blood-vessels of
which react to adrenalin like those of vertebrates. The development of
chromaphil cells is, according to J. F. Gaskell, correlated with that of a
muscular vascular system.

Abel has made the interesting observation that certain patches of skin
glands in a large American toad (Bufo aqua) furnish a white, pasty
secretion containing a large proportion of adrenalin.

STRUCTURE OF THE CORTEX

The cortex of the suprarenal is composed of polygonal epithelium-like
cells arranged mainly in columns (zona fasciculata}, but near the medulla
as a network of trabeculfe (zona reticularis). Towards the surface the
cell-columns end in rounded and sometimes hollowed-out terminations
forming the so-called zona glomerulosa, the cells of which, in some animals,
tend to have a columnar form. Those of the zona fasciculata are usually
larger than in the other parts. Characteristic of the cortical cells is the
presence of lipoid granules, which may impart a yellowish colour to this
portion of the capsule. The zona reticularis also contains pigment granules
which in some animals give it a distinct .brownish colour. The human
foetus has unusually large suprarenal capsules. It has been shown that
this is almost entirely due to a great development of an innermost part of
the cortex lying at the boundary with the medulla (boundary zone of
Elliott and Armour (fig. 33)); this is not to be confounded with the
intermediate zone of Virchow, a very thin layer, pigmented in old age,
lying at the j unction of the cortex and medulla.

The cells of the boundary zone differ from those of the rest of the cortex
in having no lipoid granules. After birth they undergo a fatty change

52

The Endocrine Organs

and the layer gradually disappears, so that it is no longer distinguishable
after the first year. At birth what will be the cortex of the adult gland
consists only of a thin peripheral layer of cells containing lipoids ; these
cells multiply, and the layer enlarges pari passu with the disappearance of

':','..-

FIG. 33. — Section of suprarenal of child twelve days old, low power. (Elliott and Armour.)

A, outer part of cortex ; B, large cells forming boundary zone of cortex ; C, thin layer of
medulla : just below is the central vein.

the boundary zone. A remarkable fact pointed out by Elliott and Armour
is that in the anencephalous foetus the boundary zone is absent and the
suprarenal resembles that of other foatal mammals.

FUNCTIONS OF THE CORTEX

Little is known regarding the functions of the cortex. Its anatomical
relation in mammals to the chromaphil part and the fact that its blood
passes directly into the medulla suggests that its cells may be concerned
in the production of materials which are utilised by the medulla ; but, as
has been above mentioned, this relation fails in many vertebrates. It has
been stated by Abelous and others that the cortex contains a precursor of
the adrenalin of the medulla, and that if left standing for twenty-four

Functions of the Suprarenal Cortex 53

hours in an incubator a considerable amount of a substance giving the
reactions of adrenalin accumulates within it. But according to the in-

n

vestigations of Bayer the results obtained are not ascribable to adrenalin,
but to products of protein decomposition. The facts that the cortex be-
comes enlarged during pregnancy and is small in cases of deficient sexual
development, and that changes have been described (in the guinea-pig by
Kolmer) in the cortical cells accompanying the phases of the cestrous cycle,
seem to afford evidence of some relationship between the functions of the
cortex and the generative glands ; but whether this is direct, or operates
through other ductless glands — such as the thyroid and pituitary — is not
known. The occurrence of a connexion between the development of the
sexual organs and that of the suprarenal cortex has been especially insisted
upon by Glynn, who is of opinion that the cortex is concerned with the
differentiation and growth of the sexual cells.

It has also been suggested that a function of the cortex may be to
neutralise deleterious products which are formed in the processes of
metabolism or which are introduced from outside. But this supposition
has received no support as the result of experiments.

One of the most striking facts connected with the cells of the cortex is
their richness in lipoids and fats. These have been chemically investigated
by many workers. In an analysis by Biedl the suprarenals of the pig
yielded 74'61 per cent, of water and 25'39 per cent, of dry residue. Of the
latter, 61 '12 per cent, consisted of proteins, etc., and 38'88 per cent, of
lipoids — besides some insufficiently distinguishable extractives. In this
analysis the medulla was included ; as this is poor in lipoids the lipoid con-
tents of the cortex must have a much higher value — far higher than any
other non-nervous tissue.

Besides globules of what appear to be fat, a doubly refracting substance
is found in the cortical cells of most animals — varying in amount and in its
position in the cortex in different species. In some it takes the form of
doubly refracting crystals. Elliott and Tuckett regard both the fatty
and the doubly refracting substance as products of secretion of the cells.
They find that the doubly refracting substance increases in amount during
rest and diminishes as the result of muscular activity. In the guinea-pig
there are numerous brown-coloured granules in the cells — chiefly in the
zona reticularis — and Elliott and Tuckett state that these also accumulate
during rest and quickly disappear with muscular work, fatty globules
taking their place. The doubly refracting lipoid substances seem to con-
sist mainly of lecithin and cholesterol — the latter in the form of esters.
Rosenheim and Tebb extracted from the suprarenal cortex of the ox various
fatty acids, cholesterol esters, and phosphatides, such as sphingomyelin ;
but not free cholesterol.

The suggestion that the suprarenal cortex may be a seat of manufacture
of the lipoids of the body and may especially be related to the formation
and development of the myelin of the medullated nerve-fibres is attractive.

54

The Endocrine Organs

And the fact that in the human foetus and infant so large a development
of suprarenal cortex occurs — which is missed in the anencephalous monster
— seems to indicate a connexion between the development of the substances
formed in the cortex and those constituting the cerebral hemispheres. But
against this idea we have the observation of Elliott and Armour that the
superadded part of the suprarenal cortex in the fostus does not contain the
doubly refracting lipoid substances which are characteristic of the ordinary
cortical cells. Nor does the doubly refracting lipoid matter occur in all
animals : in many species it is absent. This is the case with all adult
ruminants examined, although it occurs in some in the young state.
In both man and animals where normally present it tends to disappear in
various diseases ; whilst during pregnancy lipoids are said to increase in
amount, not only in the suprarenals but in all the organs of the body.

The cortex increases in proportion to the growth of the body more than

the medulla. It becomes
augmented in size with the
activity of the sexual glands
in animals; nevertheless,
castration is followed by
its hypertrophy. There is
no evidence that any kind
of active autacoid substance
is produced by the cortical
cells, and it is probable that
their function is associated
with the building up of
metabolic products which
are to find employment in
other parts of the organism.

STRUCTURE OF THE
MEDULLA

The medulla is composed
of cells which have a different
form and structural appear-
ance from those of the cor-
tex. They are arranged in
what appear in section like
irregular anastomosing columns with large blood-spaces between. But in
point of fact the medulla is better described as a solid cell-mass permeated
by sinus-like blood-vessels (fig. 34) with the cells compactly arranged
between and around them. The cells of the medulla are irregularly
polygonal in form, but where they abut on the sinuses they often assume
a more columnar aspect. There can be little doubt that the materials they
secrete find their way directly into the blood within the blood-spaces.

FIG. 34. — Section of suprarenal at thin part of medulla.
Magnified 150 diameters. In this section as well as
in that shown in fig. 32 the cells of the medulla
are stained brown with bichromate of potassium.
They contrast strongly with the cells of the zona
reticularis of the cortex. The blood-sinuses of the
medulla are seen to be continuous with those of the
zona reticularis.

Vessels and Nerves of the Suprarenals 55

The cell-protoplasm contains granules which vary in size and amount in
different cells (Carlier). Some of these granules are stained brown with
chromic acid and its salts (adrenalin or chromaphil reaction), and this gives
a yellowish-brown colour to the medulla when the suprarenals are fixed in
any solution containing these salts. Occasionally the colouration is more
diffuse. A similar reaction is sometimes given by the blood and lymph in
the vessels of the medulla in sections of the organ.

Besides the chromaphil granules above mentioned, others are found,
somewhat coarser, soluble in water and alcohol but not in ether, and stain-
ing with difficulty. Lipoid and pigment granules may also occur. The
relationship of these various granules to one another is not known.

VESSELS AND NERVES OF THE SUPRAREXALS

The blood-vessels are very numerous. The arteries enter at the surface
and give off branches to supply the cortex with a rich capillary network.
The blood-vessels do not penetrate the cell-columns of the zona glomerulosa
and zona fasciculata of the cortex, but run in the connective tissue septa
between them'. In the zona reticularis the vessels become large, take on a
sinus-like character, and come into close relationship to the cells. They
pass into the sinuses of the medulla. According to Neumann, the blood-
supply of the suprarenal is more abundant than that of any other organ in
the body, viz., as much as 6 to 7 c.c. per gramme and per minute (with a
blood-pressure of 130 mm. Hg). This is even higher than that of the thyroid,
which comes next with 5 c.c. per gramme and per minute. The respiratory
exchange is also very high (Baumann).

In birds and reptiles the suprarenals have a venous blood-supply as well
as an arterial — blood being conveyed to each gland by a "portal" vein
which is usually formed by the junction of two or three intercostal veins.

The connective-tissue septa of the cortex contain lymphatics, which
pass directly into lymph-vessels of the medulla.

The suprarenals are very richly supplied with nerves. Each receives no
less than thirty-three nervous filaments (Kolliker), derived in part directly
from the splanchnic, in part from the suprarenal plexus, which is itself
constituted by branches from the cceliac, phrenic, and renal plexuses.
After forming a network in the connective-tissue investment of the organ,
the nerves penetrate into the cortex, partly supplying its blood-vessels,
partly its cell-columns. But most of the nerves extend to the medulla,
where they form a dense plexus from which filaments pass to end between
the secretory cells. Groups of sympathetic nerve-cells are occasionally
found both in the medulla and in the deeper parts of the cortex.

CHAPTEE IX
THE SUPRARENAL CAPSULES (continued)

EFFECTS OF SUPRARENAL REMOVAL: EPINEPHRECTOMY

ADDISON'S account of the disease he described and which he termed
idiopathic anaemia led Brown- Sequard to test the effect of the removal
of the suprarenal glands in animals. The operation, which was performed
upon a number of animals of different species (rabbits, guinea-pigs, dogs,
and cats), was followed in every case of double extirpation by a fatal
termination within thirty-seven hours of the removal. But a fatal result
was produced also in all or nearly all the animals in which the lesion was
unilateral, although subsequently Brown-Sequard succeeded in keeping
some animals alive for a few days when only one capsule was removed.
Since it is now well established that careful removal of one capsule under
aseptic precautions is not fatal,1 there can be little doubt that Brown-
Sequard's results were in considerable measure the consequence of shock
and sepsis, and that they could not be relied on as a proof that the
suprarenal capsules are essential to life. This is indeed the opinion which
was formed by most of his contemporaries. Nevertheless, looked at in
the light of our present knowledge, it is certain that death must have
been either caused or greatly accelerated by the removal of both capsules —
since this is now known to be in most animals the invariable result of the
double operation and to occur within a few days. There are, however,
exceptions, especially in some species of animals: among which the
white rat may be particularly mentioned. These exceptions are probably
associated with the occurrence of accessory bodies, but whether these must
be of cortical or medullary nature — or both — is not determined.

No effect of the extirpation — especially if the operation is performed
on the two glands at an interval of a few days — is at first apparent. For
some days there is little sign of anything wrong. Presently the animal
becomes less lively and exhibits signs of muscular weakness. The body
temperature also becomes lowered, but the blood-pressure is fairly main-
tained. Ultimately the weakness becomes extreme, the pulse feeble, the
blood-pressure low, and the respiration dyspnoeic. Death soon follows,
sometimes immediately preceded by convulsions.

1 An exception must be made for the guinea-pig, in which unilateral extirpation is
frequently followed by death. It may be remarked that the suprarenals of the guinea-pig
are larger in proportion to its size than are those of any other animal.

56

Effects of Suprarenal Removal : Epinephrectomy 57

Experiments on adrenal transplantation have for the most part led to
negative results. The graft almost invariably undergoes rapid necrosis and
disappears, although Haberer and Stoerk obtained some success by im-
plantation into the dog's kidney. Administration of suprarenal extract
is unable, either in Addison's disease or in the cachexia produced by
extirpation, to prevent the usual fatal termination, although this may be
somewhat deferred. The muscular weakness characteristic of Addison's
disease may for a time tend to disappear with the administration, so that
the ergographic record may again approach the normal. But such ad-
ministration cannot, as in the case of cachexia thyreopriva, take the place of
the internal secretion of the gland, and until measures are found to induce
grafts to take in man, Addison's disease will probably continue to termi-
nate fatally. With the progress of surgery the possibility of successful
implantation seems less hopeless than was the case only a few years ago.

After extirpation of one gland only there is a compensating hyper-
trophy of the other, and also of the accessory bodies. Castrated animals
were found by Hultgren and Andersson to live much longer after the com-
plete operation than normal individuals. This is also stated to be the case
if the complete operation is performed in two stages, first the capsule of the
one side and then that of the other being removed. The result is perhaps
due to the fact that time is thus given for a process of hypertrophy of
accessory bodies. With regard to the total amount of suprarenal substance
that must remain in order to maintain life, Biedl found in cats, dogs, and
rabbits, that if one-eighth of the whole suprarenal substance is left the
animals always survive. He further found that if the interrenal body
alone is removed in the skate the animal dies in two or three weeks,
becoming progressively weaker and refusing food. In one skate in which a
small portion was left, these symptoms were absent. He concludes, after
a survey of all the experimental evidence on the subject, that it is
abundantly proved that the suprarenals are not only important but are
essential to life, and that it is probable that this is due to some material
yielded by the cortex — although the loss of the adrenalin which is supplied
by the medulla may be contributory.

It appears that in other diseases than Addison's the functions of the
suprarenal capsules to a great extent become suppressed. In diphtheria
and after injection of diphtheria-toxin in animals, it has been found that
the amount of adrenalin yielded by the medulla of the suprarenals is much
diminished, and may even in extreme cases disappear altogether. In
cholera also the amount is greatly diminished ; it is stated that in this
disease subcutaneous administration of adrenalin is markedly beneficial.
If this diminution in the amount of adrenalin formed should prove to
hold good in other acute infectious disorders, it would seem probable that
interference with the functions of the suprarenal capsules is in large
measure responsible for the cardiac weakness and general loss of tone
which are prominent symptoms in such affections.

58 The Endocrine Organs

THE NATURE OF THE AUTACOID FURNISHED BY THE MEDULLA

All the physiological effects which are about to be described as yielded
by suprarenal extracts are obtainable from extract of medulla alone :
intravenous injection of extract of cortex gives no appreciable result. In
Teleostei, where the cortex is represented by the corpuscles of Stannius,
and in the Elasmobranchs, in which the cortex is represented by the inter-
renal body and the medulla by the entirely separate " paired bodies " of
Balfour, it has been shown by Vincent that the latter yield an active
extract, whilst extracts of the interrenal body are inactive. It was proved
by Moore that the action of the extract of medulla is due to the material
within the cells which becomes stained with chromic salts, and which, as
Vulpian showed, is readily oxidised by various reagents, giving character-
istic colour reactions with ferric chloride, chlorine water, and caustic
alkalies. A similar reaction was obtained by Vulpian with a material
contained in the blood of the suprarenal vein. With phospho-tungstic
acid a blue colour is yielded even in extreme dilution.

This chromaphil substance of the suprarenal medulla, after being partly
isolated by Fraenkel, was prepared in a condition approaching purity by
v. Fiirth, and by Abel, and eventually in a crystalline form by Takamine
and by Aldrich. It has received various names, such as suprarenin
(v. Fiirth), epinephrin (Abel), adrenalin (Takamine), the last being that
by which it is most widely known.1 It has been estimated by Batelli that
the suprarenal capsules contain about 1 part of adrenalin per 1000 of the
whole gland, but as it only occurs in the medulla, which forms less than a
fourth of the gland, the proportion in this would be considerably greater.

Adrenalin can be prepared synthetically, methyl-acetyl-pyrocatechin
being first obtained. This when reduced gives a racemic salt which can
be split into cZ-adrenalin and ^-adrenalin. The latter appears to be in all
respects identical with the natural product, while the racemic salt and
c?-adrenalin are much less active physiologically.

Chemically adrenalin is ortho-dioxyphenyl-ethanol-methylamine :

CH3 . NH . CH0 . CH . OH

OH

and is related to tyrosine (oxyphenyl-amino-propionic acid).

EFFECTS OF INTRAVENOUS INJECTION OF SUPRARENAL EXTRACTS

If an extract or decoction of the medulla — made with water or Ringer's
solution — is injected into a vein, an immediate and marked rise of blood-
pressure is produced. This is caused by contraction of the peripheral

1 This name has been adopted in the British Pharmacopoeia and will therefore be
employed in this work.

Effects of Intravenous Injection of Suprarenal Extracts 59
arteries. Along with the vascular contraction a slowing of the heart's

O C7

action (or even complete stoppage of auricular beats) may occur, due to an
effect on the cardio-inhibitory centre, and this may somewhat limit the rise
of blood-pressure (fig. 35). But if the vagi are cut or paralysed by atropine,
the heart-beats become enormously accelerated and also augmented in force
(primarily by the action of the autacoid on the auricles, but also somewhat
on the ventricles),1 and this greatly increases the rise of blood-pressure
(fig. 36). There is some diminution in the depth of the respirations, and

FIG. 35. — Effect upon heart and blood -pressure of injecting suprarenal extract into a vein, with
vagi intact (dog). (This figure, as well as figs. 36 and 38, are from Oliver and Schafer,
Journ. Physiol., 1895, vol. xviii.)

A, ventricle ; B, auricle ; C, arterial pressure ; D, signal ; E, time-marking in seconds. The tracings in this and
the next three figures have been reduced to rather less than half the size of the originals.

occasionally a temporary cessation of breathing, especially in the rabbit.2
But this disappears long before the effect on the blood-vessels has ceased
to show itself. The effect upon the vessels lasts a few minutes, gradually
passing off; after its passage the blood -pressure is usually a little lower than
before. The arteries which are most affected are those of the splanchnic
area (fig. 37) : those of the limbs and trunk rather less, although the
cutaneous vessels are usually strongly contracted : those of the pulmonary
system and of the brain only very slightly if at all, while those of the
coronary circulation are unaffected : indeed, in some animals these last are

1 In birds, as Noel Paton has shown, the augmentation is confined to the auricles.

2 Garrelon and Langloi* find that in the dog either diminution or increase of respirations
may occur, these effects depending upon the condition of the respiratory centre at the time.

60

The Endocrine Organs

dilated by the extract. (According to Barbour, the human coronary arteries
are constricted, whilst those of the calf, sheep, pig, and other mammals are
dilated (inhibited).) It is always the smaller vessels which are most
affected, and in consequence of the great rise of pressure which their con-
traction produces the larger arteries tend to become passively dilated : this
dilatation may be very great. The effect upon the vessels is seen after com-
plete destruction of the central nervous system, and after severance of the
nerves to the part (fig. 38) : still more after the nerves to the vessels have
been severed for a long time. It is therefore due to a direct action of the

FIG. 36. — The same as fig. 35, but with vagi cut.

autacoid principle of the gland upon the contractile tissue. Nevertheless,
in the case of suprarenal extract such action only occurs in tissues which
are supplied with nerves from the sympathetic system, and in the embryo
in these tissues only after they have received their nerve-supply (M'Fie).
And, as has just been stated, severance of the nerves, so far from stopping
the action, tends on the contrary to make the tissues supplied by the
severed nerve more easily excited by the autacoid. This has been found to
apply not only to the blood-vessels, but also to the pupil (Meltzer and Auer)
and to the retractor penis (Fletcher), and is probably of general application.
Gunn and Chavasse have further shown that adrenalin acts upon the
muscular coat of veins, causing tonic contraction of the peripheral veins and
increased rhythmic contraction of the superior vena cava near the heart.

If the vagi are paralysed by atropine, as small a dose of adrenalin as -0003 milli-
gramme per kilo body-weight injected into a rabbit's vein will cause a distinct rise of

Effects of Intravenous Injection of Suprarenal Extracts 61

FIG. 37. — Effect upon blood-pressure, kidney volume, and flow of urine of injecting suprarenal

extract into the vein of a dog. (From Schafer and Herring, Phil. Trans., 1906.)
A, blood.pressure tracing ; B kidney volume change (oncograph) : the full extent of the shrinkage is not recorded •
'3 gnetO'electdc si«nal ' D- tin'e in ''"-second larval. ; E, abscissa of b.oodi

A>

FIG. 38. — Effect upon blood-pressure and limb volume of injecting suprarenal extract into

a vein (dog).

rhn^nf grite"rSV *? "f*6"!?-1 p™88nre : B> volume <'han^s of left fors limb, nerves intact ; D, volume
changes of right fore limb, brachial plexus cut ; E, signal ; the line records abscissa of blood-pressure.

62 The Endocrine Organs

arterial pressure (J. D. Cameron). Moore and Purinton found that with very minute
doses a fall of pressure may be obtained instead of a rise. If the amount injected is
considerable, the rise of blood-pressure caused by vascular contraction and heart
acceleration may be enormous — three or four times the normal — and the amount of
strain put on the heart is correspondingly great. Sometimes the heart muscle is
\inable to respond properly xinder these circumstances and the ventricular action
becomes fibrillar — delirium cordis being produced, generally leading to instant
death. This seems especially liable to occur in a particular phase of early chloro-
form anaesthesia (Levy).

As a general rule a number of successive injections can be made into a vein, and
each one will produce an amount of rise of blood-pressure proportionate to the
amount of autacoid in the extract : the activity can in fact be gauged by this
method. Other modes of testing the activity of suprarenal extracts are (1) by

FIG. 39. — Etl'ect of solution of adrenalin upon an isolated portion of uterus of rat.

The contractions are inhibited.

their action when added to Ringer's solution perfused through the blood-vessels of
a frog the central nervous system of which has been destroyed, (2) by the effect
produced upon the pupil of the excised eye of a frog when immersed in Ringer's
solution to which a definite amount of the extract is added, (3) by immersion of the
excised uterus of a rat in a similar solution kept aerated by a stream of oxygen and
maintained at body temperature, (4) the same, using a piece of intestine instead
of uterus, and (5) the same, using strips of artery cut transversely.

The effect of suprarenal extract upon the heart and vessels is not the
only action upon plain muscle, although it is the most obvious. Other-
involuntary muscular tissue supplied by sympathetic fibres is also affected.
This may be in the direction of increased contraction (sphincters of pylorus
and of ileocsecal valve, spleen, vagina, uterus,1 vas deferens, retractor penis),

1 Cushny finds that the uterus of a pregnant cat is contracted by adrenalin, whilst the
non-pregnant uterus is usually inhibited. In the rat inhibition is the usual effect (fig. 39),
but in the rabbit (fig. 40) and most animals contraction is produced.

Effects of Intravenous Injection of Suprarenal Extracts 63

or of inhibition (intestine (fig. 41), stomach, oesophagus, gall-bladder, urinary
bladder). Certain of the plain muscles of the orbit and globe of the eye
are excited when suprarenal extract is injected intravenously, so that the

FIG. 40. — Effect of solution of adrenalin on cornu uteri of rabbit, the contraction of which is
>*• . ^increased. I am indebted to Dr M. Itagaki for the tracings shown in figs. 39 and 40.

FIG. 41. — Effect of immersing a strip of the longitudinal coat of the ileum of a cat in
one-in-a-million solution of adrenalin. (A. W. Young.)

eye tends to protrude and the palpebral fissure becomes large, the third
eyelid is retracted and the pupil widely dilated (Lewandowsky).1

1 Dropping a solution of adrenalin into the conjunctival sac does not produce dilatation
of the pupil unless the superior cervical ganglion of the sympathetic has been previously
removed on that side. The removal causes the dilatator pupilla? to be more sensitive to the
action of the atitacoid (see p. 60). It is stated by Lb'wi that in diabetes produced by extir-
pation of the pancreas, the pupil will react to the instilled solution of adrenalin without
such removal of the ganglion.

64 The Endocrine Organs

A llow of saliva similar to that caused by excitation of the cervical
sympathetic is also produced, and is accompanied by contraction of the
vessels of the glands : the flow of saliva is little apparent in the dog, but
it is well marked in the cat, in which animal, as is well known, excitation
of the sympathetic in the neck provokes an abundant flow from the salivary
glands. The lacrimal glands are caused to secrete as well as the mucous
glands of the mouth, throat, and windpipe. These effects are accompanied
by pallor due to vasoconstriction, followed shortly afterwards by flushing.
There is increase of flow of gastric juice and bile, but not of pancreatic
juice. The sweat glands are said to be stimulated in the guinea-pig, but not
in the cat. The skin glands of the dog are caused to secrete. The
mammary secretion is unaffected. The flow of urine is increased by sub-
cutaneous but diminished by intravenous injection. The blood-flow is
increased in the suprarenals themselves.

The autacoid has further been found to defer the onset of fatigue of
muscle and to assist its recovery. The arrectores pilorum, especially those
of certain parts, contract. Adrenalin also causes contraction of the pig-
ment cells both of the skin and retina of the frog. It is noteworthy that
sympathetic stimulation also produces this effect ; at least this is so for the
pigment cells of the skin. In birds some of the effects are different from
those obtained in mammals. Noel Paton and Watson found that in the
duck the effect of adrenalin is to cause decrease in the strength of the
ventricular beats, which may more than compensate for the arterial contrac-
tion simultaneously produced, so that a fall of blood-pressure may result.
There is also contraction of the intestine instead of inhibition.

Although the rule is perhaps not entirely without exception, it may be
stated as a general principle that the result of suprarenal injection is
identical with that of stimulating the endings of the sympathetic nerves
throughout the body (Langley).

As has already been pointed out, the above results are obtained even
if the sympathetic nerves have been divided and allowed to undergo de-
creneration. It has, therefore, been concluded that under the influence of
these nerves the tissues produce, either at the junction of nerve and muscle
{" myo-neural junction " of Elliott) or throughout the cell-protoplasm, a
material ("receptive or excitable substance" of Langley) wThich reacts
with adrenalin, and not only with it but also with drugs, such as those
alkaloids which have a pronounced physiological action. And, further,
that this receptive substance increases either in amount or sensitivity after
the action of the nerves is withdrawn by their severance.

Abolition of the effect of adrenalin in producing contraction of plain
muscle (and the same applies to the effects of sympathetic excitation) can,
as Dale has shown, be obtained by administering ergotoxine — an amine
base obtained from ergot, and also obtainable from the products of breaking
down of histidine. Ergotoxine does not, however, paralyse the inhibition-
producing effect of adrenalin (nor the inhibition caused by sympathetic

Effects of Intravenous Injection of Suprarenal Extracts 65

excitation). Therefore, if, as sometimes happens, both contraction and
inhibition can normally be brought about through the sympathetic and
also by adrenalin, when the contraction effect is abolished by ergotoxine,
the inhibition effect alone appears, and this may produce a reversal of the
normal action. Thus after a sufficient dose of ergotoxine, adrenalin pro-
duces vasodilatation in place of vasoconstriction, and inhibition of uterine
contractions instead of increased contraction. In the ferret the urinary
bladder is contracted by suprarenal extract if ergotoxine is previously
administered (Elliott), although it is usually inhibited. This corresponds
with the effect of administering the same drug prior to stimulating the
sympathetic nerves passing to that viscus. Ergotoxine doubtless acts, like
adrenalin, on the juiictional or receptive substance. Dixon obtained like
results with apocodeine.

The action of adrenalin upon the terminal apparatus of the sympathetic
system is common to a number of primary and secondary amines: the
action has been termed sympatho-mimetic by Barger and Dale. The
more nearly the structure of the amine approaches that of adrenalin the
more marked is this action. A knowledge of these facts has led to the
production of various synthetic drugs having similar properties. The
chemical history of adrenalin furnishes, indeed, a striking illustration of
the drug-like character of autacoids.

Repeated intravenous injections into the ear- vein given at intervals of
a few days produce (in the rabbit) degenerative sclerosis of arteries (Josue).
This action is not specific to the suprarenal autacoid, but is the result of
prolonged abnormally high blood-pressure, however produced.

Applied directly to the smaller blood-vessels, the suprarenal autacoid
produces marked contraction of the muscular coat, and it is therefore of
value in surgery as a styptic for arresting haemorrhage from small arteries.

It was found by Oliver and myself (and confirmed by other workers) that
the contractions of skeletal muscle are prolonged under the influence of suprarenal
extract. The effect we obtained must, however, have been due to something in
the extract used other than adrenalin, for I have since failed to get any effect
with small doses of that substance. In larger doses adrenalin has a paralysing
action on muscle somewhat similar to that produced by excess of potassium salts
(Takayasu). Nevertheless, administration of suprarenal by the mouth has been
shown to be favourable to muscular action, fatigue being less easily produced : this
was found by Langlois to be the case in Addison's disease (fig. 42). Lucien and
Parisot find postponement of fatigue in frog muscle to be an effect of the autacoid.

Effects of Subcutaneous and Buccal Administration. — Subcutaneous in-
jection of the extract does not produce the rapid effect on involuntary muscle
which is so characteristic of intravenous injection — although, as Meltzer and
Auer have shown, intramuscular injection may show this result. But large
doses of the extract, or of the separated autacoid substance of the medulla,
produce in rabbits and some other animals serious or even fatal symptoms.

5

66

The Endocrine Organs

After a preliminary period of excitement, with rapid pulse and respira-
tions, a period of depression supervenes. Accompanying this depression
the muscular movements are first slowed; there is then paralysis of the
limbs and later of the respiratory muscles, with asphyxial convulsions.
The body temperature becomes lowered some little while before death.
The paralysis is central. Post-mortem a general hypersemia of the viscera
is evident, and abundant hfemorrhag-es are seen to have occurred in various

O

parts. If a first dose is not fatal, a certain amount of immunity may be
produced to a subsequent dose (Vincent).

Subcutaneous injection of adrenalin was found by Blum (1901) in-
variably to produce hyperglycaemia and glycosuria. This occurs even if the
animal had been fed on a diet free from carbohydrates (Noel Paton) ; it is
then accompanied by increased excretion of nitrogen. This observation

A B

FIG. 42. — A, ergograph tracing from a person suffering from Addison's disease. B, tracing
from the same person after six weeks' administration of suprarenal. (Langlois. )

A, natural size ; B, reduced to one-half.

seems to indicate that under these circumstances the sugar is formed
from protein, but according to the observations of Herter and Richards
glycosuria does not occur if the liver glycogen has been got rid of by
the combined effects of fasting and phloridzin injection. Pollak states,
however, that in rabbits the liver of which has been rendered glycogen-
free by fasting and administration of strychnine, adrenalin may, in
addition to producing glycosuria, cause glycogen to be again stored in
that organ.

The effect of adrenalin in producing glycosuria appears due in part to
an action on the liver nerve-endings, in part to an effect on the pancreas ;
for Herter and Wakeman found that the direct application of the autacoid
to the pancreas will cause glycosuria. This will be again referred to in
considering the influence of the suprarenal on other organs, and also in
connexion with the internal secretion of the pancreas.

Several observers have found the administration of adrenalin to cause
increase of metabolism both of fats and proteins.

Effects of Intravenous Injection of Suprarenal Extracts 67

Considerable amounts of the extract can be taken into the stomach
without producing any immediate physiological result such as is caused by
intravenous injection. This is probably due to the fact that the active
material, although not destroyed by gastric juice, is absorbed but slowly
and becomes destroyed in the tissues as fast as it is absorbed. That
such destruction is readily produced is obvious from the fact that even
when large doses are injected into a vein the effects pass off within a few
minutes. Where the destruction is effected is not known, although it
has been conjectured that it may be in the tissues generally, especially
the muscles and liver. It was found by Oliver and myself that adrenalin
is not destroyed by prolonged contact with blood, nor is it eliminated
by the urine. Meltzer finds that it is destroyed by cerebro-spinal fluid.
Since it has been shown (W. Cramer) that the autacoid is rapidly inacti-
vated in vitro by dilute formaldehyde, it may well be that the inactivation
in vivo is brought about by this substance, which is believed to be one of
the intermediate products of protein-metabolism.

CHAPTER X
THE SUPRARENAL CAPSULES (continued)

EVIDENCES OF THE PASSAGE OF ADRENALIN INTO THE BLOOD

THAT the passage of adrenalin into the blood is always proceeding in
sufficient amount appreciably to raise the tone of the blood-vessels seems
somewhat doubtful. It was found by Oliver and myself that even in the
blood of the suprarenal vein there is not always enough of the autacoid
to cause a rise of blood-pressure when a few cubic centimetres are injected
into a vein. But it is possible by employing more delicate physiological
tests — e.g. the dilatation of the pupil which occurs in the enucleated eye of
the frog, or by passing extracts of dried and deproteinised mammalian
blood through the vessels of the frog — to obtain evidence in some animals
of its presence not only in the blood of the suprarenal vein, but to a less
degree in the blood generally. The amount is, however, normally very
small, even in the suprarenal vein : not more than about one part in a
million, according to Hoskins, M'Clure, and O'Connor, whilst Fraenckel
estimates it at very much less. This indicates that the rate of passage
into the blood is usually slow : probably it varies at different times. If
only a very small percentage is present, the blood-pressure may be lowered
instead of raised : we cannot, therefore, assume that the normal tone of
the vascular system depends on the presence of adrenalin in the blood,
although, that the maintenance of vascular tone is in some animals assisted

o *

in this manner, is shown by the experiment of compressing the suprarenal
vein. Such compression is followed by a gradual fall of blood-pressure,
which quickly recovers, and, indeed, more than recovers, its former height
on relieving the compression. Temporarily compressing the abdominal
aorta produces somewhat similar results. It is possible that the partially
resumed tone of peripheral vessels which comes on after section of their
nerves may be due to a compensatory increase of adrenalin in the blood,
perhaps assisted by an increase of the pressor autacoid of the posterior lobe
of the pituitary. The circumstance that after section of its nerves plain
muscular tissue becomes more sensitive to the influence of adrenalin must
be borne in mind in considering this question.

Trendelenburg estimated the amount of adrenalin in the blood of the supra-
renal vein of a cat, and found that on the average '003 mg. was passed out of the
two organs per minute. From the data thus obtained he reckons that about 5 mg.
per kilo, body weight is formed in twenty-four hours. After draining off a large
quantity of blood and thus causing a considerable fall of blood-pressure, the amount of

68

The Effect of Nerves upon the Secretion 69

adrenalin passed per minute was not increased. G. N. Stewart states that massage
of the suprarenals leads to the passage of an increased quantity of adrenalin into
the blood : when the massage is light a depressor effect is caused, when vigorous
a pressor effect; but, according to Hoskins and M'Clure, there is never so large
a pressor effect as with "ordinary therapeutic dosage."

Hoskins and Rowley find that administration of adrenalin does not increase the
excitability of the vasomotor nerves to faradisation, but rather tends to depress it.

With regard to the amount of adrenalin required to produce a physiological
effect upon plain muscle, it may be mentioned that Cannon obtained inhibition
of a strip of intestinal muscle with a solution containing 1 in 20 millions, and
Jane way and Park observed inhibition of a strip of coronary artery of the sheep
with a solution of 1 in 50 millions.

THE INFLUENCE OF NERVES UPON THE SECRETION

It was shown by Biedl that stimulation of the splanchnic nerves is
accompanied by increased blood-flow through the organ. The result is
even better marked when these nerves have been cut and allowed to de-
generate for two or three days so that only the vasodilators are acting.
Tscherboksaroff, in confirmation of an observation by Dreyer, found that
during excitation of the splanchnic in a dog the blood passing from the
suprarenal capsule by its vein produces a greater effect in raising the blood-
pressure of another dog than the blood of the suprarenal vein under ordinary
circumstances, and concluded that adrenalin is passed into the traversing
blood under the influence of impulses conveyed by this nerve. He also
obtained a larger amount of adrenalin from the suprarenal capsule as the
result of such stimulation. But the actual proof of secretion under the
influence of nerves is most satisfactorily furnished by the experiment of
Asher, who found that after ablation of the stomach, intestines, and all the
other abdominal organs, in order to eliminate the direct effect which would
be obtained on their blood-vessels, stimulation of the splanchnics still causes
a marked rise of blood-pressure, which fails if the suprarenal blood-vessels
are compressed. Elliott and Tuckett were able to exhaust the suprarenal
of its adrenalin by stimulation of its nerves.

Section of the splanchnics diminishes the amount of adrenalin which
is passed into the blood : according to Elliott, it is only the reflex secretion
which is affected ; an automatic solution goes on all the time. Pende found
that section of the splanchnics leads eventually to atrophy of the medulla.

Von Anrep noticed that stimulation of the splanchnic produces a double
rise of blood -pressure; he ascribes the first to direct stimulation of the
vasomotors, the second to the outpouring of adrenalin into the blood.
This latter phase fails to appear if the suprarenals are extirpated (figs. 43,
44). In the cat Cannon found that the dilatation of the pupils and up-
standing of the fur which accompany sudden alarm or excitement are
associated with an increased outpouring of adrenalin into the suprarenal
veins, and he has drawn attention to the fact that many of the phenomena

70

The Endocrine Organs

which characterise violent emotional states (both in animals and man) are
similar to those which are produced by excess of the suprarenal autacoid
in the blood.

It is conjectured that the hyperglycsemia and glycosuria which result
from Bernard's sugar puncture are accompanied by and probably largely due
to stimulation of the suprarenals through the splanchnics causing the passage
of an excess of adrenalin into the blood, which in turn produces increased

Fio. 43. — Effect on blood-pressure of stimulating the splanchnic nerves. The first rise in blood-
pressure is caused by constriction of the vessels of the splanchnic area, the second by out-
pouring of adrenalin into the blood. The numbers above the abscissa denote the number
of pulse beats in ten seconds, (v. Anrep. )

FIG. 44. — The same as in fig. 43, but with the suprarenal capsules removed. Only the rise. of
blood-pressure caused by the direct effect of the stimulation on the vessels of the splanchnic
area is now seen. (v. Anrep.)

transformation of the liver glycogen into glucose. This will be referred to
more fully in the next section.

Dale has suggested that certain alkaloids (e.g. nicotine and pilocarpine)
exert their action on involuntary muscle, not directly, but by stimulating
the suprarenals to increased activity. This has also been shown to be
probably true for morphia, chloroform, and ether by Elliott ; the effect
appears to be brought about through the splanchnic nerves.

RELATIONS OF THE SUPRARENALS WITH OTHER ENDOCRINE ORGANS

AND SECRETING GLANDS

Ott and Scott state that various organ extracts, viz., thyroid, parathyroid,
pituitary, thymus, pancreas, testicle, and ovary, produce an increased

Relations of the Suprarenals with Other Endocrine Organs 71

secretion of adrenalin into the blood. The variety of these does not,
however, indicate specific relationship. On the other hand, the secretion
of the suprarenal medulla has an influence upon many diverse organs and
glands — including most of the other ductless glands ; this is probably due
to the fact that adrenalin activates sympathetic nerve-endings throughout
the body.

With the Sexual Glands. — A direct relationship between the develop-
ment of the sexual glands and that of the suprarenals may be regarded as
well established, although the nature of the relationship — whether through
the nervous system or, as is more probable, through chemical agencies — is
not precisely known. The connexion appears to be more with the cortex
of the adrenals than with the medulla. During pregnancy the whole gland
undergoes enlargement : the cortex much more than the medulla. Whilst
hypertrophy of the cortex is stated to occur as the result of castration, various
observers have found that increase is also associated with sexual precocity.
Further, in diseased conditions resulting in hypoplasia of the adrenals,
changes in the testicles, especially in their interstitial cells, have been noted.

Elliott and Tuckett do not admit any special connexion between the
suprarenals and the sexual glands. They associate the cortex more
particularly with the development of the muscular system. They also
point out that the lower the animal in the vertebrate, or at any rate
in the mammalian series, the greater is the relative development of
the cortex.

With Externally Secreting Glands. — Injection of suprarenal extract
was found by Langley (in the cat) to produce an active secretion of all
the salivary and mucous glands of the mouth, gullet, and trachea. The
secretion is not arrested by small doses of atropine and is similar to that
produced by sympathetic excitation. The lacrimal glands are also stimu-
lated to active secretion : and this is said to be the case also with the
gastric glands.

With the Liver. — The secretion of bile is increased by adrenalin. But
the most noteworthy effect on this organ is upon its glycogenic function,
for the autacoid of suprarenal medulla even in small doses produces a rapid
conversion of the liver glycogen into sugar, which passes into the blood and
eventually into the urine. The effect is similar to that caused by Bernard's
sugar puncture of the medulla oblongata and by excitation of the splanchnics
It will be remembered that after section of the splanchnics Bernard found
that puncture of the medulla oblongata fails to cause glycosuria. The
effects on the liver are probably in large measure, if not entirely, due to
reflex or other excitation of cells in the nerve-centre. These give origin
to nerve-impulses travelling along sympathetic fibres to the suprarenals,
and thus cause the outpouring of an excess of adrenalin into the blood ;
this again excites the terminal apparatus of the sympathetic nerves in
the liver-cells. Kahn noticed that if one suprarenal is left, its medulla
shows indications of over-activity and far less adrenalin is stored within

72 The Endocrine Organs

it than normally. He states that in the guinea-pig the blood can be shown
to contain an excess of adrenalin after the sugar puncture. A. Mayer
found that Bernard's puncture is not effective after removal of the supra-
renals. Macleod and Pearce observed that adrenalin produces hyper-
gtycaemia even after division of the hepatic plexus (which is not the
case with the hyperglycsemia caused by stimulation of the splanchnics),
and that only when the suprarenals are intact is it possible to produce
hyperglycaBmia by stimulation of the nerves of the liver. Adrenalin is
therefore in some way necessary to the activity of these nerves : possibly
by rendering them more sensitive. It is stated that the effect of adrenalin
on the liver glycogen can be prevented by atropine (Doyen and Gautier).
Ergotoxine also antagonises this action of adrenalin (see p. 64).

As already stated, if the liver is rendered free from glycogen, adrenalin
injection will not only produce hyperglycsemia and glycosuria as before,
but may, even in fasting animals, cause glycogen to be stored : this is
associated with the fact that the metabolism of proteins is increased under
the influence of adrenalin, and the protein is in this case the source of
the carbohydrate which is formed (Noel Paton). On the other hand,
O. Schwarz found the liver glycogen to disappear in rats in which the
suprarenals had been removed, although it could be restored by liberal
feeding with glucose and cane sugar (but not by Isevulose or starch).
If the glycogen of the liver is got rid of by phloridzin, administration
of adrenalin does not increase the glycosuria (A. I. Ringer).

With the Pancreas. — Pemberton and Sweet found removal of the supra-
renals to cause a flow of pancreatic juice which is stopped by injection of
adrenalin, although under normal conditions the flow of pancreatic juice
seems not to be affected by the intravenous injection of adrenalin, at least
in moderate doses. But it is the internal secretion which is mainly
affected by this hormone. Herter and Wakeman found that the mere
swabbing of the exposed pancreas with adrenalin solution provokes
intense glycosuria, comparable with that produced by extirpation of the
organ. The glycosuria and the hyperglycajmia caused by pancreatic
extirpation is, however, increased, as several observers have found, by
adrenalin, so that the whole of its effect on carbohydrate metabolism
is not exerted through the pancreas, but part must be directly on the
liver. We have, in fact, already seen that adrenalin has a direct effect on
the glycogen storage of the liver. But this again is influenced by the
internal secretion of the pancreas. Thus Zuelzer failed to get adrenalin
glycosuria when he injected pancreas extract at the same time as the
adrenalin ; on the other hand, he states that tying the suprarenal veins is
effectual in preventing glycosuria pancreatopriva. These experiments
show that carbohydrate metabolism is in some way regulated by the inter-
action of the suprarenals and pancreas upon the liver-cells. Graham Lusk,
however, from a study of the respiratory quotient in a glucose-fed dog
to which adrenalin was administered, comes to the conclusion that this

Relations of the Suprarenals with Other Endocrine Organs 73

autacoid does not act on carbohydrate metabolism by specifically inhibiting
the internal secretion of the pancreas, but that its effect on carbohydrate
metabolism is related to its vasoconstrictor action. The subject will
again come up for discussion when the internal secretion of the pancreas is
dealt with.

With the Thyroid and Pituitary Body. — The mutual relations of the
thyroid and suprarenals have already been discussed under the former
organ. Those of the pituitary and suprarenals will be considered when the
functions of the pituitary are dealt with.

A concise account (with bibliography) of the structure and functions of the
suprarenals is to be found in Lucien and Parisot, Glandes surrenales et organes
chromaffines, 1913.

CHAPTER XI
THE PITUITARY BODY (HYPOPHYSIS CEREBRI)

THE next of the endocrine glands to claim our attention is the pituitary
body. The study of this organ has sprung into prominence within quite
recent years. Although somewhat vaguely connected with growth pheno-
mena, and shown (1887) to be related to certain forms of abnormal de-
velopment of the body, and especially of the skeleton, it was not until 1895
that it was suspected of having an active function: by most it was
regarded as a rudimentary structure having some morphological interest
but little or no physiological importance. Now, on the contrary, it is
known that from one part of the gland autacoid principles can be extracted
which exert an active influence upon some of the most essential organs of
the body ; whilst from another part it seems probable that principles are
furnished to the blood which serve as chemical regulators of nutrition and
growth. Moreover, by most of those who have worked at its functions
it is thought to be essential to life. Like most of the other special
endocrine organs it is found, with very few exceptions, throughout
the whole series of Vertebrata, and these exceptions may ultimately prove
only apparent.

STRUCTURE OF THE PITUITARY

The pituitary body is in man a small organ about the size of a hazel-
nut without the shell, weighing a little more than half a gramme. It lies
at the base of the brain in the sella turcica of the sphenoid bone. It is
connected with the floor of the third ventricle by a short, hollow, funnel-
shaped stalk — the infundibulum. This stalk is composed of nervous
tissue, and expands in the interior of the gland into what is known as
the nervous portion — pars nervosa — which when examined by appropriate
methods is found to be mainly composed of neuroglia fibres and cells
(Herring). In some animals the cavity of the infundibulum with its lining
of ependyma is prolonged in the form of a blind canal far into the pars
nervosa, but in man this canal has become obliterated, although it existed
in the early embryo.

In front of and partly surrounding the pars nervosa the organ is formed
of a mass of epithelium cells, granular in appearance. This constitutes the
pars anterior seu glandularis. It is highly vascular. In the middle of
the organ the pars anterior is separated from the pars nervosa by a cleft
lined by columnar, cubical, or flattened epithelial cells and filled with glairy

74

Structure of the Pituitary

75

fluid. In the adult human subject the cleft is generally found to be
obliterated or broken up into isolated cysts containing a colloid-like
material. The cleft is all that remains of the original tubular structure
of the pars glandularis, which in the early embryo was formed by a pouch-
like outgrowth of the buccal ectoderm (Rathke's pouch) communicating at
first with the cavity of the mouth, although ultimately the communication
has become obliterated.

c d

h

FIG. 45. — Mesial sagittal section through the pituitary body of an adult monkey (semi-
diagrammatic). (Herring.)

a, optic ehiasma ; b, third ventricle (infundibulum) ; c, d, extension of pars intermedia round neck of pituitary ;
e, pars anterior seu glandularis ; /, intraglandular cleft ; g, pars intermedia ; h, pars nervosa.

Traces of the original connexion with the buccal ectoderm may persist in
exceptional cases even in the adult, as the so-called pharyngeal hypophysis.
Another vestigial structure — the paraliypopliysis — has been described as
occurring in the dura mater lining of the sella turcica, and other small
accessory bodies similar in structure to the anterior lobe have also been
described. It is possible that these may undergo hypertrophy after extirpa-
tion of the main gland and partly supply its function.

But the pars nervosa does not actually abut against the intraglandular

76

The Endocrine Organs

FIG. 46.— Mesial sagittal section through the pituitary body of an adult cat. Photograph.
(Herring.) The intraglandular cleft is accidentally broken open in the section. Notice
the extension in the cat of the infundibulum into the middle of the pars nervosa.

d

f

&3\ •' »

•e

m^m^'^W

FIG. 47. — Sagittal section of pituitary of adult cat. Blood-vessels injected. Photograph.
(Herring.)

a, optic chiasma ; b, tongue-like ar.terior process of pars intermedia ; c, third ventricle ; d, pars
.interior; e, extension of pars intermedia round neck of gland ;/, points to pars intermedia; g,
larger blood-vessels entering pars nervosa ; h, posterior limit of gland.

Structure of the Pituitary

77

cleft. It is separated from it by a layer of epithelial tissue of varying
thickness, which although also originally derived from the epithelium
of Rathke's pouch, differs in certain respects from the pars anterior —
its cells being less granular and its blood-vessels much less numerous.
This portion of the gland is known as the pars intermedia since it lies
between the pars anterior and the pars nervosa. From the former it is
separated by the cleft just described : from the pars nervosa there is not
always a well-defined line of separation — indeed cells of the pars inter-

A B

FIG. 48. — Blood-supply of the pituitary body. (Dandy and Goetsch.) A. Arterial blood-supply,
seen from the ventral aspect. A large number of small arteries are seen converging from
the circle of Willis to the neck of the gland, which has itself been removed. B. Venous
blood-supply. The principal veins are shown passing from the pituitary to a venous circle,
which roughly corresponds with the arterial circle of Willis. Both figures show the parts
somewhat magnified.

media may extend for some distance into the pars nervosa between its
neuroglial fibres ; they impart to it an important functional significance,
which will be referred to later in considering the mode of secretion of
the pars intermedia. It is not difficult to split the gland across the middle
in the situation of the intraglandular cleft, thus separating the larger pars
anterior from the combined pars nervosa and pars intermedia. When such
a separation is effected the term posterior lobe has been given to pars
nervosa plus pars intermedia, the pars anterior being termed in contra-
distinction anterior lobe.

Pars anterior seu glandularis. — As already mentioned, this is formed
of trabecular masses of epithelium-like cells between which are very
numerous sinus-like blood capillaries lying in intimate relation to the cells,

78

The Endocrine Organs

which are indeed sometimes set closely round the blood-spaces. So
abundant are the blood-vessels that a photograph of a section of this part
of the injected organ appears almost black (fig. 47): the contrast with the
pars intermedia and pars nervosa being marked. The pars anterior is
supplied with blood by about eighteen to twenty small arterioles which
converge towards the infundibulum from the circle of Willis and pass into
it along the stalk (Dandy and Goetsch). They open into the sinus-like
channels which in this part take the place of capillaries ; the blood from

SSB

FIG. 49. — Section of ox pituitary at intraglandular cleft (&), showing on left side (a) a portion
of the highly vascular pars anterior, and on right side (c) a portion of pars intermedia.
Magnified 200 diameters.

these passes away by corresponding venules (fig. 48). The pars anterior of
the pituitary constitutes one of the most vascular organs in the body.

The cells of the pars anterior appear as two varieties, viz., clear, non-
staining (chromaphobe), and granular, staining (chromaphil) : and the
granular cells are again divisible into oxyphil and basiphil, i.e. those
staining with acid and basic dyes respectively, the oxyphil cells being
normally by far the more numerous. It has been suggested that these
three types of cells represent different stages of the same cell ; this is
probably only true for the chromaphobe cells and for the cells with oxyphil
granules. The last-named cells are very distinct (figs. 49 and 50, a, and
fig. 51). They may sometimes be seen placed around the blood-sinuses like

Structure of the Pituitary

79

the cells of an ordinary secreting gland around the lumen of the alveolus.
In some animals all the cells of the pars anterior are set like a columnar
epithelium round blood-sinuses — this is strikingly shown in Elasmobranch
fishes such as the skate. In the tortoise columnar cells surround closed
vesicles containing a colloid material. The basiphil cells are, when present,
mostly found near the periphery of the trabecular masses. In pregnancy

3H

ta.*£V'fcl

t 4

d

Flo. 50. — Section of pituitary of cat at intraglandular cleft (b), showing on the
left side (a) the highly vascular pars anterior, and on the right side of
the cleft the pars intermedia (c), in which several vesicles are seen, and
which abuts on the pars nervosa (d). Magnified 200 diameters. ( Figs. 50,
52, and 54 are from sections prepared for me by Dr M. Kojima. )

large, finely granular oxyphil cells are observed in unusual number (Erdheim
and Stumm) : these cells have been designated pregnancy cells. Oxyphil
cells are also unusually abundant in the enlarged gland of acromegalic
subjects, where they form adenoma-like masses. Most of the cells also
contain numerous fine fatty globules.

There is a small amount of reticular connective tissue between the cells.
A few nerves have been traced into the pars anterior from the pars nervosa.

Under certain circumstances in man and mammals, especially in cases
of thyroid absence or insufficiency, a product of secretion of the anterior

80

The Endocrine Organs

lobe cells which has the appearance of colloid appears to accumulate
between the cells. These in some parts come to be arranged round the
colloid in the form of vesicles which are not very unlike those of the
thyroid gland. Even normally this appearance may be observed in the
pars anterior (fig. 52), although it is more characteristically seen in the
pars intermedia (figs. 50, c, 53, 54).

Pars intermedia. — As has been stated, the pars intermedia, although
well provided with blood-vessels, is far less vascular than the pars anterior.
At the circumference of the intraglandular cleft these two parts are con-
tinuous into one another without a sharp line of demarcation, although it is

, i

-

^10 •••

FIG. 51. — Portion of pars anterior of ox pituitary. Magnified 300 diameters. A large blood-
vessel is seen near the middle of the field. Nearly all the cells are oxyphil.

possible to distinguish them by the character of their cells. Behind the
intraglandular cleft the pars intermedia forms a well-marked layer of
varying depth (figs. 49, 52) ; it also extends as a thin stratum over the
surf ace, of the pars nervosa, as well as over the neck of the gland which
connects the pars nervosa with the infundibulum. The cells of the pars
intermedia have not the coarse oxyphil granules which are characteristic
of the granular cells of the pars anterior, but they contain fine neutrophil
granules staining neither with acid nor with basic dyes. They often
surround well-defined vesicles occupied by an oxyphil colloid material :
occasionally these vesicles are unusually large and numerous, especially
in the neighbourhood of the intraglandular cleft (fig. 52). In addition to
these colloid masses, some of the cells of the pars intermedia may often
be seen in different stages of conversion into globular hyaline bodies, their
protoplasm and nucleus becoming swollen : the latter may have become
indistinct or have disappeared. Some of the globules thus produced are

Structure of the Pituitary

81

granular in character rather than hyaline. In both cases the cells ultimately
break down, setting free the hyaline or granular substance.

As has already been mentioned, the pars intermedia is by no means every-
where sharply marked off from the pars nervosa, for strands of the cells
of the pars intermedia may extend a variable distance between the fibres
of the pars nervosa. The hyaline and granular globules which have been
derived from its cells also pass into the substance of the pars nervosa and

FIG. 52. — Portion of pars anterior of cat's pituitary, showing the groups of
oxyphil cells with vascular spaces between the groups. Several vesicles,
surrounded by cells, are included in the section. Magnified 400 diameters.

are seen between its fibres : they can, in fact, be traced as far as the con-
tinuation of the third ventricle into the stalk. This fact was pointed out
by Herring, who concluded that the hyaline and granular substances which
are produced by conversion and breaking down of the cells of the pars
intermedia form the secretion of this portion of the pituitary, and that this
secretion passes into the cerebro-spinal fluid. In confirmation of Herring's
conclusion, evidence that the active principle of the posterior lobe of the
pituitary is present in cerebro-spinal fluid has been obtained by Gushing
and Goetsch, although their results have been traversed by Carlson. It
has, however, been shown by Cow that intravenous administration of

6

82

The Endocrine Organs

duodenal extract indubitably causes the appearance of the pituitary

'"..-.•'.

FIG. 53. — Section of pars intermedia of ox pituitary where it abuts on pars nervosa.
Two colloid vesicles are seen amongst the cells. Magnified 200 diameters.

FIG. 54. — Section of cat's pituitary, showing on the left a thickened portion of pars inter-
media, with several vesicles amongst its cells, and on the right pars nervosa with
two hyaline masses amongst its fibres. The sharp edge of the pars intermedia on
the left forms part of the boundary of the intraglandular cleft ; the free edge on the
right of the pars nervosa is part of the boundary of the extension of the third ventricle
into the gland.

autar.oids in the cerebro-spinal fluid ; a fact which makes it evident that
they must normally be passed to some degree into that fluid. The Iryalme

Structure of the Pituitary

83

globules are greatly increased as the result of thyroidectomy (Herring).
Gushing states that this increase also results from extirpating the
pancreas, and that it occurs as the result of section of the infundi-
bular stalk.

Pars nervosa (also known as the neuro-hypophysis or infundibular
body). — This is formed almost entirely of neuroglia fibres with neuroglia
cells scattered amongst them. Many of the fibres arise from these cells,
others from the ependyma cells of the infundibulmn and of its extension
into the gland. Between the neuroglia fibres, especially in the neighbour-

FIG. 55. — Section of posterior lobe of pituitary of cat, including a portion of the central
cavity which is continuous with the infundibulum of the third ventricle. (Herring. )

a, ependyma of central cavity ; b, colloid or hyaline matter in central cavity: some of it is seen passing
through the ependyma of the pars nervosa ; c, ependyma fibres ; d, hyaline masses ; e, a granular
mass in pars nervosa.

hood of the stalk, but also in other situations, is to be seen the hyaline and
granular matter already referred to ; sometimes in the form of swollen
cells such as have been described in connexion with the pars inter-
media, sometimes as amorphous masses ; these masses are traceable, as
already mentioned, to the infundibulum, where they may be seen passing
through the ependyma into the cavity of the ventricle (fig. 55). There can
be little doubt that the physiological activity of extracts of the pars nervosa
is connected with the presence of this substance within it, since extracts of
ordinary nervous and neuroglial substance have not the same action. Some
authors have described nerve-cells within the pars nervosa — but according
to Herring these do not occur, and there are very few nerve-fibres. The
pars nervosa is the least vascular portion of the pituitary, its blood-vessels
being comparatively few in number.

CHAPTER XII
THE PITUITARY BODY (continued)

THE ACTIVE PRINCIPLE OR PRINCIPLES OF THE PITUITARY '

VARIOUS attempts have been made to isolate the active principles of this
organ, and more than one investigator has succeeded in obtaining from
extracts of the posterior lobe a crystallisable material which produces the
stimulation of plain muscle characteristic of such extracts. Clear, protein -
free, sterilised solutions containing the active principles are met with in
commerce under the names pituitrin, hypophysin, etc., but it is not claimed
that these represent pure chemical substances. There is reason to believe
that, unlike the suprarenal medulla, the posterior lobe of the pituitary
body yields more than one active autacoid (see p. 96). On the other
hand, no active principle has been extracted from the pars anterior. This,
however, does not negative the idea to which we are led by the evidence of
many experimental and clinical observations, that the pars anterior forms
a substance or substances which pass into the blood and exercise important
effects on metabolic processes in various organs.

EFFECTS OF EXTRACTS OF THE POSTERIOR LOBE

Effects on Plain Muscle. — The announcement in 1895 that extracts of
pituitary, as well as those of suprarenal, have a remarkable influence upon
the vascular system, producing a great rise of blood-pressure with contrac-
tion of vessels and increase in force of the heart-beats (fig. 56), led to the
attention of physiologists being drawn to this gland, which had until then
been neglected by them. Howell (1898) found that the action is confined to
extracts of the posterior lobe — which, as we now know, includes pars inter-
media and pars nervosa — and it has since been shown that it is yielded by
extracts of either pars intermedia or pars nervosa alone, but rather more
distinctly by the pars nervosa than by the pars intermedia (Herring). The
effect of the extract upon the blood-vessels is a direct one, and is not
due, as in the case of the suprarenal hormone, to its stimulant action on
sympathetic endings. The effect on the heart was also shown by Howell
to be different from that of adrenalin ; for whereas — with the vagi cut
or paralysed — adrenalin causes a marked acceleration of the heart (sym-
pathetic stimulation), the pituitary autacoid causes slowing with increase
in force of the individual beats. In the bird it augments both auricular

o

and ventricular contractions, whereas adrenalin affects the auricles only

84

Effects of Extracts of Posterior Lobe of Pituitary 85

(Noel Paton and Watson). Moreover, while adrenalin either produces no
action on the coronary vessels or, in some cases, causes them to dilate,

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the autacoid of the pituitary constricts them as it does most other systemic
arterioles ; this is true also for the pulmonary vessels. The pressor
hormone also has the peculiarity that the effect of a second dose admini-
stered a short interval (thirty minutes or less) after the first usually causes

86

The Endocrine Organs

no effect (tachyphylaxis l) ; or, if any, not a rise but a fall of blood-pressure
which may or may not be followed by a slight rise (fig. 57). Frequently

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a preliminary fall precedes the rise produced by the first dose. Probably,
therefore, there is present in the extract a second autacoid which is
antagonistic to the first and should be classed with the chalones or in-
hibitory autacoids. The substance which causes the fall of blood-pressure
is not choline, although the curve obtained resembles that caused by

quick, and <pv\a£is, protection.

Effects of Extracts of Posterior Lobe of Pituitary 87

choline, for it is not affected by atropine. In birds only dilatation of vessels
is produced, and this is antagonised by atropine (Noel Paton and Watson).
On the heart's action the repeat dose has the same effect as the first
dose, i.e. the beat is strengthened (Biedl). The effect on the uterus (see
below) is also repeated if administration of the autacoid is repeated. The
pressor effect and the effect on the heart produced by the stimulating
(hormonic) autacoid usually lasts a considerable time (a quarter to half an

FIG. 58. — Tracing to show the effect of the addition of extract of posterior lobe
of pituitary body to Ringer's solution in which a longitudinal strip of
intestinal muscle was suspended. (A. W. Young.) Notice both the increase
in force of the individual contractions and the increase in tone of the muscle.

hour or more), varying, however, with the dose ; the depressor effect of the
chalonic autacoid has a much shorter period of activity.

The extract of pituitary acts upon other plain muscular tissue besides
that of the blood-vessels. Thus it powerfully affects the bladder and
intestine (fig. 58) (Blair Bell and Hick), the stomach (Houssay),1 the uterus
(fig. 59) (Dale),2 even in minute doses ; it also produces dilatation of the pupil

1 Houssay states that the secretion of gastric juice is at the same time increased ; this is
perhaps the result of setting up contractions in the muscularis mucosae.

2 The uterus is also rendered more excitable to influences reaching it through its nerves.
According to Dale, pituitary extract acts on plain muscle more by increasing its sensitiveness
to normal stimuli than by acting as a direct excitant. Thus when administered in pregnancy
before the commencement of parturition it produces no effect ; whereas its action during
parturition is well established. Engeland and Kutscher claim to have isolated an autacoid
which affects the uterus only.

88

The Endocrine Organs

of the excised eye of the frog (W. Cramer). In some of these actions it re-
sembles adrenalin, but the stimulating autacoid of the pituitary is certainly
different both chemically and in its physiological reactions from that of
the suprarenal. For it does not specifically stimulate structures innervated
by the sympathetic as does adrenalin ; moreover, neither apocodeine nor
ergotoxine affect the results obtained with it. Probably it acts as a direct
stimulus upon the contractile substance of the cells which it influences.

Effects on Kidney. — The renal arteries form an exception to the con-
strictor effect produced by pituitary extract, since they dilate as a con-
sequence of the addition of the extract to the circulating blood (fig. 60) :
the dilatation is correlated with an increase of secretion of urine (figs. 60,

FIG. 59. — Tracing showing the action on an isolated cornu of rat's uterus suspended in Locke's
solution, of the addition of extract of posterior lobe of ox pituitary to the solution. (M. Itagaki.)

61, 62): it is often preceded by a slight contraction, and the increase of
urine by a temporary diminution. The increased secretion may be in part
brought about by the increased flow of blood through the kidney vessels,
due to the circumstance that they undergo dilatation, while all the other
systemic arteries are contracting ; but that it is to a certain extent caused
by a specific effect of one of the pituitary autacoids is probable from the
fact that it may occur in the absence of any obvious arterial change.

Moreover, an increased rate of flow is maintained after the blood-pressure
has come back to the level at which it stood before the injection. And the
effect of a second and subsequent doses of the autacoid administered soon
after the main result of the first dose has passed off is again to produce an
increase in the urine flow (fig. 62), although the blood-pressure as the result
of these after-doses does not rise, or falls instead of rising, and although
the kidney volume may now be unaffected. This experiment clearly

Effects of Extracts of Posterior Lobe of Pituitary

89

demonstrates that the autacoid affects not only the blood-veasels of the
organ, but also its secreting cells, which it renders more active (or more

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permeable). The secretion must therefore in these circumstances be induced
by a direct chemical excitation of the renal cells by the autacoid, which
thus bears the same relation to the kidneys as is borne by the secretine of
the duodenum to the pancreas. In this respect also the action of the auta-

90

The Endocrine Organs

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coid of the pituitary is comparable to that of those drugs which act as
specific diuretics upon the secreting cells of the kidney, as distinguished

from those which pro-
duce diuresis by increas-
ing the water content
of the blood or by merely
increasing the general
blood-pressure.

The diuretic action
of the pituitary autacoid
is not antagonised by
atropine. This may be
taken as a sign that
it does not act through
nerves or nerve-endings,
but directly upon the
kidney cells ; in this re-
spect also it resembles
the action of secretine
upon the pancreas.

Effect on Secretion of
Cerebro-spinal Fluid. —
It has been shown by
Weed and Gushing that
extracts of posterior lobe
also contain an autacoid
which stimulates the
flow of cerebro - spinal
fluid (fig. 63). This is
not dependent on in-
crease of blood-pressure,
for it may be accom-
panied by a fall instead
of a rise of pressure, and
by an increase in depth of
the respirations : the in-
creased flow of cerebro-
spinal fluid seems to
be independent of these
circumstances.

Effect on Milk Secre-
tion.—It was found by Ott and Scott that in the goat an injection of
pituitary extract into a vein greatly increases the quantity of milk which
can be drawn from the udder in a given time after the injection, as com-
pared with that which could be obtained in a similar period immediately

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Effects of Extracts of Posterior Lobe of Pituitary 91

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2

before. This galactagogue action of pituitary extract was confirmed in
lactating cats by Mackenzie and myself. The method we employed con-
sisted in canalising or in-

o

cising the nipple of one
or two of the mammas so
as to allow any milk which
was secreted to run out.
The milk was conducted
to the side and registered
by allowing it to fall upon
an electrical drop recorder.
This modus operandi per-
mits the conditions of the
experiment to be con-
trolled and the results ac-
curately recorded. It can
in this way be shown that
even a very minute dose
of the pituitary autacoid
— whether the same hor-
mone as that which affects
the muscular tissue of the
blood-vessels and viscera,
cannot certainly be said —
will cause milk which has
accumulated in the gland
to be immediately poured
out (fig. 64), whilst a
somewhat larger dose will
produce complete empty-
ing of the alveoli. If the
nipple is not canalised
or incised, the resistance
which is afforded in the
passage through its ducts,
controlled as they are by
the plain muscle tissue
which abounds in the
nipple, does not permit
of this emptying, and no
actual outpouring of the
secretion takes place. If
tract is made in the arm

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intramuscular injection of pituitary ex-
a nursing woman, a feeling of tingling
is felt in the mamma and a sensation of milk flowing towards the
nipple is experienced like that which occurs when the child is put

92

The Endocrine Organs

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Effects of Extracts of Posterior Lobe of Pituitary 93

to the breast, although there may be no actual outpouring of the
secretion.

If in the experiment upon the cat the animal is killed immediately after
one of its glands (with nipple incised) has been emptied by an intravenous
injection of extract of posterior lobe in the manner above described, and if
a portion of tissue comprising parts of two adjacent mammae — one emptied

d

FIG. 64. — Effect on blood-pressure and mammary gland of a lactating cat of injecting extract
of 0'125 g. of posterior lobe of pituitary. (From K. Mackenzie, Quart. Journ. Exper. P/iysioL,
1911, vol. iv.)

a, tracing of blood-pressure : notice that the main rise is preceded by a preliminary fall ; b, drops of milk
exuding from a fine canula introduced into one of the lactiferous ducts ; c, drops of milk exuding from
incised gland ; d, signal ; e, time in ten seconds.

of its secretion as the result of the injection, the other with its alveoli still
full of milk — is fixed and sections are made passing through both full and
empty mammae, the contrast in appearance is remarkable (fig. 65). In the
one, where the alveoli are distended with secretion, they are large and
rounded and the lining cells are flattened against the limiting membrane,
whilst in the other, from which the secretion has been discharged, the alveoli
are irregular, shrunk, and empty, their walls are folded, and the lining cells
stand prominently out from the limiting membrane.

94

The Endocrine Organs

If after a first full dose of pituitary extract has been given, a second
dose succeed it at a short interval, no further flow of secretion from the
exhausted mamma can be produced.1 The effect of the autacoid, therefore,
is not — at any rate immediately — to cause the cells to form and secrete
milk, but only to cause the alveoli to empty themselves of the milk which
has been previously formed and secreted within them. The simplest
manner in which one can conceive this to occur is by contraction of (plain)
muscular tissue around the alveoli. In support of this conception, I have

succeeded in detecting in the
walls of the mammary alveoli
long, rod-shaped nuclei im-
mediately external to the
epithelium. These nuclei
exactly resemble those of in-
\ . H voluntary muscle-cells, and

•-' "v'

&

>,

probably belong to a thin
muscular layer which is situ-
ated, like the muscular tissue
of the sweat glands, between
the basement membrane and
the epithelium of the alveoli.
The action of pituitary ex-
tract upon milk secretion
differs therefore from its
effect upon the secretion of
urine in the fact that in the
last-named case there is an
actual stimulation of the
renal cells to abstract fluid
from the blood, whilst in the
mammary gland there occurs
merely a contraction of the walls of the alveoli and discharge of fluid
previously secreted.

Apart from the pouring out of the contents of the alveoli — which, when
the gland is intact, shows itself as a tendency of the alveoli to empty
themselves towards the nipple, — the pituitary galactagogue has little
or no effect on the total production of milk. This at least is the result
which was obtained in the goat by Findlay, and in cows by Gavin. Later
observers (Hammond, Sutherland Simpson) have obtained a slight increase
in the diurnal yield of both goats and cows ; and also a slightly increased
amount of fat in the milk produced under the influence of the autacoid.

Mackenzie found (in the cat) that atropine does not arrest the flow of
milk obtained as the result of pituitary injection (an observation which has

1 This is not an instance of tachyphylaxis, but is due to the fact that there is now no
milk left in the alveoli.

FIG. 65. — Section including the adjacent parts of two
mammary glands of a lactating cat. One of them had
discharged the whole of its milk as the result of an
intravenous injection of pituitary extract, the nipple
having been excised to allow the milk to flow out freely.
In the other the alveoli are distended with milk. Low
power.

Effects of Extracts of Posterior Lobe of Pituitary 95

been confirmed for the cow by Houssay). He obtained, however, an in-
hibitory action from extract of placenta, which, when injected into a vein
just previously to the injection of pituitary extract, prevents the effect of
the latter from influencing the mammary gland. It is reasonable to con-
clude from this that placenta extract contains a chalonic autacoid which
restrains the outpouring of the secretion of the mamma and antagonises
the hormonic action of the pituitary autacoid.

Galactagogue autacoids are also contained in extracts of other organs
than the pituitary, viz., the corpus luteum of the ovary, the involuting
mucous membrane of the uterus after parturition, the lactating mammary
gland itself, and to a slight extent the pineal gland. Their effect on
the mamma is exactly like that of the pituitary galactagogue, but the effects

a

d.

FIG. 66. — Electric change accompanying the flow of milk from the mammary gland under
the influence of a dose of pituitary extract administered intravenously.

a, record of string galvanometer : each millimetre of ordinate = 20 microvolts ; b, record of drops
of milk ; c, time in seconds ; d, signal of injection. The waves on a are respiratory.

on blood-pressure are either nil or are different from that of pituitary
extract. Their galactagogue action will be described later.

The blood, even in non-lactating animals, sometimes contains enough

o o

galactagogue autacoid to provoke the mammary secretion of a lactating
animal, although the other effects of pituitary extract are not seen. In
one experiment performed by me, as little as 5 c.c. of the blood-serum of a
guinea-pig injected into a lactating cat provoked a marked secretion from
a mamma the nipple of which had been incised, without producing any
effect on the blood-pressure.

The action of pituitary and other extracts in causing secretion from the
gland is accompanied by a change in the electric potential of the organ
(fig. 66), so that the alveoli tend to become negative to the duct. This
change is somewhat similar to that which is produced in other secreting
glands which have been investigated.

From what has been stated regarding the mammary gland, it is obvious that
this is an organ which is singularly under the influence of autacoids circulating in

96 The Endocrine Organs

the blood. It is, moreover, well known that its secretion is not directly under the
influence of the nervous system. Excitation of its nerves produces no effect on the
secretion, which continues normal after all nerves are cut (Eckard). Even a
gland which has been transplanted to a totally different situation will secrete milk
(Ribbert). The case of the pyophagus twins, Rosa-Josepha Blaz^k, who are united
by a common sacrum, with anus and vulva in common but with two uteri and
vaginse, is particularly interesting in connexion with this question. For when one
of the twins became pregnant the mammary glands in both underwent hypertrophy
and eventually secreted milk. The well-known effects of nervous conditions
(emotions and the like) upon milk secretion must therefore be produced through
the internal secretions of organs such as the pituitary.

EFFECTS ON METABOLISM AND IN DISEASE

It is found, as with adrenalin, that the autacoids of the posterior lobe of
the pituitary have an important influence upon carbohydrate storage. When
injected either into a vessel or subcutaneously they cause disappearance of
glycogen from the liver. They also facilitate the production of alimentary
glycosuria by lowering the limit of assimilation of sugar (Borchardt).

Subcutaneous and intramuscular injections — especially the latter —
produce effects similar to those caused by intravenous administration,
although less rapidly.1 On the other hand, buccal administration has little
or no effect on the blood-vessels, heart, and plain muscle. This is not due
to destruction of the active material by the gastric juice, but probably to
its slow rate of absorption from the alimentary canal. Addition of the
gland substance to the food of growing animals, or its administration by
subcutaneous injection, has been stated to check growth and delay ossifica-
tion (especially in males), but this statement appears not to be of general
application. In white rats the growth is not obviously affected by the
addition of small amounts of pituitary to the ordinary food, nor is any
obvious effect produced upon nitrogenous metabolism. In animals in which
the gland has previously been experimentally removed or injured (see below),
Gushing has described amelioration of the symptoms as the result of adding
large amounts of the gland substance to the food. Pituitary extracts and
derivatives from them have been administered in a variety of disorders,
including surgical shock, intestinal inertia, uterine inertia, amenorrhcea,
vesicular inertia, deficiency of milk secretion, haemoptysis, exophthalmic
goitre, hay fever, rheumatoid arthritis, rickets, and osteomalacia, but it is
only in the first three that they have proved of distinct value.

ARE THE VARIOUS EFFECTS OBTAINED FROM EXTRACTS OF THE POSTERIOR
LOBE DUE TO ONLY ONE OR TO MORE THAN ONE AUTACOID ?

Whether all these effects are produced by one and the same active
principle has not yet been definitely determined. For example, in the case

1 Large doses administered subcutaneously are fatal to rabbits, the symptoms being
similar to those caused by adrenalin (see p. 65).

Autacoids of Posterior Lobe of Pituitary

97

of the kidney we may be dealing with the action of a single autacoid
which acts as a chalone upon the blood-vessels of the organ, producing
inhibition of their tone, and as a hormone upon the secreting cells, stimu-
lating them to increased activity ; or two separate autacoids may be con-
cerned, one of which affects the blood-vessels and the other the cells of
the organ. The latter view was taken by Herring and myself, but was
combated by Dale, who adduces other examples of the action of drugs in
which the same active substance produces a double result. If Dale's con-
tention is correct, we are, so far as the action upon the kidney and its
vessels is concerned, dealing with a single autacoid capable of acting either
upon both tissues, viz., blood-vessels and secreting cells, or, under certain

A B

FIG. 67. — A. Tracing showing the effect of extract of pars nervosa of ox pituitary on isolated
muscular tissue of rat's uterus. (Herring.) The strip was acted upon by the extract during
the period marked by the signal. B, this tracing was made from the same preparation
as that employed to obtain the last tracing. It shows the effect produced by an equivalent
amount of extract of pars intermedia. The resulting contraction is smaller and less prolonged.

circumstances, upon one only. When its action is produced upon one only
this may be interpreted to mean that the other is temporarily insensitive
to its action : when, for example, in the action of pituitary upon the kidney
the diuretic action (upon the cells) fails to be produced whilst the vascular
effects are pronounced, or vice versa. But even if this were valid for the
kidney, there are strong reasons for the belief that the posterior lobe of
the pituitary yields more than one autacoid. For there is distinct evidence
that a specific hormone affects the secretion of milk ; quite possibly the
effect upon the uterus is due to another ; while there is very little doubt
that the fall of blood-pressure produced by a second dose of pituitary
extract is due to a chalonic agent entirely different from the hormone
causing the initial rise. Bayer and Peter have also produced evidence
that there are two autacoids which act upon intestinal muscle, one produc-
ino; inhibition and the other contraction.

o

Important observations bearing upon this question have been made

7

98

The Endocrine Organs

by Herring, who finds well-marked differences of effect according as
extracts are prepared from pars intermedia or pars nervosa.1 Thus pars

FIG. 68. — Effects on blood-pressure and kidney volume of injecting 3 c.c. of a 2 per cent, extract
of pars intermedia of fresh ox pituitary into the jugular vein of a cat. (Herring.)

a, blood-pressure ; l>, kidney volume ; c, urine drops ; d, signal ; e, time in ten-second intervals.

a

WWWWiAM/, f

FIG. 69. — Effects on blood-pressure and kidney volume of injecting 3 c.c. of a 2 per cent, extract
of pars nervosa of fresh ox pituitary into the jugular vein of the same cat. This injection
was made eight minutes later. (Herring.) Lettering as in fig. 68.

nervosa of the ox excites the uterine muscle much more powerfully than
does pars intermedia, whilst pars intermedia excites both uterine muscle
and mammary gland more easily than it excites the plain muscular tissue

1 Most workers have employed extracts of the whole posterior lobe, which contains
both parts.

Autacoids of Posterior Lobe of Pituitary 99

of the blood-vessels ; in this respect it differs from pars nervosa. Further,
extract of pars intermedia seems not to exhibit the specific effect on the
kidney and urine which are so marked with extracts of the whole posterior
lobe — nor do repeat doses show any lessened effect, or prevent extracts of
pars nervosa from producing the usual results on blood-pressure, kidney,
uterus, and milk secretion.

Herring has also found that extracts of the pituitary of the skate injected
into mammals, although they affect the uterus and mammary gland, have
no influence on blood- pressure or kidney.

These observations appear to indicate that there are at least two specific
autacoids of the posterior lobe, both of which are present in the pars
nervosa of the ox and only one in the pars intermedia (and in the whole
pituitary of the skate). These autacoids are irrespective of that which
produces a fall of blood-pressure, the specific nature of which, although
probable, is less certain.

CHAPTER XIII
THE PITUITARY BODY (continued)

EFFECTS OF COMPLETE REMOVAL: HYPOPHYSECTOMY

A LARGE number of experiments have been made with the view of de-
termining the nature of the symptoms which follow removal of the
pituitary. The results of these have been somewhat conflicting in character
— due in some measure to the differences of method employed to arrive at
the position of the organ, which is obviously a difficult procedure, deeply
placed as it is at the base of the brain. Thus, while one set of operators
(e.g. Horsley and Handelsmann, and Aschner) have preferred to approach
it (in animals) through the buccal cavity and basis cranii, in order to avoid
disturbance of the brain, others (e.g. Paulesco, Gushing, Biedl) have not
hesitated to attack it through a large aperture in the side of the skull,
another similar aperture being made on the opposite side so as to enable
the hemispheres to be pushed over in order to obtain a good view of the
gland ; in some animals, such as the dog, the organ can be got at without
much difficulty by this procedure. The former method has the dis-
advantages (1) that the operator is working at the bottom of a deep pit
from the walls of which blood is constantly oozing so as to obscure the parts,
and (2) that it is impossible to secure asepsis. By the use of the lateral
method these disadvantages are for the most part avoided, but it has been
alleged that the serious results which are described as following removal
of the organ by this operation are due to shock and paralysis caused by
the unavoidable insult to the brain.

Effects of Complete Removal. — Paulesco was the first to state definitely
that complete removal is in every case sooner or later fatal. This result
was obtained with animals from all classes of Vertebrata. Most of the
hypophysectomised mammals died within two or three days. He also
found that mere severance of the stalk connecting the pituitary body to
the base of the brain is fatal. Paulesco's statements were confirmed by
Harvey Gushing and his fellow- workers, who for the most part restricted
their experiments to dogs. They found that adult animals usually succumb
after total deprivation in from two to five days, whilst puppies survive
longer (ten to thirty days); they ascribe this difference to the greater
functional adaptability of accessory glandules which are probably present
in the roof of the pharynx in young animals. In all cases of long survival
a fragment of the gland, including some of the anterior lobe, was found

100

Effects of Removal of Pituitary 101

post-mortem, and they attribute the survival to such a remnant. On the
other hand, they obtained no definitely recognisable symptoms by severance
of the infundibular stalk, a procedure which, as we have seen, Paulesco
alleged to be fatal. Removal of part only of the anterior lobe leads to
certain definite changes in metabolism, which are considered by Gushing
to be due to deficient secretion, a condition to which he has given the name
hypopituitarism. Similar results to those of Paulesco and Gushing have
been obtained by Biedl, and recently by Ascoli and Legnani.

The symptoms of complete removal or apituitarism (cachexia hypo-
physeopriva) are described by Gushing as follows : " On the day after the
operation the animal (dog) usually appears normal, with fair appetite and
no characteristic signs of loss of secretion. Gradually it becomes lethargic,
refuses food and responds slowly or not at all to the voice. Later the
respiration becomes slow and the pulse both slow and feeble, the musculature
limp, often with tremors and fibrillar twitching ; the back is arched, and
the temperature subnormal ; finally, often within forty-eight hours, the
animal becomes comatose and dies in this condition." According to Gushing,
immediate reimplantation of the removed gland in some other structure
causes an abatement of the symptoms and prolongs life ; but whether in-
definitely or not is uncertain, and would doubtless depend upon whether the
graft underwent subsequent degeneration. In Cushing's later experiments
extirpation of the gland seems to have been less certainly fatal or longer
delayed, the animals exhibiting the symptoms rather of hypo- than of
a-pituitarism. This may be due to small portions of the gland having
been left behind, or to the employment of younger animals, or to the
vicarious activity of some other organ or organs. The fact is interesting
because Aschner, who has performed a large number of extirpations mainly
by the inferior operation (through the base of the skull), has not found the
gland to be essential to life — or at least has obtained very considerable
prolongation of life after its entire removal. It must, however, be regarded
as doubtful if it is possible to effect complete removal by this operation.
Aschner himself, who admits the difficulty, regards the small residue as
unimportant. In all his cases symptoms of hypopituitarism showed them-
selves. His animals, if young, remained small : their milk teeth were
retained and also their lanugo hair: their epiphyses did not ankylose.
The thyroid was enlarged, the thymus persistent, and the cortex of the
suprarenal thickened. The development of the sexual organs was markedly
retarded. The animals laid on fat. In the adult the chief effect of the
removal was the putting on of fat. The secretion of carbonic acid was
found by Benedict and Homans to be diminished. In pregnant animals
Aschner found removal of the pituitary to be always followed by abortion.

The experiments of others have yielded different results. Thus Horsley
and Handelsmann, who attempted complete extirpation in a number of
animals, chiefly by the operation through the base of the skull, state that
although a large proportion of their cases died within forty-eight hours,

102

The Endocrine Organs

they consider this was due to causes incidental to the operation (shock,
haemorrhage, infection). Those that survived showed none of the symptoms
above described as characteristic of apituitarism. But in view of the
results of clinical observations on the effects of destructive disease of the
pituitary, it must be regarded as doubtful whether the removal of the gland
has been as complete in these cases as in those described by Paulesco and
Gushing, the operative method employed by whom seems less open to objec-
tion than that in which the gland is reached through the basi-sphenoid.

EFFECTS OF PARTIAL REMOVAL AND INJURY

The results of lesions which involve only partial removal are even

more interesting than those in
which the extirpation is complete
and the symptoms more acute.
The most striking effects are ob-
tained in young animals. Re-
tardation of growth after hypo-
physectomy has been described
by various authors, and that this
is a characteristic of diminished
amount of pituitary substance
and concomitant diminished
secretion of autacoids by the
gland has been established by the
experiments of Gushing and of
Biedl. The work of Aschner,
which has already been alluded
to, also obviously has an im-
portant bearing upon this point,

FIG. 70. — Twelve-months'-old hypophysectomised
dog (left) and control of same litter (right).
(Aschner.) The operation was performed at
eight weeks.

although Aschner himself be-
lieves that in most of his operations the removal was complete and that
the condition was one of apituitarism. The retardation in development
shows itself in a general diminution in size, in the ossification process,
which is imperfect, and in the sexual organs, which long retain their
infantile condition. Mental dullness has also been generally noted.

In spite of retardation in development, there is a marked tendency to
fat formation, so that the actual weight of the operated animal may exceed
that of the control. Even in adult animals a tendency to obesity is a
characteristic feature after partial hypophysectomy. Accompanying this
tendency, and possibly acting as a causative agent, is a high tolerance for
sugars, the limit of alimentary glycosuria being markedly raised. This
is the contrary effect to that produced by injection of posterior lobe
extract, and is doubtless the result of deficiency of posterior lobe secre-
tion, which in Cushing's opinion " is essential to effective carbohydrate
metabolism."

Effects of Injury of Pituitary

103

If mos

It was found by Gushing (in conjunction with Goetsch and Jacobson)
that immediately after the operation of partial hypophysectomy a temporary
glycosuria would at first usually ensue. This result is perhaps due to a
dislodgemnt of accumulated secretion and irritation due to the injury. The
effect, however, soon passes off, and is followed by the permanent condition
of increased tolerance for sugar. Animals which have acquired this tolerance
will suffer loss of the pancreas without becoming diabetic. Injury to the
posterior lobe or even its manipula-
tion is, probably for the same reason
(release of accumulated secretion and
possibly temporary irritation due to
the injury), often immediately fol-
lowed by marked glycosuria and also
by polyuria, which may persist long
after the glycosuria has disappeared
or may be present from the first with-
out glycosuria (diabetes insipidus).
In one case of such injury to the
pituitary in a dog operated upon by
me the amount of urine rose from
40 c.c. per diem to 230 c.c.,and during
the following nineteen days remained
at an average of 119 c.c. In another
it rose from 110 c.c., the average of
eleven normal days, to 182 c.c., the
average of the eleven days immedi-
ately succeeding the operation. It
was, however, much higher than this
on the third, fourth, and fifth days,
averaging 266 c.c. Mere exposure of
the pituitary was found to have no
such effects. A case in man has been
recorded by Simmonds in which there
was a malignant tumour of the pars
nervosa extending to the pars inter-
media, with marked diabetes insipidus (10 to 19 litres of urine per diem).
This is probably a case of the cells of a malignant tumour assuming the
functions of the tissues they are growing from (see p. 33).

It has been found by Gushing that stimulation of the cervical
sympathetic or of its superior ganglion causes diuresis; he considers this
is brought about by provoking the secretion of the posterior lobe, since
stimulation of the superior cervical ganglion produces no effect if the
pituitary be first removed. He therefore concludes that secreting nerves
pass through this ganglion to the pituitary. Gushing also states that ex-
cision of the posterior lobe or separation of the stalk is sometimes followed

FIG. 71. — Young dog, eight months old. four
months after removal of the greater part
of the pituitary body. (Gushing.) Notice
the tendency to adiposity, and the de-
ficient development of the sexual organs.

104

The Endocrine Organs

by prolonged polyuria : this may be caused by irritation of portions of pars
intermedia which remain. According to Weed, Gushing, and Jacobson,
puncture of the pituitary gives as definite results regarding glycosuria as
Bernard's puncture of the fourth ventricle. In both cases there must be

FIG. 72. — Adult dogs, male and female, some months after removal of the greater part of the
pituitary body. In each case a control of the same litter is shown on the right of the
operated animal. (Gushing.) The tendency to adiposity is well marked in both sexes.

" available " glycogen present, i.e. glycogen resulting from recent ingestion
of carbohydrates. Both this and Bernard's puncture are ineffective after
section of the cord at the fourth thoracic level.

EFFECTS OF GRAFTING AND FEEDING WITH PITUITARY

Many attempts have been made to increase the internal secretion of the
pituitary — especially of the pars anterior — by grafting the organ or portions
of the organ from an animal of the same species into various parts of the
body ; but these have always so far resulted in failure, the graft disappear-
ing, or at any rate undergoing degeneration, in the course of a few days.
In white rats, rabbits, and guinea-pigs I have repeatedly implanted the
organ as a whole or in small pieces under the skin of the groin, in the
peritoneal cavity, in the kidney substance, in the spleen, and in the substance
of the brain, but always with no result or with only a temporary effect
upon the amount of urine secreted, which has obviously been due to the
autacoid of the posterior lobe. Only after extirpation of the animal's own
gland did Gushing and his fellow-workers succeed in occasionally getting a
graft to take (for at least a month). A. Exner seems to have obtained
something like a positive result in rats without previous removal of the

Effects of Grafting and Feeding with Pituitary 105

animal's own gland, for he states that he was able to observe a temporary
increase of growth of animals in which he implanted an extra pituitary as
compared with controls. Other methods which might be expected to pro-
duce hyperpituitarism consist (1) in the addition of pituitary substance to
the food, (2) in the subcutaneous injection of extracts at regular intervals
during a prolonged period of time. The second method has been stated by
some observers to produce a retardation of growth of the skeleton and of
the body generally — a result exactly the contrary to what would be ex-
pected if, as there seems no reason to doubt, the symptoms of acromegaly,
presently to be described, are due to hypertrophy of the gland, especially
of the anterior part. A series of experiments by the first method which
were carried out by me upon white rats and extended over several months
showed no constant effect in facilitating the growth of young animals —
although there was no sign of retardation. R. Wulzen records, on the

o o

contrary, a retardation of growth in chicks when pituitary was added to
the food, the effect being more marked in males than in females. But

O

the most remarkable result of feeding with pituitary substance (anterior
lobe) is that described by L. N. Clark (Journ. Biol. CJtem., Oct. 1915),
who experimented on laying hens. In the first experiment, 35 White
Leghorn hens, as well as 2 cockerels of the same breed with which they
were mated, each received daily during eight days the equivalent of 20 mg.
of fresh pituitary substance in addition to their usual food. By the fifth
day the egg production of the batch was raised from an average of 18 per
diem to 33 ; the beneficial effect, although diminishing, was maintained for
several days after the pituitary had been taken off. And not only was
the output of eggs largely increased as compared with the controls, but
the fertility of the eggs and the hatching out of the chicks was extra-
ordinarily enhanced. In order to test the matter further, a second experi-
ment was performed with as many as 655 one-year-old White Leghorn
hens (kept without males), the same dose as before being administered to
each hen during four days. The average daily number of eggs laid by
the batch during the four days preceding the pituitary feeding was 233,
during the four days succeeding the administration, 352 ! These experi-
ments were made at a time of year when the egg production of the hens
was tending to diminish rather than to increase.

CHAPTER XIV
THE PITUITARY BODY (continued)

CLINICAL EVIDENCE

THE clinical symptoms due respectively to overgrowth of the gland and
to deficiency of its secretion are very various. Although many of these
symptoms have long been described, some of them have only recently been
interpreted as the result of alterations in the pituitary, and certain affections
which were previously obscure are gradually becoming elucidated. This
advance in knowledge has mainly been due to the experiments on animals
of which a description has just been given. The literature of the subject
is rapidly becoming enormous. A large number of cases in which the
pituitary probably played a causative part have been described by Harvey
Gushing in The Pituitary Body and its Disorders, 1910, a work which
marks an epoch in the study of this organ from the clinical aspect.

The course of many cases of disorder of the pituitary body (termed by
Gushing dyspituitarism) is as follows : Starting with enlargement of the
anterior lobe, they are heralded by symptoms of excessive function (hyper-
pituitarism). After a variable time — which may be greatly prolonged —
degenerative changes in the enlarged organ supervene, and there results
from this a gradual diminution (hypopituitarism), or even eventually an
entire loss of function (apituitarisiii). The primary enlargement is usually
first recognised by diminution of the visual field, caused by the pressure of
the enlarging gland upon the optic chiasma ; hence these affections generally
come first under the notice of the ophthalmic surgeon. Although there is
loss of vision, this may not be produced by actual destruction of nerve-fibres,
for it has frequently been noticed that after operation for removal of the
tumour or alleviation of the pressure produced by it the patient's vision is
speedily restored. Accompanying or preceding the visual symptoms certain
other signs are developed which point to the advent of a peculiar affection
(figs. 73, 74), termed acromegaly1 by Marie (1886). The affection to which
this name was given by him had been already described by others, and
its association with enlargement of the pituitary body had been re-
cognised. It is, nevertheless, to Marie — associated later with Marinesco —
that we owe the first complete account of the syndrome in question. The
name which he bestowed upon it expresses its most prominent sign,
" hypertrophie singuliere non-congenitale des extremites superieures, in-

, point, extremity ; pfyas, large.
106

Clinical Evidence regarding Functions of Pituitary 107
ferieures et cephalique " —a marked non-congenital enlargement of the

FIG. 73. — Case of acromegaly, front and side view. (From Klebs and Fritsche.) The
illustration sliows the enlarged hands, feet, and joints, the massive elongated face and
thick lips, the dorsal curvature (kyphosis), the apathetic look.

B

c

D

FIG. 74. — Four photographs of the same person showing the gradual development of the
facial appearance characteristic of the acromegalic. (Gushing. )

A, at 24 years of age (prior to the commencement of the disease) ; B, at 29 (onset of disease) ;

C, at 37 ; D, at 42 years of age.

limbs and head. The hands (fig. 75), feet, and face are especially hyper-
trophied, and X-ray photographs show a typical mushrooming of the ungual

108

phalanges (fig. 76).

The Endocrine Organs

FIG. 75. — Typical hand of acrome-
galic. (Gushing.) Notice the
broad palm and digits and the
relatively small nails, which lack
lunulee.

But the enlargement is not confined to the bones of
the extremities ; it affects the whole skeleton,
which becomes thickened and hypertrophied.
There is often considerable muscular develop-
ment ; the subject being abnormally strong.
If the affection does not supervene until adult
life is attained, i.e. until the epiphysial carti-
lages are ossified, the long bones do not grow
in length and the height is but little affected,
any increase of stature that is produced by
increase of the vertebral column being usually
more than compensated for by a kyphosis
(fig. 73), which supervenes after the disease
has made some progress. But if the hyper-
pituitarism commences whilst the cartilages
are still unossified, there is a considerable
growth in length of the long bones, so that
the patient attains an unusual height. This

condition is known as pituita/ry gigantism 1 (fig. 77) ; it is of essentially the

same nature and origin as acromegaly (Tam-

burini, Woods-Hutchinson, Lannois and Roy).
In acromegaly there is always enlargement

of the pituitary. This increase in bulk often

takes the form of a considerable tumour, which

can usually be detected during life in skiagrams

of the skull, the sella turcica showing a well-
marked enlargement. The tumour is usually

found to affect mainly or entirely the anterior

lobe, and if large is, as already mentioned,

liable to affect vision and to produce headache

and other symptoms of intracranial pressure.
In addition to the skeletal changes, others

occur. The integument becomes thickened ;

there is increased activity of the skin glands

and a tendency to an abnormal increase in the

growth of the hair over the body (hypertri-

chosis). Diminution of sexual activity often

supervenes early in the disease, although it

may be preceded by the opposite condition.

There is often glycosuria or simple polyuria : 2

when present these conditions are probably associated wTith hypertrophy of

1 There is another kind of gigantism, without pituitary enlargement, but associated
with defective sexual development and analogous to the increase of stature which occurs
as the result of castration before puberty (see Byrom Bramwell, Clinical Studies IV., Edin.
Med. Journ., June 1915).

2 Byrom Bramwell, Intracranial Tumours, 1888, and op. cit., 1915.

FIG. 76. — X-ray photograph of
two digits of an acromegalic
patient (Gushing) showing
the peculiar mushrooming of
the ungual phalanx.

Clinical Evidence regarding Functions of Pituitary 109

the pars intermedia rather than of the pars anterior. As the case advances
they may be replaced by high degrees of sugar tolerance, due to a sub-
sequent hypoplasia or degeneration of
pars intermedia. According to Andre
Levi, glycosuria occurs in 30 to 50 per
cent, of cases of acromegaly. It is in-
teresting to note that in pregnancy
also — in which the pituitary is found to
undergo enlargement— glycosuria not
infrequently occurs.

Marie and Marinesco were originally
inclined to the opinion that acromegaly
is due to destructive disease of the
gland, since in many cases it is found
post-mortem that the tumour is of
malignant character and that the sub-
stance of the gland has been destroyed.1
It was this idea which led to the carry-
ing out by various investigators of ex-
periments for the removal or destruction
of the organ in animals, in order to
produce, if possible, a similar syndrome.
But so far from producing increased
growth, this operation led to the opposite
result, the development of the skeleton
and body generally being retarded and
restrained. It is now recognised that

o

the tumours of the gland which are
associated with acromegaly are in the
first instance of a glandular (adeno-
matous) type ; although they may later
become of a malignant or of a cystic
nature and lead to the destruction of the
glandular tissue. It is therefore held
by most authorities that the char-
acteristic symptoms of acromegaly are
originally due to hyperpituitarism, i.e.
to increased function, although it may
be that there is also some degree of
perversion of function. In later stages effects of destruction may un-
doubtedly become apparent and supersede the symptoms of hypertrophy.
Sometimes the tumour of the gland is from the first malio-nant, but

FIG. 77. — Case of pituitary gigantism.
(Gushing.) The patient was 36 years of
age and 8 feet 3 inches high. Notice
the large elongated face, the dull heavy
expression, the long limbs, narrow chest,
enlarged joints, enormous hands and feet,
and the deficiency of hair (hypotrichosis).
The last is not a constant feature.

1 Marie appears more recently to have modified his views ; inclining on the whole to
the belief that it is a perversion and not a suppression of the secretion which leads to the
abnormal growth.

110

The Endocrine Organs

even then many of the cells tend to resemble those of the normal gland
(malignant adenoma) and symptoms of acromegaly may still be produced.
No one has yet succeeded in producing the effects of hyperpituitarism
experimentally, either by operation or by feeding with the gland.

It must be stated that by no means every case of tumour of the pituitary
is accompanied by the symptoms of acromegaly. For the disease may from
the first be destructive and at once tend to the opposite condition, viz.

hypopituitarism. There is, as we have seen, evidence
derived from the results of partial destruction in
animals as to the symptoms which may result from
such deficiency (p. 102). When similar symptoms
occur in man, it is therefore natural to conclude that
they have the same cause, viz., pituitary insufficiency;
and in some cases it has been possible to obtain, by
skiagrams or post-mortem examination, evidence of
diminution in size of the organ.

Hypopituitarism, produced either by diminution
in size or in activity of the gland, is probably the
cause of the syndrome described by Frohlich (1901)
and termed by Bartels dystropkia adiposogenitalis.
The symptoms of this affection closely simulate those
of animals which have undergone partial or com-
plete removal of the gland. A case in which such
symptoms made their appearance was described by
Madelung in 1904, in a girl of nine years of age
(fig. 78) whose pituitary was destroyed by a bullet
which lodged in the sella turcica.

The symptoms which are believed to be due to
pituitary insufficiency are, as might be supposed, the
reverse of those ascribed to hyperpituitarism. If the affection commence
before adolescence, the stature (instead of becoming gigantic as in hyper-
pituitarism) remains small (fig. 79). This is generally associated with
marked adiposity, so that the weight of the body may be large relatively
to the height. Sexual development is delayed and may remain consider-
ably in abeyance, producing a more or less permanent condition of sexual
infantilism. In the female the menses are irregular or absent, and in both
sexes there is deficient development of secondary sexual characters such
as the hair on the face (in the male) and over the pubes in both sexes.
Such hair as occurs in the last-mentioned situation in the male does not
extend to the umbilicus as is usual in that sex, but assumes the disposition
characteristic of the female, being limited to the mons veneris. On the
other hand, the hair of the head is generally abundant. Nor is the
character of the trichosis the only sign of feminism in subjects affected by
hypopituitarism. They usually have a broad pelvis, a certain amount of
genu valgum, rounded limbs, small feet and hands with tapering fingers,

FIG. 78.— Case of bullet
wound of pituitary.
(Madelung.)

Clinical Evidence regarding Functions of Pituitary 111

and occasionally well-marked mammary development. Skiagrams of the
bones generally exhibit persistent epiphysial lines (fig. 80). The skin is
smooth and delicate and free from moisture. The nails are small and
thin, and the crescents at their base are absent.

The tendency to adiposity is attributable by Gushing to deficiency of
posterior lobe secretion. This deficiency is usually associated with unusual
tolerance to sugar and an excessive assimilative power for carbohydrates,
which become transformed into fat and
thus produce adiposity.

A subnormal body - temperature is
generally present with the above symp-
toms, as well as low arterial tension
and a slow pulse ; there is also often
drowsiness and torpidity.1 Sometimes
evidences of psychic derangements and
occasionally a tendency to epilepsy have
been described.

Hypopituitarism and its accompany-
ing symptoms may result from simple
atrophy of the gland, as appears to
have been the case in the instance of
infantilism shown in the accompanying
figure from Byrom Bramwell (fig. 79);
in this subject the skiagram showed a
small sella turcica. Or it may be caused
by destruction of the gland, e.g. by the
formation of a cyst, or as the result of
pressure from a neighbouring tumour.

When the hypopituitarism comes on
after adolescence certain of the above
symptoms will be missed ; but the lowered
temperature, the tolerance to sugar, and the supervention of excessive
adiposity are generally present, as well as dryness of skin and loss of
hair, besides a tendency in the male to adopt the feminine type of trichosis,
even in cases where the male type has already been established. According
to Gushing, " pigmentation of the skin is a conspicuous feature of many of
the adult states, and as it is apt to be associated with asthenia or a low
blood-pressure it is natural to ascribe it to an associated adrenal insuffici-
ency, though it hardly reaches the degree of bronzing seen in some of the
Addisonian examples of adrenal tuberculosis."

As has already been stated, the history of some cases of affections of
the pituitary shows symptoms characterising hypopituitarism following
those characteristic of hyperpituitarism, although of course little or no

1 Gushing has pointed out that these symptoms closely resemble those which occur in
animals about to undergo hibernation.

FIG. 79. — Case of pituitary infantilism.
(Byrom Bramwell.) The patient was
27 when the photograph was taken.
His height was 4 feet 1| inches.
Notice the arrested development of
the sexual organs, the deficiency of
hair, the adiposity, the slender limbs
and digits, and the general approach
to the feminine type of body.

112

The Endocrine Organs

retrogression in the growth of the skeleton and body can generally be
expected. Thus the occurrence of hyperplasia and hyperpituitarism during
adolescence leading to a general overgrowth of the body and unusual growth
of hair, and sometimes accompanied by sexual precocity, may be followed
by glandular hypoplasia and diminution of the sexual instinct even
proceeding to impotence; as well as by excessive adiposity and the

FIG. 80. — X-ray photograph of hand from the case of infantilism shown in the preceding
figure. (Byrom Bramwell.) Notice the slender phalanges and the still detached
epiphyses. Reduced from 6J inches.

assumption by the male of some of the feminine characteristics which
have been above described as associated with hypopituitarism. This altera-
tion in the signs of disease complicates the clinical features of many
cases ; the complications can only be unravelled by a careful study of the
history of each case.

In many instances where the affection begins with hyperplasia of the
gland and subsequent changes produce destruction or degeneration of the
enlarged organ, leading eventually to apituitarism, these changes may
occupy years in their development, but the patient ultimately loses strength
and gradually wastes. Under such circumstances death results under

Clinical Evidence regarding Functions of Pituitary 113

conditions which are probably analogous to those of cachexia Jtypophyseo-
priva described by Paulesco, Gushing, and Biedl in the animals operated on
by them (pp. 100-102). It seems likely that this is the usual course of the
disease known as acromegaly. That the acromegalic skeletal growth is pro-
duced by hypertrophy and over-secretion of the anterior lobe is highly prob-
able, both as the result of partial extirpations in animals and from the effect
of operative removal of pituitary tumours in man. One case in particular
has been described (by Hochenegg) as having shown within a few days of
operation for removal remarkable amelioration of the symptoms, with
gradual diminution in size of the enlarged extremities, and eventually com-
plete cure. The thyroid gland both in this and in another instance which
was also successfully operated upon by the same surgeon became perman-
ently enlarged. In both, the pituitary tumour was a malignant adenoma.
In other cases operated on by Hochenegg, Gushing, and others, in some of
which an enlarged anterior lobe only was removed, the results have been
less striking than in the above example, but the retrogression of the disease
symptoms which resulted from the partial extirpation of the tumour has
occasionally been well marked. We are therefore warranted in believing
that the enlargement of the skeleton and the other signs which are
characteristic of acromegaly are due to hypertrophy of the anterior lobe
of the pituitary, whilst hypertrophy of the posterior lobe produces totally
different effects.

The symptoms due to hypopituitarism vary according as the anterior
or the posterior lobe of the gland is mainly affected. In the former case
the chief effect seems to be upon the stature. When, however, it is the
posterior lobe which is affected, a tendency to fat formation and to deficient
sexual development are usually manifested, without being necessarily
accompanied by diminution in stature; indeed, these conditions may be
associated with increased growth of the body, although not especially affect-
ing the skeleton, a characteristic infantile condition being retained. Rarely
such symptoms of deficiency of posterior lobe occur along with acromegalic
symptoms, and are then associated with concomitant enlargement of anterior
lobe. That the adiposity is related to a deficiency of the posterior lobe is
further indicated by the fact that, according to Strada, it is never accom-
panied by glycosuria or polyuria, symptoms which are almost certainly the
result of increased activity of that lobe.

In connexion with the influence of the anterior part of the organ on
growth, cases of dwarfs have been described in which the pituitary has
been noticeably small and atrophied; although it must be stated that
others have been recorded in which the contrary condition has been found.
The supposition that in these latter cases the enlargement is not a true
glandular growth as in acromegaly, but of an abnormal or destructive
character, is attractive. WTe must, however, be careful not to adopt it too
readily simply because it seems to fit in with what is believed to be the
effect of overgrowth of the organ in producing giants and acromegalics.

8

114 The Endocrine Organs

c*1

Nevertheless, it may be noted that in more than one such case of a dwarfish
stature apparently associated with enlargement of pituitary, the tumour
has been found to be really outside the gland and to exercise compression
upon it. It must be remembered also that increased activity of the natural
function of an organ may not necessarily accompany increase in volume :
this is exemplified in cases of endemic goitre. There is, on the whole,
reason to believe that a dwarfish habit of body is associated with diminution
either in size or in activity of the anterior lobe of the pituitary. These
changes may commence in infancy or even in the fostus.

Assuming, which there is no reason to doubt, that the two parts of the gland
have different functions, it is obvious that as the result of increase or diminution
of function of either part the clinical symptoms manifested in affections of this organ
may take very various characters. Thus both anterior and posterior lobes, or the
anterior lobe alone, or the posterior lobe alone, may exhibit either increased or
diminished activity ; and there is the further possibility of the one lobe having its
activity increased whilst that of the other is diminished. Under all these condi-
tions the clinical appearances would be different. The suprarenals and the thyro-
parathyroid apparatus may each, it is obvious, furnish clinical problems of similar
complexity.

CHAPTER XV
THE PITUITARY BODY (continued)

RELATIONS OF THE PITUITARY WITH OTHER ENDOCRINE ORGANS

THE relationship of the pituitary to other internally secreting organs is
extensive. Cow has recently shown that the secretion of the posterior
lobe is excited by duodenal extract, which causes its hormones to be poured
out in unusual amount into the cerebro-spinal fluid. The secretion of
this lobe is also related to the glycogenic functions of the liver, and there
seems to be a mutual interaction between its autacoids and those of the
pancreas, suprarenals, thyroid and sexual glands. Further, Ascoli and
Legnani found, in dogs which survived for a sufficient time the operation
of removal of pituitary, a diminution in volume of the spleen, with dis-
appearance of the Malpighiaii corpuscles, precocious retrogression of the
thymus, enlargement of the thyroid due to accumulation of colloid within
its follicles similar to that seen in endemic goitre, and an increase of lipoids
in the cells of the cortex of the suprarenals. The relationship with certain
of these organs may be considered more particularly.

With the Sexual Glands. — The relationship of the pituitary to the
sexual glands and secondary sexual characters has been dealt with in con-
sidering the symptoms associated with hypo- and hyper-pituitarism. Be-
sides the effect of these conditions on the state of development of the
secondary sexual characters and on the activity of the essential organs of
reproduction, the latter appear to have some reciprocal effect on the pituitary.
Several observers have described enlargement of the gland and increase in
the number of large oxyphil cells of the pars anterior as the result of
castration. Livingston finds that in rabbits the effect is greater in the female
than in the male. Further, Steinach and Scheldt aver that the changes in
the pituitary which would result from castration are prevented by im-
plantation of either ovary or test/is in the castrated animal, and since the
generative cells undergo atrophy under these circumstances they ascribe
the result to the interstitial cells of the implanted organs. Moreover, it
is found that both menstruation and pregnancy are associated with hyper-
trophy of the gland. Indeed, as the result of pregnancy it may attain to
twice or three times its normal weight.

o

With the Thyroid and Parathyroids. — That after the removal of the
thyroid the pituitary body becomes altered and enlarged was first shown
by Rogowitsch in 1886. His statements have been confirmed by all other

115

116

The Endocrine Organs

observers. Degener finds the increase in weight directly proportional to
the time which has elapsed after removal of thyroid (in rabbits). The
hypertrophy produced by thyroidectomy affects all parts, but most the pars
anterior, in which it is not uncommon to observe a development of colloid-
containing vesicles not unlike those of the thyroid : the same appearance is
seen in myxoedema (Hale White) and other affections involving atrophic
changes in the thyroid, or interference with its function, in the human
subject. A. E. Livingston found thyroid feeding to prevent the increase in

size of the pituitary which
would be caused by thy-
roidectomy.

Another striking effect
of thyroidectomy upon the
pituitary is increase of
wri*^ *v '• '&HP * hyaline and granular

*$:?' S£&& $> ' l^ife* masses in the ?ars inter-

media, and their passage
in large numbers through
the pars nervosa into the
infundibular extension of
the third ventricle (fig. 81)
(Herring). This denotes

„ .v an increased activity of the

* s ''jjj&ffi. pars intermedia. Whether

the phenomenon also occurs
in myxoedema has not been
noted, but it will probably
be found to be the case.

Halpenny and Thomp-
son describe enlargement of
the pituitary, and a con-
siderable increase of colloid-containing vesicles in the pars intermedia, as
the result of parathyroidectomy also.

The pituitary colloid is not identical with that of the thyroid. It is
noteworthy that it does not contain iodine, which is a characteristic com-
ponent of the thyroidal colloid in all animals. Even many months after
thyroid removal Sutherland Simpson and Andrew Hunter were unable to
detect the least trace of iodine in the sheep's pituitary. The pituitary
cannot take the place of the thyroid in animals affected with cachexia
thyreopriva, nor is pituitary extract able to take the place of thyroid
extract in the treatment of goitre and myxosdema. There is, therefore, no
•evidence that these two organs act vicariously. The effect of the injection
of their extracts is, moreover, entirely different. But that they have a
certain similarity of function in relation to growth and development is
shown by the results of their removal in young animals. In both cases

>i

'

FIG. 81. — Section through infundibular recess and neck of
posterior lobe of pituitary of a rabbit killed three months
after removal of thyroids. Magnified 200 diameters.
(Herring. ) Cells and colloid bodies streaming through
the pars nervosa and passing into the infundibular recess.

Relations of the Pituitary with Other Endocrine Organs 117

growth is slowed or arrested, the development of the body generally and of
the sexual organs in particular is checked, and that of the higher functions
of the nervous system is interfered with. There is also a tendency to adi-
posity, which is particularly marked in cases of hypophysial deprivation,
but is also seen after thyroidectomy and in myxoedema.

With the Suprarenals. — That there is some relationship between the
pituitary and the suprarenals would appear from the fact that, as
Gottlieb has shown, extracts of the posterior lobe of the pituitary and of
the suprarenal medulla mutually facilitate one another's action upon the
blood-vessels. Thus an immediately prior injection of even a small dose
of adrenalin will increase the effect of a dose of pituitrin, and vice versa.

There is also some evidence that an excess of adrenalin is secreted into
the blood as the result of injection of extract of the posterior lobe of
the pituitary.

With the Pancreas and Other Organs concerned with Carbohydrate
Metabolism. — Hypopituitarism. whether the result of disease or of surgical
interference, is associated with an increased tolerance for su^ar. This

p

function is, as we have seen, connected with the posterior lobe. Accord-
ing to Gushing, animals which have suffered deprivation of this lobe
will even bear removal of the pancreas without exhibiting glycosuria. But
the result of removing the pancreas in causing glycosuria is produced
through the liver, the glycogen of which becomes converted into sugar.
And an effect similar to removal of the pancreas is produced by excess
of adrenalin in the blood or by swabbing the exposed pancreas with
adrenalin solution.

There seems, indeed, to exist a functional correlation between pituitary,
suprarenal, pancreas, and liver, so that the disturbance of the function of
any one of them may affect the metabolism of carbohydrates through its
influence upon others. And to these we may add the thyroid, since, as has
already been noticed, the mechanism of carbohydrate metabolism is also
affected, in some manner as yet imperfectly understood, by variations in its
secretion. For hypothyroidism, like hypopituitarism, raises the assimila-
tion limit for sugar in the body. On the other hand, according to Asher
and Flack, the presence of an unusual amount of thyroid secretion in the
blood acts as an excitant to the suprarenals, causing an increased outpour-
ing of adrenalin, and thus producing a lowering of the sugar assimilation
limit. As we have seen, a deficiency in thyroid secretion is associated with
increase of secretion of the posterior lobe of the pituitary.

Gushing states that after removal of the pancreas the amount of
hyaline substance of the pars intermedia and pars nervosa is increased.

CHAPTER XVI
THE PINEAL GLAND

STRUCTURE OF THE PINEAL

THE pineal gland or epiphysis cerebri (conarium), which is present in
nearly all vertebrates, is in man a small solid organ less than half the size
of the pituitary body. It projects from the roof or dorsal wall of the third
ventricle (fig. 82, from the cat), and is connected on each side by a short stalk

:\- ^-" ^'

FIG. 82. — Sagittal section of pineal of cat. Magnified 50 diameters. I am indebted to
Dr Kojima for the specimen from which this microphotograph was taken.

or peduncle to the habenular commissure. The base of the gland has a
small infundibular depression (pineal recess) leading from the ventricle
just above the entrance of the aqueduct. This recess is the remains of an
evagination from the third ventricle, from which the pineal was originally
developed. In some reptiles a median eye is developed as a secondary out-
growth from this evagination (Baldwin Spencer). The gland is proportion-
ately larger in the child than in the adult, and in the female than in the
male. Its average weight in man is 0'22 gramme. It lies between the
anterior corpora quadrigemina, and is closely invested by pia mater, so

118

Structure of the Pineal

119

that it usually becomes detached from the brain if the pia mater is
torn away.

FIG. 83. — Section of pineal, new-born child. Magnified 400 diameters. Three or four
large sinus-like vessels gorged with blood are included in the section.

FIG. 84. — -Section of pineal of ox, stained with iron-hsematoxylin. Magnified 300 diameters.
I am indebted to Mr Edgar Beard for the specimen from which this microphotograph was
taken. The cell protoplasm and the reticular tissue between the cells are well shown.

Sections of human pineal show it to be composed of epithelium-like cells
arranged in loosely disposed trabeculse with large sinus-like blood-vessels
between the trabeculae (fig. 83). In some animals plain muscular tissue,
and even striped muscle, has been described in the intertrabecular tissue.

120 The Endocrine Organs

The blood-vessels are very numerous. There are no true nervous elements,
with the exception of a few fibres perhaps destined for the blood-vessels,
but neuroglia cells and fibres are present in abundance. Embedded both
in the interstitial tissue and in the covering of the pia mater are small
round globules of calcareous matter — corpora amylacea, brain sand—
which are much more common in man than in other animals, and more
numerous in the adult than in the child. The cells of the organ are not
uniform in character. Most have fine oxyphil granules in their protoplasm,
but some possess basiphil granules. Cells with large oxyphil granules such
as are seen in the anterior part of the pituitary are not found in the pineal.
Vesicles containing colloid are also absent, but cysts are not infrequent :
these may, however, be pathological. The gland undergoes retrogressive
changes after puberty : there is marked hypertrophy of the intertrabecular
tissue, which shows a characteristic reticular appearance resembling neuroglia
and at the same time considerable diminution in the number of epithelial
cells (fig. 84).

EFFECTS OF INJECTING EXTRACTS OF PINEAL

According to my own observations, extract of pineal injected intra-
venously produces a marked but temporary fall of blood-pressure accom-
panied by a diminution in volume of the kidney; the last is probably passive,
for no effect is manifest on the flow of urine (fig. 85). The substance which
produces these results is extracted from the gland by alcohol.

Ott and Scott state that the result of intravenous injection of extract
of pineal is to produce a fall of blood-pressure followed by a prolonged
rise with dilatation of kidney volume and diuresis. They describe some
increase of contraction of the uterus. They also found a slight galacta-
gogue action. These effects are similar to those produced by pituitary
extract. They further obtained dilatation of the pupil on dropping the
extract into the eye of an animal in which the superior cervical ganglion
had been extirpated. Many of the above statements appear to require
confirmation, but the galactagogue action has been noticed by Mackenzie
(fig. 86). Previous workers, including Howell, Cyon, Dixon and Halliburton,
and Jordan and Eyster, have obtained no definite result from pineal ex-
tracts so far as arterial pressure and kidney secretion are concerned ; if
we except the fall in blood-pressure, which Dixon and Halliburton consider
to be non-specific.

EFFECTS OF EXTIRPATION. RELATIONS OF THE PINEAL WITH THE

SEXUAL GLANDS

Extirpation of the pineal is a difficult operation to carry through with-
out provoking severe haemorrhage, to which the animals operated on have
generally succumbed. The most complete series of experiments as yet
made are those of Foa on the domestic fowl, and those of Sarteschi on

Effects of Extirpation

121

gland was

young rabbits and puppies. In pullets in which the pineal
destroyed no difference could be noted on comparison with controls, but in
cockerels Foa describes not only a more rapid growth of the body, but an
earlier development of the testicles and of the secondary sexual characters.
The results obtained by Sarteschi agree generally with these.

FIG. 85. — Effect on kidney volume and blood-pressure of intravenous injection of a
solution in Ringer's fluid of dried alcohol extract of sheep pineal.

a, kidney volume; b, blood-pressure ; c, urine drops ; d, time in ten seconds ; e, signal.

In connexion with this it is noteworthy that abnormal growth of the
skeleton with sexual precocity and early development of secondary sexual
characters have been observed in young boys affected by pineal tumour ;
although this is by no means true for all cases in which such tumours have
been found. In some in which secondary sexual characters were present
there was an unusually large amount of the interstitial tissue in the
testicles, although these organs had otherwise remained small. It is pro-

122

The Endocrine Organs

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Effects of Extirpation 123

bable that the sexual precocity is associated with the development of this
interstitial tissue (see p. 135). The symptoms resemble those described as
the result of pineal removal, and have therefore been regarded as due to
hypopinealism. On the other hand, it has been found (Dane and Berkeley,
M'Cord) that the administration of pineal extract, both by feeding and by
subcutaneous injection, is also followed in young animals by precocious
sexual development, particularly but not exclusively in males. The rate of
body growth of the pineal-fed animals is also greater than that of the
controls. The addition of even a small amount of gland substance to the
food is said to be sufficient to produce a marked result.

Another condition which has been sometimes observed to accompany
pineal tumours is unusual adiposity of a nature somewhat similar to that
accompanying hypopituitarism, although not, like that, associated with
deficient development of the sexual organs. It is suggested that this may
be caused by hyperpinealism.

The accounts of the effect on the pineal of removal of the generative
glands have been conflicting. The experiments of Sarteschi on male
animals of several different species proved negative : whereas Biach and
Hulle described in cats, both male and female, the production of an
atrophied condition of the pineal. In connexion with this it may, however,
be mentioned that the pineal is often normally very small in the cat.

It must be admitted that the results of clinical observations and experi-
mental work in animals are at present difficult to reconcile, and do not
enable us to come to any definite conclusion regarding the functions of
this organ and the nature and mode of action of its autacoids.

CHAPTER XVII

THE INTERNAL SECRETIONS OF THE ALIMENTARY
MUCOUS MEMBRANE AND OF THE PANCREAS

SECRETINES

BAYLISS and Starling discovered in 1902 that an extract of the duodenal
mucous membrane, or even of its epithelium alone, if injected into the
circulating blood, produces a rapid secretion of pancreatic juice (fig. 87).
In Bayliss and Starling's experiments the active substance was obtained by
boiling the mucous membrane with dilute hydrochloric acid and afterwards

a

b
c

d

FIG. 87. —Effect on blood-pressure and secretion of pancreatic juice of injecting into a vein
extract of mucous membrane of duodenum, made by boiling with dilute hydrochloric
acid and subsequently neutralising. (Bayliss and Starling.)

a, blood-pressure : notice the sharp fall followed by return to normal ; b, drops of pancreatic juice ;
c, signal ; d, time in seconds.

neutralising and filtering : the autacoid (hormone) is contained in the filtrate.
They observed little or no activity from extracts of membrane which
had not been treated with acid, and concluded that the active substance
(secretine) is present in the cells in an inactive form (pro-seer 'etine), and be-
comes activated (converted into secretine) by the action of the acid. It had
been previously found that rinsing the duodenum with dilute mineral acid 1

1 According to Babkin and Ishikawa, fatty acids introduced into the duodenum have a
similar effect.

124

Secretines 125

would provoke secretion of pancreatic juice. This had been put down to a
reflex effect through nerves and nerve-centres, but the experiments of Bayliss
and Starling made it clear that the effect is due to the formation and absorption
into the blood of an organic chemical agent which is dialysable and not des-
troyed by boiling, and is presumably of a fairly simple chemical constitution.

Hustin finds that perfusion of pancreas with Locke's solution -f- secretine
is without effect, but if blood + secretine is used an abundant secretion,
containing all the ferments, is poured out by the duct.

That there is some mutual interaction between pancreas and duodenum
would appear from the observations of Evans, who found that pro-secretine
•disappears from the duodenum after complete extirpation of pancreas, but
not if enough pancreas is left to prevent the occurrence of glycosuria.

Duodenal extracts do not act only on the pancreas ; they also increase
the flow of bile and of succiis entericus, but to a less extent.

Cow has made the interesting observation — already referred to in con-
nexion with the pituitary body — that intravenous injection of duodenal ex-
tract produces a discharge of pituitary secretion into the cerebro-spinal fluid.

In 1906 Edkins announced that a substance of similar nature to secretine,
but acting upon the glands of the stomach, can be extracted from the
pyloric mucous membrane by boiling water or dilute hydrochloric acid, or
by solutions of dextrin, maltose, or albumose. According to Edkins extracts
of the mucous membrane of the fundus do not yield a similar substance.
The hormone in question is termed gastric secretine or gastrine. It exists
in the mucous membrane in the form of a precursor (pro-gastrine} which is
activated by the above reagents. These observations have recently been
confirmed by experiments in Pawlow's laboratory.

Atropine, which, in small doses, operates through the nerve endings of secret-
ing organs, does not inhibit the action of these secretines. Their activity is
therefore probably manifested directly upon the cells of the organ they stimulate
and not through the nerve terminations.

THE INTERNAL SECRETION OF THE PANCREAS. THE ISLETS

OF LANGERHANS

The pancreas contains, besides its alveoli and the ducts which conduct
their secretion into the duodenum, a peculiar epithelial tissue occurring
in most animals in the form of small isolated masses interspersed through-
out the gland, and known from their discoverer (1869) as the islets of
Langerhans (fig. 88). Although quite distinct in appearance and in the
characters of their cells from the epithelium of the alveoli, the study of
their development shows that they originally grew out from the budding
ducts, and that their cells have therefore an origin in common with those
of the alveoli. But they have no open communication with the ducts or
alveoli. The number of islets in the pancreas is very variable, and this
variability has led to inferences being drawn regarding their appearance

126

The Endocrine Organs

FIG. 88. — Section of pancreas of dog, showing an islet
of Langerhans between the alveoli. Magnified 200
diameters.

and disappearance which in many cases are probably not justifiable. Thus
Bensley found a variation in the guinea-pig in animals of different ages

of from 10 to 189 islets per
milligramme of pancreas: in
the mature animal the varia-
tion was from 10 to 25. The
enumerations of Clerk led
him to the conclusion that
in the normal human pan-
creas there may average 10
to 20 islets in each milli-
gramme of the gland, which
roughly would give about
three-quarters of a million
to a million and a half for
the whole pancreas.

In Teleostean fishes
Rennie has shown that there
is one very large mass of islet
tissue which is encapsuled by
connective tissue and practi-
cally forms a separate organ.
But in other animals the
islets are closely encircled by and in contact with the alveolar tissue, and
sometimes appear to be continued into it. According to Pensa, they have an
abundant supply of nerve fibres.
Each islet has a specialised blood-
supply (fig. 89) in the form of
a network of irregular-shaped
sinus-like capillaries which are
both larger and relatively more
numerous than the capillaries of
the alveoli (Klihne and Lea).

The cells of the islets are
generally much less stained by
the ordinary dyes used in histo-
logy than are those of the alveoli.
They are therefore usually de-
scribed as chromophobe. But
they have an especial affinity, as
Bensley has shown, for neutral

red and janus green, employed as intra vital stains. Although they contain
granules, these are much finer than the zymogen granules of the alveolar
cells. According to Lane, there are two kinds of cell in the islets, dis-
tinguishable from one another by the nature of their granules. The cells

^

§ ^

FIG. 89. — An islet of Langerhans of the pancreas,
with its blood-vessels injected. (Kiihne and Lea.)

The Internal Secretion of the Pancreas 127

come into very close relation — indeed, in actual contact — with the walls
of the blood capillaries. If the duct of the pancreas is tied, the ordinary
alveolar tissue disappears after a time, although for a long while there are
remains of the ducts. But most observers are agreed that the islet tissue
does not — at least to any great degree — participate in the atrophy of the
alveoli, and the statement that it persists under these circumstances —
although denied by some authors — is generally accepted.

EFFECT OF SURGICAL REMOVAL OF PANCREAS. DIABETES

Since the discovery in 1889 by v. Mering and Minkowski that removal
of the pancreas, or even of the greater part of the organ, is immediately
followed by hyperglycsemia leading to severe and fatal diabetes, whereas
this effect is not obtained from mere ligature of the duct (in spite of
the disappearance of all the alveolar tissue and the complete cessation of
formation of pancreatic juice), attention has been especially directed to the
islet tissue as the probable source of an internal secretion which serves
to regulate carbohydrate metabolism. For, as has just been stated, the
cirrhosed and atrophied gland which remains after ligature of the duct
contains none of the ordinary secreting epithelium, except perhaps that of
a few remaining ducts, but does, in all probability, still contain the islets
of Langerhans. Nevertheless, this atrophied gland is sufficient to furnish
the internal secretion which regulates carbohydrate metabolism, so that
this is maintained normal for an indefinite time. But if now the atro-
phied gland is removed, diabetes at once shows itself. Further, if a portion
of pancreas, whether thus atrophied or not, be successfully transplanted
to another site and the rest of the gland be then removed, diabetes does
not occur — although on removal of the graft it immediately makes its
appearance. The evidence for the action of an internal secretion which is
yielded by the gland — and in all probability by its islet tissue, — and serves
to maintain carbohydrate metabolism in a normal condition, is therefore
very complete. In support of this conclusion it has frequently been noted
in cases of diabetes in man that the cells of the islets have undergone some
kind of degenerative change.

If the pancreas removal is complete, the percentage of sugar in the urine
is very large, even during fasting or on carbohydrate free diet. Minkowski
found the relation of dextrose to nitrogen in the dog under these circum-
stances to be 2*8 : 1. With protein diet the sugar rises (and falls) with the
nitrogen : with fatty foods there is an increase in the quotient : while carbo-
hydrates of the food are almost wholly passed out by the urine as dextrose.
Lsevulose is, however, utilised in the body to a considerable degree, and the
glycogen which had disappeared from the liver and muscles may to some
extent reappear when this sugar is given with the food.

The glycosuria is accompanied by hyperglycasmia, which is indeed the
actual cause of the glycosuria; but according to de Meyer the latter is

128 The Endocrine Organs

augmented by the fact that the permeability of the kidneys to blood-sugar
seems also to be somewhat increased by absence of the pancreas. The
hyperglycsemia is produced in the first instance by transformation of the
liver glycogen into sugar, which is passed into the blood ; while the glycogen
of the muscles is also diminished.1 The sugar thus produced from the liver
glycogen is not utilised in the body, but is for the most part at once got rid
of by the kidneys. Since, therefore, the carbohydrates of the food are not
used for nutrition, there is a comparatively greater call upon the proteins
and fats both of the food and of the body, so that the animal loses flesh
rapidly and death may ultimately result from inanition, unless the end has
arrived sooner as the result of the accumulation in the body of abnormal
by-products of the metabolism of proteins and fats (such as the acetone-
bodies) tending to acidosis and the production of diabetic coma.

Kausch, and independently Noel Paton, have shown that in birds re-
moval of the pancreas does not cause glycosuria although hyperglycaBinia is
produced ; on subsequently administering adrenalin, glycosuria supervenes.

NATURE OF THE PANCREATIC AUTACOID

The results of pancreas extirpation and pancreas grafting can, as we
have seen, be best explained by supposing that the islet tissue produces
an autacoid which passes into the blood and affects carbohydrate meta-
bolism and carbohydrate storage in such a manner that there is no undue
accumulation of glucose in the blood. Provisionally, it will be convenient
to refer to this hypothetical autacoid as insuline. It must, however, be
stated that it has yet to be determined whether the active substance is
present as such in the pancreas or whether it exists there as pro-insuline,
which becomes elsewhere converted into the active autacoid. It is not found
that pancreas extracts have the effect of antagonising the results of pancreas
extirpation : in this respect they offer a parallel to the negative results of
suprarenal extracts in antagonising the effects of adrenal deprivation. On
the other hand, it has been shown by Hedon and others that the blood of a
normal dog contains substances which, when allowed to circulate through
the system of a depancreatised dog, prevent the occurrence of glycosuria.
It has also been shown by Carlson and Drennan that if a pregnant bitch
be deprived of the pancreas she does not suffer from glycosuria as long as
her foetuses remain in utero. This experiment indicates that the autacoids
produced by the fretal pancreas can pass to the maternal circulation through
the placenta ; and both experiments afford a clear indication that the influ-
ence of the pancreas upon carbohydrate metabolism is due to a chemical
agent circulating in the blood. Later experiments of Hedon seem to show
that the autacoid is inactive whilst within the pancreatic vein, and only
becomes activated on passing through the liver.

] Ehrlich found the glycogen of the blood-leucocytes to be markedly increased in amount
in pancreatic diabetes.

Nature of the Pancreatic Autacoid 129

There are various ways in which the prevention of an undue accumula-
tion and mobilisation of glucose and the consequent appearance of hyper-
glycsemia might be supposed to be effected by an internal secretion of the
pancreas islets.

(1) The active agent may itself be a glycolytic ferment (Lepine) and
may be the source of the glycolytic ferment which is known to be present
in blood. If so, removal or disease of pancreas would tend to produce
glycosuria in consequence of the absence of sufficient of this ferment to
effect the splitting of glucose, so that the sugar of the body would not be
metabolised further and would be passed out as such by the urine. As
against this theory, it is found that in diabetes the glycolytic power of the
blood is not diminished, and although in support of it the fact has been
urged that a glycolytic ferment can be got from the pancreas, it must be
pointed out that this is by no means peculiar to that organ, for a similar
enzyme is yielded by most organs and tissues of the body.

(2) It may be of the nature of a kinase, the function of which is to
convert a pro-ferment into ferment, or perhaps to promote the activity of
an already existing ferment which serves to break down the molecule of
glucose and prepare it for ultimate oxidation in the muscles, liver, etc. In
support of this hypothesis it is stated by O. Cohnheim that a combination
of muscle juice with pancreas juice (obtained from the cells by hydraulic
pressure) is far more active glycolytically than either of the two employed
singly ; although, as Levene points out, the disappearance of sugar which
is caused cannot be definitely regarded as glycolysis. According to De
Meyer, a glycolytic pro-ferment which is activated by pancreas extract is
contained in the blood-leucocytes. Anything which tends to prevent the
formation of insuline, such as disease of the islet tissue, the entire removal
of the pancreas, and perhaps the action of adrenalin, would therefore
necessarily interfere with the glycolysis and prevent the utilisation of
glucose by the tissues, so that hyperglycsemia and glycosuria would be
produced. According to this theory, the tissues of a depancreatised dog
should be unable or less able to utilise glucose for the production of muscular
work. Experiments on heart muscle which seemed to support this were
published by Knowlton and Starling. But other experiments by Forges
and Salomon (on skeletal muscle) gave a contrary result, and Starling has
since come to the conclusion that his results with Knowlton were within
the limits of individual variations of the normal heart muscle.

(3) The substance (insuline) produced by the pancreas islets may be a
chalonic autacoid which tends to inhibit the formation of glucose from
glycogen, and incidentally to promote the storage of glycogen, so that in
its absence the glycogen which is present in the liver is rapidly converted
into glucose and the sugar absorbed from the alimentary canal or formed
in the body is not stored by the liver. The result again will be hyper-
glycaemia and glycosuria. The fact that the conversion of glycogen into
glucose occurs rapidly in the excised liver seems to indicate that there is

9

130 The Endocrine Organs

something which under ordinary circumstances acts as an inhibitory agent,
and we may suppose this to be present in the blood, and that it has been
furnished by the pancreas.

The hypothesis that there exists a chalonic or inhibitory agent in the
internal secretion of the pancreas which affects carbohydrate metabolism
is probably the correct one. Whether this is of the nature of an autacoid or
of an enzyme cannot be definitely stated, although the supposition that it
is an autacoid is most in accordance with what is known regarding the
effective agents of other internal secretions.

RELATION OF INTERNAL SECRETION OF PANCREAS WITH OTHER

ENDOCRINE ORGANS

Hyperglycaemia is produced not only by extirpation of the pancreas, but
in various other ways, such as by Bernard's sugar-puncture of the medulla
oblongata, by stimulation of the splanchnics, and by the introduction of an
excess of adrenalin into the blood.

We have seen that brushing the pancreas with adrenalin provokes
marked hyperglycaemia and glycosuria, and that this is not merely due to
absorption of the autacoid into the general circulation is shown by the fact
that the excess of sugar is far greater than when other organs are so treated.
It is not, however, only through the pancreas that adrenalin glycosuria is
produced, for it has been shown by various observers that there is an in-
crease of sugar in depancreatised animals (also in cases of pancreatic diabetes
in man) as the result of adrenalin injection. Moreover, the effect of
adrenalin is produced immediately both in normal and in depancreatised
animals, whereas it takes some hours for the effect of depancreatisation
upon carbohydrate metabolism to show itself. On the other hand, Zuelzer
and others have found that adrenalin glycosuria is prevented by pancreas
extracts and even by pancreatic juice ; this effect is, however, according
to De Meyer, not due to an antagonising autacoid, but to the effect of the
extracts upon the permeability of the kidney for sugar. The result of
administering pilocarpine, which produces marked secretion from the
pancreas by exciting the secreting endings of the vagi, is also to prevent
adrenalin glycosuria ; possibly it acts by stimulating nerve-endings to the
islet cells as well.

Loewy finds that after removal of the pancreas, adrenalin causes dilata-
tion of the pupil when dropped into the eye ; this does not occur in
the normal animal. The same observation has been made in cases of
diabetes in man — presumably these cases are of pancreatic origin.

With regard to the relations between the pancreas and the thyroid and
parathyroids, it is found that removal of the thyroid tends to prevent, and
removal of the parathyroids to facilitate, both pancreatic and bulbar
glycsemia and glycosuria. The thyroid autacoid may therefore be regarded
as in this matter antagonistic to that of the pancreas, whilst the parathyroid

Relation of Pancreas with Other Endocrine Organs 131

assists it. It may be that the increased tolerance to sugar which is
associated with diminished activity of the thyroid, the posterior lobe of
the pituitary, and the medulla of the suprarenals respectively, is brought
about through the effect of the changes in those organs upon the pancreas.

The mode of pi-oduction of pancreatic diabetes is in need of further elucidation.
It would appear, however, from what has been above stated, that, apart from the
liver, which acts as the main storehouse for carbohydrates, a number of organs
are concerned in governing the metabolism and mobilisation of those bodies, all
these organs being mutually interdependent. Of such organs the pancreas, pro-
bably by virtue of the internal secretion of its islet tissue, may be regarded as
occupying the central position.

The interrelations of these endocrine organs (particularly the thyroid, pancreas,
and suprarenals) in connexion with the production of glycaemia and glycosuria
have been especially dwelt upon by Eppinger, Falta, and Rudinger. The relations
of the internal secretion of the pancreas with glycogenic functions of the liver are
dealt with at length by De Meyer, Secretion interne du pancreas, 1910.

CHAPTER XVIII

THE INTERNAL SECRETIONS OF THE GENERATIVE
GLANDS IN THE MALE1

THE INTERSTITIAL CELLS OF THE TESTICLE

IT was noticed by Leydig in 1850 that the intertubular connective tissue
of the testicle is characterised by the presence of strands of epithelium-like
cells ; these have been termed the cells of Leydig, and, collectively, the

^

FIG. 90. —Section of testicle, human, showing groups of interstitial cells between the

tubules. Magnified 50 diameters.

interstitial gland of the testis. They vary in development in different
species of animals, being very well marked in the cat (fig. 92), less so in
the dog and mouse, and still less in the rat and rabbit : in man they may
be quite conspicuous (figs. 90, 91). The cells are always present to some
extent, and Tandler and Grosz have shown that in animals which undergo
seasonal changes in sexual activity the interstitial cells may be even better
developed when the seminiferous tubules are inactive than during the time

1 For a fuller discussion of the subject of internal secretion in connexion with the sexual
organs, F. H. A. Marshall's Physiology of Reproduction may be consulted.

132

The Interstitial Cells of the Testicle

133

of their activity, their increased development generally immediately pre-
ceding that of the seminiferous epithelium. The tissue may also be found
well developed in cases where there is atrophy of the contents of the
seminiferous tubules, as in cases of cryptorchidism and after ligature of the
vas def erens ; although if the whole of the spermatic cord be included in
the ligature, so that the circulation and nerve-supply to the testicle is inter-
fered with, the interstitial cells share in the general atrophy of the organ
which ensues, and the result is the same as castration (Vincent and Coleman).

rap

i '

FIG. 91. — Interstitial cells of testicle, human. Magnified 200 diameters. One tubule
and parts of two others are shown. The groups of interstitial cells lie in the
loose intertubular reticular tissue. (Figs. 90 and 91 are from an iron-haematoxylin
preparation given me by Professor Martin Heidenhain.)

These interstitial cells are polygonal in shape with spherical nucleus, a
well-marked nucleolus, and a double centrosome. The cytoplasm often
contains lipoid granules of a yellowish colour, which are blackened by
osmic acid ; besides other granules of protein nature, which may be either
oxyphil or basiphil. Frequently there are crystals within the cells, but
the exact nature of these has not been determined.

EFFECTS OF CASTRATION

The results of removal of the testes are well known. If the operation
is performed in the child the secondary sexual organs — especially the
prostate and seminal vesicles — remain in an undeveloped condition, and the
special secondary sexual characters, such as the growth of hair on the face,
the enlargement of the larynx, and the development of the male characters

134 The Endocrine Organs

of the skeleton, are not seen. In such animals as birds and deer, in which
the external characteristics of the male sex are well marked, these
characteristics fail to show themselves, the general features of development
approaching those usual to the female sex. In the skeleton, the epiphyses
long remain separate ; the limb bones are longer and more delicate than
usual, and the sutures of the skull slower in ossifying. The mental char-
acter also tends to retain a more infantile type. Most of the ductless
glands are in some way affected, the growth of the thyroid being
diminished, that of the suprarenal cortex, pituitary, and thymus increased :
the last-named organ shows arrest of its normal retrogressive changes.

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FIG. 92. — Interstitial cells of testicle, cat. Magnified 200 diameters. Parts of three
tubules are included in the photograph.

If castration is performed in the mature animal, and therefore after the
secondary sexual characters have become developed, there may be some
retrogression of these, and such accessory generative glands as the prostate
tend to undergo atrophic changes. But the effects are now mainly upon
metabolism, and are shown in a tendency to increased formation of fat,
although the limit of assimilation of carbohydrates is lowered and alimentary
glycosuria is more easily produced. How far these effects on metabolism
are direct or how far indirect, through other endocrine organs, it is not pos-
sible to say, but the fact seems to be well established that the pituitary body
becomes hypertrophied after castration (Fichera, Cimorini). The increased
length of limb bones which occurs when the operation is performed before
adolescence may be associated with this change in the pituitary (Tandler).

In certain animals which undergo seasonal variations in sexual activity the
secondary sexual characters which generally accompany these variations are
also abolished or modified by castration. Thus if a stag is castrated, the antlers

Effects of Castration 135

either remain undeveloped or if developed are shed prematurely and are not
replaced, or replaced only by incomplete growths. But structures which are
common to both sexes — in species, for instance, in which both sexes possess horns-
are not modified by castration. In Arthropoda the correlation between the
generative glands and the secondary sexual characters (which in many species are
even more marked than in Vertebrata) does not hold good. Experiments upon
caterpillars show that removal of the generative glands has no influence on the
development of the male sexual characters of the imago ; nor do the glands, if
transplanted into individuals of the other sex, affect the secondary sexual characters
or instincts of the host. This need not be taken to mean that the secondary
sexual characters in these animals are not the result of an internal secretion, but
may be interpreted by supposing that some organ other than the generative glands
furnishes the internal secretion which produces those characters.

In Vertebrata, at any rate, there can be little doubt that the internal secretions
of the generative glands are an important if not the chief factor in determining
the development of the secondary sexual characters. And that this development
is independent of the normal functions of the generative glands is shown by the
fact that ligatiire of the vas deferens has no effect in preventing it. Moreover,
transplanted testes and portions of testis (in which the generative cells themselves
may completely disappear) have been found capable (in birds) of preventing the
results of castration : the comb, wattles, spurs, etc., of the cock being developed
in the usual way (Shattock and Seliginann and others). Nussbaum's experiment
on the effect upon the development of the thumb-pad of grafting pieces of testis
from another frog into the dorsal lymph sac of a castrated male frog also points
to the existence of an internal secretion of the testicles in these animals.

THE NATURE AND SOURCE OF THE TESTICULAR AUTACOID

It seems certain, therefore, that the development of the secondary
sexual characters in the male sex is dependent upon an internal secretion
of the testicle, and it is highly probable that it is yielded not by the gener-
ative cells (gonads) but by the interstitial cells. In cryptorchids, and also
after experimental ligature of the vas deferens, in both of which, as we
have seen, the seminiferous epithelium is atrophied but the interstitial
tissue is well developed, the secondary sexual characters and sexual desire
are normal. Successful implantation of the whole or part of a testicle in
a young castrated animal is also followed by development of those char-
acters, although in most cases the seminiferous epithelium of the graft dis-
appears. Loewy found male secondary characters developing in caponised
cockerels fed with testicle-substance. Bouin and Ancel state that extract of
testicle freed from all morphological elements may, when injected, produce
a similar result. In support of the theory that an autacoid which affects
the development of the secondary sexual organs and characters is formed
by the interstitial cells, they have found that if one testicle is removed
from a rabbit and the remaining one has the vas ligatured its interstitial
tissue becomes hypertrophied. Further, it is known that if the testicles
are exposed to the action of X-rays the seminiferous epithelium undergoes

136 The Endocrine Organs

degeneration, although the interstitial tissue is not, at first at any rate,
attacked. Young animals so treated develop normal secondary sexual char-
acters. Moreover, remarkable cases have been described, in both the male
and female sex, in which tumours of the testicle and ovary, apparently
malignant in character, occurring in children, have been accompanied by a
general growth of stature and by premature appearance of secondary sexual
characters, such as growth of hair on the face in the male and in the arm-
pits and on the pubes in both sexes, development of breasts and external
generative organs : in short, all the signs of puberty ; which, on removal
of the tumour, have been found to disappear. These seem to be cases of
tumour cells taking on the functions of normal cells (in this case interstitial
cells) from which they have developed (see p. 33).

EFFECTS OF EXTRACTS OF TESTICLE

Brown-Sequard was of opinion that subcutaneous injection of testicular extracts
has the effect of producing a bodily and even more a mental rejuvenation, and he
ascribed this to the occurrence in such extracts of certain principles which are
taken up into the blood, and through this act upon the nervous system. He
supposed that similar principles are produced also in the ovaries, but to a less
extent. The results he announced ikave not, however, been obtained by others
who have tested the physiological effects of such extracts, and the views he enunci-
ated have not obtained general assent, although certain observers claim to have
obtained positive effects on the growth and development of young castrated animals,
and also of immature entire animals.

Intravenous injections of testicular extracts produce no immediate results
except a fall of blood-pressure, due, according to Dixon, to cardiac inhibition.

CHAPTER XIX

THE INTERNAL SECRETIONS OF THE GENERATIVE
ORGANS IN THE FEMALE

THE INTERSTITIAL CELLS OF THE OVARY

THE ovary contains — besides the Graafian follicles with their ova, follicular
epithelium and liquor folliculi and the corpora lutea — a highly vascular
stroma formed of a peculiar connective tissue, firm in texture and containing

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FIG. 93. — Section of the wall of a Graafian follicle of the rabbit, from which the ovum
and follicular epithelium have just been discharged. The cavity is occupied by a
blood-clot of which part of the fibrin-network is shown in the photograph. Notice
the large cells in the wall of the follicle (theca) from which the luteal cells become
developed. Magnified 200 diameters.

numerous spindle-shaped cells. In some animals it is possible to discover
in the stroma groups of cells of a different appearance from that of the
ordinary stroma cells. These have been named the interstitial cells of
the ovary, and have been thought to be analogous to the interstitial cells
of the testicle. But the interstitial cells of the ovary do not form so
distinct a tissue as those found in the testicle ; they are, moreover, said to be
destroyed by the X-rays, whereas those of the testicle are not so affected :
they appear therefore not to be of identical nature. As the Graafian follicles
mature, their wall (theca) is found to contain peculiar large epithelium-like
cells (fig. 93) (theca cells), derived from the stroma and not improbably

137

138

The Endocrine Organs

from the interstitial cells. It is from these theca cells that the cells of the
corpora lutea are derived; while, on the other hand, as the latter disappear,
many of their cells tend to lose themselves in the substance of the stroma.

THE CORPORA LUTEA

The manner of development of the corpora lutea appears to be as
follows : — The larger follicles become gradually more distended with liquor

folliculi, and ultimately
'''• ••':'.:• ,• .-" •' ' split open at the thinnest

and most prominent part.
When the follicle bursts,
the ovum and discus pro-
ligerus escape, and the
rest of the follicular epi-
thelium also becomes de-
tached from the follicular
wall and extruded or dis-
integrated. The cavity
of the follicle is now usu-
ally occupied by a blood-
clot (fig. 93), derived from
vessels at the point of rup-
ture of the follicle. The
enlarged cells in the wall
of the theca multiply and
grow into the cavity, dis-
placing the clot towards
the hilum of the follicle.
They are filled with lipoid

-^Sg^cHBj

•^v''^J$&:X

FIG. 94. — A stage in the development of a corpus luteum of
the rabbit in which the cells form trabeculaj converging
towards the remains of the blood -clot which originally
occupied the cavity of the Graafian follicle. Magnified
60 diameters.

droplets which give the
structure the yellowish
colour from which the name corpus luteum is derived. The cells are now
known as luteal cells ; in most animals they arrange themselves in trabeculse
converging towards the remains of the clot (figs. 94, 95), which becomes
gradually organised, its place being taken by fibrous or cicatricial tissue.
Sinus-like blood-vessels grow in from the theca along with the luteal
cells, and the whole structure eventually forms, in most animals, a solid
gland-like vascular mass, which is usually much larger than the follicle it
replaces. In animals which have several young at a birth, and in which
therefore several follicles come to maturity at about the same time, the
resulting corpora lutea may appear to occupy almost the whole ovary,
which becomes greatly enlarged as they develop.

From the above account, which is based upon observations in the rabbit and
corresponds with that originally furnished by von Baer, since confirmed by many

The Corpora Luten

139

histologists, it seems clear that the corpus luteum is developed entirely from the
theca cells of the burst follicle : these cells are themselves derived from stroma
cells, so that the follicular epithelium takes no part in the formation of the
corpus luteum.

Some authorities hold, however, that the follicular epithelium is not lost when
the follicle bursts, but that its cells undergo proliferation and become enlarged
and transformed into luteal cells,
so that a part if not the whole of
the corpus luteum is formed from
the epithelium which originally lined
the Graafian follicle.

In the human subject,- as in
the lower mammals, the luteal
cells at first form a layer lining
the wall of the follicle. Pre-
sently this layer becomes plaited
into thick folds tending to con-
verge towards the cicatrix of
the follicle. After a time the
cells forming the folds undergo
a peculiar change ; they lose
their distinct outlines, become
stained with great difficulty, and
are closely clumped together in
thick trabecula3, the whole hav-
ing a characteristic appearance
and distinct yellow colour.

The corpus luteum is well
marked throughout pregnancy,
although towards the end it be-
comes less sharply defined from
the ovarian stroma. Similar
changes occur — but with far less

increase in size — in burst follicles where pregnancy has not supervened.
The corpora lutea thus produced have been termed corpora lutea spuria
to distinguish them from the corpora lutea vera of pregnancy.

k

FIG. 95.— Part of the section shown in fig. 94.
Magnified 200 diameters.

EFFECTS OF REMOVING AND REIMPLANTING OVARIES

The effects resulting from removal of both ovaries (oophorectomy ; spay-
ing) are externally not so striking as with the similar operation in the
male sex. If the operation is performed in young animals, or if the ovaries
are congenitally atrophic, it is not infrequently found that characters
distinctive to the male are to some extent assumed. In the human subject,
as well as in animals, a constant result is that the uterus remains small :

140 The Endocrine Organs

the external changes characteristic of puberty either do not occur or are
greatly modified : there is absence of menstruation. A tendency to the male
type of trichosis is often also exhibited. When the operation is performed
subsequently to puberty the results are less marked — but menstruation
ceases, and there is sometimes atrophy of the mammae ; in animals a
diminution in size of the uterus and Fallopian tubes has been sub-
stantiated (Carmichael and Marshall, in rabbit ; Marshall and Jolly, in
white rat). According to Hatai the suprarenal capsules are diminished
in size in the female white rat, whereas in the male castration causes a
marked increase of those organs : the same author states that although
there is an increase in size of the pituitary, it is very slight as compared
with the effect of castration in the male. Metabolism is affected mainly,
as in males, in the direction of a tendency towards adiposity. This,
however, may be indirect and through other ductless glands, which are
affected much in the same way as they are in the male sex by removal of
the testicles (p. 134).

Doubtless, as in the male sex, the effects which are produced by the
ovaries in determining the female secondary sexual characters are due to
an internal secretion. And reasoning from analogy one would be disposed
to refer the production of this not to the generative epithelium but to
special cells, like the interstitial cells above referred to. The periodical
changes (heat, menstruation) which occur in the female appear to be due
neither to the Graafian follicles nor to the corpora lutea. For heat in
animals still occurs if the corpora lutea are destroyed, or if none are
present in the ovary. Moreover, the changes which follow spaying can
be prevented by ovarian grafts, and these may contain no corpora lutea.
The grafts may also show after a time no Graafian follicles — these having
undergone degeneration and disappearance.1 And even in the absence of
Graafian follicles from the implanted ovarian tissue, Marshall and Jolly
and A. L. M'llroy have shown that the atrophic changes in the uterus which
ordinarily follow spaying are prevented by the graft.

1 This is not, however, a necessary consequence of reimplantation, for instances are
recorded of development of Graafian follicles and formation of corpora lutea, or even of the
supervention of pregnancy, after reimplantation of ovaries in spayed animals. Such an
occurrence in the case of a woman has been reported by Halliday Groom.

CHAPTER XX

THE INTERNAL SECRETIONS OF THE GENERATIVE
ORGANS IN THE FEMALE (continued)

EFFECTS OF OVARIAN EXTRACTS

On the Uterus. — Extracts of ovary influence the contractions of the uterus
and of plain muscular tissue in general. These effects, which have recently
been worked out in my laboratory by Dr M. Itagaki, of Kyushu University,
but are as yet unpublished, are illustrated by the accompanying tracings
(figs. 96 to 101).

The methods employed to obtain these tracings have been (1) immersion of
a length of uterine cornu, or of a strip of uterine mxiscle, in warmed and oxy-
genated Locke's solution, the Locke's solution being replaced for a short period of
time by the extract to be investigated, which is itself made with Locke ; (2) injection
of the extract into the circulation, and recording the effect upon the uterus or
intestine, and at the same time the blood-pressure and kidney volume. The extracts
have been made separately from corpora lutea, Graafian follicles, liquor folliculi, and
hilum ovarii (i.e. stroma without corpora lutea or Graafian follicles, but presumably
containing interstitial cells), and always by boiling the tissue, either fresh or
dried, with Locke's solution (without glucose). The ovaries of the sheep and cow
were used for preparing the extracts, and the testing was performed on the tissues
of the rat, guinea-pig, rabbit, cat, and dog. Occasionally the desiccated organ was
extracted first with chloroform and then with absolute alcohol ; these extracts were
evaporated down and the dry residue extracted with Locke ; the remainder of the
gland which was left after the chloroform and alcohol had acted upon it being also
extracted with Locke.

A striking effect of intravenous injection is obtained with extracts of
hilum (interstitial cells). This usually causes inhibition of the normal
rhythmic movements, if present, and diminution of tone of the uterine
muscle, which may be preceded by an increase (fig. 96). Accompanying
this change there is a considerable fall in blood-pressure, even in atropinised
animals, and a diminution in volume of the kidney. Corpus luteum extract
injected into the veins causes the uterus if quiescent to begin contracting, if
already contracting to increase its contractions and to assume an increased
tone. Little or no effect on blood-pressure or kidney volume is produced
by this extract.

The result of immersing portions of uterus or strips of uterine and
most other plain muscle in extract of follicular tissue or liquor folliculi is

141

142

The Endocrine Organs

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Effects of Ovarian Extracts

143

generally to cause an increase of force and rate of the rhythmic movements,
and increased tone of the muscle. With hilurn ovarii the effect is inhibition

FIG. 97. — Effect of addition of extract of hilum ovarii of cow to Locke's solution in which a
cornu of uterus of rat was suspended. Notice the cessation of rhythmic contractions and
diminution of tone.

FIG. 98. — Effect of addition of liquor folliculi of cow to Locke's solution in which a cornu of rat
uterus was suspended. Notice the increase of tone with cessation of rhythmic movements.
At "Locke" the liquor folliculi was removed and Locke's solution substituted.

with marked diminution of tone. Rarely this inhibitory effect rather than
increased contraction is obtained with the other extracts.

It appears probable from these observations that ovarian extracts con-
tain two different kinds of autacoid acting upon plain muscle, especially upon

144

The Endocrine Organs

that of the uterus. One of these is a hormone, and either excites the muscle
to contraction or renders it more excitable to the natural stimuli which are
producing the contractions ; the other is a chalone, tending to prevent or
diminish the contractions. The difference of result obtained would depend

uterus

kidney

carotid

respira-
tions

time in 10"
signal

FlG. 99. — Effect of intravenous injection of extract of corpus luteum on uterus, kidney volume,
blood-pressure, and respirations of cat. The small waves on the uterus curve are caused
by the respirations.

upon«the relative amount of one or other autacoid in a particular extract,
and on the sensitiveness of the tissue under examination to the effects of
excitatory or inhibitory agents. Whether the action is exercised through
nerve end-organs, or whether it is a direct effect upon the contractile tissue,
is a point which it has not been easy to determine.

On Milk Secretion. — One of the effects of intravenous injection in
lactating animals of extract of corpus luteum is to provoke an outpouring

Effects of Ovarian Extracts

145

of milk (Ott and Scott). This galactagogue action was found by Mackenzie
to be absent in extracts of ovary minus corpus luteum. It resembles that

FIG. 100. —Effect of extract of corpus luteum of cow on isolated cornu uteri of rat.
Marked increase of tone is produced.

. -

J/ c.l.

FIG. 101. — Effect of extract of corpus luteum of cow on isolated cornu uteri of rabbit. Inhibition,
followed by increased rapidity of rhythm, is produced. (I am indebted to Dr M. Itagaki for
the tracings shown in figs. 97, 98, 100, and 101.)

of pituitrine, and seems to be the result of stimulation of plain muscle in
the walls of the mammary alveoli (see p. 94).

METABOLIC EFFECTS PRODUCED BY CORPUS LUTEUM

Th. Sack found that if corpus luteum be added to the food of white
rats it promotes retention of nitrogen, i.e. laying on of flesh, in females ;

146

The Endocrine Organs

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in the male this re-
sult was not obtained.
That corpora lutea are
related to the develop-
ment of the mammary
gland during preg-
nancy appears from the
experiments of Ancel
and Bouin and of
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virgin rabbit a Graatian

O

follicle be ruptured
(even by mechanical
means) so that a corpus
luteum develops, the
mammae undergo evo-
lution ; whereas if a
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form there is no such
evolution. Hammond
and Marshall state that
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lutea are destroyed in
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development of the
mammary gland is

Metabolic Effects produced by Corpus Luteum 147

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148 The Endocrine Organs

arrested, and it is inferred that their secretion is necessary for such develop-
ment. It must, however, be pointed out that it is next to impossible to
destroy the corpora lutea without practically destroying all the ovarian
tissue, for the corpora lutea of the pregnant rabbit form by far the
greater mass of the ovary. This applies also to Fraenkel's experiments
(see below).

An important function of the internal secretion of the ovary — perhaps
of the corpus luteum — relates to the formation of the uterine decidua
and the fixation of the embryo. Fraenkel — working upon a hypothesis
suggested b}' Born — found that if in rabbits the corpora lutea are destroyed
at an early period of pregnancy the embryo does not become adherent to
the mucous membrane of the uterus, and ceases to develop. Marshall and
Jolly, working with dogs and rats, obtained similar results from double
ovariotomy in early pregnancy. L. Loeb observed that mechanical stimuli
are able to produce the formation of decidual membrane and uterine hyper-
plasia if corpora lutea are present in the ovary, but that there is no such
change in their absence. Extracts of corpus luteum are not in this respect
able to replace the functions of the removed organs.

Loeb has shown that in the guinea-pig extirpation of the corpora
lutea accelerates bursting of the ripe Graafian follicles, i.e. is conducive to
ovulation ; this suggests that their presence militates against ovulation.

INTERNAL SECRETION OF UTERUS

There is some evidence that in certain states the uterus itself may
yield an internal secretion. Blair Bell has suggested that menstruation
and ovulation depend on such a secretion, and Bond has described experi-
ments which appear to indicate that an internal secretion from the uterus
promotes the growth of the corpus luteum. But these views find no
support in the experiments of Carmichael and Marshall, who obtained typical
development of the ovaries, with ovulation and formation of corpora lutea,
in animals (young rabbits and adult rats) from which the uterus had been
completely removed. Bouin and Ancel have described an epithelium-like
formation in the muscular coat of the uterus of the rabbit and guinea-pig
during the latter half of pregnancy which they consider to be related to
the development of the mammary glands during the final period of gestation
and the production of milk. To this formation they have given the name
of " glande myometricale endocrine." Mackenzie found that extracts from
the involuting uterus of the cat shortly after parturition cause a free flow
of milk from the incised nipple of lactating animals (fig. 103). He obtained
no such results with extracts made from the non-pregnant uterus, or from
the pregnant uterus at other times. He infers, therefore, that the uterus
contains a galactagogue hormone only at this period.

Internal Secretion of Mammary Gland

149

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150 The Endocrine Organs

INTERNAL SECRETION OF MAMMARY GLAND

A similar galactagogue effect was obtained by Mackenzie as the result
of intravenous injection of extract of lactating mammary gland (fig. 104) :
no result was obtained from the gland of non-lactating animals.

Adler found subcutaneous injection of extract of mammary gland to produce
enlargement of the suprarenals and increase of adrenalin in the blood, some-
times sufficient to cause glycosuria. He also found it to arrest the development of
the embryo, and even to produce abortion in pregnant animals. These observations
require confirmation.

INTERNAL SECRETION OF PLACENTA

Halban has suggested that the placenta furnishes the stimulus for the
development and growth of the mammary glands, whilst inhibiting the
pouring out of their secretion. That the former is improbable is indicated
by the fact that the mammae may become developed in exceptional cases
in the virgin, and even in the male sex.1 The second suggestion has
received some support from the experiments of Mackenzie, who found that
injection of placental extract tends to inhibit the effect of such galactagogue
extracts as pituitary or corpus luteum. A similar result was obtained by
Mackenzie with extract of fretus, which also has been described as promot-
ing mammary development.'2 It would seem, therefore, that both placenta
and foetus produce chalonic autacoids which have an inhibitory effect on
milk secretion. As a commentary on this, it may be noted that secretion
by the mammary gland does not begin until the removal of any influence
which might be derived from placenta or fcetus.

1 As W. Heape has pointed out, this objection is also applicable to the foetal hormone
theory of Starling and Lane-Claypon (see below).

2 By Starling and Lane-Claypon, and by Foa. There seems to be some doubt whether
the changes described were a specific effect of the fcetal extract.

INDEX

Acetonitrile, resistance to poisonous action in

mice, 38.

Acromegaly (see also under Pituitary), 106.
causation, 109.
symptoms of, 107, 109.

Addison's disease (see also under Suprarenal), 49.
administration of suprarenal extract in, 57.
pigmentation in, 49.
prognosis of, 49.

suppression of functions of suprarenal in, 57.
symptoms of, 49.
Adiposity, relation to pituitary, 101, 102, 111,

112.
relation to sexual organs, 134, 140.

to thyroid, 31.

Adrenalin (see also Suprarenal capsules), chem-
istry of, 58.

chromaphil reaction, 50.
in diphtheria, 57.
disappearance of, in the body, 67.
inactivation of, by cerebro-spinal fluid, 67.

by formaldehyde, 67.
medulla of, 58.

occurrence in skin glands of Bufo, 51.
painting pancreas with, 66, 130.
passage into blood, 68.
physiological effects of, 58.
production of hyperglycsemia and glycosuria

by, 66, 70, 72, 128, 130.
relation to melanin, 49.
synonyms, 58.
synthesis of, 58.

Adrenals (see Supiarenal capsules).
Adrenine (see Adrenalin).
Amines, sympatho-mimetic action of, 65.
Animal extracts (see also under the various

organs), 8, 10.
Apituitarism, 101, 106.

Apocodeine, effect on action of adrenalin, 65.
Arteries, as test for adrenalin, 62.
Atheroma, caused by suprarenal extract, 65.
Atropine, effect on action of adrenalin, 59, 71,

72.

effect on milk secretion, 94.
on pituitary activity, 90.
on secretine, 125.
Autacoids or autacoid substances (see also under

the various organs), 6.
in blood, 2, 5, 6, 24, 40, 95, 123.
classification of, 6.
compared with drugs, 6, 8, 90.
definition of term, 6.
Autotherapy, 10.

Basedow's disease (see Exophthalmic goitre).
Blood, action on adrenalin, 67.

151

Blood, adrenalin in, 68.

autacoids in, 2, 5, 6, 24, 125.

galactagogue in, 95.

glycolytic ferment in, 129.

passage of internal secretions into, 2.

secretine in, 125.
Branchial organs (see Cleft organs).

Cachexia, hypophyseopriva, 101, 113.

strumipriva rcl thyreopriva, 32.
Calcium metabolism, affected by thyroidectoniy,

47.
in tetany, 26.

salts, administration in tetany, 26.
Cancer cells and internal secretions, 33.
Carbohydrate metabolism (see Metabolism,

carbohydrate).
Carotid gland, 51.
Castration, effects of, 108, 133.
Cells, chromaffine, 51.

chromaphil, 51.

internally secreting, 2.

interstitial, of ovary, 137.
of testicle, 132.

of islets of Langerhans, 126.

luteal, 138.

of parathyroid, 17.

of pineal, 119.

of pituitary, pars anterior, 79.
pars intermedia, 80.

pregnancy cells, 79.

of suprarenal cortex, 51.

of suprarenal medulla, 54.

of thymus, 46.

of thyroid, 12.

Cerebro-spinal fluid, effect on, of extracts of
pituitary, 90.

effect on, of intravenous injection of duodenal
extract, 82.

secretion into, of pars intermedia of pituitary,

81.

Chalones, origin and meaning of term, 5.
Chalonic autacoids, 6.
Chemical messengers, 5.
Chromaffine bodies. 51.

cells, 51.
Chromaphil bodies, 51

development of, 50.

reaction, 50.

substance, 58.
Cleft organs, 12.
Coccygeal gland, 51.
Colloid of parathyroid, 20.

of pituitary, 75.

of thyroid, 14.
Conarium (see Pineal gland).

152

The Endocrine Organs

Corpuscles, concentric, of Hassal, 46.

of Stannius in Teleostei, 58.
Corpus luteum or corpora lutea, spuria, 139.

vera. 139.
cells of, 138.
development of, 1 38.
extracts of, 141
influence of, on fixation of embryo, 148.

on mammary growth, 146.

on ovulation, 148.

on secretion, 146.

on uterus, 148.

metabolic effects caused by, 145.
Cretinism, association with thyroid, 32.
endemic, 30.
sporadic, 30.

Diabetes (see also Glycosuria).

insipidus, produced by pituitary lesions, 103.

Langerhans' islets in, 127.

pancreatic, 127.

Diphtheria, disappearance of adrenalin in, 57.
Drugs, internal secretions compared with, 5.
Ductless glands, 1.
Duodenum, autacoid of, 124.

epithelium of, 3.

extract of, 3, 124.
action on bile, 125.
on pancreas, 124.
on pituitary, 82, 125.
on succns entericus, 125.

interaction with pancreas, 125.

internal secretion of, 73.
Dwarfism, in connexion with pituitary, 113.
Dysparathyroidism, 24.
Dyspituitarism, 106.
Dystrophia adiposogenitalis, 110.

Elasmobranch fishes, suprarenals of, 57, 58.
Endocrine glands, groupings of, 7.
organs, definition, 2.
extracts of, 8.

methods of determining functions of, 8.
Enzymes, compared with active principles of

endocrine organs, 4.
Epinephrectomy, 56.
Epinephrin (see also Adrenalin), 58.
Epiphysis (see Pineal gland).
Ergotoxine, effect on action of adrenalin, 64.
Extracts (sec Animal extracts, and under the
several organs).

Fatigue, effect of suprarenal extract upon, 65.
Fecundity in fowls, effect of pituitary feeding

upon, 105.

Feminism, due to pituitary insufficiency, 110.
Fish, pancreas of, 126.

pituitary of, extracts of, 99.
suprarenals of, 7, 57, 58.
Foetus, extract of, influence on growth of

mamma, 150.

influence on milk secretion, 150.
pancreas of, influence on mother, 128
parathyroids of, influence on mother, 23.
suprarenal of, 51.

chemistry of cortex, 53.
structure of cortex, 51.
Formaldehyde, effect of, on adrenalin, 67.

Frohlich's disease (see Dystrophia adiposo-
gemtalis).

Galactagogue action of blood-serum, 95.
of extract of corpus luteum, 144.
of mammary gland, 148.
of pineal, 120.
of pituitary, 90.
Gastric secretion, 125.
Gastrine, 125.

Generative glands or organs, female, internal
secretions of, 137. (See also Ovary,
Corpus luteum, etc.)
male, internal secretions of, 132. (See also

Testicle.)

relations with pineal, 121.
with pituitary, 110, 112, 115.
with suprarenal cortex, 53.
with thyroid, 37, 41.
Gigantism, pituitary, 108.
relation to acromegaly, 108.

to defective sexual development, 108.
Glands, ductless, 1.
endocrine or internally secreting, 1. (See

also Endocrine glands),
externally secreting, 2.
generative (see Generative glands).
Glyctemia (see Hyperglyceemia).
Glycolysis (and glycolytic ferment) in relation

to internal secretion of pancreas, 129.
Glycosuria, caused by adrenalin, 66, 70, 72, 130.
by injury of pituitary, 103, 104.
by mammary gland extract, 150.
by removal of pancreas, 72, 127, 128, 129.
in acromegaly, 108, 109.
alimentary, affected by exophthalmic goitre,

37.

affected by hypopituitarism, 111.
by pituitary extracts, 96.
by pituitary removal, 102.
by thyroid atrophy, 36.
by thyroidectomy, 32.
by thyroid extracts, 36.
Goitre, 33.

endemic, remedial effect of thyroid feeding, 32.
structure of thyroid in, 33.
symptoms, 33.
exophthalmic, 36.

adrenalin in blood in, 41, 43.
condition of blood in, 38.

of thymus in, 37.
hypersecretion in, 37.
metabolism in, 37.
structure of thyroid in, 37.
symptoms of, 37.

Grafting of internally secreting organs, 4.
ovary, 139.
pancreas, 127, 128.
parathyroid, 23.
pituitary, 104.
suprarenal, 57.
testicle, 135.
thyroid, 32.
Graves' disease (see Goitre, exophthalmic).

Hair (see also Trichosis).
in parathyroidectomy, 22.
in thyroid extirpation and atrophy, 29.

Index

153

Harmazones, 5.

Hormone or hormones, definition, 6.

examples of, 6.

origin and meaning of term, 5.
Hormonic autacoids, 6.
Hyperglycaemia, 130.

caused by adrenalin, 66, 72, 130.
by Bernard's puncture, 70, 72.
by pancreas removal, 127, 128, 129.
Hyperparathyroidism, 24.
Hyperpituitarism, 106.

Hyperthyroidism, caused by extract of thyroid,
36.

in exophthalmic goitre, 38.
Hypertrichosis, in acromegaly, 108.
Hypoparathyroidism, 24.
Hypophysectomy (sec Pituitary, removal of).
Hypophysin, 84.
Hypophysis, 74. (See also Pituitary body.)

pharyngeal, 75.

Hypopituitarism, 101, 106, 110, 111.
Hypothyroidism, in endemic goitre, 33.

in myxoedema, 31.

after thyroidectomy, 32.

Infantilism, connected with hypopituitarism,
111.

relation to pituitary, 102, 110.

sexual, thyroid in, 42.
Infundibulum (see Hypophysis).
Insuline, 128.
Internal secretions, classification of, 5.

definition, 1, 2.

materials of, 5.

mode of action of, 7.
Interrenal body of Elasmobranchs, 7.
Interstitial cells (see Generative glands, Testicle,

Ovary).

Iodine, absence in pituitary even after thyroidec-
tomy, 116.

in thyroid, 40.
lodo-thyrin, 40.
lodo-thyro-globulin, 40.
Islets of Langerhans (see Langerhans).

Kidney, permeability of, affected by absence of

pancreas, 128, 130.
affected by pituitary extract, 89.

Langerhans, islets of, in pancreas : —

cells of, 126.

changes in diabetes, 127.

internal secretion of, 127.

nerves of, 126.

origin of, 125.

structure of, 126.

in Teleostei, 126.

variations in, 125.

vascular supply of, 126.
Leucocytes, glycogen in, 128.

glycolytic pro-ferment in, 129.

Mammary gland, electrical changes in, during

secretion, 95.
extracts of, effect on development of embryo,

150.

effect on suprarenals, 150.
galactagogue action of, 148.

Mammary gland, growth of, influenced by corpus

luteum, 146.

influenced by foetus extract, 150.
by ovary, 140.
by placenta extract, 150.
internal secretion of, 148.
plain muscle in walls of alveoli of, 94, 145.
secretion of, effect on : —
of blood-serum, 95.
of extract of corpus luteurn, 144.
of ovary, 143.
of pineal, 120.
of pituitary, 90.
Melanin, formation of, in relation to adrenalin

49.
Menstruation, affected by extirpation of ovaries,

140.

affecting size of thyroid, 41.
Metabolism, action of internal secretions on, 5, 9.
affected by corpus luteum, 145.
carbohydrate, influenced by castration, 134.
by pancreas removal, 127, 128.
by parathyroid removal, 25.
by pituitary extirpation and disease, 102.
by thyroid extracts, 9, 36.
by thyroid removal, 29.
in exophthalmic goitre, 37.
in myxoedema, 32.
Morphogenetic substances, 5.
Myoneural junction, acted on by drugs and

autacoids, 64.
Myxcedema, effect of thyroid administration in,

32.

history of, 31.
metabolism in, 32.
post-operative, 32.
relation to thyroid atrophy, 31.
to thyroid extirpation, 32.

Oophorectomy (see Ovaries, removal of).
Opotherapy, 10.
Organotherapy, 10.
Ovary or ovaries, autacoids of, 143.
corpora lutea (see Corpus luteum).
effect of grafting, 139.
extracts of, effects on uterus, 141.
interstitial cells of, 137.
effect of X-rays on, 137.
influence on development of secondary

sexual characters, 180.
liquor folliculi of, action of, 141.
relation to mammary development, 140.

to puberty, 140.
removal of, 139.

effects on menstruation, 140.
on metabolism, 139.
on uterus, 139.

Paired bodies of Elasmobranchs, 7, 58.
Pancreas, autacoids of, 128, 129.
diseases of, and diabetes, 127.
external secretion of, 125.
extirpation of, '2, 127.

effect on dilatation of pupil caused by

adrenalin, 130.
of pregnancy on, 128.
grafting, 127, 128.
internal secretion of. 2, 125, 128.

154

The Endocrine Organs

Pancreas, islets of Langerhans, 3, 125, 126.

(See also Langerhans. )
relation to carbohydrate metabolism, 2, 127,

129.

Pancreatic duct, ligature of, 127.
juice, secretion of, excited by acid in duo-
denum, 125.

excited by secretine, 125.
Parahypophysis, 75.
Parathyrine, 27.

Parathyroid or parathyroids, accessory, 12.
anatomy of, 16.
in animals, 12.
autacoids of, 24, 27.
blood-vessels of, 21.
colloid in, 20.
development of, 21.
in disease, 25.
external or lower, 11.
extirpation of, 22.
differences, 24.
effects of, 22.

on metabolism, 24.
on thyroid, 24.
tetany from, 23.
extracts of, 26.
grafting of, 23.
history of, 16.
internal crupper, 11.
position of, 11.
relation to pancreas, 130.
to pituitary, 28.
to thyroid, '20, 27.
to other endocrine organs, 28.
structure of, 17.
Parathyroidectomy, 22.

influence on liver cells, 28.
Pigmentation, in Addison's disease, 49.
in hypopituitarism, 111.
after suprarenal removal, 50.
Pineal or pineal gland, anatomy of, 118.
extirpation of, 120.
extracts of, 120, 123.

galactagogue action of, 120.
feeding with, 123.

relation of, to generative organs, 121.
structure of, 119.
tumours of, 121.
Pineal eye, 118.
Pituitary body, 74.

accessory glandules, 100.
anterior lobe of, 77.

effect of deficiency of, 106, 110, 111.

of increase of secretion of, 106.

relation to acromegaly, 100, 109.

autacoid or autacoids of, 84, 86, 96.

compared with suprarenal, 84, 85, 88.
blood-vessels of, 77, 78, 83.
cells of, 78, 79, 80.
clinical evidence relating to, 106.
colloid in, 75, 80.
development of, 75.
feeding with, 96, 104.

effect on egg production in hens, 105.
on fertility of eggs, 105.
on growth, 105.
grafting of, 104.
hyaline bodies in, 80.

Pituitary body, injury of, 103.
intraglandular cleft of, 74.
iodine in, 116.
operations on, 113.
pars anterior seu glandularis, 77.
blood-vessels of, 78.
cells of, 78.
colloid vesicles in, 80.
pars intermedia of, 80.
action of extracts, 98.
cells of, 80.
colloid vesicles in, 80.
pars nervosa of, 83.

effect of thyroidectomy on, 83, 116.

extracts, action of, 98.

hyaline and granular substances in, 83.

passage into third ventricle, 81.
posterior lobe of, 77.
extracts of : —

administration of, in disease, 96.
effects of, on bladder, 87.
on blood pressure, 84.

in birds, 87.
on heart, 84, 87.

in birds, 84.
on intestine, 87.
on kidney, 88, 89.
on metabolism, 96.
on milk secretion, 90.
on plain muscle, 84.
on pupil, 87.
on stomach, 87.
on urine, 88.
on uterus, 87.
in pregnancy, 79.

puncture of, effect in causing glycosuria, 104.
relation to acromegaly, 106.

to Bernard's sugar puncture, 104.
to carbohydrate metabolism, 102, 117.
to dystrophia adiposogenitalis, 110.
to fat formation, 101, 102,110, 112, 113.
to feminism, 110, 112.
to gigantism, 108.
to growth, 102.
to menstruation, 110, 115.
to pancreas, 117.
to parathyroid, 116.
to pregnancy, 101, 109, 115.
to respiration, 101.
to sexual organs, 101, 110, 115.
to suprarenals, 117-
to thyroid, 113, 115.
removal or extirpation of, complete, 100.
methods, 100.
partial, 102.

secretion of, into third ventricle, 81, 83, 115.
structure of, 74.
after thyroidectomy, 116.
tumours of, 106, 109, 110.
Pituitrin, 84.

Polyuria, resulting from pituitary lesions, 103.
Post-branchial bodies, 16.
Pregnancy, affected by parathyroidectomy, 23.
cells, in pituitary, 79.
relation to corpus luteum, 148.
to exophthalmic goitre, 37.
to pituitary, 79, 101, 109, 115.
Progastrine, 125.

Index

155

Prosecretine, 3, 124.

affected by removal of pancreas, 125.

Receptive substance, acted on by drugs and
autacoids, 64.

Secretine, action on, of atropiue, 125.
gastric, 4, 125.
history of, 3.
production of, 3, 124.
Secretion or secretions, external, 2.
internal, classification, 5.
definition, 1, 2.
history, 2.

methods of investigating, 8.
mode of action of, 7.
nature of active principles of, 4, 5.
(See also under the various organs.)
Sexual characters, secondary, influence on, of
interstitial cells of generative glands,
135, 140.

organs (see Generative glands or organs).
Spaying (see Ovary, extirpation of).
Spleen, 1.

affected by thyroidectomy, 47.
Stannius, corpuscles of, 58.
Substitution therapy, 10.
Sugar in blood and urine (see Diabetes, Glyco-

suria, Hyperglycaemia).
Suprarenal capsules or suprarenals : —
accessory, 50, 57.

action of drugs through suprarenals, 70.
activity of, due to adrenalin, 50.
in Addison's disease, 49.
autacoid of, 58.
blood-supply of, 55.
buccal administration of, 65.
cortex, chemistry of, 53.
in fcetus, 51.
functions of, 52.
lipoids of, 53.

relationship to sexual organs, 53.
structure of, 51.
effects of extirpation, 56, 57.

of transplantation, 57.
medulla, extracts of (see also Adrenalin) : —
action in Addison's disease, 57.
effect of nerve section on, 60.
seat of, in myoneural junction or re-
ceptive substance, 64.
on arteries, 58.
on bladder, 63.

on carbohydrate metabolism, 66.
on eye, 63.
on hair-muscles, 64.
on heart, 59.
on intestine, 62.
on lacrimal glands, 64.
on membrana nictitans or third eyelid, 63.
on muscle, 64, 65.
on pupil, 60, 63.
on respiration, 59.
on retractor penis, 62.
on salivary glands, 64.
on sweat glands, 64.
on urine, 64.
on uterus, 62.
on vas deferens, 64.

Suprarenal capsules or suprarenals : —
medulla, extracts of, action on veins, 60.

subcutaneous administration of, 65.
morphology, 50.

relations to generative glands, 71.
to liver, 66, 71.
to metabolism, 66.
to pancreas, 66, 72.
to salivary and lacrimal glands, 71.
to sympathetic nervous system, 64.
effects of apocodeine, 65.

of ergotoxine, 64.

secretion of, influence of drugs, 79.
influence of fright, 69.

of nerves, 69, 72.
structure of, 54.
vessels and nerves of, 55.
Suprarenin, 58.

Tachyphylaxis, in connexion with pituitary
extract, 86.

meaning of term, 86.
Testicle, autacoid of, 135.

effect of X-rays on, 135.

extracts of, 136.

grafting of, 135.

influence of, on secondary sexual characters,
134.

internal secretion of, 132.

interstitial cells of, 132.

removal of, 133. (See also Castration.)

tumours of, 136.
Tetania parathyreopriva, 23.
Tetany, caused by extirpation of parathyroids, 23.

toxin, 27.

Thymectomy (see Thymus, extirpation of).
Thymus, development of, 45.

effect of inanition upon, 47.

in exophthalmic goitre, 37.

extirpation of, 47.

functions of, 47.

relationship to generative organs, 47.
to thyroid, 43.

result of feeding with, 47.

structure of, 45.

in thyroid, 11, 47.
Thyrine, 40.

Thyro-globulin (see lodo-thyro-globulin).
Thyroid or thyroid gland, 11.

accessory, 12.

atrophy of, 29, 31.

autacoids of, 32, 40.

blood-vessels of, 13.

chemistry of, 40.

colloid of, 14.

comparative anatomy of, 12.

development of, 15.

effect of parathyroidectomy on, 20.

in endemic goitre, 33.

in exophthalmic goitre, 36.

extirpation of, 29.

extracts of, administration by mouth, 32, 36.
effect on excitability of nerves, 36.
intravenous injection, 35.

grafting of, 32.

internal secretion of, 40.

influence of nervous system on, 44.

iodine in, 40.

156

The Endocrine Organs

Thyroid or thyroid gland, in myxcedema, 31.
position of, 11.

relation to carbohydrate metabolism, 42.
to generative organs, 29, 41.
to liver, 42.
to pancreas, 42, 130.
to parathyroids, 24, 27.
to pituitary, 43, 113.
to suprarenals, 42.
to thymus, 41, 43.
structure of, 12.
theories regarding connexion with cretinism,

30.

with exophthalmic goitre, 37.
with myxoedema, 31.

Thyroidectomy (see Thyroid, extirpation of).
Transplantation (see Grafting).

Trichosis, sexual characteristics of: —
affected by pituitary insufficiency, 110.

by removal of generative glands, 133, 140.
Tumours, malignant, relation to internal secre-
tions, 33.
of pineal, 121.
of pituitary body, 106, 108.
of testicle, 136.
of thyroid, 33.

Uterus, elFect of extracts on milk secretion,

148.

effect of pituitary extracts on, 87.
of removing ovaries on, 140.
of suprarenal extracts on, 62.
influence on growth of mammary gland, 148.
internal secretion of, 148.

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