BIOLOGY
LIBRARY

G

GLANDS

IN HEALTH AND DISEASE

BY

BENJAMIN HARROW, Pn.D.

ASSOCIATE IN PHYSIOLOGICAL CHEMISTRY, COLLEGE

OF PHYSICIANS AND SURGEONS,

COLUMBIA UNIVERSITY

NEW YORK

E. P. DUTTON & COMPANY
681 FIFTH AVENUE

COPYRIGHT,

BY E. P. DUTTON & COMPANY

All Rights Reserved

BIOLOG^

Printed in the United States of America

PINEAL
PITUITARY

(feRATHYftOtlXS
THYROIp

THYMUS

SPLEEN ,L •

..LIVER
-.PANCREAS

—I— ADRENALS

-,,... REPRODUCTIVE
ORQAN5

THE DUCTLESS GLANDS

To
PROFESSOR WILLIAM J. GIES

TEACHER AND JRIEND

PREFACE

Monkey glands; clever men and stupid ones;
glands as the cause of crime; the origin of races; the
mentally unbalanced; many acute diseases; "the
bearded lady, the giant, the fat boy and the midget" ;
— all these and more have been dealt with under the
subject of glands of internal secretion (also called
ductless or endocrine glands). As in any subject
that fires the popular imagination, fact and fancy
have been mixed, — several drops of fact have been
largely diluted with many drops of fancy. The
achievements, judged by rigid scientific standards,
are no more than modest, but the possibilities are
limitless. It is because of these vast possibilities
that an imagination, not sufficiently tempered by
self-criticism, is apt to enlarge a molehill into a
mountain.

The glands discussed in this book, the ductless or
endocrine glands, regulate the activities of the or-
ganism little less than does the brain itself. Let but
one of these bodies stop functioning, or let it func-
tion imperfectly, and injuries to various parts of the

IX

x PREFACE

body become manifest. Since glandular disorders
are among the commonest causes of disease, ranging
from slight mental or physical derangement to com-
plete mental or physical breakdown, a general sur-
vey of the subject, told in popular but not sensa-
tional language, faithfully recording what has been
accomplished, should prove of interest. There is a
crying need, in the opinion of the author, of simple,
yet clear and clean-cut statements of scientific work
to which the layman can refer. The half-baked
knowledge that he often gets at present is worse
than no knowledge at all.

Not the least interesting part of this fascinating
field of research is the evidence we possess that the
activities of these glands are dependent upon rela-
tively simple chemical substances contained in them,
to which the name "hormones" or "chemical mes-
sengers" has been given. Without in any way at-
tempting to exaggerate their importance, we may say
of these hormones that they are as indispensable to
the life process as are vitamines, a subject treated
by the author in an earlier volume.

I am indebted in various ways to the following:
Professor W. B. Cannon (Harvard) ; Professor W.
J. Gies (Columbia); Dr. Max Kahn (Columbia);
Dr. E. C. Kendall (Mayo Clinic, Rochester, Minn.) ;
Dr. E. G. Miller, Jr. (Columbia) ; Mr. A. L. Robert;
Mr. Thomas Spector; Professor G. N. Stewart

PREFACE xi

(Western Reserve Univ.) ; and Mrs. N. J. Waller-
stein. Dr. Kendall, Prof. Stewart and Mrs. Wal-
lerstein have been kind enough to read the manu-
script and to offer several helpful suggestions.

BENJAMIN HARROW.

CONTENTS

CHAPIEB PAGB

I INTRODUCTORY . . . . .: . > w .. 1

II THE THYROID ^ . . 14

III THE PARATHYROIDS .... . . . 43

IV THE PITUITARY GLAND ...... 47

V THE ADRENAL GLANDS 70

VI THE ORGANS OF REPRODUCTION .... 89

VII THE PANCREAS AND THE LIVER .... 115

VIII THE INTESTINAL HORMONE ..... 127

IX THYMUS, SPLEEN, MAMMARY GLAND, AND

KIDNEY 135

X THE RELATION OF THE DUCTLESS GLANDS

TO ONE ANOTHER 147

XI THE INFLUENCE OF THE DUCTLESS GLANDS

ON GROWTH AND METABOLISM .... 156

XII THE NERVOUS SYSTEM AND THE DUCTLESS

GLANDS 158

XIII ORGANOTHERAPY 185

XIV PLANT HORMONES 190

REFERENCES 195

INDEX 213

xiii

GLANDS IN HEALTH
AND DISEASE

CHAPTEE I

INTRODUCTORY

An analogy. — The Headquarters Staff is often
spoken of as the "brains" of the army. We can
speak with equal justice of the brain as the Head-
quarters Staff of an army consisting of the millions
of cells of the body. These cells are organized in
units made up of army corps, just as every modern
army is ; only in the body such units are spoken of
as "organs."

We can carry the analogy one step further. The
movements of the several army corps, it is true, are
controlled by the Headquarters Staff; but it must
be evident that for complete cooperation, not only
should the units be in touch with the General Staff,
but also with one another. If the Staff breaks
down, the army goes to pieces; if connections be-
tween the several units are broken off, the army
also goes to pieces. Likewise with the body : a dis-

1

2 GLANDS IN HEALTH AND DISEASE

turbance in the brain immediately registers its
effect on the rest of the body; so does a breaking-
off of communications between the organs of the
body.

Now while we have long been familiar with the
functions of the brain, we have not until recently
been aware of distinct means of intercommunica-
tion between the organs themselves, apart from
their connection with the brain. The study of the
ductless glands — the subject of this book — has led
to this discovery, and with it the origin of a number
of diseases has been made clear.

Glands. — When food is taken into the mouth it
is met by a fluid called the saliva. Where does this
fluid come from, and what is its function? This
fluid, this saliva, is manufactured in factories situ-
ated in front of the ears and between the lower
jaw and the floor of the mouth. The factories get
their raw materials from the blood, and the cells
in these factories convert the raw materials into a
product which we call saliva. Tubes connecting
these factories with the interior of the mouth enable
the manufactured fluid to be sent to the mouth.
These tubes are spoken of as "ducts."

Now what is the function of this saliva, the
product of cellular activity in these factories or
"glands" of the body? It has in reality several
functions, but there is one that stands out far above
the others: it converts the starch of foods into

INTRODUCTORY 3

chemically simpler products. This conversion is
due to the presence in the saliva of "ptyalin," a
substance that belongs to a class of compounds
known as "enzymes" or "ferments." Much of the
chemical work of the body — and this includes the
plant as well as the animal kingdom — is due to the
activity of these enzymes.

A gland, then, is an organ that has the power of I
taking certain materials from the blood and manu- /
facturing from these raw materials a product/
which plays a part in the activities of the body.'
The salivary glands, wherein saliva is manufac-
tured, are an example. The gastric glands lining
the wall of the stomach, manufacturing gastric
juice for the stomach needs, are another. The
pancreatic and intestinal juices arising, respec-
tively, from the pancreas and the small intestine,
are still others. These examples could be multi-
plied.

Ductless or endocrine glands, or glands of inter-
nal secretion. — So far we have been considering
glands that have tubes or "ducts" connecting them
with an outer surface, such as the mouth or stom-
ach. Glands are known, however, that have no such
ducts, but that pass their products directly into the
blood stream. Such glands are known as "duct-
less" glands. Sometimes they are spoken of as
glands of "internal secretion," to distinguish them
from those glands with ducts whose secretion is

4 GLANDS IN HEALTH AND DISEASE

poured out on a surface. Sometimes they are called
"endocrine" glands, "endocrine" being derived from
two Greek words meaning "to separate within";
that is to say, an "internal secretion." 1

It is these "ductless" glands that constitute the
subject matter of this book ; for recent research has
shown us that they play an enormously important
part in health and disease.

That the brain through its nervous mechanism
controls the various parts of the body is common
knowledge to-day; but that any portion of the
body's activity should not be directly responsible
to the brain for its controlling mechanism, is an
idea that may sound revolutionary enough. Yet
such is the case; and to illustrate it, a classical
experiment due to Bayliss and Starling, two gifted
English physiologists, will be described.

An illustration. — The food that we take into the
mouth passes through the stomach into the small
intestine. Here the food meets not only the intesti-
nal fluid, but also the fluids coming from the bile
on the one hand, and the pancreas! on the other.
The bile and the pancreatic fluid are led into the
small intestine by means of tubes. Now why when-
ever food appears in the small intestine do bile and
pancreatic juice also flow into it? The answer un-
til recently was considered a very simple one. The

1This definition does not take into account the conception of
the histologist as to what constitutes a "glandular" structure.

INTRODUCTORY 5

physiologists said that the nervous mechanism
controls the flow of the fluids ; that whenever food
appears in the intestine, a nervous reaction calls
forth the flow of bile and pancreatic juice. Bayliss
and Starling showed that this conception needed
modification.

These investigators, in experimenting with dogs,
cut off all nervous connections with the small
intestine; yet the fluids still continued to flow into
it. They then suspected that possibly the acid
from the stomach, upon reaching the small intes-
tine, liberates something from the walls of the
organ, which "something" finds its way to the
pancreas and the bile, and thereby gives warning
of the need of these fluids. They thereupon ex-
tracted a piece of the intestinal wall with hydro-
chloric acid — which is the acid found in the
stomach — and injected this extract into the blood
stream. There was an immediate and copious flow
of pancreatic juice into the intestine.

What then happens in the course of digestion
in the small intestine? The food that arrives from
the stomach is acid, due to the hydrochloric acid
that is formed in the stomach. This acid liberates
a substance present in an otherwise inactive state
in the wall of the intestine, and this substance
travels through the blood to the pancreas, where
it stimulates that organ to discharge its fluid.

Hormones. — Note that all this is performed with-

6 GLANDS IN HEALTH AND DISEASE

out any help from the brain.1 Note that one organ
of the body — the intestine in our example — manu-
factures a substance which finds its way into the
blood stream and affects another organ of the
body, the pancreas. Here we have a classical ex-
ample of the workings of a ductless gland; for in
every gland of the ductless variety a specific sub-
stance is manufactured that finds its way into the
blood stream and influences another organ or or-
gans of the body. The substance so manufactured
is called a "hormone" (from the Greek "to excite"
or "arouse") or "chemical messenger." The hor-
mone in the intestinal wall has been given the
name of "secretin" by its discoverers. Without
this secretin no pancreatic juice could find its way
into the intestine, and without pancreatic juice
no digestion of food could take place.

The small intestine is an example of a tissue
which gives rise both to an internal and an ex-
ternal secretion. Its internal secretion, the secre-
tin, has already been described. But as a matter
of fact it also develops a secretion, the intestinal
juice, which is carried by ducts to the surface of
the intestine, in the same way that salivary or

1 1 do not want the impression to be conveyed that there is no
connection between the hormones on the one hand and the nervous
system on the other. As a matter of fact there are connecting
links, as the chapter on nervous disorders will attempt to make
clear. All I want to point out at this stage is that a particular
mechanism, for which the brain is held responsible, can be ex-
plained without involving the brain at all.

INTRODUCTORY 7

gastric juice is, and which, like these two, plays an
important role in the digestion of foodstuffs.

The double property of producing both an in-
ternal and an external secretion, which character-
izes the small intestine, is found in a number of
other tissues. The external secretion of the pan-
creas, for example, is the pancreatic juice, which
is carried by means of a duct to the small intestine.
But it has been shown that the removal of the
pancreas, or, what is the same thing, the removal
with it of an internal secretion developed by the
organ, and which finds its way into the blood,
gives rise to the dreaded sugar disease commonly
known as "diabetes." It would seem, therefore,
that the utilization of sugar by the liver — the organ
that stores sugar and gives it out when necessary —
is controlled by an internal secretion developed
by the pancreas.

The generative glands (ovary and testicle) show
an internal and external secretion. The external
secretion contributes to the reproduction of the
species; the internal secretion plays a part in the
development of male and female characteristics.
One has but to think of the eunuchs in oriental
countries, or of animals from which, for commer-
cial reasons, the generative glands are removed, to
realize what effects are produced by removal of
these glands. But this will be treated more ex-
tensively later.

8 GLANDS IN HEALTH AND DISEASE

The thyroid, the pituitary, the sexual organs, the
adrenals, all contain hormones, and much of the
influence these organs exert upon our general well-
being is due to these chemical messengers.

The composition of hormones. — Just what the
hormones consist of is not clear in most cases. Yet
the physiological chemist has been able to isolate
in a pure condition a hormone present in the adre-
nal glands, and another in the thyroid; and the
organic chemist has been able to start with very
simple chemicals and synthesize these hormones
in his laboratory. So that at least in two instances
we know what the composition of a chemical mes-
senger is; and the organic chemist will tell you
that their composition is by no means terrifying.

Relation of hormones to vitamines, etc. — Ridic-
ulously small amounts of hormone are sufficient to
restore the normal equilibrium of the body. That
is to say, where, as in thyroid deficiency, the di^
ease can be cured by the administration of the
corresponding hormone, the amount necessary is
almost infinitesimal. Neither is the percentage of
hormone in the active gland anything but slight.
For example, Kendall, of the Mayo Clinic at
Rochester, found that he had to use 6,550 pounds
of fresh thyroid in order to get one ounce of thy-
roxin, the thyroid hormone !

These facts immediately suggest a relation be-
tween hormones and vitamines, and 6ther sub-

INTRODUCTORY 9

stances present in the body in small amounts, but
which nevertheless exert powerful effects — such as
the enzymes or ferments.

Vitamines, as every reader of the press must
know by this time, are unknown factors in food,
probably present in amounts that defy weighing
by the ordinary chemical balance. They are neces-
sary for a continuation of the life cycle. As I have
said elsewhere,1 without vitamines there can be no
life.

To what extent are we justified in comparing
vitamines with hormones? As we have indicated,
both are present in minute quantity, and a small
quantity seems to go a long way. Both are there-
fore "catalytic" in their action; that is to say,
they accelerate or hasten chemical action, without
themselves undergoing any permanent change.

There are one or two direct clinical observations
that are of interest also. Professor Butcher, of the
Pennsylvania State College, has performed a num-
ber of experiments which show that thyroxin, the
thyroid hormone, has anti-neuritic properties;
which means that it, like yeast, for example, can
cure birds suffering from polyneuritis, — a disease
first shown by Funk to be due to a lack of one of
the vitamines.2 If this is so, thyroxin has vitamine-
like characteristics.

*See the author's book, Vitamines: Essential Food Factors.
New York, E. P. Button & Company, 1921.

J See the chapter on Beriberi in the author's book on Vitaminea.

10 GLANDS IN HEALTH AND DISEASE

Then again, McCarrison, an English investiga-
tor stationed in India, has shown that the adrenal
glands of birds suffering from polyneuritis are
much enlarged, and that the adrenaline content of
these glands is increased. As we shall see, the
adrenals, like the thyroid, are glands of internal
secretion, and adrenaline is the active hormone
present in these glands. Even more remarkable
is his discovery that though the adrenals become
enlarged, the other ductless glands degenerate and
tend to disappear altogether. It would seem as if
there were some connecting link between vitamine
B (the vitamine the absence of which causes poly-
neuritis) and adrenaline; as if a diet containing
adequate amounts of vitamine B had a restraining
influence upon the output of the adrenal hormone.

But we must not stretch these points too far, —
at least, not until these experiments have been re-
peated and extended. In the meantime it is well to
point out some obvious differences, if only to
strengthen our judicial attitude.

Vitamines are very susceptible to heat; or more
accurately, to a combination of heat and oxidation
(exposure to air) ; hormones do not seem to be
destroyed at a temperature even of boiling water;
at least, the last statement is true of secretin (the
intestinal hormone) and one or two others that
have been studied. Then again, in two instances —
adrenaline (from the adrenal gland) and thyroxin

INTRODUCTORY 11

(from the thyroid) — hormones have not only been
isolated in the pure state, but they have actually
been synthesized in the laboratory from relatively
simple compounds. So far, not only have we been
unable to synthesize a vitamine, but we have even
been baffled in our attempts to isolate one in a pure
condition.

It would, perhaps, be more in harmony with
what we know to compare hormones with amino-
acids, substances that are obtained when the pro-
teins of food are broken up by the enzymes in our
digestive system, or by acids used in the chemist's
laboratory.1 Chemically, thyroxin shows striking
relations to tryptophane; and adrenaline, certain,
though not such striking relations to tyrosine.
Both tyrosine and tryptophane are among our best-
known amino-acids.

One important point that is brought out in a
discussion of this kind is to emphasize the impor-
tance of the "littlest things." Enzymes (or fer-
ments), the substances that act on our food in the
digestive tract, the compounds that are largely re-
sponsible for much of the metabolic activity of
every cell, whether plant or animal, have long
been known to illustrate the property that certain
substances possess, of bringing about chemical
changes in a large quantity of material, though the

'See the chapter on Ammo-Acida in the author's book on
Vitamines.

12 GLANDS IN HEALTH AND DISEASE

enzyme present may be there in relatively small
amount. Still more remarkable are such reactions
in that the enzymes do not seem to undergo any
permanent change : at the end of the reaction we
still find our enzymes, and for all the balance tells
us, in the same amounts as before the reaction.

Substances that act like enzymes are called
"catalysts." A catalyst may be defined as a sub-
stance that accelerates a chemical reaction without
itself undergoing any permanent change. Hor-
mones and vitamines are probably catalysts.

These catalysts are not confined to substances
that take part in the activities of the living organ-
ism. The best method for the manufacture of oil
of vitriol, or sulphuric acid, is by the employment
of platinum as a catalytic agent : provided all im-
purities are rigidly excluded, the same platinum
can be used over and over again. The manufacture
of synthetic ammonia by the Haber process in-
volves the use of a catalyst, probably nickel. I say
"probably" because the details of the process are
carefully guarded as trade secrets. At any rate,
the production of ammonia from the nitrogen of
the air, and the hydrogen that can be obtained
either from the electrolysis of water, or as a by-
product in the manufacture of lye, can be brought
about with the help of a catalytic agent. Since
this Haber process is on the road to solving the
"nitrogen-fixation" problem, and hence many of

INTRODUCTORY 13

our fertilizer difficulties, the catalyst in industry
seems destined to play a part no less important
than the catalyst that helps to maintain the chemi-
cal equilibrium of the body.

CHAPTER II

THE THYROID

This is the most frequently referred to of the
ductless glands, not necessarily because it is the
most important, but because much of the history
of the ductless glands centers around this one ; and
also because of the success that has attended the
treatment of at least one form of thyroid disease.

The thyroid, which usually weighs anywhere be-
tween one and two ounces, is situated -in the neck.
It consists of two parts on either side of the larynx
(organ of voice) and windpipe, usually con-
nected by a narrow strip of tissue. In contact
with the thyroid are the "parathyroids," still
smaller bodies, which were for a long time not
sharply distinguished from the thyroid proper, and
which as a consequence gave rise to much confusion
in the interpretation of experimental results.
These parathyroids will receive treatment pres^
ently.

That the thyroid is an organ that plays an all-
important part in the various activities of the body
becomes apparent when for any reason it behaves

14

THE THYROID 15

abnormally. The fluid, or still better, the active
hormone that the body secretes, is under certain
conditions largely increased. We get then a con-
dition of hyper-thyroidism. The disease known as
"exophthalmic goiter" (Graves's disease and Base-
dow's disease are synonyms) is probably a case in
point. On the other hand, a condition may arise
wherein the quantity of secretion and the supply
of hormone become deficient. This may develop
"myxedema" in the adult and "cretinism" in the
infant; such being examples of hypo-thyroidism.
We shalltake these up in turn, and we shall begin
with hypo-thyroidism.

Eypothyroldlsm. — In medicine definite clues as
to the type of disease are usually obtained by pre-
liminary experiments with animals. We find that
as early as 1859 Schiff, a Swiss physiologist, in-
vestigated the effect of thyroidectomy on animals
( "thyroidectomy" is a convenient word to describe
the idea of the surgical removal of the thyroid.
"Dectomy" is derived from a Greek word meaning
"excision.") His results, though suggestive, were
inconclusive, due to the fact, as we know to-day,
that Schiff removed the parathyroids as well as
the thyroids. But this physiologist went a step
further. Having removed the thyroid, he next in-
vestigated the effect of implanting thyroid from an
animal of the same species. The results in a num-
ber of cases were highly encouraging.

16 GLANDS IN HEALTH AND DISEASE

Fired by the work of the English physicians
Gull (1872) and Ord (1878), and the German
Kocher (1883), Schiff, in 1884, published his cele-
brated paper, "On the Effects of the Removal of the
Thyroid Body," in one of the Swiss medical jour-
nals. How clearly Schiff recognized the gland to
be an internal secretory one may be gathered from
this quotation: "We may wonder if the thyroid
body produces in its interior a substance which it
delivers into the blood stream and which consti-
tutes a nutritive element for another organ (ner-
vous), or whether it acts mechanically by its ana-
tomical position. To decide between these two
alternatives, it is necessary to find a means of
transplanting it, by grafting it into another part
of the body. If, after this has been done, the acci-
dents resulting from its removal are avoided or re-
duced to a minimum, it is evident that the action
of the thyroid is due to its composition and not to
its anatomical relations ; this will prove the thyroid
to have a chemical function."

The grafts Schiff tried disappeared in time, but
not before it was noticeable that there was an im-
provement in the condition of the animal. From
these results he concluded that "the substance of
the grafted organ, taken up by the blood, serves
to counterbalance the untoward effect of thyroi-
dectomony" ; — clearly a case of hormonic action.

He had another idea which, however, he did not

THE THYROID 17

put to the test of experiment, and thereby fell short
of another great discovery : "It would be curious,"
he writes, "to investigate if the macerated extract
of the thyroid, introduced into a cavity, or injected
into the rectum, has the same immunizing power."

A repetition of Schiff's experiments by other in-
vestigators did not always corroborate Schiff's
findings. We have already suggested that an in-
complete knowledge of the parathyroids may have
been the cause of this. We may also add that not
only do animals of different species behave differ-
ently, but even animals of the same species do, pro-
vided there is a marked difference in age.

Symptoms. — Where the operation in an animal
has been successfully performed, some such symp-
toms as the following develop: The skin becomes
thick and dry; there is a loss of hair; the animal
shows a tendency towards obesity, particularly in
certain portions of the body; the muscles become
weak and the tissues renew themselves but slowly.
The blood is poor, in quality and quantity; the
temperature is below normal ; and the sexual func-
tions are interfered with. This interference with
the sexual glands is of uncommon interest, since
it suggests a close interrelationship between the
various hormones of the body — an observation that
is strengthened every time a disease due to a hor-
monic disturbance is examined. The nervous sys-
tem is also attacked, dullness and general apathy

18 GLANDS IN HEALTH AND DISEASE

being markedly apparent. A histological examina-
tion shows many of the nerve cells to have shrunk
in size.

Cretinism. — If instead of removing the gland it
atrophies or wastes away, the symptoms are quite
identical. In a child where such a condition occurs
we find growth to be arrested. The head and face
look deformed; the expression is decidedly idiotic.
The face is pale, the hair thin, the skin dry, the
abdomen swollen. The development of the genera-
tive organs is delayed. Deaf -mutism is quite com-
mon. These are all symptoms of the "cretinous"
child, the disease being spoken of as "cretinism."

Professor Falta describes a cretinous child, four
and one-half years old, as follows : "Head at birth
already large. Speech up to second year of life
consisted of the simplest words only, such as <tata/
'mama' ; and since this time the child has not spoken
much otherwise. Head extremely large. Very low
forehead, eyes stand wide apart. Saddle-nose;
thick broad tongue that protrudes from the mouth.
Cheeks very thick, throat very thick and stubby.
Thyroid not palpable. Thick hair on back. Skin
of the body springy, elastic; hands and fingers
chubby. Abdomen much distended. The child
often stares into space for a long time, but at times
is lively and cries loudly. No trace of speech.
Puts all objects into his mouth. Impressions of

THE THYROID 19

hearing entirely absent ; no reactions of the eyelids
to sounds."

If now there still remains some question as to
the soundness of the diagnosis, all doubts are im-
mediately removed by prescribing extracts of the
thyroid gland to the young sufferer. The recovery
as a consequence is little short of miraculous.

Thyroid feeding and the development of frogs. —
In his fascinating article on "Natural Death and
the Duration of Life" (Scientific Monthly, Decem-
ber, 1919), Professor Jacques Loeb describes the
remarkable effect of thyroid feeding on the devel-
opment of the frog and salamander. He writes:
"It is possible that some of the changes underlying
metamorphosis are due to changes in the circula-
tion of the blood. Gudernatsch made the remark-
able discovery that this metamorphosis, which in
our climate usually occurs during the third or
fourth month of the life of the tadpole, can be
brought about at will even in the youngest tadpoles
by feeding them with thyroid gland, no matter from
which animal. By feeding very young tadpoles
with this substance, frogs not larger than a fly
could be produced. Allen added the observation
that if a young tadpole is deprived of its thyroid
gland, it is unable ever to become a frog ; and that
it remains a tadpole which can reach, however, a
long life and continue to grow beyond the usual size

20 GLANDS IN HEALTH AND DISEASE

of a tadpole. When, however, such superannuated
tadpoles are fed with thyroid they promptly under-
go metamorphosis.

"These observations cleared up an old biological
puzzle. Salamanders also undergo a metamorpho-
sis which is, however, less striking than that of the
tadpole of a frog. In the salamander the meta-
morphosis consists chiefly in the throwing off of
the gills, and in changes in skin and tail. In
Mexico a salamander occurs which through its
whole life maintains its tadpole form, namely, the
axolotl. Attempts to induce the axolotl to meta-
morphose failed until after Gudernatsch's discov-
ery an investigator fed the axolotl thyroid gland,
and this brought about metamorphosis. ... It
seemed possible that the iodine contained in the
thyroid was the active principle causing metamor-
phosis in tadpoles. This was confirmed by Swingle
who succeeded in inducing metamorphosis in tad-
poles by feeding them with traces of inorganic
iodine."

Administration of thyroid extract. — Thyroid ex-
tract may be administered in one of three ways:
by mouth, by injection beneath the skin (subcu-
taneous), or by injection into a vein (intravenous).
The last method yields the quickest response. This
might be expected if we remember that the thyroid
hormone, and all other hormones, reach the various
parts of the body by means of the blood stream.

THE THYKOID 21

Usually, however, the physician prefers to mix the
thyroid extract with the patient's food, this being
a much simpler proceeding, and in the long run
just as effective.

Thyroid gland transplantation. — Why when the
administration of thyroid gland is so efficacious,
thyroid gland transplantations should be under-
taken to cure patients suffering from hypothyroid-
ism, is not clear. I take up a New York newspaper
for Dec. 9, 1920, and in it is the following (special
dispatch from Chicago) : "Mary Zembok, 19, of
Joliet, 111., may become a normal girl of 19 — that
is if the grafting of a monkey gland into her neck
to-day restores her mentality and physical develop-
ment. Physicians who performed the operation
said that it had been successful. Mary had been
mentally defective almost since birth, and com-
paratively paralyzed. The mother, a Pole, has five
children besides Mary, all of them normal. When
Mary was two years old it became apparent that
she would not develop into a normal child, and
Mrs. Zembok relegated her to the basement of their
home, where she lived in perpetual darkness until
two months ago, when the health authorities learnt
of the case. The child, when found, was immedi-
ately removed to a hospital here. It was decided
that the only hope for a full recovery would be the
gland transplantation operation. To-day the
monkey, a full-grown animal, and the child were

22 GLANDS IN HEALTH AND DISEASE

taken to the operating room, the thyroid gland re-
moved from the animal and transplanted into the
neck of the child."

I submit that this is excellent material for a
novel, play or "movie."

As I write this paragraph I am informed that
J. R. Brinkley, M.D., C.M., Se.D., Chief Surgeon,
Brinkley-Jones Hospital and Training School for
Nurses, Milford, Kansas, graduate of the medical
department of Loyola University, who has travelled
"all over the world" — that this same doctor has
completed a 96-page book on the Goat Gland Trans-
plantation. Dr. Van Buren, reviewing the book
for the New York Times, says : "A fair commen-
tary on this book, I should say, is that one of its
outstanding features is its delightful naivete."

Is the absence of hormone responsible for cre-
tinism?— The very fact that administration of thy-
roid extract causes recovery in the case of cretin-
ism, a specific disease, points to the presence of
some hormone in the thyroid that is responsible —
some substance, then, that reaches the other organs
of the body by means of the blood stream. Unfor-
tunately for the welfare of the community, the
other ductless glands do not exhibit this specificity
to the same marked degree. With them the situa-
tion that arises is often of a character so compli-
cated as to baffle the sharpest intellects of the
medical profession.

THE THYROID 23

Myaedema. — The atrophy of the thyroid in the
adult gives rise to a condition quite similar to that
described in the child. Here, however, instead of
calling the disease "cretinism'' we call it "myxe-
dema," to denote the mucous fluid that gathers be-
neath the tissues and that gives rise to swellings
all over the body. There is a belief that the
immediate cause of this disease is due to the pres-
ence of an excess of "mucin," a substance that gives
the "ropy" consistency to saliva, and that is also
found in various parts of the body. The thyroid
hormone presumably prevents the accumulation
of an excess of mucin.

Symptoms in myxedema. — A person afflicted
with myxedema, which, by the way, is more com-
mon in woman than in man in the proportion of at
least two to one, gradually assumes an appearance
that is beyond all recognition. The dull mind, the
sluggish movement, the unsteady gait, combine
with the general alteration of features to make the
person a most pitiable spectacle. The patient may
eat quite little, yet so poor is the assimilatory
mechanism, that even that little is not easily taken
care of ; so that there is a marked accumulation of
food reserve in the body, and the individual be-
comes abnormally fat.

Treatment with thyroid extract. — Here again,
as with the child, cures may be obtained by the ad-
ministration of thyroid extract. But in both cases

24 GLANDS IN HEALTH AND DISEASE

the extract must be administered at regular inter-
vals and kept up indefinitely, otherwise there is a
relapse. The discordant results that have been
reported with thyroid feeding in myxedema are
almost invariably due to the type of thyroid extract
used. The various samples of these on the market
vary greatly in efficacy, due no doubt to the method
and source of extraction. Two commercial houses
justly famous for the preparation of such extracts
are Burroughs Wellcome, of London, and Parke,
Davis, of Detroit, Mich. Now that Kendall has
succeeded in isolating the active principle of the
thyroid, there need be little occasion for future
variation.

Evidently the administration of the thyroid sub-
stance does not give rise to any accumulation of
the material in the system. A certain amount is,
as it were, used up in each operation. Under nor-
mal conditions, when the gland in the body func-
tions properly, the amount of hormone necessary
for regulating metabolic processes and nerve re-
sponses is manufactured whenever required. This,
of course, is no longer possible when the gland is in
an atrophied condition.

Many cases are on record which show the de-
velopment of myxedema when the thyroid is re-
moved— removed because, let us say, of a tumor
growth. Both the removal of the thyroid and the
atrophy of this organ give rise to the same disease.

THE THYKOID 2S

A number of investigators — among them the justly
famous Mayo brothers of Rochester — showed that
where surgical removal of the thyroid becomes im-
perative, myxedema may be prevented by leaving
intact at least one-fourth of the organ.

Iodine in the thyroid. — It would have been
strange if no attempts had been made to isolate
the hormone or active principle present in the thy-
roid gland. As a matter of fact, many such at-
tempts were made, particularly after the success-
ful isolation of the active principle of the adrenal
glands. The first important discovery that was
made in this direction was by Baumann in 1895,
who showed that the thyroid is rich in the element
iodine. Until Baumann's time no one had had the
slightest suspicion that such an element as iodine
existed in the body; yet a careful analysis of the
thyroid showed it to be there in appreciable quan-
tity. That naturally suggested two things: that
the active principle of the gland was an iodine com-
pound, and that iodine, or more likely foods con-
taining iodine, have to be supplied to the body.

Isolation of the thyroid hormone. — Much work
has since been done on the chemistry of the iodine
compound in the gland. Various substances have
been isolated from it containing percentages of
iodine greater than that in the whole gland, show-
ing that the preparations, if not pure, did at least
represent concentrated fractions. These sub-

26 GLANDS IN HEALTH AND DISEASE

stances were given various names, and their dis-
coverers claimed that their iodine compounds could
do all that the gland extract itself could do : that,
in short, such substances could be employed in the
place of the gland extract in the treatment of cre-
tinism and myxedema. Many have been the state-
ments for and against the use of such preparations.
Lately, however, E. C. Kendall, working at the
newly-created Mayo Foundation in Rochester, has,
after some ten years of intensive work, actually
succeeded in isolating the iodine compound in a
pure form. He calls it "thyroxin," and the com-
pound contains no less than 60 per cent, of iodine.
It has already been extensively used by Kendall
and others in the treatment of thyroid deficiency
diseases, with marked success in almost all cases.
"This could be made even stronger, as we have
not found a single case of thyroid deficiency that
has not responded to an intravenous injection of
thyroxin ; and, furthermore, the response is a quan-
titative one. That is, for every milligram (one-
thousandth of one gram, and 2% grams correspond
to one ounce) injected, the basal metabolic rate
(see p. 39) increases 2~y2 per cent." (E. C. Ken-
dall.) This constitutes another triumph for the
chemist in his application of chemistry to medi-
cine.1

1 Kendall's work. This work of Kendall's is of such importance
that it warrants further discussion. As, however, some knowl-

THE THYEOID 27

Endemic goiter. — Before dismissing the subject
of hyposecretion a word must be said about the
cases known as endemic goiter. In such cases the
front part of the neck becomes swollen, due to the
enlargement of the thyroid gland (hence the name

edge of chemistry must be assumed at this point, I would suggest
that those readers who do not possess such knowledge had
better skip this footnote.

The first detailed account of the isolation of the active prin-
ciple appeared in 1919, when Kendall published his paper, "On
the Isolation of the Iodine Compound Which Occurs in the
Thyroid," in the Journal of Biological Chemistry. The research
was begun in 1910, so that no less than nine years of continuous
work were spent in attempts to isolate the hormone. Up to 1919,
33 grams (a little over an ounce) of the hormone "thyroxin" had
been isolated from 6.550 pounds of fresh thyroid.

Kendall's method of isolating thyroxin is as follows: Fresh
thyroid gland is hydrolized with sodium hydroxide. The fats
are removed by rendering the sodium soaps insoluble, and the
clear alkaline filtrate is acidified. Acid soluble and acid insoluble
portions are obtained, each containing one-half of the total
iodine. (Kendall has confined his attention to the acid-insoluble
portion, which contains all the thyroxin, but what type of
iodine compound is in the acid soluble portion, and to what
extent that iodine combination is of importance, remains to be
seen.) The acid insoluble portion is filtered off, the precipitate
redissolved in sodium hydroxide and reprecipitated with hydro-
chloric acid. The substance is next air-dried and dissolved in 95
per cent, alcohol. A hot, concentrated, aqueous solution of barium
hydroxide is added to the alcoholic filtrate, and the mixture
heated under a reflux condenser. This is next filtered, a small
amount of sodium hydroxide added to the filtrate, and carbon
dioxide passed through the solution. Barium and sodium car-
bonates are removed by filtration, and the alcohol is removed by
distillation.

The product is purified by redissolving in alcoholic sodium
hydroxide and again passing in carbon dioxide. The sodium car-
bonate is filtered, and the alcohol evaporated. The last traces of
alcohol are removed by heating on a water bath. At this point
the monosodium salt of thyroxin separates. The thyroxin itself
is obtained by dissolving the salt in alcoholic alkali, and pre-
cipitating with acetic acid.

28 GLANDS IN HEALTH AND DISEASE

"goiter"), and a pressure is exerted on neighbor-
ing glands such as the trachea and esophagus. The
enlargement of the thyroid gland would lead one
to suspect that there is a hyper-, rather than a hypo-
secretion of the hormone. This, however, is not
true of this type of goiter, which is quite prevalent
in Switzerland, and in the Lake sections of our
country (hence called "endemic" to denote its local
character) . That we here deal with a type of hypo-
secretion is made evident by the general symptoms

Thyroxin is 4,5,6 tri-hydro-4,5,6 tri-iodo-2-oxy-beta indolepro-
pionic acid
I H

V

H H 0

c-J-A-o'

OH

It is a colorless, odorless, crystalline substance, insoluble in
aqueous solutions of all acids, including carbonic; soluble in
sodium, potassium and ammonium hydroxides; slightly soluble
in sodium and potassium carbonates. It forms salts with metals
and acids. It contains 65 per cent, of iodine.

The above formula was established by an analysis of the sub-
stance, and by a study of its derivatives.

An interesting observation, made by Dr. Dutcher, but not yet
confirmed, so far as I am aware, is to the effect that thyroxin
has vitamine properties; it behaves like yeast, for example, in
curing birds of polyneuritis and men of beriberi (see the chapter
on Beriberi in the author's book on Vitamines). Are we after
all on the eve of discovering some relationship between vitamines
and hormones?

THE THYROID 29

that develop, and by the ready response to treat-
ment with thyroid extract. Poultices of burnt sea-
weed— a fruitful source of iodine — and iodine itself
painted on the skin, were used for this disease long
before it was known that the thyroid contained this
element.

Iodine an essential element. — Now as to the io-
dine itself, is it really essential to the body? An
element can neither be synthesized in the labora-
tory nor in the body ; it can merely be obtained from
nature or from compounds that already contain it.
If we deprive our food of all iodine we deprive the
thyroid of what seems to be its essential element.
Yet the situation is not as clear as it seems; for
though many experiments have shown that thyroid
activity and the iodine content of the gland go hand
in hand, yet cases are known — of animals, it is
true — where the thyroid contains no iodine at all,
and yet the animal seems quite normal. On the
other hand, in endemic goiter some remarkable
cures have been obtained by the administration of
simple inorganic iodides. Marine and Kimball, of
the Western Keserve University, Cleveland, started
in 1917 with a survey of the incidents and types of
thyroid enlargement in the schoolgirls of Akron,
Ohio, from the fifth to the twelfth grades inclusive.
For treatment they used sodium iodide, which was
taken in doses of three grains daily for ten consecu-
tive school days, repeated each spring and autumn.

30 GLANDS IN HEALTH AND DISEASE

Becently (June, 1920) they published results of
studies which covered a period of some thirty
months. Of 2,190 pupils that had received the
sodium iodide treatment, five had shown enlarge-
ment of the thyroid, while of 2,305 pupils who had
not received any such treatment, 495 showed an
enlarged thyroid.

In a later article (Oct. 1, 1921) they write: "Of
1,182 pupils with thyroid enlargement at the first
examination who took the prophylactic, 773 thy-
roids have decreased in size ; while of 1,048 pupils
with thyroid enlargement at the first examination
who did not take the prophylactic, 145 have de-
creased in size. . . Klinger has recently (1921)
reported even more striking curative results in the
school children of the Zurich district. He worked
with school populations in which the incidents of
goiter varied from 82 to 95 per cent., while our
maximum incidence in Akron was 56 per cent.
With such a high natural incidence of goiter, his
observations naturally deal more with the curative
effects. Thus of 760 children, 90 per cent, were
goitrous at the first examination. After fifteen
months' treatment with iodine, only 28.3 per cent,
were goitrous, of a total of 643 children re-ex-
amined."

Hypersecretion. — An excessive secretion (hy-
persecretion) developed by the thyroid gland may
give rise to the disease commonly known as "ex-

THE THYROID 31

ophthalmic goiter/' though the English sometimes
call it "Graves's disease," and the Germans, "Base-
dow'sche Krankheit," to denote the work done by
pioneers. Often these diseases present a greater
complexity than a mere hypersecretion. Here
again much of the preliminary work was done by
experiments on animals. Instead, however, of re-
moving the thyroid gland — which we do when we
study the effects of hyposecretion — extra doses of
extracts of the gland are administered. When this
is done we almost invariably produce symptoms in
the animal that bear a strong resemblance to ex-
ophthalmic goiter in man.

Symptoms in exophthalmic goiter. — As might be
suspected, the symptoms of this disease are very
much the reverse of those in cretinism and myxe-
clema. The slowing up of cellular processes, so
characteristic of myxedema sufferers, gives place
to a decided acceleration of these processes. The
stupid, apathetic expression is replaced by an anx-
ious, restless one. In the place of a deposit of fat
there is a wasting away of the tissues. The subject
becomes thin because of excessive metabolism (we
shall take up the question of metabolism later).
The pulse is rapid — it may vary from 100 to 140
per minute — and irregular. The thyroid is usually,
though not invariably, increased in size (hence
"goiter"). There is also usually, though not in-
variably, an abnormal protrusion of the eyeball

32 GLANDS IN HEALTH AND DISEASE

(hence the name "exophthalmos," ) giving the sub-
ject a "startled" expression ; and this goes hand in
hand with his anxious, restless appearance. Very
often the patient suffers from profuse perspiration.

The Komans were evidently not unfamiliar with
this disease, for it is stated that they refused to
buy a slave if he had an enlarged goiter, or if he
showed protruding eyeballs, on the very practical
grounds that he was not a fit subject for hard
work.

One or more of the symptoms enumerated show
themselves in the individual suffering from exoph-
thalmic goiter; but one symptom that is always
present and that, so to speak, gives the clue to the
type of disease, is the excessive rapidity in the
action of the heart (tachycardia).

Not distantly related to the physical condition
of the patient is his mental state. The relation of
the ductless glands to the general mental make-up
of the individual is of sufficient importance to war-
rant special treatment, and a chapter will be de-
voted to that subject later on. Here it may be
mentioned that the patient suffering from exoph-
thalmic goiter becomes, as Dr. Cobb puts it, an
^intractable, selfishj__restless and inconsiderate
being. The medical attendant as a rule~receives
the full benefit of this, and can do little that is
right. He is either old-fashioned when he explains
that the reason for rest in bed, for example, is to

THE THYROID 33

avoid straining an already weakened heart; or an
ignoramus if he insists that the rest combined
with hygienic principles offers the best hope for
alleviating the disease. If he suggests trying a new
remedy he is experimenting with her ; if he persists
with the old he is a 'stick-in-the-mud.' "

Dr. Cobb in his example deliberately uses the
feminine gender because the disease is really far
more common in the female than in the male. The
proportion is placed by some authorities as high
as five to one. An attempted explanation for this
"partiality" is based on the fact that in the female
the gland is enlarged usually at puberty and dur-
ing pregnancy.

Treatment. — When we come to the means at our
disposal in bringing about a cure, we find no such
definite road to success as in cases of hypothyroid-
ism. There, as will be remembered, definite
amounts of extracts of the thyroid gland, when
regularly administered, changed the secretion of
the gland from subnormal to that approaching nor-
mal. Here, with an excessive secretion, it might
be surmised that a partial removal of the gland
would be successful in restoring the health of the
sufferer. This has been tried many times, and
with success in a fair number of cases. But the
operation is a difficult one, and only a surgeon
of extraordinary skill and much experience can
perform it; and even then a successful operation

34 GLANDS IN HEALTH AND DISEASE

is often followed by post-operative changes that
are quite discouraging — a factor that of course
enters into many other types of operations. In
any case, unless the disease has taken a very grave
turn, when the individual is pretty much on the
borderland between life and death, the treatment
is apt to be anything but surgical.

Treatment other than surgical centers around
the word "rest." No particular insight on the part
of the lay reader is required to understand the
reason for this. If the body machine is perform-
ing its cycle of operations at an accelerated speed,
anything that will tend to decrease the rate will
prove beneficial. Dr. Charles Mayo says: "The
opinion of an eminent surgeon (Kocher) that 90
per cent, of all goiters can be improved so as to
make operations unnecessary, was probably based
upon observations of the effect of rest, for rest is
the common element in all the various forms of
treatment that have proved successful."

The attending physician has, of course, to con-
sider the question of diet and the use of drugs.
Food containing iodine should, ipso facto, be barred
from the table, on the assumption that since the
hormone responsible for thyroid activity is prob-
ably an iodine compound, we need do nothing to
increase the quantity of iodine in the body. Then
again a drug that will tend to decrease the rapid
action of the heart may prove advisable. These

THE THYKOID 35

items can be safely left to the discretion of the
medical adviser.

So far attempts to find some direct and simple
cure for exophthalmic goiter have failed. The
"rest" cure in many cases, and removal of part of
the gland in a number of cases, have proved suc-
cessful. 'Other methods of "cure" include the pro-
duction of a substance that will act as an anti-
toxin, and neutralize the excessive quantity of
hormone present; the application of X-rays; and
the administration of extracts of parathyroids or
the thymus gland, or of calcium salts.

It may not be amiss to point out at this time
that the psychic factor in the treatment of hyper-
thyroidism cannot be overlooked. Psycho-analysis,
handled by pseudo-scientists, has become a laugh-
ing stock, just as glandular treatment and the gen-
eral subject of the ductless glands threatens to
become ; but psycho-therapy, practised by the skill-
ful physician, is at times of inestimable aid in put-
ting the patient on his feet.

Metabolism studies. — Cases of hyper- and hypo-
thyroidism have fairly well-recognizable symptoms.
These have already been discussed. But we have
to describe a method which helps the diagnosis a
great deal. This depends upon the fact that the
thyroid is par excellence the organ that regulates
the metabolism of the body.

But before we go any further we must explain

36 GLANDS IN HEALTH AND DISEASE

what we mean by the word "metabolism." Food
is taken into the system, and with the help of
enzymes or ferments and the oxygen of the air,
undergoes chemical changes in the body, yielding
carbon dioxide, moisture, and various nitrogenous
products that are eliminated principally through
the kidneys. The processes involved are digestion,
assimilation and excretion. Under the heading
of metabolism we may include all those changes
that occur in foodstuffs from the time they are
absorbed to the time they are excreted. Huxley
used the word "metabolism" to "denote the sum
total of those chemical changes which take place
in living matter, and in virtue of which we speak
of it as living" (metabolism comes from the Greek
meaning "change.")

Lavoisier. — Lavoisier, a Frenchman, more than
a hundred years ago showed that valuable infor-
mation as to the metabolic changes that go on in
the body can be obtained in one of three ways:
by estimating the amount of oxygen consumed, or
of carbon dioxide eliminated, or of heat evolved.
With regard to the heat evolved, it must be remem-
bered that the reactions of the body, like all chemi-
cal reactions, are accompanied by temperature
changes — usually by an increase of temperature,
as in the case of the body.

Since Lavoisier's time, chemists and physiologists

THE THYROID 37

have given much attention to the study of "respira-
tory exchange" — to the relationship of oxygen in-
take and carbon dioxide output, — and to the meas-
urement of the heat evolved in the reaction. Vari-
ous types of calorimeters have been invented for
that purpose.1 In Germany, Voit, Pettenkofer,
Kubner and Zuntz, and in this country, Atwater,-
Eosa and Benedict, have done much to advance our
knowledge in this direction. The sum of such
knowledge has been to supply us with exact data
regarding the heat evolved in individuals under
varying conditions. If a certain amount of heat
is evolved, that amount of heat must also be sup-
plied, and the supply of such heat can come only
from the food supplied and "burnt" in the body.
That is how we arrive at certain fundamental food
requirements.

Constant Temperature. — Not the least remark-
able of the many remarkable phenomena noticeable
when we study the living organism is the way the
temperature within us remains constant. The
temperature outside may vary considerably, yet
under normal conditions the temperature within
us varies very little. A constant temperature
means a constant heat production.

Of course this is true only of warm-blooded ani-
mals, not of cold-blooded ones, such as the frog;

1 See the chapter on Calories in the author's book on Vitamines.

38 OLANDS IN HEALTH AND DISEASE

its temperature is but slightly higher than that of
its environment, and its metabolism, therefore,
varies considerably from winter to summer.

Surface area. — Though for a long time the metab-
olism (measured in calories) of man and warm-
blooded animals was taken to be proportional to
their weight, Eubner, of the University of Berlin,
has shown that a closer relationship is obtained if
instead of the weight we substitute the surface area
of the man or animal — that is to say, the area of
the surface exposed. Then we get such figures as
the following:

Calories produced

A

Per square

Per kilo meter of
surface

Weight in kilograms
(1 kilo equals 2% pounds)

Horse 441 11.3 948

Pig 128 19.1 1078

Man 64.3 32.8 1042

Dog 15.2 51.5 1039

Goose 3.5 66.7 969

Mouse 0.018 212.0 1188

(A calorie is the amount of heat necessary to raise one kilo of
water one degree centigrade. A meter is a little over a yard.)

Making allowances for experimental difficulties
and inaccuracies, the last column of figures is fairly
constant, unlike the second, which varies consider-
ably. We may say then that there is an evenness of
heat production per unit of body surface.

The difficulty in referring to surface area is a

THE THYEOID 39

difficulty connected with measuring such an area.
Mathematicians have not been wanting to devise
a formula which connects weight with surface area.
All you have to do is to weigh your man and then
multiply the cube root of the body weight squared
by 12.3, and you have your surface area ! Du Bois,
however, working at the Kussell Sage Institute of
Pathology, connected with the Bellevue Hospital,
New York, has shown a method by which the sur-
face area can actually be measured. "He covered
the body surface with light-fitting underwear, ap-
plied melted paraffin, and then paper strips to
prevent change in area when the covering was re-
moved. This model of the surface when cut into
flat pieces was photographed upon paper in which
equal areas were of equal weight. From the weight
of paper which received the photographic impres-
sion the area of body surface could be calculated." *
So accurate is this method, that a ball having an
area of 0.1490 square meter, when measured in
this way, gave the figure 0.1488. Du Bois also
showed that the calculation of surface area by the
formula method involved an average inaccuracy
of 16 per cent.

Basal Metabolism. — Using the Du Bois method,
the heat production per square meter of surface is
39.7 calories per hour, provided the individual is
resting and is "normal," and provided the experi-

aLusk, The Science of Nutrition, p. 214.

40 GLANDS IN HEALTH AND DISEASE

merit is carried out before the administration of
food in the morning (that is, after he has fasted
for 12 to 14 hours). This is the so-called "basal
metabolism," and constitutes the unit of reference
whereby we can measure what are the deviations
from the normal.

Metabolism in thyroid disease. — All this is a
long, but, I believe, a necessary preface to what we
are now coming to : metabolism in thyroid disease.
We started out by saying that the thyroid, by
means of its hormone, regulates, perhaps more than
any other organ of the body, the amount of metab-
olism in the body. Under normal conditions, with
a normal thyroid, the metabolism of the individual
is such as to show a normal abasal metabolism."
When, however, hyper-thyroidism sets in, with a
gland that is excessively active, the rise in metab-
olism above the normal amount is considerable.
Vice versa, where the patient suffers from hypo-
thyroidism, with a decreased activity of the thy-
roid, there is a decided drop in the metabolic rate.
For example, when the metabolism of a patient
suffering from exophthalmic goiter (hyper-thyroid-
ism) was investigated it was shown to be 75 per
cent, above the normal basal of 39.7 calories (usu-
ally written +75) ; on the other hand, with a cretin
the metabolism was 22 per cent, below normal
( — 22). Incidentally the same cretin, after being

THE THYEOID 41

fed with thyroid extract, showed a normal basal
metabolism.

Value of basal metabolic studies. — Of what value
are these metabolic studies? Of the very highest
in thyroid disease; for, taken together with the
other symptoms, a metabolism experiment will
confirm or disprove the diagnosis. But there is
a still more important point to be brought out:
once the diagnosis has been made and a method of
treatment adopted, its progress can be followed by
periodically carrying out such metabolic experi-
ments. If the patient suffers from hyper-thyroi-
dism, a successful treatment will gradually show
a lowering of the metabolic rate; if from hypo-
thyroidism, successful treatment will reveal an in-
crease in the metabolic rate.

There is one drawback to the method : It is not
easy to carry out, and requires skillful scientists to
handle the instrument.

It may be mentioned in passing that metabolic
studies have been undertaken in other ductless
glandular diseases, notably the pituitary, but so
far with little result ; the plus and minus variations
are not of a sufficiently pronounced character.

In any case we may conclude with Dr. Boothby,
of the Kochester Clinic, that "the basal metabolic
rate, which is a determination of the heat produc-
tion in a person under standard conditions, serves

42 GLANDS IN HEALTH ANP DISEASE

as a measurement of the most fundamental process
of life itself. Variations of the heat production,
and alterations in the body temperature are to be
considered rightly a means of fundamental disease
classification, and the basal metabolic rate serves
as an accurate diagnostic aid in the recognition of
the presence or absence of hyper- (and hypo-) thy-
roidism."

All this is very true provided the diagnosis does
not merely confine itself to a determination of
the basal metabolism of the patient; for increases
in basal metabolism are obtained in pernicious
anemia or leukemia (increase in the number of
leucocytes in the blood) or fever. These, however,
can be readily differentiated from goiter afflictions.

CHAPTER in

THE PARATHYROIDS

Attached to the thyroid are four small organs,
weighing in all not more than two grains, which
are known as the "parathyroids" ("para" means
"near"). For a long time these organs were
not distinguished from the thyroid proper, and
even when discovered and described, they were —
and by some still are — regarded as part of the
larger gland. The concensus of opinion, however,
seems to be in favor of the belief that the para-
thyroids are independent organs with an indepen-
dent action all their own; and that if they are re-
lated to the thyroid, the relationship is no closer
than that of any other two ductless glands in the
body. For much of our knowledge of the para-
thyroids we are indebted to the French physiolo-
gist, Gley.

Tetcmy. — The removal of the parathyroids in an
animal, or their decay or removal in man, gives
rise to the condition known as "tetany" (which,
by the way, must not be confused with tetanus or
lockjaw). This "tetany" is characterized by the

43

44 GLANDS IN HEALTH AND DISEASE

sudden involuntary contractions of the muscles
and extremities. "The fits are sometimes frequent,
but more often occur at long intervals." The res-
piratory tract, the heart, and the body temperature
are also affected. The illness is very often pro-
longed, and often terminates fatally. There is a
loss in weight, indicating a disturbed metabolism.
The presumption that the metabolism of bone, and
particularly that relating to calcium, is affected,
has experimental support, in that the administra-
tion of calcium sometimes relieves the sufferer.

That tetany is the result of the absence of the
parathyroids is clear enough when we consider
that the administration of parathyroid extract
relieves the patient, at least temporarily. You see,
we are here dealing with a case of hypo-parathy-
roidism, just as in cretinism and in myxedema we
dealt with instances of hypo-thyroidism ; and just
as the thyroid secretes a specific hormone the ab-
sence of which gives rise to cretinism in the child
and myxedema in the adult, so the parathyroid
secretes a hormone the absence of which gives rise
to tetany. Notice that the most important piece
of evidence for this view is that in both cases the
symptoms disappear upon the administration of
the extract of the appropriate gland.1

*The results with parathyroid extracts are more conflicting
than those with thyroid ones. A safer position to take would be
to say that the symptoms of tetany can be removed by "grafting"
the gland, rather than by administering an extract of the gland.

THE PARATHYROIDS 45

Koch has found that in tetany there is an ex-
cessive elimination of guanidine, an important
nitrogenous substance that plays a part in the
metabolism of the body ; and he has postulated the
theory that tetany is due to an intoxication of the
central nervous system by this guanidine, — a view
that has a number of opponents.

It may now be asked, if hyper-secretion of the
thyroid may give rise to exophthalmic goiter, what
does hyper-secretion of the parathyroid give rise
to? We are not very sure. We have reached the
end of the land of fact and have now begun our
journey in that of speculation. Since one of the
chief objects in writing this book is to distinguish
fact from fancy, and therefore to combat much that
has been written on the subject of the ductless
glands, we shall avoid entering this land of specu-
lation.

The study of the parathyroids makes clear why
in operations involving the removal of thyroid tu-
mors, the earlier surgeons were much troubled,
because very often an apparently successful opera-
tion would be marred by the development of tetany
in the patient. We now can attribute such a re-
sult to the removal of the parathyroids as well as
to that of the thyroid. The surgeon of the present
day, engaged in an operation of this kind, invari-
ably leaves at least two of the four parathyroids,
for not the least remarkable of the many remark-

46 GLANDS IN HEALTH AND DISEASE

able facts gathered about these ductless glands is
that even when only part of the organ remains in
the body, it still functions, though, of course, not as
well as the entire organ would.

CHAPTER IV

THE PITUITARY GLAND

It seems hardly credible that a piece of tissue
weighing one-sixtieth of an ounce, "the size 'of a
hazel-nut," and lying at the base of the skull,
should, perhaps, be involved in the production of
giants on the one hand, and dwarfs on the other;
that it, like the thyroid gland, should profoundly
influence metabolic and brain functions, growth
and life itself; yet such seems to be the case with
the pituitary gland (sometimes called "hypophysis
cerebri"). The conflicting results that encumber
much of the work on this gland — and on other
ductless glands for that matter — are due to the
almost insurmountable difficulties that the surgeon
encounters in locating and removing the gland,
without at the same time bringing about secon-
dary reactions that are due to causes other than
the removal of the pituitary. Much of what we
know we owe to the genius of Harvey Gushing,
professor at Harvard.

The pituitary described. — The pituitary body,
like the thyroid, consists of two parts, two "lobes,"

47

48 GLANDS IN HEALTH AND DISEASE

and is situated in a depression of a wedge-shaped
bone lying at the base of the skull. It was an organ
not unknown even to such ancients as Galen and
Vesalius, who thought that it was involved in the
formation of nasal secretions (hence the name
"pituitary" from the Latin "pituita," meaning
"phlegm") . Yet, as Professor Gushing has pointed
out, Lower, as far back as 1672, in a paper entitled
"Dissertatio de Origine Catarrhi" says, "For
whatever serum is separated in the ventricles of
the brain and tissues, out of them through the in-
fundibulum to the glandula pituitaria distils not
upon the palate, but is poured again into the blood
and is mixed with it" — which is a very modern way
of defining a ductless gland.

The vagueness attaching to the function of the
pituitary remained such that the French were fond
of calling it "Porgane enigmatique." A distinct
advance was made in 1886 when Marie, a French
scientist, associated a peculiar disease character-
ized by the enlargement of certain bones of the
body, and which he called "acromegaly," with a
tumor of the pituitary. The next step was a per-
fectly natural one; the tumor had to be removed.
When this was done other strange symptoms made
themselves manifest, due in most part, as we know
to-day, to glandular insufficiency, and also, to some
extent, to imperfect operations. Marie formed the
opinion that "acromegaly" was a disease due to a

THE PITUITAEY GLAND 49

deficiency of pituitary activity, and for years scien-
tists blindly believed in this theory, attempting by
extirpation experiments on animals to reproduce
acromegalic symptoms. All such experiments re-
sulted in failure. To-day we know the reason why.
The acromegalic in all probability suffers from an
excess rather than from a deficiency of pituitary
hormone, or hormones.

Only since 1895 has intelligent guesswork given
place to a fair amount of knowledge.

Removal of the pituitary. — Complete removal of
the pituitary gland causes death. Innumerable
experiments with puppies show that death results
in from two to thirty days. Where the life of the
animal is prolonged, a post-mortem examination
reveals that a portion of the gland still remains.
Gushing, as the result of some 200 such extirpa-
tions on dogs, has come to the following important
conclusions: that a prolongation of life, if not a
complete recovery, is possible by transplanting the
gland into an animal that had had its pituitary
removed; that whenever the animal survives the
operation, it is because the gland, and more particu-
larly the anterior 1 portion of it, has not been com-
pletely removed; and that when the posterior por-
tion alone is removed, the animal does not die. It
follows then that the pituitary is a gland essential

1Any part nearer the head than another part is anterior to
the latter ; if farther away it is posterior.

50 GLANDS IN HEALTH AND DISEASE

to life, and that the anterior portion is more essen-
tial than the posterior.

Partial removal of the gland, giving rise to hypo-
pituitarism, does not as a rule end fatally, but
brings about changes in the animal that in some
respects resemble hypo-thyroidism ; it becomes fat,
it looks dull, and the sexual organs are very im-
perfectly developed. The animal also shows a
greater tolerance for sugars (see the chapter on
the pancreas), so that more than the normal quan-
tity of carbohydrate can be taken care of ; and the
animal converts it into fat and stores it as such.
But more characteristic still is the effect on growth.
If two pups of the same age and from the same
litter are taken, and one has part of its pituitary
removed, at the end of twelve months the experi-
mental animal will look less than one-half the size
of the control one. This remarkable influence that
the pituitary has on the growth of an animal can
best be shown with young pups. In the mature
animal the other features alone become dominant.

In man, as in the animal, the growth factor is
more involved if hypo-pituitarism shows itself be-
fore adolescence. The individual remains small
and fat; his sex organs show little development;
and such secondary sexual features as the forma-
tion of hair on the face fails to appear. The tem-
perature is subnormal, the pulse slow. He exhibits
a drowsiness and torpidity "like an animal about

THE PITJJHTARY GLAND 51

to undergo hibernation." Sometimes there are
psychic derangements; and even epilepsy is not un-
common. Dr. Tucker, in summarizing 200 cases
of epilepsy, declares that 63 of this number showed
some pituitary disturbance, 28 with an inclination
toward the hypo- condition. He further states that*
feeding these patients with extracts of pituitary
gland had a beneficial effect, "not infrequently
leading to a cure."

The dwarf and hypo-pituitarism. — Of uncommon
interest is the inference that the dwarf is really
one who suffers from hypo-pituitarism. While we
need much more proof to clinch the matter, some
evidence is not wanting in this direction. The few
studies that have been made show such pituitaries
to be small and atrophied. However, as Professor
Cushing says : "It is not unlikely that under the
term ateliosi and prageria, introduced by Gilford
to designate continuous youth and 'premature old
age', examples of pituitary disease may have been
incorporated. Yet Herter describes a type of in-
fantilism which is clearly attributable to chronic
intestinal infection ; and Osborne and Mendel have
shown that feeding young rats with isolated pro-
teins markedly inhibits their growth, though nor-
mal weight is maintained.1 There are still other
factors. Hence it is unwise to lay too great stress

*See the author's chapter on Amino- Acids in his book on
Vitamines.

52 GLANDS IN HEALTH AND DISEASE

on anything other than the possibility of an indirect
pituitary participation in the dwarfed stature
characterizing the many types of infantilism."

Different parts of the pituitary have different
properties. — It has recently been shown that in
reality the two parts of the pituitary have two
very different functions — the anterior part being
the one that affects stature, and the posterior por-
tion the one that influences fat formation and the
development of the sexual organs. That the an-
terior fragment of the pituitary is the growth-
promoting factor may be inferred from an experi-
ment already cited: if the entire pituitary is re-
moved, death results ; if part of it is removed, and
a portion of the anterior lobe remains behind, death
does not result, but we get a dwarfed condition.
To prove that this dwarfed condition of the animal
is the . result of an insufficient anterior lobe — of
insufficient hormone produced by that lobe — and
not due to the removal of the posterior portion, the
latter alone may be removed, when it will be seen
that there is no alteration in stature.

The growth-promoting factor in the pitwtary.—
Professor Kobertson, formerly at the University of
California, and now at the University of Adelaide,
Australia, has published an extensive series of
studies within the past few years on the growth-
promoting factor in the anterior lobe of the pitui-
tary. He has isolated a substance from it which he

THE PITUITARY GLAND 53

calls "tethelin" (from the Greek "tethelos," grow-
ing) , and which he considers the growth -promoting
factor. Its analysis shows it to be related to the
phosphatids, a group of important physiological
compounds present in all cells. These results need
confirmation.1

The function of the posterior lobe of the pitui-
tary.— If surgical methods and clinical observation
point to the anterior lobe as the growth-promoting
portion of the pituitary, what, it may be asked, is
the function of the posterior body? We have al-
ready seen that surgical removal of the posterior
body is not followed by any extreme changes in the
animal; on the other hand, an extract of the pos-
terior lobe, when injected into the blood, produces
an increase in blood pressure, much like adrenaline
from the adrenal glands (which see). Though
Oliver and Schafer were the first (in 1895) to show
the effects on blood pressure of an injection of an
extract obtained from the whole gland, it was left

1For the benefit of the student of science the principle that
Robertson employs in isolating his tethelin will be given; un-
doubtedly much of value is to be found in this pioneer, though
somewhat inconclusive study: The anterior lobe is ground with
anhydrous sodium and calcium sulphates, dried over the water
bath, pulverized and extracted with boiling alcohol, filtered, and
the filtrate evaporated somewhat under reduced pressure, mixed
with one and one-half times its volume of ether, the precipitate
redissolved in alcohol and reprecipitated with ether. The final
product is dried over sulphuric acid at 30 to 35 degrees (cent.).
"From the constancy of its phosphorus and its nitrogen content
the substance would appear to be a chemical unit." Professor
Robertson has not yet ascertained its exact chemical configuration.

54: GLANDS IN HEALTH AND DISEASE

to Howell, the physiologist at Johns Hopkins, to
prove three years later that the effect was due to
the posterior lobe alone.

While there are resemblances between the action
of adrenaline and that of the hormone in the pos-
terior lobe of the pituitary, there are also some
striking differences. For example, the action of
the pituitary hormone is apt to be of a more pro-
longed nature. Again, a second injection of
adrenaline repeats the action of a first injection;
a second injection of the pituitary hormone may
reverse the action of a first injection. There may
actually be a decrease, instead of an increase in
blood pressure. Or again, on the arteries of the
kidney the two behave diametrically opposite:
adrenaline constricts them and pituitary hormone
(which we shall refer to as "pituitrin," and to
which we shall refer subsequently) dilates them.
Pituitrin, indeed, causes quite a remarkable in-
crease in urinary flow, and has established itself
as a useful diuretic (a substance that increases the
secretion of urine).

Properties of pituitrin. — The action of pituitrin
on the flow of milk from the mammary gland is
no less striking than its property as a diuretic, to
which reference has just been made. It does not
seem, from the experiments conducted, that the
pituitrin actually increases the quantity of milk
secreted; rather, it accelerates the discharge once

THE PITUITAKY GLAJSTD 55

the milk has accumulated. "The pituitrin," says
Macleod, "stimulates the muscular fibers of the
ducts of the mammary glands, thus squeezing out
the milk contained in them."

One other property of this pituitrin must be re-
ferred to. We have noticed that partial removal
of the pituitary in animals, giving rise to hypo-
pituitarism, is followed by an increased capacity
for carbohydrate storage (in the shape of fat).
We find, on the contrary, that injection of pituitrin
decreases sugar tolerance to such an extent as to
give rise to sugar in the urine. Evidently it is
the lack of a sufficient quantity of this hormone in
the animal suffering from hypo-pituitarism that
gives rise to an increased sugar tolerance. All of
which is in favor of the view that pituitrin, like
adrenaline, like the pancreatic hormone ( see under
pancreas), plays a part in carbohydrate metabo-
lism, though it by no means follows that the three
parallel one another in their action.

Pituitrin not a chemically pure product. — We
have given the name "pituitrin" to the hormone (or
hormones) present in the posterior lobe of the
pituitary. It should now be made quite clear that
this hormone has not been isolated in the pure state
at all ; that "pituitrin," of which there are several
varieties on the market, is merely a concentrated
extract of the posterior portion of the lobe, usually
obtained by first getting rid of the protein present

56 GLANDS IN HEALTH AND DISEASE

in the gland, and then sterilizing the remainder.
The fact that sterilization does not destroy the
activity of the hormone is further evidence that
hormones and vitamines (and enzymes) are prob-
ably not very closely related (see also under secre-
tin). The suggestion that the active principle of
the posterior lobe is none other than histidine, an
amino-acid familiar enough to the organic and
physiological chemists1 (suggested by Professor
Abel, of Johns Hopkins, in 1919) has not been
confirmed.

Difficulty in interpreting data. — While in a sense
our knowledge of the properties of the posterior
and anterior lobes of the pituitary is increasing, our
difficulty in interpreting data is not diminishing.
If the anterior lobe is affected and not the posterior
one, we get diminished size and little else. If both
are affected, we get a combination of symptoms.

And still another complication arises. As we
shall see in a minute, it does not always follow
that when the pituitary is affected we get hypo-
pituitarism. It may result in hyper-pituitarism —
in an excessive formation of pituitary hormone or
hormones. Now it is quite conceivable that when
one lobe shows such a tendency, another may show
the opposite tendency; and yet, since the function
of each lobe is different, this does not mean that a

aSee the chapter on Amino- Acids in the author's book on
Vitamines.

THE PITUITARY GLAND 57

neutral or normal condition will result just because
the two lobes pull in opposite directions. If we
bear these factors in mind — and they probably
apply to the thyroid and to other ductless glands —
we shall appreciate the tasks of the physiologist
and the physician.

Professor Cushing's opinion of the problem. —
Professor Gushing in a recent (June, 1921) article
on the disorders of the pituitary gland, has this
to say : "In the case of pituitary disorders we are
not far beyond the stage of the tumor. One may
recognize outspoken acromegaly without a roent-
genogram of the sella (the place where the pitui-
tary is situated), just as one may recognize ex-
ophthalmic goiter without seeing the neck. But in
the absence of neighboring pressure signs, to say
that a child who is undersized, or fat, or whose
dentition or adolescence is delayed, or that an adult
who has the texture and color of skin, the adiposity,
impotence, subnormal temperature, and so on,
known to characterize certain individuals with hy-
pophyseal adenomas (pituitary tumors), is really a
subject of pituitary want, is purely a matter of
guesswork. If this admission must be made regard-
ing these fairly characteristic symptoms, what is
there to say of a pluriglandular (affecting several
glands) complex except to acknowledge an abysmal
ignorance? . . . Only of late with the development
of roentgenology and the more extended use of the

58 GLANDS IN HEALTH AND DISEASE

ophthalmoscope (a mirror used in examining the
interior of the eye) and perimeter (an instrument
that measures the field of vision) can a diagnosis of
pituitary disease apart from acromegaly be made
with any probability. Unlike the thyroid enlarge-
ment, a hypophyseal growth can be determined
only by indirect methods; for next to the brain
itself, the hypophysis lies in possibly the best pro-
tected and most inaccessible place in the body —
one reason for assuming that it may be a most im-
portant member of the endocrine series."

Use of pituitary extract. — Now it is time to
answer the question that must arise in the minds
of readers: If a person suffering from hypo-
thyroidism, and showing symptoms of myxedema,
can be cured by being fed with thyroid extract, is
it possible to cure sufferers from hypo-pituitarism
by feeding them with pituitary extract? It is in
many cases, though one can point to just as many
cases where such treatment has been of no avail.
Pituitrin extract has been given by mouth and by
means of an injection; and a few transplantation
experiments have been performed on animals; but
the results have been only moderately successful;
certainly not nearly as successful as when thy-
roid extract is administered in the corresponding
thyroid disease. Why this should be is not clear,
unless we admit that a hypophyseal insufficiency
creates at times such a disordered organism, that

THE PITUITARY GLAND 59

treatment by means of an extract obtained from
any one gland, or even from a number of glands,
is no longer sufficient.

Quackery in medicine. — Perhaps in no depart-
ment of medicine has quackery flourished so much
as in that dealing with the ductless glands, and
more particularly with the pituitary. The over-
enthusiastic scientist has joined hands with the
pseudo-scientist, and both have provided ample ma-
terial to the charlatan to advertise his goods, and to
ingratiate himself with an all-too-credulous public.

I cannot resist quoting Professor Cushing's very
pertinent remarks : "Children are either too short
or too tall, too fat or too lean. Their adolescence
is too early or too late ; they have too little or too
much hair. They are intellectually backward or
stupid, even defective or epileptic ... all this
needs attention and can be corrected by some whole-
gland extract, usually with a pinch of thyroid
thrown in.

"Pituitary extract is advocated in parturition,
shock, baldness, impotence, epilepsy, and a multi-
tude of other conditions which have hitherto
baffled us ; and if it does not suffice by itself you are
earnestly recommended, according to the directions
'in the enclosed folder, to try this or that combina-
tion of hormones which contains the active prin-
ciple of several glands . . .

"I know of nothing comparable to the present

60 GLANDS IN HEALTH AND DISEASE

furore regarding the administration of glandular
extract unless it be the plant pharmacology of the
middle ages. ... A patient is bilious — therefore
he has some disease of the liver. The leaves of a
certain plant resemble in their color and appear-
ance the surface of the liver — therefore a concoc-
tion of these leaves is good for biliousness, and the
plant comes to be called hepatica. But then, lest
it may not really do this, we will add several other
things to the concoction as well. This is about the
basis on which the glandular extracts are admin-
istered to-day. And it will be noted that most of
them contain a certain amount of thyroid extract,
which possibly is the only one of these sub-
stances having any definite action when given by
mouth. , . .

"Surely nothing will discredit the subject so
effectively as pseudo-scientific reports which find
their way from the medical press into advertising
leaflets, where, cleverly intermixed with abstracts
from researches of actual value, the administration
of pluriglandular compounds is promiscuously ad-
vocated for a multitude of symptoms, real and fic-
titious. The Lewis Carroll of to-day would have
Alice nibble from a pituitary mushroom in her left
hand and a lutein (a pigment obtained from a por-
tion of the ovary) one in her right hand and presto!
she is any height desired !"

Pituitary extract and the development of chick-

THE PITUITARY GLAND 61

ens.— One rather remarkable experiment with
chickens, performed by Dr. L. N. Clark, must be
cited: "In the first experiment, 35 white Leghorn
hens, as well as two cockerels of the same breed
with which they were mated, each received daily
during eight days the equivalent of 20 milligrams
(0.0006 ounces) 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 fincreased
as compared with the controls, but the fertility of
the eggs and the hatching out of the chicks was
extraordinarily enhanced. In order to test the
matter further, a second experiment was performed
with as many as 655 one-year-old white Leghorn
hens (kept without males), the same dose as be-
fore being given to each hen during four days. The
average daily number of eggs laid by the batch
during the four days preceding the pituitary feed-
ing was 233; during the four days succeeding the
administration, 352. These experiments were made
at a time of the year when the egg production of
the hens was tending to diminish rather than to
increase." ( Quoted by Professor - Schafer. )

Hyper-pituit&rism* — Marie, a French physician,
active some forty years ago, was the first to give

62 GLANDS IN HEALTH AND DISEASE

the name "aeromegaly" (enlargement of the ex-
tremities) to that disease which produces an en-
largement of bones, soft part of hands and feet, and
face, and in which the individual assumes giant-
like proportions. He rightly diagnosed such cases
as being due to some pituitary disorder, but for
some time he was of the opinion that aeromegaly
was due to lack of secretion in the gland. When,
however, experiments on animals showed that the
partial removal of the gland gave rise not to giants
but to dwarfs, the view was adopted that aerome-
galy was a disease resulting from a hyper-, rather
than a hypo-secretion; that is to say, then, to an
excessive secretion of pituitary hormone. It is un-
fortunate in the extreme that so far all attempts to
simulate aeromegaly by feeding animals with large
quantities of pituitary extract have failed ; so that
our evidence at best is somewhat unsatisfactory.
The reader will remember that in this respect thy-
roid therapy stands on firmer footing; for hyper-
thyroidism can be fairly closely imitated in the ani-
mal by feeding it with sufficient quantities of thy-
roid extract.

Symptoms in aeromegaly. — The symptoms in
aeromegaly do not make their appearance sud-
denly; the changes in the individual are quite
gradual, as with many of the diseases involving
the ductless glands. At first the person may notice
nothing more than eye strain and dimmed vision.

THE PITUITARY GLAND 63

This may be due to a tumor in the gland pressing
on the optic nerve. But then comes the gradual
enlargement of the head and extremities that can
leave no further room for doubt. The face becomes
big and coarse-looking, the head rather flattened.
An X-ray examination of the fingers shows the
bones to be enlarged. The entire skeleton in-
creases in size, sometimes to huge proportions.
Then also we have an overgrowth of hair, under-
developed sexual glands, and a probable onset of
diabetes, — which may, however, be of a temporary
nature.

Cure in acromegaly. — We have no easy cure for
this disease. Surgical interference may seem an
obvious remedy. This is a dangerous procedure,
however, and is undertaken only in extreme cases.
Fortunately, true cases of acromegaly are rare, and
experience has shown that nature and time often
act as effective curative agents.

As a rule the case presented to the physician and
surgeon is by no means a clear-cut one. It may
be one where hyper-pituitarism predominates, giv-
ing us an example of gigantism if the patient is
affected early in life, or acromegaly — not so pro-
nounced as gigantism — if later in life; or it may
belong to the hypo-pituitary class, with reverse
symptoms, such as under-size, adiposity and sexual
infantilism, if early in life; or the latter two, if
later. But a far more common case, and one that

64: GLANDS IN HEALTH AND DISEASE

complicates the situation, is the mixed or transition
type, exhibiting some features of the hyper- and
the hypo- conditions (cfo/s-pituitarism).

Of 255 cases that have come under Professor
Cushing's care, 200 showed evidence of a tumor —
which of itself may give rise to a hyper- or hypo-
condition, or to a mixture of both. Of these 200,
180 were operated on, and among the latter there
were few acromegalics. The majority exhibited
various forms of dyspituitarism.

Professor Gushing writes: "In view of the fact
that hyper-pituitarism, so far as glandular secre-
tion is concerned, is a condition which tends to
right itself, it must remain for the time being a
matter of uncertainty as to whether or not in the
absence of a degree of hyperplasia (excessive multi-
plication of tissue elements) sufficient to cause
neighborhood symptoms, operative measures can
hold out any promise of permanently controlling
the disorder. When, however, neighborhood symp-
toms have arisen owing to the extreme enlargement
of the gland, due to the' formation of an adinoma-
tous struma (a tumor in an enlarged gland),
whether or not there have been antecedent symp-
toms of acromegaly, the surgical aspects of the
matter stand on firmer ground."

Do giants suffer from hyper-pituitarism? — One
is attracted by the hypothesis that giants are ex-
amples of men suffering from hyper-pituitarism.

THE PITUITARY GLAND 65

Arthur Keith, the sponsor of attractive theories on
behalf of the endocrine glands, writes, "In giants
this gland [the pituitary] is always greatly and
abnormally overgrown. We have reasons for sup-
posing that it has thrown a drug or drugs into the
blood which set all the bone-builders into a state
of frenzied activity, producing the dire disease of
growth called gigantism." These claims cannot be
maintained without many qualifications.

A case of acromegaly. — Of a number of instruc-
tive cases described by Gushing in his book on the
pituitary — a book that has become a classic in
medical literature — I shall cite one as illustrating
the acromegalic who in time actually suffers from
hypo-pituitarism — in other words, a complex type.

The case was that of a farmer, age 35, of Dutch
extraction and of excellent family history. A hypo-
physeal tumor caused pronounced neighborhood
symptoms with almost total blindness. There had
been a former glandular activity, shown by a ten-
dency to excessive overgrowth, traceable to the ado-
lescent period ; and by subsequent addition of acro-
megalic changes of unusual degree. When admit-
ted to the hospital the patient, on the contrary, in-
dicated a condition of glandular insufficiency, as
shown by adiposity and high sugar tolerance.

As to his history, nothing unusual was noticed
in the farmer until he was 13 years old, when he
began to grow with extreme rapidity, and at 19

66 GLANDS IN HEALTH AND DISEASE

measured about six feet four inches, having de-
veloped into a powerful man of unusual strength,
weighing 222 pounds. He was intelligent and a
good student. So far all had gone well. The man
was an excellent type of a physically well-developed
youth.

At 23 he had a severe illness; he was said to be
"threatened with consumption." At 25 there seem
to have been no traces of acromegaly. He and his
father were positive that a second growth began
when he was 27.

About 1903 — at 28 — he began to have violent
headaches (due to a tumor of the pituitary, and to
the consequent pressure on adjacent parts) ; also
pains in the extremities. These attacks would be
followed by the discharge from the nose of quan-
tities of "slimy mucus/' occasionally tinged with
blood, and relief would ensue for some days or
weeks. He was told at the time that he had acro-
megaly. Two years later difficulty in sighting his
rifle first called attention to a failure of vision.

In 1907 his parents realized that his "features
were changing/5 and that he was "getting large all
over," and was losing his strength (this was dur-
ing his "second period of growth" ) .

When admitted into Dr. Cushing's clinic — in
1910 — he had become very weak and drowsy, and
tired easily. There had been a complete loss of
libido et potentio sexu&lis. Beading vision was lost

THE PITUITAKY GLAND 67

the year before. The left eye was blind and the
right nearly so. His appetite was large and he
always had a box of sweets at hand. He had be-
come very constipated.

The patient's height was six feet six inches. He
weighed 269 pounds. "Neither these measurements
nor the photographs give more than a scant indica-
tion of his extraordinary size and the disproportion
of such parts as the head, hands and feet. He is
a veritable Gargantua."

The X-ray indicated tumor enlargement of the
pituitary. The eyes were large, protruding,
widely separated, and showed a divergent squint
(neighboring symptom).

The hands, always large, were now huge. The
feet were colossal : formerly he could wear a num-
ber eleven shoe, but now he had to have them spe-
cially made.

He had practically no beard, and except for a
scant pubic growth of feminine distribution, the
skin of the trunk and extremities was practically
hairless. On the scalp the hair was abundant and
coarse.

The patient was operated on nine days after ad-
mission, and the glandular tumor thereby removed.
The convalescence was uneventful.

On December 23, six days after the operation,
there was an improvement in vision.

Since the later symptoms were those of hypo-

68 GLANDS IN HEALTH AND DISEASE

pituitarism as well, glandular feeding was insti-
tuted.

On January 28 the patient felt so much stronger
and less nervous, that he was discharged.

A letter received from the patient February 27
reported a further improvement in vision, a normal
temperature, and no constipation. On May 4 he
reported an increase in weight to 281 pounds (just
before the operation this weight was 269). On
June 27 the patient was seen in Los Angeles. The
vision in the right eye had further improved. He
recognized colors. He was less nervous and less
drowsy than before.

A bit of fancy? — At the International Congress
of Eugenics, held in New York in September, 1921,
a session was given over to the influence of the
endocrines on the organism. The papers presented
were of the type that belong to the borderland sepa-
rating fact from fancy. At any rate, one of New
York's very respectable papers had headlines such
as these : "Says glands cause gloom and crime.
A criminal is the victim of chemical reactions.
Scientist explains why a white man is white and
why man is superior to woman." One of the papers
dealt with the development of man from the mon-
key, and Professor Polk, Director of the Depart-
ment of Anatomy in the University of Amsterdam,
discussed the first change in man's ape ancestor, —
the suppression of his hairy covering. He argued

THE PITUITAKY GLAND 69

that this suppression was connected with pituitary
activity ! It would seem that Darwin in developing
his theory of Natural Selection, quite overlooked
the subject of endocrinology!

CHAPTER V

THE ADRENAL GLANDS

These glands consist of two small bodies situated
near the kidney (hence "adrenal"), each weighing
about one-seventh of an ounce. Sometimes they
are called "suprarenal bodies," to indicate that
they are found above the kidney. Sometimes they
are referred to as part of the "chromaffin system,"
to indicate that their cells are colored brown with
chromic acid.

There are really two very distinct parts to the
adrenal gland : the "medullary matter," a marrow-
like body, in which is found the hormone adrena-
line (also known as epinephrine and suprarenine),
and the outer organ, the "cortex," which also se-
cretes a vitally necessary substance that so far,
however, has baffled isolation.

History. — Eustachius, the great anatomist of the
sixteenth century, may be regarded as the discov-
erer of the adrenal glands. As early as 1789
Cassan made the observation that the adrenals of
the Negro are larger than those of the European,
from which he drew the somewhat far-fetched con-

70

THE ADRENAL GLANDS 71

elusion that the gland and the pigment of the skin
are related. In a modified form, this view of
Cassan's was recently brought forward at the
International Congress of Eugenics. Meckel, an-
other observer, noticed a similar enlargement of
the gland in the Negro, but he decided that the rela-
tionship did not rest with the pigment of the skin,
but rather with the genital organs.

Little was known with regard to the function of
the adrenals until 1849, when Thomas Addison,
physician at Guy's Hospital, London, made the
observation that a disease characterized by bronz-
ing or pigmentation of the skin, was invariably
accompanied by the decay of the adrenal glands.
This observation of the English physician led to
little new work, however; and it was only as late
as 1894 that a further impetus was given to the
entire subject by Professor Schafer's discovery
that the injection into the body of an adrenal ex-
tract increased the blood pressure.

Removal of the gland.— Complete removal of the
gland in animals is followed by death within a few
days, though the first day or two after the opera-
tion may fail to show any abnormality or disease.
Partial removal is not as a rule fatal, though vari-
ous symptoms may make their appearance. The
administration of adrenal extract has little or no
effect. Even in the case of Addison's disease, which
we have reason to believe is due to a decreased se-

72 GLANDS IN HEALTH AND DISEASE

cretion of the gland, feeding with an extract of the
gland is followed by no beneficial results — at least
none that last.

Brown-Sequard, whose name we shall encounter
when we come to discuss the function of the sex
glands, did pioneer work on the adrenals as far
back as 1856. He removed adrenal glands from
44 rabbits, nine guinea-pigs, two rats and several
dogs and cats. Not one of these animals survived
the operation beyond the thirty-seventh hour. The
critics, ever after poor Brown- Sequard, severely
criticized his work; they claimed that death in all
cases was due to the nature of the operation, and
not to the removal of the gland. Brown- Sequard
repeated and extended his observations. His con-
clusions are shared by the majority of physiologists
to-day. Even his claim that partial extirpation
does not as a rule result in death has been amply
verified. In his over-enthusiasm — and Brown-
Sequard was a most enthusiastic gentleman — he
declared that the adrenals were even more impor-
tant to well-being than the kidneys themselves.

Not the least remarkable thing to be noticed in
these extirpation experiments is the way the ani-
mal will appear quite normal for some time after
the operation, and then quite suddenly begin to
exhibit effects. Let us illustrate this by giving the
protocol in the case of a female Macacus monkey,
whose adrenals were removed by Dr. Kahn ( quoted

THE ADKENAL GLANDS 73

by Mathews). The animal weighed a little over
four pounds and fed on fruit. "Right suprarenal
removed under ether Nov. 9, 1911. The wound
heals quickly. On 4 December, 25 days after the
operation, when the weight was 62 ounces, took out
the left suprarenal. On the fifth the animal is very
well and eats heartily. On the sixth she eats with
normal appetite. Is active. There is a little edema
(swelling) at the edges of the wound. On the
seventh, normal. On the eighth, normal, but appe-
tite a little less. On the ninth at 9 a.m. is fairly
weak, lies stretched out on the bottom of the cage ;
no appetite; wound in best state. At 9:12 a.m.
great increase in prostration. Apathetic. The eyes
are open and look about. At 1:45 p.m., being
nearly moribund, was killed with chloroform. The
liver was examined for glycogen ; only a trace was
found. The animal lived five days. For four days
it could not be told from a normal animal. The
sudden onset of the symptoms of extreme depres-
sion has the appearance of an intoxication."

Why the "normalcy" for some days after the
operation, and then the sudden change for the
worse, is not at all clear. Perhaps the body has
a hormone reserve that holds out for four days
and then gives out.

Addison's disease. — The equivalent — or what is
supposed to be the equivalent — of the removal of
the adrenals may be seen in man in Addison's dis-

74 GLANDS IN HEALTH AND DISEASE

ease. Dr. Addison regarded the disease as "asthe-
nia (loss of strength), irritability of the stomach
and change of color in the skin." In a recent
(Feb., 1921) issue of the New York Medical
Journal, Dr. Eidelsberg records a case; let us see
how the symptoms agree with Addison's. The man,
aged 30 years, was admitted to the medical ward
of the Post-Graduate Hospital, complaining of
abdominal pain, vomiting, and weakness. The ill-
ness began suddenly ten days previously. There
was loss of appetite, weakness, vomiting immedi-
ately after each meal, constant pain in the abdo-
men, marked constipation, dizziness, and fainting
sensation on slightest exertion. These symptoms
continued throughout the entire ten days, increas-
ing in severity. The patient appeared "tanned,"
as though he had exposed himself to the sun's rays.
There were about 15 small, pale scars scattered over
his body. The weakness rapidly increased until
the patient could not turn in bed. The vomiting
grew worse, and no food was retained.

On the evening of the sixth day after admission
to the hospital, the patient suddenly became un-
conscious, his pulse became imperceptible, and in
five minutes he ceased to breathe. An autopsy
examination revealed that both suprarenals were
markedly enlarged and soft, and on cutting, ap-
peared, except for a thin cortical portion, to con-

THE ADKENAL GLANDS 75

sist of a soft, cheesy material. Several areas typi-
cal of a tuberculosis lesion were found.

The "pigmentation" is usually a characteristic
feature of the disease. Sometimes it is absent, and
sometimes it is present in diseases other than Addi-
son's. Where it is present the color may vary any-
where from the dark hue of the Negro to a faint
sunburn brown. Characteristic also of Addison's
disease are the signs of muscular weakness (with
no corresponding emaciation). "The patient is
very easily tired, and is never able to get properly
rested." One may add that in most cases the blood
pressure is very low, the heart feeble in action, the
temperature is usually subnormal, and the patient
presents an anemic appearance.

The marked pigmentation of the skin in Addi-
son's disease is supposed to be due to a disturbed
relationship between adrenaline and melanin, the
characteristic pigment present in the skin. When
the adrenals are diseased and the amount of adrena-
line reduced as a consequence, the factor that con-
trols melanin formation is removed, and an excess
of the skin pigment is deposited.

The reader will notice analogies between this
theory and the one advocated by Cassan more than
a hundred years ago.

Effect of adrenal extract. — We have seen that
cases of hypothyroidism, such as myxedema, can

76 GLANDS IN HEALTH AND DISEASE

be cured by administering thyroid extract; can we
cure an analogous disease of the adrenals by the
administration of adrenal extract? Can we re-
lieve patients suffering from Addison's disease by
any such method? We have already indicated that
the answer must be in the negative. We can supply
no good reason for the failure, unless we assume
that the adrenal hormones, unlike the thyroid ones,
are quickly destroyed in the system ; and even then
a veil of obscurity still overshadows the situation.
We must remember in this connection, as pointing
to how far from a complete solution we really are,
that the most characteristic feature of Addison's
disease, the pigmentation of the skin, has never
been experimentally produced.

"Grafting." — From what has been, and what will
be said on the subject of grafting (see more par-
ticularly Chapter VI), one might suppose that the
use of such a method would be an improvement
over the use of extracts. If the graft takes and a
circulatory system is set up, the gland ought to
behave like any organ of the body that is "alive"
and that functions properly. Theoretically it
ought to do so; in practice it seldom does. Sur-
geons in the late war have shown much ingenuity
in grafting pieces of skin; occasionally thyroid
grafts have been carried out successfully ; but when
we come to adrenal grafting we can record little
else but failure. The gland atrophies and the med-

THE ADRENAL GLANDS 77

ullary portion disappears altogether. Some ex-
perimenters have recorded temporary successes,
but nothing that as yet warrants much optimism.
Jaboulay, a French surgeon, transplanted the
adrenals of a dog into a patient suffering from
Addison's disease. The surgeon does not tell us
what happened to the transplanted gland, but he
does record that the patient died within 24 hours!
Dr. Voronoff might reply that one of two reasons
would explain this : either the surgeon was a bun-
gler and did not perform the operation skillfully
enough; or, what is more probable, the adrenal
of a dog cannot replace that of man. Biology
and chemistry certainly have taught us that
"specificity" is a distinguishing feature of many
dynamic reactions. In any case, before we con-
demn adrenal grafting, many more such experi-
ments will have to be performed.

Hyper-adrenalism. — Neither is our information
less obscure with regard to conditions where there
is an excessive production of the adrenal hormone
— here again in striking contrast to our knowledge
of hyper-thyroidism. "The whole subject," writes
Vincent, an eminent English authority, "is very
obscure and requires further and continuous inves-
tigation."

The cortex. — To what extent our ignorance of the
entire subject of the adrenal glands is due to our
ignorance of the part played by the cortex of the

78 GLANDS IN HEALTH AND DISEASE

gland, it would be hard to say. You will remember
that at the beginning of the chapter we stated that
the gland consists of two very distinct portions,
the cortex and the medulla. The latter, as we shall
wee, contains adrenaline, the best known of all the
homiones, and indeed a very important substance.
But evidence is accumulating to show that, the
medulla, which contains this hormone, is no more
important, if indeed as important, to life than is
the cortex, which does not contain adrenaline.
Biedl, a celebrated Austrian investigator, claims
to have succeeded in removing the cortex from
mammals, leaving behind the medulla intact; the
animals did not- survive. This leads him to the
view that the cortex, and not the medulla, is the
portion of the organ essential to life. Schafer, the
Edinburgh physiologist, has criticised Kiedl's con-
clusions because he considers it impossible to
separate completely the medulla from the cortex.
"I think," he writes, "the experience of most people
will lead them to believe such a separation impos-
sible." Yet the view docs persist, that the cortex,
if anything, is even more important to the body
than the medulla.

What hormone, if any, the cortex contains, is not
clear. No substance corresponding to the adrena-
line of the medulla has been isolated from it. A
theory has, however, been advanced that the real
seat for the manufacture of adrenaline is the cor-

THE ADRENAL GLANDS 79

tex; that the hormone is there made from tyrosine,
one of the best known of our amino-acids, which
in turn are decomposition products of proteins ; *
and that the adrenaline, once formed, is passed to
the medulla, where it is stored. This is an attrac-
tive hypothesis, but, like many attractive hy-
potheses, lacks experimental proof.

Another view of the function of the cortex is
that it destroys poisons — either those produced in
(he course of body metabolism, due perhaps to
muscular activity (theory of auto-intoxication), or
(hose entering the body from the outside. Si ill
another theory is the one that stresses the close
relationship existing between the cortex on the one
hand, and (lie generative glands on the other. It
lias been said thai (he enlargement (hypertrophy)
of the adrenal gland goes hand in hand with pre-
cocious development of the reproductive organs.

The medulla. — When we come to discuss the
function of the medulla we are on much firmer
ground, for here we shall see we have a tissue that
contains a substance which itself induces some re-
markable changes. We must now discuss this sub-
sin nee — adrenaline.

Adrenaline.2 — The most significant advance made
in our study of the adrenals is the isolation, in a

1 Sec tho chapter oft Ammo-Acids in the author's book on
Vitaniinrs.

a'llic relation of adrenaline to the nervous system is reserved
for Chapter XII.

80 GLANDS IN HEALTH AND DISEASE

chemically pure state, of one of its hormones,
.adrenaline. This substance has not only been iso-
lated from the gland, but it has also been synthe-
sized in the laboratory. The organic chemist gives
to it the name orthodioxy phenyl-ethanol-methyla-
mine, and he knows that it is therefore related to
tyrosine, an important amino-acid obtained when
proteins are decomposed.1 With the help of a little
fancy and a little fact, the physiological chemist
explains the indispensability of some of these
amino-aeids by declaring that they constitute the
raw materials for the manufacture of hormones.

If we except the isolation of the hormone from
the thyroid, the isolation of adrenaline remains the
only case on record of the extraction of a hormone
in a pure condition from its gland. "It is one of
the greatest triumphs of physiological chemistry,"
writes Vincent, "that within seven years of the dis-
covery of the powerful effects of extracts of the
adrenal medulla by Oliver and Schafer (Schafer's
discovery was made in 1894), the active principle
was obtained in crystalline form, and that five
years later its composition has been so completely
ascertained that it has been synthesized, and the
pure active synthetic products can be obtained
from the manufacturing chemists."

The men primarily responsible for the isolation

'See the chapter on Ammo- Acids in the author's book on
Vitamines.

THE ADRENAL GLANDS 81

of adrenaline from the adrenals are von Ftirth, an
Austrian; Abel, professor at Johns Hopkins; and
Takamine, a Japanese domiciled in the United
States. Friedmann, a German, succeeded in pro-
ducing adrenaline synthetically in the chemist's
laboratory. While it is not my intention in a
volume of this kind to enter into any details re-
garding the chemical steps involved in the isola-
tion of hormones, the briefest outline of Abel and
Takamine's methods for isolating adrenaline from
its gland will be given. Even though such an out-
line proves too "technical," it can hardly be omit-
ted from a book purporting to deal with hormone
action.

Preparation of adrenaline. — Very concentrated
adrenal extracts are largely freed from inactive
substances by treatment with alcohol, lead acetate,
etc.; then the active substance is precipitated in
microscopic crystals by the addition of concen-
trated ammonia. The precipitate is then purified
by repeatedly dissolving in acid and reprecipitat-
ing with ammonia. The resulting prismatic needles
or rhombic plates are those of the purified or iso-
lated active principle — adrenaline.1

JFor the benefit of students of chemistry who may read this
volume, a word may be added as to the synthetic production of
adrenaline. This may be obtained by the action of methylamine
upon chloroaeetopyrocatechin :

CCH3 ( OH ) aCOCH2C14-NH2CH3-»C^ ( OH ) a . COCH, . NHCH8 . HC1
The methylamino aceto-pyrocatechin so obtained yields adrena-
line on reduction.

82 GLANDS IN HEALTH AND DISEASE

Properties of adrenaline. — Before entering upon
a discussion as to the various uses that adrenaline
is put to, it may be said that, in a general way,
adrenaline affects the body tissues in much the way
that the sympathetic nervous system does. By way
of further explanation it should be remarked that
the nervous apparatus consists of two sets of nerves
connected, to be sure, and yet standing out apart
from each other : the cerebro-spinal system and the
sympathetic system. The former is made up of
the brain and the spinal cord with its correspond-
ing (cranial and spinal) nerves; the latter con-
sists of a chain of nerve cells extending on each side
of the spinal column, connected with each other and
with the spinal nerves. From the sympathetic sys-
tem, nerves generate that follow to a large extent
the distribution of the blood vessels, and that form
large networks around the heart, stomach, etc.
This system controls the internal organs, such as
the heart, the blood vessels, kidneys, etc., and the
sweat glands and vessels of the skin; it controls
involuntary muscular movement, and is related to

The synthetic adrenaline is optically inactive, — that is, it is
the d-l- adrenaline; whereas that obtained from the adrenals is
the optically active Z-adrenaline. However, not only has the
inactive or "racemic" mixture been separated into its active com-
ponents, but the interesting fact has been brought out by Abder-
halden that the ^-adrenaline is about 15 times as strong in ita
action on blood pressure as the d-adrenaline.

For a fascinating account of optically active substances, the
general reader can do no better than read Pasteur's investigation
of tartaric acid, as related by his son-in-law, Valery-Radot, in
his book dealing with the life of that immortal French scientist.

THE ADKENAL GLANDS 83

such processes as contraction and dilation, secre-
tion, and various nutritional processes.

In their action the sympathetic nerves are often
antagonistic to the cranial ones. The stimulation
of the latter stops the heart beat; the stimulation
of the sympathetic fibers quickens the heart beat.
So, indeed, does adrenaline : its action is to quicken
the heart beat.

It would be difficult to name a substance used in
medicine that has proved of greater value than
adrenaline. It causes a contraction of the arteries
and is an excellent hemostatic, — that is, it checks
the flow of blood. In shock and collapse, often fol-
lowing surgical operations, the procedure adopted
by Crile, the well-known Cleveland surgeon, of
administering adrenaline solutions, has been gen-
erally adopted. Though we know little as to the
cause and nature of shock,1 we do know that in
such a condition the arteries contain less blood,
and the veins more blood than usual. Since adrena-
line constricts the arteries, its use under these con-
ditions provokes attempts on the part of the body
to restore equilibrium.

The suggestion has been made that trench life in
war leads to depression of adrenal activity, and
that this is connected with the clinical picture of
shock in war. We shall return to this later.

It might be expected that cases of hemorrhage,.

*For further information see Chapter XII.

84 GLANDS IN HEALTH AND DISEASE

with the copious loss of blood that accompanies
them, would be benefited by adrenaline treatment.
This is in fact true of many such cases. Injection
of the hormone constricts the blood vessels, and, as
Professor Cannon, of Harvard, has shown, actu-
ally hastens the formation of a blood clot, which
in turn acts as a seal to any further escape of blood.

The extensive use of adrenaline in conjunction
with a local anesthetic dates from 1903, when
Braun, a German surgeon, found that a subcutane-
ous injection of the hormone produces a bloodless
or bleached area — of great importance to the sur-
geon in giving him a "clear field of operation" —
even better than the method of bandaging or freez-
ing. Then, as a further incentive to its use, it was
shown how, applied in conjunction with cocaine or
novocaine, the effects of the anesthetic are in-
creased and last longer; neither are there such un-
pleasant after-effects. Since then adrenaline in
conjunction with anesthetics has been used more
and more.

One may cite its invariable use in ophthalmolog-
ical surgery. In eye operations and examinations
the application of adrenaline has opened up many
new possibilities.

Since we are on the subject of the eye, it may be
of interest to record that in a state of mental dis-
order which goes under the name of "dementia
precox," it has, at times, been found possible to

THE ADKENAL GLANDS 85

differentiate this disease from others showing cer-
tain similarities by injecting the hormone into the
membrane that lines the eyelid and covers the eye-
ball (t'he "conjunctiva") ; after a few minutes there
follows a ma»rked dilatation of the pupil ("mid-
riasis"), provided the patient has true "dementia
precox."

The amount of adrenaline used in these opera-
tions and tests is ridiculously small; perhaps as
little as five to ten drops of a solution containing
one part of hormone to 1,000 parts of water.
Small as such a quantity is, it is yet strikingly
effective. What is true of adrenaline seems to be
true of all hormones : that their effect is altogether
out of proportion to the small amounts of material
used. It is this disproportion between amount of
material used and the profound changes brought
about by such a quantity, that has caused investi-
gators to compare hormones with vitamines and
enzymes. What connection there is between them
remains a mystery.

Adrenaline in blood. — We know that even under
normal conditions the blood always contains a
small quantity of adrenaline — so small, indeed, that
it has been estimated at one part in 500 million of
blood. For reasons that will soon be apparent,
much attention has been given to methods for the
quantitative determination of adrenaline. It must
be remembered that the quantities involved are

$6 GLANDS IN HEALTH AND DISEASE

almost infinitesimal in amount, and to devise not
only qualitative, but quantitative methods for de-
tecting such amounts, appears to be a problem
beset with endless difficulties. Yet what seems to
approach the impossible has been accomplished.
In this connection it is of interest to note that
physiological methods, like spectroscopic methods
in many cases, and the electroscopic method in the
case of radium, have proved themselves more deli-
cate than chemical ones. For example, Meltzer
has devised a physiological procedure which de-
pends upon the action of adrenaline in dilating the
pupil of the enucleated eye of a frog; and claims
that a strength of hormone one part in 20 million
can be detected. Using a loop of intestine and re-
cording how its movements are inhibited by adrena-
line, is said to be so delicate as to detect one part
of hormone in 400 million.

The best chemical method so far devised is one
based on colorimetric comparisons, due to Professor
Folin, of Harvard. It depends on the blue color
obtained when adrenaline is added to phosphotung-
stic acid. This blue color can be noticed in dilu-
tions of adrenaline of one part to three million.

Adrenaline and sugar metabolism. — The relation
of adrenaline to sugar metabolism will be referred
to in Chapter VII. Here it should be said that the
injection of this substance into the body of an ani-
mal increases the quantity of sugar normally found

THE ADKENAL GLANDS 87

in blood, and may give rise to a temporary glyeo-
suria (sugar in the urine) , which is a form of what
is commonly called "diabetes." It will be shown
that the pancreatic hormone acts antagonistically
to the adrenal hormone, thereby helping to regulate
body equilibrium.

Professor Cannon has shown that an increase of
adrenaline in the blood occurs without any addition
of hormone from outside sources whenever an ani-
mal gets excited — for example, when a cat gets
ready to defend itself against a dog's attack; and
also that such an increase is followed by a hyper-
glycemia (an increase of sugar in the blood) . This
suggestion that the adrenal gland is involved in
emotional outbursts is certainly of extraordinary
interest. The fact remains too that when a cat be-
comes frightened its "pupils dilate, the stomach and
intestines are inhibited, the heart beats rapidly,
the hairs of the back and tail stand erect — all
signs of nervous discharges along the sympathetic
paths" ; and we have already seen how similar the
action of adrenaline and the stimulation of the
sympathetic fibers are.1

Summary. — We may briefly summarize our
knowledge of the adrenals by stating that they are
unquestionably essential to life, though conflicting
theories are current as to their precise function.
Of the two parts into which the adrenals may be

1 See further, Chapter XII.

88 GLANDS IN HEALTH AND DISEASE

divided, the cortex and the medulla, the former, if
anything, seems to be more essential to life than
the latter, though so far no one has succeeded in
showing that the cortex contains any specific hor-
mone. On the other hand, the medulla contains the
best known of all the hormones, adrenaline. This
hormone, adrenaline, has not only been isolated in
the pure state, but it has actually been synthesized
in the laboratory. Adrenaline has already taken
its place among the most valuable drugs in medi-
cine.

CHAPTER VI

THE ORGANS OF REPRODUCTION

We have convincing evidence that the organs of
reproduction, or the "sexual" glands, produce both
an external * and an internal secretion ; in this re-
spect showing a similarity to the pancreas and the
small intestine. The external secretion contributes
to the reproduction of the species; the internal
secretion — like the secretions from the other duct-
less glands that we have studied, contributes to the
molding of the species. In this chapter we are, of
course, primarily interested in the internal secre-
tion of the sexual glands, though the two secretions
cannot always be sharply separated.

Proof of an internal secretion. — The removal of
the testes or ovaries, an operation commonly known
as "castration," if carried out before puberty, pre-
vents the development of "secondary sex character-
istics." In the female the periodic act of menstrua-
tion from a very early age until perhaps her fiftieth
year, is indicative of a .functional ovary. The

1Some physiologists are opposed to regarding the external
secrefion of the reproductive system as a true secretion, on the
ground that the active constituents are not enzymes.

89

SO GLANDS IN HEALTH AND DISEASE

"coming on of heat" or "rut" in animals seems to
be related to menstruation in human females. Now
it is a remarkable fact that this "rut" is no longer
noticed upon the extirpation of the ovary, but is
again brought on by the transplantation to another
part of the body of the ovary belonging to a similar
animal. From what has already been said on the
subject of transplantation, it must be perfectly evi-
dent that an experiment of this kind admits of but
one conclusion : that the nervous mechanism plays
but a secondary part, if it plays a part at all ; but
that on the other hand, the ovary must discharge
into the blood some substance or substances which
give rise to the phenomenon in question. This, of
course, means that the ovary, in addition to giving
rise to an external secretion in the form of ova,
that contributes to the reproduction of the species,
must be the seat of an internal secretion.

We now know that the two types of secretion are
produced by two different types of cells. The in-
ternal secretion is developed by the so-called "in-
terstitial cells," the name of which has become fa-
miliar to the lay reader ever since topics on reju-
venation have become popular with newspaper
editors. These cells lie altogether outside of the
tubes that are responsible for the flow of the ex-
ternal secretion. It is, in fact, possible to tie the
tube that, in the male, connects the testes with the
ejaculatory tube (the "vas deferens"), thereby

THE OEGANS OF REPRODUCTION 91

causing the sexual elements to disappear; yet the
interstitial cells not only are left, but actually in-
crease in number. And what is far more remark-
able, the sexual instincts remain as strong as ever.
This is therefore further evidence in favor of the
view that puberty is dependent not upon the pres-
ence of the reproductive elements, but rather upon
the production of an internal secretion due to in-
terstitial cells.

Brown-Sequard. — In 1889 Brown-Sequard, one-
time professor at Harvard, and later professor at
the College de France in Paris, presented a paper
before the Academic de Medecine that created a
sensation. He described experiments in which he
had himself injected with extracts obtained from
the sexual organs of a ram; the result was that he
had become quite "rejuvenated." Despite his
seventy years he felt, he said, like a youth, with
all a youth's vigor. The newspapers, quite justi-
fiably, gave much prominence to this get-young-
quick method, and for a short time Brown-Sequard
was an international hero. Then came cries from
opposition forces. The experiments were repeated
and nothing like what was alleged by the French-
American could be discovered. Brown-Sequard
answered his critics by charging that his technique
had not been followed with sufficient care. But
his replies did not satisfy the critics ; they attacked
him mercilessly, and continued the attack until the

93 GLANDS IN HEALTH AND DISEASE

one-time famous physiologist became a thoroughly
discredited man. We shall presently have occasion
to discuss the objections that may be advanced to
the use of testicular extracts; but it is only bare
justice to the memory of an illustrious man of sci-
ence to point out at once and emphatically that
Brown- Sequard seized upon the germ of a great
discovery, and one which, even to-day, is but dimly
perceived. Moreover, he was the first one to per-
ceive clearly the intimate relation that exists be-
tween the various organs, due to their internal
secretions.

He writes: "Each tissue, and, more generally,
each cell of the organism, secretes for its own use
special products which are poured into the blood
and which influence, through the intermediary
agency of this liquid, and not through the mecha-
nism of the nervous system, all the other cells, thus
rendering all of them mutually interdependent."
To say that each tissue and each cell plays such a
part may, or may not be the entire truth; but we
have here a wonderfully clear presentation of the
functions of hormones.

We shall see presently how, in the hands of
Steinach, Voronoff, and others, the Brown- Sequard
view was adopted and extended. In the meantime
we must take a step backward and examine in
more detail the effects of castration. You will re-
member that this type of approach to the subject

THE ORGANS OF REPRODUCTION 93

is the one that so often yields valuable clues as to
the function of any particular part of the organism.

Castration. — Here the history of mankind sup-
plies us with an abundance of material — at least,
in so far as the male part of the population is con-
cerned ; for our information concerning the female
portion is slender. Castration was extensively
practised in antiquity, and still is in oriental
countries where there are watchers of the harem.
Professor Falta informs us that it was carried out
in Italy "for musical purposes," and that the prac-
tice ceased only recently. In Eussia a religious
sect known as the "skopzen" include castration as
a necessary part of their religious ritual. Perhaps
the most pathetic account that has been handed
down to us is that of the famous Abelard, who was
castrated by order of Heloise's uncle, Fulbert.

The results of castration are much dependent
upon the age at which it is performed. If this is
done before puberty, the sexual instinct disappears,
never to return. The eunuch often grows to be very
tall, those reaching six feet eight inches being
common. The voice, due to the non-development
of the larynx, retains the sound of a childish so-
prano. The face is livid, the skin poor in pigment
and the flesh flabby. Very often the breasts are
abnormally developed, and almost always such in-
dividuals are beardless. These last two symptoms
have often been taken as an indication of the devel-

94 GLANDS IN HEALTH AND DISEASE

opment of female characteristics, and as showing
that the sex characters owe their presence to the
genital organs. The very name suggests that the
sexual organs are involved in the development of
sex characters ; but why when such organs of a male
are cut out of his system he should then tend to
revert to the female type is not clear. The view
is gaining ground that castration produces a
"neutral" rather than a female variety.

What effect castration has upon mental develop-
ment is not beyond dispute. From the accounts of
some eunuchs that have come down to us, who at-
tained distinction in their day, it would seem as if
the mind of the person is not affected. Unfortu-
nately our information as to their age at the time
of castration, and as to the completeness of the
operation, is meager; and both these factors need
to be known before we pass judgment. Experi-
ments with animals have shown that castrated
animals lack the courage, the animation and the
passions of normal male animals; and many ob-
servations on eunuchs lead to the belief that there
is a distinct tendency towards the suppression
of the finer emotions, these in turn being sup-
planted by a general air of indifference and mental
inertia.

The absence of certain sex characteristics — wThich
does not always imply the formation of sex charac-
ters belonging to the opposite sex — after castration

THE ORGANS OF REPRODUCTION 95

is also noticeable in animals. Thus stags when
castrated young do not develop antlers; and even
if the operation is performed after the antlers have
appeared, the animals no longer shed them annu-
ally. If horns are on they fall off. This is true of
sheep. The cock loses its plumage, its wattles and
its characteristic male type of voice.

The records of castration in the female are
meager. The operation is rarely performed before
puberty, and after this stage has been reached, the
changes are not so marked. This applies also to
domestic animals. The few experiments that have
been performed make it seem likely that one of
the functions of the female genital organs is to
suppress a tendency to revert to the male type; in
their absence the duck and pheasant, for example,
assume male plumage.

In both the male and female, whether man or ani-
mal, castration is followed by an accumulation of
fat in the body, making it appear that the general
metabolism of the system has been disturbed.

The results of castration can be observed in those
persons whose sexual organs have for one reason
or another not developed normally. Professor
Tandler refers to such "eunuchoids" as "tall, or if
complications are absent, at least not stunted in
growth; they show the typical fat distribution of
eunuchs. The skeletal dimensions are character-
ized by an especial length of extremities. There

96 GLANDS IN HEALTH AND DISEASE

is a more or less pronounced disturbance of the
development of the genitalia, with faulty develop-
ment of secondary sex characteristics. It is prob-
able that in such cases we have to do with a de-
velopmental disturbance beginning primarily in
the sexual glands, and indeed the interstitial
glands, as functional disturbances of the generative
glands alone do not lead to eunuchoidism."

The last statement receives support from experi-
ments already described, wherein the reproductive
elements were suppressed, yet the gland consist-
ing of the interstitial cells thrived, and the several
sex characteristics were retained; also where a
tumor arises that interferes with the supply of the
reproductive elements, yet does not attack the inter-
stitial cells, we may get a similar result. On the
other hand, where the interstitial cells themselves
are affected, the clinical picture obtained represents
that of castration ; which in itself suggests that the
primary results of castration are probably due to
the absence of a hormone which is normally elabo-
rated by the interstitial cells.

Further confirmation of the views just advanced
is obtained from X-ray studies. These rays have
a selective action in the sense that they destroy
the cells of the testes, yet not those belonging to
the interstitial gland. If the testicles of a roebuck
are exposed to X-rays, the antlers do not undergo
any alteration; here the generative cells proper

.,

THE ORGANS OF REPRODUCTION 97

,ve been destroyed. When the animal is cas-
trated, which involves removal both of the external
and internal glands, it loses its antlers. Clearly
then the result of castration must be attributed
to the loss of the interstitial hormone.

From the evidence presented we may conclude
that the hormone or hormones that give rise to the
male characteristics are due to the interstitial
gland. The hormone is elaborated by the gland and
passes directly into the blood stream. We are here
therefore dealing with a gland belonging to the
"ductless" group.

Professor Biedl says that "it is highly probable
that, by the agency of its secretory product, the
interstitial gland is responsible for the develop-
ment of the male sexual gland from the indifferent
genital trace. That it has a determining influence
upon the normal development and maturity of the
generative portion of the sexual gland, upon the
formation of the secondary genital organs, and
upon the existence and persistence of those morpho-
logical and biological characters which are the
property of the male sex, is undoubted."

Our information regarding the interstitial cells
of the female is meager, but whatever we do know
points to their presence, and to their possessing a
function similar to the cells of the male.

Grafting. — Brown- Sequard's suggestion that the
active genital glands impart vigor to the body, due

98 GLANDS IN HEALTH AND DISEASE

to the elaboration of an internal secretion, and the
further fact that with old age the interstitial cells
become fewer and smaller, must have suggested to
physiologists a possible connection between old age
and the interstitial glands. To test out such a
possibility has led to a number of extremely inter-
esting experiments. Kesearch workers following
Brown-S£quard showed that the addition to the
food, or the injection into the blood, of testicular
extracts, failed to change castrated into normal
animals, or old animals into young ones. The rea-
son for this is not easy to give, unless we assume
that a chemical process involving an extraction of
the hormone from the interstitial gland — an opera-
tion which is usually carried out by triturating the
gland with sand and water, filtering and using the
filtrate — causes an alteration of the hormone.

Dr. Voronoff remarks that "the injections of
testicular juice have not had the result which
Brown-S£quard expected from them, because the
glandular extracts undergo rapid changes, do not
contain the whole of the product of the internal se-
cretion, and are even, at times, toxic." * This is
obviously not true of some of the other ductless
glands, notably the thyroid.

Next came the suggestion that a much better
method than that of injection of gland would be the

*See Life by Serge Voronoff. E. P. Dutton & Company, New
York.

THE ORGANS OF REPRODUCTION 99

grafting of a new tissue to take the place of the
old. This held out hope, for many experiments
with glands of the ductless variety pointed to the
fact that they could be removed from their original
positions in the body and grafted on to some distant
tissue of the body, with no ill-effects, provided the
graft "took" ; that is, provided a healing condition
set in whereby the blood vessels of the gland and
those of the rest of the body would connect up, so
as to allow the hormone of the ductless gland to
enter the general circulation.

Upon ideas such as these are based the much-
talked-of experiments of a Steinach and a Voronoff.
"The grafting of a young sex gland in full activity,"
writes Dr. Voronoff, "means incorporating in the
organism the very source of our organic action.
Thus the body would be supplied not with a dead
product, incomplete, often changed, introduced
from time to time by means of subcutaneous injec-
tions, but a living organ carrying out its functions
itself. To graft this gland is to place it in direct
communication with our blood vessels, which will
undertake to transport the precious fluid in pro-
portion to its formation in the intimacy of our
tissues."

Before we proceed to these experiments a word
must be said as to the methods used in the trans-
planation of tissues. There are two ways of doing
this: either by merely inserting a small strip of

100 GLANDS IN HEALTH AND DISEASE

tissue in the desired place, or by first carefully
connecting the engrafted with the main tissue by
stitching suitable blood vessels together. In the
first case general circulation in the engrafted tissue
is for a time delayed; in the second, it is immedi-
ately set up. The first method has been exten-
sively used in replacing small portions of skin in
burns. It has even been employed, and with suc-
cess, to interchange the ovaries in hens, and to re-
place the thyroid and parathyroid. The second
method, more difficult to execute, has the advantage
in that the transplanted tissue may be of much
larger size. By this method the kidney, the spleen,
and even a limb have been transferred from one
dog to another ; and segments of arteries that have
been kept in cold storage, or preserved in formalde-
hyde, have successfully replaced portions that had
been removed from their positions in the body.

It should be pointed out that, as a rule, trans-
plantation is successful only if tissues of the same
species are used, though experiments have shown
that the arteries of a dog can be transplanted to a
cat; and that further, much of the work recorded
has been done on animals rather than on human
beings. In the hands of Carrel and other famous
surgeons active in the late war, the art of grafting
has made long strides. The French doctors have
proved themselves particularly skillful in the art.

The famous Siamese twins illustrate a perfect

THE OEGAJSTS OF REPRODUCTION 101

graft for which Nature is responsible. Here the
circulatory system resembled that of one rather
than of two beings. An imitation of this kind has
been produced in white rats by opening up the
membrane enclosing the abdomen and stitching the
skin and connective tissues together.

Steinach's contribution. — In approaching the
work of Steinach and others we must be more than
ever careful to distinguish fact from fancy; to re-
late actual experiments without drawing fanciful
conclusions from them. Professor Steinach, one
of the best known among the workers on the func-
tions of the sex glands, is a member of the Vienna
Academy of Sciences, and Director of its Biological
Institute. His work as a biologist has commanded
the respect and admiration of his colleagues
throughout the world, though some of his interpre-
tations of his work have not gone unchallenged.

These prefatory remarks are necessary because
the impression seems to have gained ground that
he is one of many quacks that fatten on the public's
credulity. Such, in fact, was the impression
gained by many newspaper readers after hearing of
the sudden death of a rich Australian, who was to
deliver a public lecture in London on "How I was
made twenty years younger by the method of Dr.
Steinach," and who died under somewhat mysteri-
ous circumstances on the very eve of the lecture.
The newspaper drew the moral of St. Mark that

102 GLANDS IN HEALTH AND DISEASE

new wine should not be poured into old bottles!

Prior to 1910, when Dr. Steinach published the
first of his experiments, it had already been known
that the generative apparatus consists of an inter-
nal and external secretion, and there were even
then indications that the hormone, or hormones,
produced by the internal secretion (in the inter-
stitial cells) controlled sex characteristics. Pro-
fessor Steinach wished first to convince himself
that what was generally believed had foundation
in fact: that the internal secretion actually con-
trolled sex characters. With this in view he cas-
trated a number of male rats and guinea-pigs and
planted ovaries under the skin. The animals de-
veloped marked feminine features: their breasts
and nipples increased in size and they were sought
by the males. Previous experiments on the trans-
plantation of the testes had shown that though the
reproductive glands proper decayed and the inter-
stitial glands did not, yet the sex desire remained.
These experiments indicated two things : first, that
the generative glands have much to do with deter-
mining the sex of the animal; secondly, that the
portion of the glands particularly responsible is
the interstitial gland.

Old age. — As already pointed out, the work of
Brown- Sequard suggested a connection between
the decay of the genital glands and the onset of old
age. This was the next problem that Steinach set

THE OEGANS OF KEPEODUCTION 103

himself to elucidate. His idea was to transplant
the sexual glands of young rats to the system of
old ones — to put "new wine into old bottles."
Much preliminary work was necessary in order to
determine the conditions for developing healthy
breeds of rats. The extensive vitamine studies, in
which rats are very largely employed, had then
hardly begun ; otherwise such difficulties could have
been avoided. Steinach succeeded not only in im-
proving the general condition of the old rats, not
only in renewing the sex instinct, but actually in
prolonging the life of the animal. "Three weeks
after the operation the whole behavior changed*
the rat (an old one) began to keep its head erect,
came forward from its hole, paid a lively interest
toward the outer world, and its hair began to
grow smooth and shiny. When another male rat
had been let into its cage it attacked him immedi-
ately, and when a female rat was let in, it eagerly
performed the sexual function, and as only one
vas deferens (see subsequent paragraph) was li-
gated, the coitus was successful. The young of the
female fecundated by the rejuvenated rats thrived
well, and propagated further."

Our discussion of the interstitial glands has al-
ready shown that in the investigations of this duct-
less gland, one of three methods in operating tech-
nique may be employed : the duct from the testicle
connecting the testis with the ejaculatory tube

104 GLANDS IN HEALTH AND DISEASE

(the vas deferens) is cut off, thereby stopping the
production of the external secretion, and hence the
production of the reproductive elements; or the
genital glands are submitted to the effects of
X-rays, causing the less resistive reproductive ele-
ments to be destroyed. In either case the inter-
stitial cells are not only left intact, but actually
multiply and produce hormone in quantity (and
quality?) sufficient to rejuvenate (?) the organism.
There is still a third method, and that is to trans-
plant the gland from a vigorous animal to the one
under experimentation. We have already pointed
out that the transplantation of testicles has shown
that under such conditions, the reproductive ele-
ments disappear, but the interstitial cells continue
to thrive. Here again the organism is favorably
affected.

All three methods point to the interstitial gland
as the source from which rejuvenation springs.

With Steinach the question now arose as to which
of the three methods would be the one best adapted
for his purpose. In his experiments with human
beings he decided upon the first one — the ligature
of the vas deferens — as being the simplest to per-
form, and the one least likely to give rise to unfa-
vorable post-operative symptoms. "By stimulat-
ing the action of the interstitial gland at the ex-
pense of the generative function, it is Steinach's
idea to bring about a rejuvenation process in older

THE ORGANS OF REPRODUCTION" 105

people by the resuscitation and renewal of the
weakening secondary characters." We shall see
that Dr. Voronoff selected the more difficult graft-
ing procedure.

"The operation is a very simple one," writes Dr.
Steinach; "absolutely painless. Quite free of any
risk whatever. Takes no longer than fifteen min-
utes to perform. Seven to ten days in the hospital
are all that's needed afterwards. But the opera-
tion must be performed with minute precision ; and
for that reason I cannot guarantee results unless
I am personally present."

With the help of a local anesthetic a small in-
cision is made and the vas deferens tied and cut off.
Care is taken not to injure the blood vessels near
by. The result is that the seminal vesicle (either
one of the two reservoirs for the semen) and the
interstitial gland are completely cut off from one
another ; and this in turn gives rise to a multiplica-
tion of the interstitial cells, and to an increase of
the hormone produced by them.

Professor Steinach has performed the operation
on men on several occasions. In some instances
these men were fairly young but physically weak;
in others, the subjects were senile men. "The ap-
pearance of the subjects became youngish, fresh,
their bodily strength increased, the tremor of their
hand disappeared, memory and will power re-
turned, and the sexual power was restored."

106 GLANDS IN HEALTH AND DISEASE

Dr. Steinach has not had the same success with
females as with males. With females the X-ray
method holds out the most hope, but even with this
method the results have not been very encouraging.
Just why this should be so is not clear.

Of the cases described, one may be quoted as
typical. "He was 71 years of age, controller of a
large business. The man was actually ill, and
showed the usual signs of old age and decay, such
as dizziness, poor breathing, heart weakness,
shakiness and intense fatigue. For eight years
ambition had been practically non-existent. Some
months after the operation there was remarkable
evidence that the conditions of senility had been
checked. The man's power came back. It is still
increasing. We got a letter from him recently
(Dec., 1919) in which he told us of the extraor-
dinary change that had taken place in his condi-
tion. His appetite had come back. His old-time
spells of depression had given way to a new joy in
life. He had become fresh in looks and elastic in
body. His dizziness had gone. His hand had be-
come firm again. He specially mentioned the fact
that he was again able to think clearly, as in
earlier years, and that his memory had greatly
improved. Also, that whereas in earlier years he
had needed the barber once only in two or three
weeks, he now visited his beard-trimmer once a
week."

THE OEGANS OF REPBODUCTION 107

Dr. Steinach has recently summarized his work
in an article for a technical journal entitled Ver-
jungung durch experimentelle Neubelebung der
alternden Pubertatsdruse; which may be translated'
into "Rejuvenation through experimental revivify-
ing of the senescent puberty (interstitial) glands."
This article under the short title of Verjungung
has since been published in book form (by Springer,
of Berlin).

Professor Steinach's work receives support from
that of Dr. Lichtenstern, a lecturer at the Univer-
sity of Vienna, who has successfully performed 21
transplantations and 36 operations in cases of
senility. Yet we must also observe that Professor
Kolber, another colleague of Dr. Steinach's, who
has made a careful histological study of the inter-
stitial cells with the view to elucidating their func-
tion, is not wholly in agreement with Steinach ; and
perhaps in the form of a word of warning, if only
to ward off too much optimism, it may well be asked
why the repairment of a part of the organism — a
very important part, we admit — that has become
very generally dilapidated, should rejuvenate the
entire bodily machine. It must be remembered that
not only the interstitial gland, but the other duct-
less glands, are affected with the onset of old age, —
to say nothing of the rest of the organism.

Voronoff. — Dr. Serge Voronoff is another inves-
tigator who has lately appeared before newspaper

108 GLANDS IN HEALTH AND DISEASE

readers. He is the Director of Experimental
Surgery at the Laboratory of Physiology of the
College de France, a position once held by perhaps
the greatest of all physiologists, Claude Bernard.

Unlike Steinach, Voronoff decided on the graft-
ing procedure. His preliminary experiments on
animals — on sheep and goats — are valuable contri-
butions to the literature of the subject. His sub-
sequent work on man was limited to two recorded
cases, and here the graft does not refer to the sexual
glands at all, but to the thyroid. We are, however,
assured that but for the scarcity of orang-utangs
more cases could have been presented, and the effect
of the transplantation of the sex gland of the mon-
key to man could also have been recorded. But
let us proceed to those portions of VoronofFs work
that are of value to us.

Dr. Voronoff tells us that he has made some 120
different experiments on the effects of testicular
grafting in sheep and goats. Grafts were at-
tempted on normal males and females, castrated
males and females, and old males incapable of re-
production. As the results with the females were
in no instance encouraging, these may be dismissed
altogether, and our attention confined to the males.

Of the two methods of grafting which are em-
ployed, and which have already been described,
Dr. Voronoff chose the simpler, namely, the trans-
plantation under the skin or in the peritoneum.

THE ORGANS OF REPRODUCTION" 109

Later on he found that the very best results were
obtained when the grafts were placed in the vaginal
tunics. As this simple method of grafting gives
better results when fragments rather than whole
organs are used — in other words, when smaller
rather than larger pieces are used — Voronoff
grafted fragments obtained from a whole testicle.

In one set of experiments three he-goats were
castrated and testicular grafts introduced. One at
the end of four, another at the end of twelve, and a
third at the end of sixteen months all showed
"magnificent horns such as are never seen on cas-
trated animals." They were lively, belligerent, did
not grow fat, and showed much sex ardor.

In another experiment a ram 12 to 14 years old, —
corresponding to about 80 years in man — which
could hardly totter, had implanted the fragments
of a testicle obtained from a young ram. "Two
months after the graft had been effected the ani-
mal was completely transformed. His urinal in-
continence had disappeared; so had tremblings of
the legs ; and he no longer looked afraid. His bodily
carriage had become magnificent, he behaved in a
lively and aggressive manner. The old ram had
taken on the appearance of remarkable youth and
vigor. He was isolated in a small stable, together
with a young ewe-lamb, which afforded the oppor-
tunity for observing not only the awakening of his
sexual instincts, which he had lost years ago, but

110 GLANDS IN HEALTH AND DISEASE

also the following more tangible result: the ewe-
lamb covered by him in September, 1918, dropped a
vigorous lamb in February, 1919. There is nothing
in the fact to cause surprise. Old animals, like
very aged men, occasionally still possess spermato-
zoids which are altogether alive, but it is the atro-
phy of the internal secretive glands which prevents
their experiencing the sexual appetite and mani-
festing their virility."

Dr. Voronoff's next procedure with the rejuve-
nated animal was excellent from the scientific
standpoint. He removed the graft. Three months
later the animal had completely aged. Then he re-
implanted another graft from the testicle of a
younger animal. Once again the animal showed
signs of rejuvenation. Nothing in the whole book
approaches in value this particular experiment.

At the time of writing the graft had been in its
place for a year and the animal was still in excel-
lent condition. Even if we could reason by analogy,
— which in this instance we should be careful not
to do — we could hardly draw any far-reaching con-
clusions as to the length of time old age could be
warded off in man.

Having successfully performed experiments on
animals, Dr. Voronoff next turned his attention to
man. Here a difficulty immediately arose. How
was he to get a healthy young man's gland in order
to implant it into an old man's system? If only

THE ORGANS OF REPRODUCTION 111

the foolish public would permit him to preserve the
glands of all healthy young men that are acciden-
tally killed ! But the foolish public will do nothing
of the sort, and experience has shown that only
glands of the same species are of any value. There
is one way out of the difficulty. It is to make use
of the higher form of ape, such as the orang-utang
or chimpanzee, whose near relationship to man is
to-day firmly established.

Why in the only two recorded cases of grafts of
monkey glands on human beings, men suffering
from a deficiency of the thyroid hormone were se-
lected is not clear. It is possible that no aged men
willing to be experimented on with testicular ex-
tracts were just then on hand; neither is it easy to
obtain monkeys whenever you need them.

"There is no question," writes Dr. Nagel, "that
Voronoff had a great idea and that operations ac-
cording to his theory were temporarily encourag-
ing. They do not, however, last. As 'soon as the
gland that has been transplanted has been absorbed
by the body, the subject of the experiment returns
to- his original condition.

"In Steinach's operation this is not the case.
He does not transplant. He merely ties off the
offending gland, the inert part is absorbed by the
body, and a new one is grown by nature in place
of the old, useless one.

"What does a gardener do when he wants to in-

GLANDS IN HEALTH AND DISEASE

vigorate a tree? He cuts off the dead and dying
branches and immediately new ones are thrown out
by nature.

"An illustration may be had in common surgery.
When it becomes necessary to sever an artery the
surgeon ties it off. Very shortly the checked cir-
culation would cause serious trouble. But nature
takes care of that.- The moment the artery is tied
off little shoots spring out from the walls of both
ends of the main artery, growing rapidly until they
unite around the useless part and the artery is
whole again.

"It is just that way with the gland tied off by
Steinach. A new one grows, and, being new, is far
better than any attempted rejuvenation of the old,
dying one."

We may summarize the work both of Professor
Steinach and of Dr. Voronoff by saying that while
experiments on animals have yielded results that
are of great value and that are extremely sugges-
tive, those carried out on human beings have been
altogether too few to warrant any hasty generaliza-
tions. We are far, perhaps very far, from the time
when the mere grafting of one of the ductless
glands will cause old age with all its concomitant
horrors to disappear.

Before dismissing this subject it should be men-
tioned that Lorand, a Spanish investigator, is of the
opinion that senility is the result of primary degen-

THE OKGANS OF REPKODUCTION 113

eration of all the ductless glands, and not merely
the genital glands. In one of his latest papers
(June, 1921) he says that he has been very success-
ful in arresting the signs of senility by a combina-
tion of thyroid and genital gland extract treatment,
especially in women. But let not the enthusiasm of
a few individuals make us too credulous. The sub-
ject has pitfalls at every step, and not only the in-
nocent layman, but many a physician is apt to slip.
Pubertds preco®. — So far our discussion has
been limited to cases of diminished or hypo-secre-
tion of the interstitial gland. 'We have seen that
such cases may occur naturally, as in eunuchoids;
and we are -probably not far wrong in including old
men and perhaps old women under this heading,
though their condition is much more complex. We
have already seen how the hypo condition can be
deliberately brought 'about by means of castration.
The grafting of another gland from a more vigor-
ous animal of the same species, or the adoption
of an operative technique whereby the interstitial
cells, and consequently their hormonic output, in-
creases, brings about cures that may, or may not
be permanent (our information on this point is
nowhere near as complete as it might 'be) . Now
the question naturally arises, are instances of ex-
cessive or hyper-secretion met with? And is it pos-
sible to induce such a hyper-secretion just as, let us
say, it is possible to induce a hyper-thyroidism?

GLANDS IN HEALTH AND DISEASE

In answering the second question first, we may
point ont that the number of experiments dealing
with induced hyper-secretion of the interstitial
gland is limited. Those of Brown-Sequard on the
injection of testicular extracts have already been
described, and we know that his experiments left
much to be desired. There are, however, individ-
uals that have been known to suffer from an ex-
cessive secretion. As might be anticipated, this
occurs, if at all, at a very early age. Such cases
go under the name of pubertas precox, to indicate
early sexual maturity. They are often associated
with tumor growths.

One of the most interesting examples of hyper-
secretion is that given by Sacchi. A boy had de-
veloped quite normally until he was five and a half
years old. From that time on until he was nine
and a half the .boy changed remarkably. His voice
deepened, hair grew on his face, and when he had
reached the age of nine and a half years he actually
had a black beard. An examination of his left testi-
cle revealed a tumor growth. This was removed.
The child became quite normal again.

Another .example is that of a girl of seven, who
had already -menstruated a number of times, and
who had well-developed breasts and pubic hair. A
tumor of the ovary was removed, and the girl grew
up into normal womanhood.

CHAPTER VII

THE PANCREAS AND THE LIVER

Along the lower part of the stomach, and con-
nected with the spleen, is a gland shaped like a
dog's tongue, weighing about three and a half
ounces, and having a length of about eight inches.
This gland, the "pancreas" — from the Greek "all
flesh" — is popularly known as "sweetbread."

The pancreas. — The pancreas is the most impor-
tant organ of digestion. Its glands secrete sub-
stances (enzymes) which, by means of a duct, find
their way into the small intestine, and there attack
the food coming from the stomach, breaking the
food particles up into such simple chemical sub-
stances as to make them fit for absorption by the
blood and lymph.

It was not known — definitely at least — until
1889 that this organ had any other function than
that of taking part in the digestive process. Until
then the pancreas was regarded as a gland produc-
ing an external secretion only — that is, a secretion
which, once manufactured, is sent by means of a
tube to the surface, and, in this particular case,

115

116 GLANDS IN HEALTH AND DISEASE

ultimately finds its way to the small intestine. In
1889 Minkowski and von Mering, two German in-
vestigators, proved that in addition to its external
secretion, it also produces an internal one — a se-
cretion that passes directly into the blood stream,
and one that regulates the sugar metabolism of the
body. Since this sugar or carbohydrate metabo-
lism is one that is inseparably connected with an
important function of the liver, a few words must
be said regarding that organ.

The liver. — The liver, which is situated on the
right side of the body and partly covers the stom-
ach, is the largest gland of the body. It weighs
from three and a half to four pounds. It produces
an external secretion, the bile, which is either first
stored in the gall bladder until wanted, or is sent
directly into the small intestine, meeting the secre-
tion from the pancreas, and helping the latter in
its work of digestion. But it does far more. It is
the seat of carbohydrate metabolism in the body.

Carbohydrate* metabolism. — Now what do I mean
by "carbohydrate metabolism"? Carbohydrates
are one of the three classes of foodstuffs, and
they include such substances as sugar and starch
(in flour, say) . When we eat one or more of these
carbohydrates they may or may not be broken up in
the digestive tube into chemically simpler sub-
stances. If they are chemically complex, such as
starch, they will be ; If they are chemically simple,

THE PANCREAS AND THE LIVER 117

such as glucose, they will not be. In any case,
enzymes secreted by the • sail vary, pancreatic and
intestinal glands and sent into the digestive tract,
are ever ready to convert complex into simple
carbohydrates. The chemically simple carbo-
hydrates, of which there are three well-known
types (glucose, levulose, galactose), are absorbed
by the blood, sent to the liver and there stored in
the form of glycogen or "animal starch."

Glycogen. — Chemically, glycogen is about as
complex as starch. If, therefore, the simple carbo-
hydrates, obtained from starch and similar bodies
by the breaking up of the starch molecule, are con-
verted in the liver into glycogen, it can mean but
one thing: that there must be a recombination of
the simple carbohydrate molecules to form gly-
cogen.

But this is not all. Whenever the body needs
carbohydrate — which it does much of the time for
its energy supply — it calls on this glycogen stored
in the liver. The glycogen is first converted back
again into a simple sugar — but one only — namely
glucose, and this glucose is sent via the blood to the
various muscles, where it is "burnt" to supply the
fuel needs of the body.

Summarizing then the glycogen function of the
liver, we may say that the carbohydrates we eat,
after an appropriate preliminary simplification in
the digestive tract, are transferred to the liver by

118 GLANDS IN HEALTH AND DISEASE

the blood, and stored there in the form of glyco-
gen. Whenever the body needs carbohydrates for
its various energy purposes, the glycogen is decom-
posed into glucose, and this substance is sent to the
various tissues where it is "burnt" or "oxidized"
into carbon dioxide and water.

The liver a ductless gland. — You will remember
that we defined a ductless gland as one producing
a secretion which passed directly into the blood,
and which secretion contained a something (hor-
mone) that influenced other organs to various
modes of activity. Can the liver be viewed as a
ductless gland? It certainly produces an internal
secretion in the sense of being able to take material
(simple carbohydrates) from the blood, converting
it into other products (first into glycogen and then
into glucose), and passing the glucose directly into
the blood. But where is the hormone, -the substance
that influences the activity of other organs? We
must look to the pancreas for such a substance.

Claude Bernard. — At any rate, the glycogen
function of the liver * is of extraordinary interest,

*Not only does the liver manufacture glycogen, but it also
makes urea from ammonia and carbon dioxide. This urea is
carried away by the blood and finds its way into the urine. 80
per cent, of the total nitrogenous products (representing sub-
stances derived from protein) in the urine is in the form of urea.
The formation of urea, like that of glycogen, is evidence of the
internal secretory mechanism of the liver. This by no means
exhausts the functions of the liver, a veritable storehouse of
wonders.

It should be remarked at this point that a rigid definition of

THE PANCREAS AND THE LIVER 119

since its discovery and study led the celebrated
French physiologist, Claude Bernard, to formulate
for the very first time the conception of an internal
secretory gland. In his justly famous Legons de
physiologic experimentale, published as far back as
1855, he writes : "For a time a false conception has
been current as to what a secretory organ consists
of. It was believed that all secretions must be
poured upon an internal or external surface, and
that all secretory organs must necessarily be pro-
vided with an excretory duct for the purpose of
conveying to the exterior the products of secretion.
The case of the liver establishes in a most lucid
manner that there are internal secretions, that is,
secretions which, instead of being carried to the
exterior, are diffused directly into the blood. . . .
It is'now firmly established that the liver has two
functions of the nature of secretion. The first,

an internal secretory gland would rule out the liver, since neither
glucose nor glycogen, the substances manufactured by it, can be
regarded as hormones. However, it has historical importance in
connection with Claude Bernard's work.

If we want to stretch our definition, we could well afford to
include such a substance as carbon dioxide in a list of hormones.
It is the amount «of this gas in the'blood, and not, as has been
supposed, the amount of oxygen, that controls the process of
breathing. Increased exertion, as in running, causes increased
production of carbon dioxide, .and this in turn stimulates more
rapid breathing.

A very practical use of this new knowledge has been made by
Yandel Henderson, the Yale physiologist. It is only a too well
known fact that after anesthesia the patient's breathing is
poor. Professor Henderson shows -that this can b« improved by
adding carton dioxide to the air that is administered.

120 GLANDS IN HEALTH AND DISEASE

the external secretion, produces the bile, which
flows to the exterior ; the second, the internal secre-
tion, forms sugar which immediately enters into
the blood of the general circulation."

Claude Bernard, in fact, coined the phrase "in-
ternal secretion," though his views as to the influ-
ence of this secretion on the rest of the body, if
not vague, were misleading.

The pancreas and its internal secretion. — It is
now time to turn to Minkowski and von Mering's
experiments which proved that the pancreas regu-
lates the sugar metabolism by means of a hormone
which it develops. These investigators found that
by carefully and completely extirpating the pan-
creas in a dog, the animal develops diabetes. Such
an operation was invariably followed by the death
of the animal within a few weeks, but during those
weeks it suffered severely from the sugar disease.

Diabetes, as you may know, is the — unfortu-
nately— all too common disease wherein the body
cannot use or "burn" all the sugar that it gets, with
the result that we find it present in excessive quan-
tity in the blood (hyperglycemia), and sooner or
later an excessive quantity of sugar appears in the
urine (glycosuria). Since the liver is the central
organ for sugar metabolism, we must look for a dis-
turbance in the liver function. The German in-
vestigators showed that such a disturbance occurs
when the pancreas is cut out of the system.

THE PANCREAS AND THE LIVER 121

But you may ask, how do we know that the pan-
creas develops an internal secretion the hormone
of which travels through the blood to the liver?
Why cannot we assume that whatever influence the
pancreas exerts on the liver is due to its external
secretion — to the pancreatic juice which, by means
of a duct, is poured into the small intestine? We
can answer these questions very definitely. It has
been shown that incomplete removal of the pan-
creas— as little as one-fourth to one-fifth of the to-
tal need be left — prevents diabetes, even though
all connections with the small intestine have been
interrupted, and all flow of pancreatic juice has
stopped. Or again, the ducts of the gland may be
tied, or, what amounts to the same thing, filled with
paraffin, and no glycosuria results. But the most
convincing proof that the pancreas develops an in-
ternal secretion is this : after complete extirpation
of the gland, and after the onset of the disease, the
symptoms of diabetes disappear upon the grafting
of a piece of pancreas under the skin or into the
abdominal cavity. Here whatever communication
is open between the grafted pancreas and the other
organs of the body is by means of the blood and
the blood only.

Kecent experimentation tends to show that the
internal secretion of the pancreas is not developed
by the pancreatic cells themselves but by peculiarly
shaped groups of cells, scattered throughout the

122 -GLANDS IN HEALTH AND DISEASE

pancreas and known collectively as the "Islands of
Langerhans," after their discoverer. Ssobelow, a
Russian, tied the pancreatic duct and noticed that
the pancreatic cells decayed; but not so the cells
of the "Islands of Langerhans." We have already
noticed that such an operation is not followed by
the appearance of sugar in the urine, whereas sugar
does appear upon the complete extirpation of the
pancreas. Hence it seems logical to conclude that
the pancreatic hormone is produced by the "Is-
lands" rather than by the pancreatic cells proper.
This view finds corroboration in the observations
of clinicians who have noticed that in cases of dia-
betes the "Islands of Langerhans" show degenera-
tion.

How the amount of sugar in the blood is regvr
lated. — Just how the pancreatic hormone regulates
the sugar output is problematical. Some claim
that it takes a hand in the oxidation of glucose to
carbon dioxide and water; and that in its absence
the glucose cannot be so oxidized, whence it ac-
cumulates in the blood and finds its way into the
urine. Others, on the contrary, are of the opinion
that it has nothing at all to do with the oxidation
of glucose, but that it does regulate the amount of
glucose to be formed from the glycogen in the liver.
In the absence of the pancreatic hormone, the regu-
latory influence being absent, excessive quantities
of glycogen are converted into glucose, which finds

THE PANCREAS AND THE LIVER 123

its way into the blood and then into the urine. An
attractive hypothesis of this type claims that there
really are two opposing forces that work in the
normal man, — an accelerating force, due to the hor-
mone from the adrenal glands, which accelerates
the conversion of glycogen into glucose, and a re-
tarding force, due to the pancreatic hormone, which
tends to slow up and regulate such a reaction. To
support this hypothesis, Dr. Zuelzer, its author, de-
scribes an experiment with a dog that had had its
pancreas removed and its adrenal veins ligated.
No diabetes followed.

We may represent what happens as follows:

carbohydrates > stored in liver as glycogen >

given out as glucose. The blood, when analyzed is
always found to contain a small amount of glucose.
Under normal conditions that glucose is fairly con-
stant in amount, ranging from 0.07 to 0.1 per cent.
Even in a starving animal the blood sugar is found
to remain constant. This makes us believe that
under such conditions, with all carbohydrate vir-
tually absent from the body, part of the fat mole-
cule, and perhaps part of the protein molecule, is
converted into sugar. Only in pathological cases,
such as are met with in diabetes, does the amount
of blood sugar materially increase.

Now the question arises, by what mechanism is
the blood sugar of the normal human being kept
constant? Why despite the varying quantity of

124 GLANDS IN HEALTH AND DISEASE

carbohydrate eaten from day to day does not the
blood sugar fluctuate correspondingly? A num-
ber of hypotheses have been advanced to explain
this controlling mechanism. Very recently (April,
1921) Dr. Langfeldt has proposed a theory which
includes the best elements of the theories of other
investigators as well as a little of his own specu-
lation. In essence it is this: It is evident that
there must be at least two controlling factors, one
involving the conversion of carbohydrates into gly-
cogen, and the other the conversion of glycogen
into glucose. The first part of the reaction, the
glycogen synthesis, is controlled by the pancreatic
hormone; the second, the breaking down of glyco-
gen to glucose, with the object of meeting the en-
ergy requirements of the muscles, is a more com-
plex affair depending for one thing upon the degree
of acidity of the blood. It has been shown that the
glycogenase, the enzyme responsible for the trans-
formation of glycogen to dextrose, is most active
when the blood is slightly acid. Ingenious physical
chemists have devised quantitative methods for de-
termining the exact state of acidity not only of
blood but of any liquid. If then the acidity of the
blood is below or above a certain optimum, the gly-
cogenase is not so active, and less glucose is formed
— a rare and abnormal condition.

On the other hand, a more common occurrence
is where the pancreatic hormone fails to function,

THE PANCREAS AND THE LIVER 125

due to the failure to function of the pancreas; in
that case little of the carbohydrates is converted
to glycogen, and the excess sugar floods the blood
and the urine. We here have a typical case of dia-
betes.

The "Allen treatment" for diabetes. — No men-
tion of diabetes is possible without referring to the
Allen treatment of this disease. Dr. Allen, until
recently with the Kockefeller Institute, and now
head of the Physiatric Institute, Morristown, N. J.,
has had such remarkably good results with his
"fasting treatments/' that physicians all over the
world have adopted his method, and there can be
little room for doubt as to its success. Only re-
cently (June, 1921) at the Wiesbaden Congress of
Internal Medicine, the two foremost authorities on
diabetes in Europe, von Noorden and Minkowski,
sang its praises.

The treatment is as follows:1 A preliminary
fast is taken until the urine is free from sugar.
This will usually take less than four days. During
that time water is allowed and also, to a certain
extent, tea and coffee. Following the fast, carbo-
hydrate food is gradually added, at first in the form
of green vegetables. Coincident with the addition
of carbohydrate, or in place of it if the carbohy-
drate tolerance is very low, protein is added to the

*This is described in the Handbook of Therapy, published by
the American Medical Association.

126 GLANDS IN HEALTH AND DISEASE

diet in small but gradually increasing amounts un-
til glycosuria occurs. Fats are added in small
amounts during the time of addition of carbohy-
drates and proteins. Frequent urine examinations
are made, either by the medical attendant or by the
patient himself1 and the diet regulated accord-
ingly.

1Some Fehling's-Benedict solution, which is blue in color, is
heated in a test tube until it boils, and an equal volume of the
urine under examination is added. The mixture is heated for a
minute or two. If sugar is present, a red precipitate will make
its appearance, and the amount of precipitate will give some
rough idea of the amount of sugar present. A modification of
this method lends itself to a fairly exact quantitative estimation.

The more recent work on the subject has centered itself as much
in determining the quantity of sugar in the blood as in that of
the urine, and much ingenuity has been expended to devise
methods that are refined enough when dealing with quantities of
blood even as small as a drop or two — the amount obtained from
a prick in a finger. The blood being not only the medium by
which materials are taken in by the body, but also that by which
they are given out, it need cause little surprise that blood
analyses should throw much light on what takes place in the
body.

CHAPTER VIII

THE INTESTINAL HORMONE

We have already referred (page 4) to the work
of the English physiologists, Bayliss and Starling,
on secretin. This work is of such a fundamental
character, that it well deserves a chapter all to
itself.

In the preceding chapter we have shown how
the glycogenic function is controlled by a hormone
developed by the pancreas. We shall now proceed
to show that the pancreatic juice in turn is con-
trolled by a hormone which has its origin in the
lining of the upper part of the small intestine.

Digestion in the small intestine. — Even at the
risk of repeating what was said in the introduction,
let us state what happens in the small intestine
during digestion. You will remember that when
the valve connecting the stomach and intestine is
opened, the food passes from the former into the
latter. Here the food is acted upon by three liq-
uids, each containing either enzymes or other sub-
stances that help to simplify the food to the point
where it can be absorbed by the blood and lymph

127

128 GLANDS IN HEALTH AND DISEASE

and sent to the cells. One of these liquids is elab-
orated by the intestine itself; another, the bile,
comes from the liver ; and the third, the pancreatic
juice, from the pancreas.

The last two reach the intestine by means of
ducts or tubes. They represent typical "external
secretions," in contradistinction to the "internal
secretions" that we have studied, and that flow di-
rectly into the blood.

The hormone in the intestine. — Now the ques-
tion arises, why whenever food enters the intestine,
and only then, do bile and pancreatic juice also
begin to flow into it? The easiest answer, the most
obvious one, is that there is a nervous mechanism
involved ; that the brain correlates the activities of
these organs. Such a theory had a distinguished
supporter in the person of Pavlov, the Kussian
physiologist, whose present plight has been so
graphically described by H. G. Wells, the novelist
who is also a scientist. We are about to show that
Pavlov's theory of brain interference is untenable ;
that all nerve connections between the brain and
intestine can be severed without stopping the flow
of pancreatic juice; that the chief factor that brings
about this coordination — at least in so far as the
flow of pancreatic juice is concerned, and, to a less
extent, the bile, — is a hormone elaborated by the
small intestine; that this hormone is produced
whenever the acid food from the stomach finds its

THE INTESTINAL HOKMONE 129

way into the intestine; and that this hormone, once
produced, finds its way to the pancreas via the
blood stream. You will notice incidentally that
if what we now say is true, the intestine is similar
to the pancreas and, according to Claude Bernard,
to the liver, in that it elaborates both an internal
and an external secretion.

The proof that the flow of pancreatic juice is con-
trolled by a hormone elaborated by the intestine
is due to Bayliss and Starling, the presiding gen-
iuses of the department of physiology at Univer-
sity College, London. Their experiment marks a
milestone in the development of our knowledge of
internal secretions; and we shall offer no excuse
for quoting from part of their celebrated paper on
the subject, technical though it is.

Bayliss and Starling's experiment. — "On Janu-
ary 16, 1902, a bitch of about 6 kilos (13-14 pounds)
weight which had been fed about 18 hours previ-
ously, was given a hypodermic injection of morphia
some three hours before the experiment. The ner-
vous masses and celiac (pertaining to the abdomen)
axis were completely removed, and both vagi
(nerves situated in this part of the body) cut. A
loop of jejenum (a portion of the small intestine)
was tied at both ends, and the nerves supplying it
were carefully dissected out and divided, so that
the piece of intestine was connected to the body of
the animal merely by its arteries and veins. A

130 GLANDS IF HEALTH AND DISEASE

cannula (tube for inserting into body) was inserted
in the large pancreatic duct and the drops of se-
cretion recorded. The blood pressure in the caro-
tid (the principal artery in the neck) was also
recorded. The animal was in a warm saline bath,
and under artificial respiration.

"The introduction of about 20 cubic centimeters
(about 1-25 of a pint) or about one tablespoon of
four-tenths per cent, of hydrochloric acid x into the
duodenum (the first portion of the small intestine)
produced a well-marked secretion of one drop every
20 seconds, lasting for some six minutes; this re-
sult merely confirms previous work. But — and
this is the important part of the experiment, and
the turning point of the whole research — the in-
troduction of 10 cubic centimeters of the same acid
into the enervated loop of jejenum produced a
similar and equally marked effect.

"Now, since this part of the intestine was com-
pletely cut off from nervous connection with the
pancreas, the conclusion was inevitable that the
effect was produced by some chemical substance
finding its way into the loop of jejenum in question,
and being carried in the blood stream to the pan-
creatic cells. Wertheimer and Le Page have shown,

1 Hydrochloric acid is found in the stomach under normal con-
ditions. It is approximately four-tenths of one per cent, in
strength. Of course the object in introducing the acid is to
prove that it, and it alone, coming from the stomach, liberates
the hormone in the intestine.

THE INTESTINAL HORMONE 131

however, that acid alone introduced into the circu-
lation has no effect on the pancreatic secretion, so
that the body of which we were in search could not
be the acid itself."

This suggested that there may be a something in
the wall of the intestine which was responsible for
the action. "The next step in our experiment was
plain — namely, to cut out the loop of jejenum,
scrape off the mucous membrane (tissue covering
the surface), rub it up with sand and four-tenths
per cent, hydrochloric acid in a mortar, filter
through cotton wool to get rid of lumps and sand,
and inject the extract into a vein; . . . After a
period of about 20 seconds, we obtained a flow of
pancreatic juice at more than twice the rate pro-
duced at the beginning of the experiment by intro-
duction of acid into the duodenum."

A pretty variation of this experiment was per-
formed by Enriquez and Hallion. They conveyed
the blood stream from the vessels of one dog (A)
into those of another (B) and found that after in-
jecting acid into the small intestine of dog (A),
pancreatic juice began to flow in dog (B) !

Secretin. — Though the hormone responsible for
the flow of pancreatic juice has not been isolated in
the pure state, its discoverers have given it the
name "secretin" (from the Greek "to excite.")
Since a watery extract of the mucous membrane of
the intestine when injected into the blood stream,

132 GLANDS IN HEALTH AND DISEASE

fails to cause a flow of pancreatic juice, and since
hydrochloric acid alone is no better, but since when
the two are mixed we do get a response, Professors
Bayliss and Starling have advanced the hypothesis
that in its original form the secretin is in an in-
active state — the "pro-secretin" state they term it;
and that the hormone becomes active only when
the acid converts the pro-secretin into secretin.
The function of the acid coming from the stomach,
then, is to convert the inactive into an active hor-
mone. The fact that solutions containing secretin
can be boiled without destroying the hormone sug-
gests that this hormone — and others? — are quite
distinct from either vitamines or enzymes, both of
which are quite susceptible to increases in tempera-
ture.

An objection to the work of Bayliss and Starling.
— The Italian physiologist, Luciani, has criticized
the work of the English scientists. He writes : 1
"Popielski and his pupils have recently published
a series of experiments and conclusions which com-
pletely refute the secretin theory. Popielski states
that the substance extracted after the extraction
of the duodenal mucosa with hydrochloric acid is
not specific, but may, on the contrary, be obtained
by simple hydrolysis, from any glandular, muscu-
lar, or even nervous tissue. . . . But the follow-
ing is the most cogent of PopielskPs arguments.

1 Human Physiology, Volume 2.

THE INTESTINAL HORMONE 133

In repeating the injections of sec re tin many times
equal doses, he observed a conspicuous secretion
tfter the first dose, less after the second, still less
!ter the third, till the substance rapidly became
[effective. Now, the introduction of acid in the
luodenum, however often repeated, invariably ex-
ites pancreatic secretion proportional to the quan-
Ity of acid introduced. The body evidently reacts
the introduction of secretin by forming an anti-
>ody capable of fixing it and annulling its action ;
tis suggests that it is not a substance normally
Leveloped by the body, but is an artificial extrane-
ms product."

Despite this criticism, the secretin theory has
m very generally adopted ; to every physiologist
cites an experience in opposition to it, there
ire twenty who cite experiments that support it.

Gastric secretin. — While on the subject of diges-
tive juices, reference may be made to the gastric
juice, a fluid manufactured in the walls of the stom-
ach. Pavlov has conclusively shown that the flow
of gastric juice is unquestionably controlled by the
brain, since the severance of all nerve connections
stops the flow. This would seem to show that the
origin of the flow of gastric and pancreatic juices
is fundamentally different. However, Dr. Edkins
has been able to show that, in addition to a nervous
reflex, there is also a chemical stimulus involved.
His experiment followed the lines of Bayliss and

134 GLANDS IN HEALTH AND DISEASE

Starling. A piece of mucous membrane from the
stomach, when extracted with acid, and the acid
injected into the blood, caused a flow of gastric
juice. Edkins called the hormone responsible for
this action the gastric secretin, to distinguish it
from the intestinal secretion.

Secretin and vitamine. — We have pointed out in
this chapter that secretin withstands the tempera-
ture of boiling water, a fact speaking against its
identity with any vitamine. However, Dr. Carl
Voegtlin, the government chemist in the Hygienic
Department at Washington, has recently performed
experiments to show that secretin and vitamine B
(the anti-neuritic vitamine — that is, the one that
cures beriberi in man and polyneuritis in pigeons),1
are similar in properties, if not actually one and the
same substance. Towards chemical reagents, such
as wood alcohol, silver, lead and barium salts, they
behave alike. "Secretin preparations from the du-
odenum of hogs relieved to some extent the neuritic
symptoms, and the anti-neuritic vitamine from
brewer's yeast on injection into dogs stimulated the
pancreatic and biliary secretions." Whether this
be so or not we cannot say definitely; the work
needs confirmation.

1 See the chapter on Beriheri in the author's book on Vitamines.

CHAPTER IX

THYMUS, SPLEEN, PINEAL, MAMMARY GLAND AND
KIDNEY

I have grouped in this chapter a number of or-
ins whose exact position in ductless glandular
classification is debatable. Some of the organs are
tot glandular in the histological sense. With
>thers we are not altogether certain that they pro-
Luce an internal secretion or, more correctly, a
specific hormone. A substance like carbon dioxide
is not produced by a gland, yet as a regulator of
respiratory activity and of the respiratory center it
ought, perhaps, to be discussed in this chapter. On
the other hand, a compound like urea is the prod-
uct of an organ of internal secretion ; but it is not
yet certain whether it has any direct influence on
the kidney. This chapter, then, is full of uncer-
tainties.

THYMUS

This organ is situated in the neck near the thy-
roid. It seems to be of particular importance in
the early life of the individual, though the most

135

136 GLANDS IN HEALTH AND DISEASE

recent work tends to the opinion that it functions
throughout life. After the second year of life it
grows less in size. Here are some figures : At
birth, 13.26 grams (approximately 30 grams equal
one ounce) ; between one and five, 33 grams; be-
tween six and ten, 26 grams ; 11 to 15, 37 ; 16 to 20,
25; 56 to 65, 16; 66 to 75, 6.

Function of the thymus. — What the function of
the thymus is is a matter of constant debate. A
number of experiments point to the fact that its
activity is connected with that of the sex glands;
that the thymus, for a time, checks the development
of the reproductive organs. For example, the re-
moval of the thymus (in animals) is said to ac-
celerate sexual development, though it delays
growth; and castrated animals show an enlarged
thymus.

Uhlenhuth, of the Eockef eller Institute, has spon-
sored the theory that the thymus secretes a tetany-
producing substance (see the chapter on the para-
thyroid) which is neutralized by the parathyroids.
Some claim that the thymus is the principal reserve
organ for nucleoprotein, an important type of pro-
tein particularly abundant in the nuclei of cells.
Still others deny that the thymus is an endocrine
gland. For example, Hopkins, in an exhaustive re-
view of the subject, says: "The evidence in favor
of such a theory (that the thymus is a ductless

THYMUS 137

gland) is circumstantial at best and very meager.
It is equally difficult to prove that the thymus does
not produce a secretion, but the burden of proof
is upon those who support the former theory."

A very remarkable experiment by Gudernatsch
must be cited here, though it should be noted at the
outset that another investigator, Swingle, chal-
lenges Gudernatsch's statements. The latter found
that by feeding tadpoles with thymus extract, their
growth could be accelerated to a remarkable de-
gree, but that metamorphosis to the frog state was
delayed. We have already seen in the chapter on
the thyroid that thyroid extract behaves in an op-
posite manner, in that feeding tadpoles with such
an extract accelerates the transformation into the
frog, but retards growth. Are we to assume that
the thymus is connected, for a time at least, with
thyroid activity?

The general concensus of opinion is that the ex-
tirpation of the thymus does not necessarily result
fatally, though it does give rise to a disordered de-
velopment of the skeleton, such as may be seen in
a rickety child. Sciplades, a Hungarian investi-
gator, is of the opinion that osteomalacia, a disease
characterized by a softening of the bones, is brought
about by the absence of a functioning thymus. This
is based on experiments with young dogs whose
thymus had been completely extirpated. "The

138 GLANDS IN HEALTH AND DISEASE

changes produced in the bones coincided, histologi-
cally, with the changes characteristic of human
osteomalacia."

Thymus extract does not cure the disease, though
when injected into the blood it lowers the arterial
pressure and accelerates the heart beat.

A disease called "mors thymica," sometimes "thy-
mic asthma," connected with difficult breathing of
infants, and which has a sudden fatal termination
("thymus-death,") is said to be due to the hyper-
trophy (enlargement of organ) of the thymus.

SPLEEN

The spleen, like the thymus, is not a glandular
organ, and hence is often omitted in the treatment
of ductless glands. But it seems to develop an in-
ternal secretion, in that a hormone from the spleen
passes through the blood to the pancreas and "acti-
vates" the ferment (enzyme) that attacks protein —
trypsin. This proof, if not convincing, is of a
somewhat more positive nature than in the case of
the thymus, where our only reason for supposing
that it manufactures a hormone is the claim made
by some that when the thymus is extirpated the
skeleton does not develop properly.

The function of the spleen, like that of the thy-
mus, is shrouded in much mystery. We have just
said that it is possible that its hormone activates

THYMUS 139

the pancreatic trypsin. It should, however, be
added that Pavlov, the Kussian physiologist, has
proved that the juice elaborated in the small in-
testine also contains a hormone (or enzyme?)
which activates the trypsin.

From the large quantity of iron (in "organic"
combination) that the spleen contains, and from
studies in anemia, investigators have concluded
that it plays a part both in the formation and de-
struction of the red blood corpuscles, but this is by
no means certain. Others regard it as playing an
important part in immunity from the active pha-
gocytosis (destruction of micro-organisms by cells
such as the leucocytes, or white corpuscles of the
blood). The 'very recent work by Inlow disproves
the theory that the spleen regulates the digestive
power of the stomach — a claim based on some ex-
periments which are cited to prove that the re-
moval of the spleen diminishes the activity of the
pepsin, the enzyme in the stomach.

Curiously enough, the extirpation of the organ
was practised by the ancients, in the belief that it
improves the "wind" in runners. Extirpation is
not attended with fatal, or even particularly bad
results. It is practised in a disease called "splenic
anemia," "characterized by progressive enlarge-
ment of the spleen, attacks of anemia, and a tend-
ency to hemorrhages. . . ." Complete recovery
follows the removal of this organ. This, of

140 GLANDS IN HEALTH AND DISEASE

course, makes it quite evident that the spleen can-
not compare in importance with other ductless
glands, such as the adrenal or the pancreas, the
absence of which causes death. This, however, does
not mean that the spleen is of no importance.

Eddy in a recent review cites the following in
support of the theory that the spleen produces an
internal secretion: 1. Changes in erythrocytes
after splenectomy (removal of spleen) ; 2. Modifi-
cation of blood picture after hyperplasia (abnor-
mal multiplication of the tissue elements) of the
spleen, ameliorated in some cases at least by splen-
ectomy ; 3. Specific effects on the red blood corpus-
cles of injection of splenic extract. He acknowl-
edges that we know nothing of the chemical na-
ture of the hormone, but suggests that the chief
function of the spleen is to remove from the circu-
lation the disintegrated erythrocytes (red blood
cells), and to build erythrocytes (by stimulating
the erythrogenic, or blood corpuscle building power
of the bone marrow) .

PINEAL ("Epiphysis")

This is an organ the size of a pea, situated at the
base of the brain, behind and above the pituitary.
Descartes considered it the seat of the soul ! Like
the thymus, its importance seems to be chiefly in
the early stages of its existence — if we are to be-
lieve many of the authors who have busied them-

PINEAL 141

selves with the organ. Professor Biedl claims that
in adults "the gland is a negligible factor/' He ar-
rives at this conclusion from extirpation experi-
ments. He has not, however, settled the question
of extirpation in young animals.

Foa, an Italian, has removed the pineal from
roosters, with the result that the testes hypertro-
phied. Horrax, of Chicago, has practised pineal-
ectomy on guinea pigs; he states that the develop-
ment of the testes becomes accelerated. The feed-
ing of the desiccated pineal body to rats has had
no influence on their growth (Finney, Baltimore).
Another and more important experiment where 27
mentally deficient children at the Vineland farm
were fed with a pineal extract, led to no noticeable
effect.

We do know what pathological growths of the
pineal gland in children will give rise to. "In the
70 cases on record of tumor of the pineal gland,
most were in adults, but ten were in boys below
the age of puberty; and these all presented pre-
cocious and pronounced development of the pri-
mary and secondary sexual characteristics, and
some a certain degree of mental precocity." (Zan-
dren) ; which points to the presence of a hormone
that regulates, in some way, the sex life.

Dr. Frederick Tilney, in his book 1 gives us an

1 Frederick Tilney and H. A. Riley: The Form and Functions
of the Central Nervous System (P. B. Hoeber, New York, 1921).

143 GLANDS IN HEALTH AND DISEASE

excellent example of a case of pineal disease. The
patient, a boy of eight, had suffered from recurrent
headaches since his sixth year. In his eighth year
his headaches had become more severe and he had
suffered from vomiting attacks. "His vision was
not so good as it had been, and upon advice he be-
gan to wear glasses. During his eighth year he
grew rapidly until he had reached the height of five
feet three inches. He was as large as a boy of 14.
In addition to his increase in stature his pubic hair
made its appearance and reached full development.
His external genitalia became as large as those of
an adult and his sexual functions were fully estab-
lished. His voice underwent transition and be-
came much deepened. During this time, however,
he suffered from repeated headaches and his vision
progressively failed.

"Upon examination by an oculist he was told
that he had progressive optic atrophy. He was
admitted to the hospital because of his severe head-
aches and vomiting. At this time his vision was
practically gone. Shortly after admittance to the
hospital he was seized with a convulsion which
lasted for half an hour. After this convulsion he
never recovered consciousness but lapsed into a
somnolent condition in which he remained for sev-
eral weeks, at the end of which time he had a sec-
ond convulsion and died a few days later.

"Upon examination at the time of his entrance

PINEAL 143

into the hospital the following observations, among
others, were made: The patient gave evidence of
slight loss of volitional control in both legs and
arms. Although a child of eight years he looked
a boy of 15 or 16 both in size and development. The
mental state of the patient was difficult to estimate.
He seemed precocious in certain particulars but
definitely retarded in others. He had been unable
to attend school because of his headaches and for
this reason his actual rating could not be made.

"Furthermore, on his admittance to the hospital
he was suffering from such extreme headaches that
only the statement of his parents could be depended
on in estimating his age. The spinal fluid on lum-
bar puncture appeared to be under increased ten-
sion, but it was negative to all special tests. The
blood and urine were also negative. The lesion in
this case was a brain tumor. Evidence of the focus
of the lesion was afforded by the precocious somatic
(pertaining to the framework of the body) devel-
opment and precocious sexual development and
growth. The optic atrophy and blindness, together
with headaches, convulsions, somnolence and death,
can be accounted for by a growth involving the
pineal gland in such a way as to compromise the
aqueduct of Sylvius (a passage which connects the
third and fourth ventricle or cavity of the brain.
The pineal is connected with the roof of the third
ventricle) and thus give rise to an internal hydro*

144 GLANDS IN HEALTH AND DISEASE

cephalus ("water in the head"; an enlargement of
the head). This explains the visual as well as the
motor disturbances in the case.

"The essential clinical features of the disease
are:

1. Precocious development and differentiation
of the external genitalia, the premature appear-
ance of the axillary (pertaining to the arm-pit)
and pubic hair.

2. Precocious development of the sex functions.

3. Precocious abnormal growth of the long
bones, producing a stature of abnormal develop-
ment.

4. The appearance of signs of internal hydro-
cephalus, including visual disorder, headache, vom-
iting, with choked disk or optic atrophy.

5. The absence of all other motor or sensory
symptoms."

.MAMMARY GLAND

I can do no better than quote Professor Bayliss,
who has critically analyzed the various views ad-
vanced as to the growth of the gland in pregnancy
and the accompanying secretion of milk. "The
growth of this organ is closely connected with that
of the uterus (womb) in pregnancy, so that it is
not surprising to find that the growth is affected

MAMMARY GLAND 145

by a hormone produced in the corpus luteum ("yel-
low body" in the ovary that grows for some time
after impregnation of the ovum). . . . The sec-
ond stage, associated with secretory activity in the
later period of pregnancy, is independent of the
corpus luteum. It has been shown by Mackenzie
that the gland is not under the influence of the
nervous system, but that extracts of various or-
gans, injected into the blood current of a cat in
lactation, cause secretion of milk.

"The organs found active were the pituitary
body, the corpus luteum, the pineal body, the in-
voluting uterus (the return of the uterus to normal
size after child is born), and the mammary gland
itself. The pituitary body is by far the most active.
The fetus (the child in the womb after the third
month. Before that time it is called the embryo
and placenta (organ in uterus that establishes con-
nection between mother and child) produce hor-
mones which inhibit the gland.

"Further analysis of the action of pituitary ex-
tract was made by Hammond. The effect is said
not to be due to pressing out of milk by contraction
of muscle in the ducts . . . the daily yield of goats
was found to be only slightly increased by injec-
tions, so that pituitary extract seems to act by
setting free the constituents of milk, rather than
by causing increased formation. . . ."

146 GLANDS IN HEALTH AND DISEASE

KIDNEY

Experiments to prove that the kidney elaborates
an internal secretion have been of so conflicting a
kind, that references to them would yield little in-
formation and much confusion. The curious-
minded may be referred to BiedFs book (see Bibli-
ography).1

1 Skin. Lately Dr. Doege, writing in the Wisconsin Medical
Journal (August, 1921), discusses the evidence in favor of the
view that the skin has an internal as well as an external secretory
function. There seems to be an intimate connection between
the ductless glands and the skin. "Perhaps the most familiar
examples are the appearance of myxedema with the loss of
thyroid function; the dependence of certain skin eruptions or
pigmentations on the sex glands, pregnancy, puberty and the
climacteric period; the appearance of the bluish discoloration of
the skin in Addison's disease, an affection of the adrenals.
Again, the fact that many infectious diseases, such as measles,
diphtheria, smallpox, spotted fever, and syphilis run their course
with an essential involvement of the skin is certainly not without
deeper significance, and points to the probable fact that the skin
performs an important function in the overcoming of these
affections. . . ."

CHAPTER X

THE RELATION OF THE DUCTLESS GLANDS
TO ONE ANOTHER

The function of the hormones generated by the
ductless glands is to coordinate the various activi-
ties of the body. That there should exist a close
relationship between any one ductless gland and
any other or a group of others, is what might be
expected, but the difficulty in proving beyond all
question such relationships is great. This chapter,
then, should be read with reserve; what is related
here Is meant to be suggestive and no more. But
this chapter, like one or two others following it,
will, I trust, also serve as handy summaries of
much that has been discussed in previous pages.

The eminent French physiologist, Gley, writes:
"The connections between the various glands are
one of the fundamental facts maintained by the
doctrine of internal secretions, and to deny them
would be to deny a part of the doctrine of internal
secretions itself. But what I criticize is the in-
sufficiently demonstrated theory of reciprocal re-
lations." And well he may; there are no end of

147

148 GLANDS IN HEALTH AND DISEASE

pitfalls that must be avoided if one is to steer clear
of hypotheses that are attractive and that are based
on the flimsiest foundation of actual knowledge.

One of the earliest attempts to give us a concrete
picture of an inter-relationship between the duct-
less glands was that due to the Viennese patholo-
gists, Eppinger, Falts and Rudinger who, in 1908,

PAMCfi£AS

FIG. 1. THE RELATIONSHIP OF THE PANCBEAS TO THE
OTHER DUCTLESS GLANDS.

published a paper dealing with the influence of the
thyroid and the adrenals on the activity of the in-
ternal secretion of the pancreas. It was, in fact,
an attempt to summarize our knowledge of the
modus operandi of carbohydrate metabolism.
Their views will be understood by reference to Fig.
1, and more particularly to Fig. 2.

It will be remembered that in our discussion of
carbohydrate metabolism it was stated that the
various carbohydrates, such as starch and cane

[E RELATION OF THE DUCTLESS GLANDS

igar, after undergoing appropriate simplification
in the digestive tract are stored in the liver in the
form of glycogen ; and that whenever the body needs
to expend energy, some of the glycogen is converted
into glucose, which in turn finds its way to the
muscles, where some may be resynthesized into
glycogen, but where it is ultimately oxidized OP

1 I

?

1 ^^J"

1

A RE/VALS

1
1
1

V

^
i
i
i
•

1 f^y^/^ |

i r

GLUCOSE

FIG. 2.

THE EFFECT OF MOBILIZATION OF SUGAR IN THE LIVES.

- = stimulation ; — - - = inhibition
An arrow indicates the direction of action.

''burned," yielding, as final products, carbon di-
oxide and water. All this is a very complicated
process. There must be a regulating or guiding
mechanism involved to establish order in the place
of chaos. We have seen how a large part of this
function is taken over by the pancreas, and we have
proved that it is the internal secretion of the pan-
creas that is responsible. We have seen, for ex-
ample, how the extirpation of the pancreas re-
moves a restraining hand from the liver, with the

150 GLANDS IN HEALTH AND DISEASE

result that an excess of glucose appears in the
blood, and finally in the urine, giving rise to the
sugar disease, diabetes.

It would seem as if the thyroid, and particularly
the adrenals, accelerate the conversion of glycogen
to glucose, and that the pancreas, and perhaps to
some extent the parathyroid, retard such a conver-
sion. Eppinger and his1 colleagues reached this
conclusion from studies of the effect on protein
metabolism of injecting adrenaline. They found
that this increased protein metabolism (the amount
of protein digested and utilized) was the same as
that seen in hyperthyroidism and the opposite of
that produced by the removal of the thyroid gland.
On the other hand, the pancreas seems to prevent
the formation of an excessive quantity of sugar, for
we see that such an excessive quantity is produced
when the pancreas is removed. As for the para-
thyroid, the general feeling that it tends to neutral-
ize thyroid activity has made some investigators
class it on the side of the pancreas. These actions
are shown in Fig. 2.

Fig. 1 shows that the pancreas, thyroid and adre-
nals, in addition to influencing sugar metabolism
in the liver, influence the activity of one another.
Thus the thyroid and adrenals excite one another
to activity, whereas the thyroid and the pancreas,
and the adrenals and pancreas, inhibit one an-
other's activity.

RELATION OF THE DUCTLESS GLANDS 151

These views — particularly the one referring to
adrenal function — have been strenuously opposed
by Gley in France and Stewart in this country.
Professor Stewart's work will again be referred
to in a later chapter (see p. 165). Here it may be
said that he presented evidence to prove that adren-

1

\

PITUITARY

J A f)O

ZNALS

' ~^N

« J

^

1 , --^

^ i
1 |

! !

1 4

• (

1
1

?

THYRO/D

L-H ~*[/?fP/?C

vucr/ve

7AA/5

Ti n o*<.

\ t * i

! !

• I
•1 L

THYMUS

(/l/ler Paton)
FIG. 3. THE POSSIBLE INTEB-EELATIONSHIPS OF THE DUCTLESS GLANDS.

= stimulation ; = inhibition

An arrow indicates the direction of action.

aline is not essentially concerned in experimental
hyperglycemias (excess of sugar in the blood),
since hyperglycemia is obtained in rabbits which
have survived double adrenalectomy. It is con-
cluded that the mobilization of sugar, of which ex-
perimental hyperglycemias are an expression, is
not mediated through the secretion of the adren-
als.
Fig. 3 is a more extensive diagram to show the

152 GLANDS IN HEALTH AND DISEASE

interrelationships of the ductless glands. Let it
be emphasized again that the diagram is far from
exact, because our knowledge is so incomplete.
Where no connection between glands is shown, it
does not follow that none exists, but that so far
none has been found to exist. Where a connec-
tion is shown, we merely mean to imply that the
weight of opinion is in favor of such a view, not that
it is necessarily the correct view. Let us discuss
the meaning of the diagram, taking up each gland
in turn.

Pituitary (A) and sexual glands. — Hypopitui-
tarism often gives rise to absence of secondary
sexual characteristics. In a woman it may show
itself by absence of pubic hair, and by arrested
development of the breasts. On the other hand,
castration results in an enlargement of the pitui-
tary.

That growth depends upon the pituitary has
long been known. Growth is very largely com-
pleted at puberty. This would explain why most
women are smaller than men, since the former
reach the stage of puberty before the latter.

In conformity with the idea that the pituitary
and the sexual glands are intimately related, it has
been shown that feeding tadpoles with extracts of
the anterior lobe of the gland accelerates sexual
development ( Goetsch. )

(B) And thyroid. — The removal of the thyroid

THE EELATION OF THE DUCTLESS GLANDS 153

results in the enlargement of the pituitary, and
vice versa. Both the pituitary and the thyroid
seem to stimulate the sexual glands in the same
direction. If either is removed, not only does the
animal fail to grow properly, not only is there an
arrested development of the mind and a tendency
towards adiposity, but the sexual organs remain
undeveloped.

As showing the parallelism in action of the thy-
roid and the pituitary in certain instances, the in-
teresting experiment has been performed of feed-
ing thyroidectomized rats with "tethelin," the sub-
stance isolated by Kobertson from the anterior
lobe of the pituitary: a beneficial effect on the
growth of the animals was observed. Are we to
assume that under certain conditions tethelin can
take the place of the thyroid hormone?

Thyroid (A) and pituitary. — See under pitui-
tary.

(B) and sexual glands. — Kemoval of the thyroid
stops the growth of the sexual glands. Castra-
tion, however, does not seem to have much influ-
ence on the thyroid, though it has been stated that
hyperactivity of the latter, in the shape of exoph-
thalmic goiter, is not uncommon.

(C) and thymus. — Conflicting results.

(D) and parathyroids. — At one time the para-
thyroids were regarded as adjuncts of the thyroid;
now the view is quite firmly established that the

154 GLANDS IN HEALTH AND DISEASE

parathyroid is an independent organ, and that it
and the thyroid may be regarded as displaying re-
ciprocating actions.

(E) and adrenals. — The work of Cannon and
others tends to show that these two stimulate one
another's activity. Hyperthyroidism, such as is
found in Graves's disease, is said to increase the
adrenaline in the blood, and hypothyroidism les-
sens the activity of the adrenals. The adrenals
stimulate the production of sugar from glycogen,
and it is supposed that the thyroid also acts in this
way (see Fig. 2) . This view advanced by Eppinger
and his associates in Vienna, is based on experi-
ments which show that the removal of the thyroid
makes adrenaline less effective in bringing about
glycosuria. Professor Underbill, of Yale, disagrees
with this view. We shall see in a subsequent chap-
ter (p. 165) that Professor Stewart, of Western
Eeserve University, has also quite a number of
criticisms to offer.

) and pancreas. — We have many conflicting
theories. It has been said that the diabetes pro-
duced in an animal by removing its pancreas, can
be prevented by also removing its thyroid. If this
unlikely view is correct, then the two glands show
reciprocal actions.

Adrenals (A) and thyroid. — See latter.
J(B) and pancreas. — Conflicting. Kemoval of
the pancreas produces sugar in the urine (glyco-

THE RELATION OF THE DUCTLESS GLANDS 155

suria). On the other hand, addition, or rather in-
jection of adrenaline does the same. Hence the
view that the two act reciprocally. Direct proof
has not been forthcoming.

(C) and sexual glands. — Conflicting. It is said
that "in cases of sexual precocity the adrenal cor-
tex is much enlarged."

Thymus (A) and thyroid. — See the latter. '

(B) and parathyroids. — Uhlenhuth, of the
Kockefeller Institute, is responsible for the state-
ment that the thymus secretes a tetany-producing
substance, the action of which is neutralized by the
parathyroids. This needs confirmation.

(C) and sexwal glands. — The removal of the thy-
mus in early life brings about the development of
the sexual glands. It does seem as if the function
of the thymus in early life is to retard the onset of
puberty.

CHAPTER XI

THE INFLUENCE OF THE DUCTLESS GLANDS
ON GROWTH AND METABOLISM

These questions have been discussed in the vari-
ous portions of the book dealing with the pathology
of the subject. The essential features may be
brought together in this chapter.

It has been shown that castration in early life
may lead to abnormal growth of the skeleton. On
the other hand, the removal or atrophy of the thy-
roid, pituitary, and presumably the thyrnus, leads
to arrested growth (the cretin is an example).
Where the pituitary and (perhaps) the thymus
are overactive, we get excessive growth (gigantism
and acromegaly are types).

Whether the other ductless glands influence
growth is not clear.

When we come to the influence of the glands on
metabolism — on the various reactions that go on
within the body — we find that the ductless glands
are of great importance. The thyroid is the fore-
most metabolic regulator of the body. We have
already seen how the metabolic rate is accelerated

166

INFLUENCE OF THE DUCTLESS GLANDS 157

in hyper-thyroidism and retarded in hypo-thyroid-
ism. It has already been shown how the pan-
creas, the adrenals and probably the thyroid, di-
rectly influence carbohydrate metabolism. In pro-
tein metabolism — in the assimilation and general
utilization of meat, proteins of milk and eggs, for
example — we have reasons to believe that the thy-
roid, pituitary, adrenals and the sexual glands
stimulate, and the pancreas and the parathyroids
inhibit such metabolism. That metabolic studies
are of great value in the diagnosis of ductless glan-
dular diseases is well illustrated in diseases con-
nected with the thyroid (see p. 40).

CHAPTER XII

THE NERVOUS SYSTEM AND THE DUCTLESS GLANDS

The work of Cannon of Harvard, Crile of West-
ern Reserve University, and the war experiences
of many doctors, more particularly in cases of
"shell-shock," have emphasized the possibly close
connection between certain phases of nervous dis-
order and the derangement of the ductless glands.
Let us in the first instance review very briefly some
of the glandular diseases that are accompanied by
nervous effects, and we can then take up the work
of Cannon and others in some detail.

Diseases of the thyroid come first in order. We
have already seen, in discussing this subject, how
a hyperthyroidism, as exemplified in exophthalmic
goiter, not only increases the metabolic rate, but
affects the emotions. Irritability, hasty speech, at-
tacks of laughing and crying, and a general rest-
lessness,— all this accompanied by a tremor, and a
rapid heart beat, point to a mental as well as a
physical attack. In fact, the close connection be-
tween hyperthyroidism and the mental state of the
patient is such that an interesting discussion has

158

THE NERVOUS SYSTEM 159

r arisen as to whether the origin of the disease
o be laid at the door of "nerves," whose rupture
ys havoc with the thyroid, or at that of the lat-
, which in turn affects the "nerves." An edi-
Lal in Endocrinology (1917) has this to say:
le work of Cannon demonstrates how complete
;he cycle, and how difficult it is in a given case
tc ascertain whether the original cause was psychi-
cal or material. In no disease is this more evident
than in Graves's disease (which, you will remem-
ber, is a common form of hyperthyroidism ) . Here
a succession of nervous shocks may excite the adre-
nals until the thyroid is put into action, and hyper-
thyroidism arises. But again the stimulation of
the vagus (nerve responsible for sensation and mo-
tion) may come from so material a source as a
uterine myoma (a tumor of the womb) or other
pelvic structure — as Hertzler points out. But the
outcome is the same: the thyroid becomes stimu-
lated until the threshold becomes permanently
lowered."

That the origin may be a nervous one seems rea-
sonably clear from the experiences of the war. Dr.
Cobb, a captain in the Koyal Army Medical Corps,
writes : "It is a well-known fact that the syndrome
which we have hitherto called 'hyperthyroidism'
is frequently met with among the cases of func-
tional neuroses which arrive at the base hospitals
. . . the exophthalmos is not often marked, but

160 GLANDS IN HEALTH AND DISEASE

the fine tremor, moist skin, tachycardia (rapid
tion of the heart), prominent thyroid, and me
irritability are all present. The brisk reactio]
any emotional excitement, with exaggeration
those features, shows that the mental elemen
not negligible. Furthermore, any one who has
any lengthy experience of this class of sold
patient will agree that his mental outlook is mi
edly similar to that of the civilian patient with
ophthalmic goiter."

In hypothyroidism, as in the cretinous chuu,
and in the adult suffering from myxedema, we go
from the extreme of rapidity in action and thought
(hyperthyroidism) to complete sluggishness and
mental apathy. The child coordinates poorly; it
learns to talk late in years — sometimes it never
passes beyond the stage of inarticulate sounds; it
learns to sit and to walk late. The adult loses all
reaction to strong stimuli and resembles the hiber-
nating animal.

Professor Falta states that the English Myxe-
dema Commission "found the apathy character-
istic of myxedema to be absent in three of 109
cases. This may develop relatively early, and in
the light cases may consist in a sluggishness of
movement, in a retardation of the psychic func-
tions, in an inability to form rapid conclusions,
and in a slowing and monotony of speech. Mag-
nus-Levy, the German physiologist, claims that

THE NERVOUS SYSTEM 161

even in the light cases the 'capability of reacting
to strong stimuli' is lost. The speech may be mark-
edly slowed, 'as if/ writes the [late] Dr. Meltzer,
'the speech mechanism were frozen in.' Charcot,
the French neurologist, compares such patients to
hibernating animals.

"The English Commission found among the
myxedema patients investigated by them that 18
suffered from illusions, 16 from hallucinations, and
16 from frank psychosis. The psychoses belong to
various types, although the melancholoid condi-
tions predominate. The symptoms of the psychosis
often develop simultaneously with those of myxe-
dema, and vanish after thyroid therapy has been
instituted, to reappear again when the therapy is
discontinued."

The researches of Cannon, referred to above,
tend to show that the adrenals — and more particu-
larly one of their hormones, adrenaline, — are
closely associated with the mental state of the per-
son. The close connection between the action of
adrenaline and that of the sympathetic system has
been discussed in the chapter on the adrenals. We
must now take up Cannon's work in some detail.

The researches of Professor Cannon. — Professor
Cannon, of Harvard, working in conjunction with
a number of his pupils ( among whom must be men-
tioned de la Paz, Shohl, Wright, Washburn, Ly-
man, Nice, Gruber, Osgood, Gray and Mendelhall),

162 GLANDS IN HEALTH AND DISEASE

has brought forward evidence to show that at times
of emotional excitement, pain or asphyxia (suffo-
cation), an increased secretion of adrenaline takes
place. "Adrenal secretion has previously been
proved to be subject to sympathetic stimulation
(see page 83) ; and as excitement, pain and as-
phyxia were conditions well recognized as accom-
panied by sympathetic activity (manifested, for
example, by inhibition of digestive functions), an
attendant adrenal secretion was naturally to be ex-
pected. In a series of papers which follow the first
two in 1911, experiments were described showing
that adrenal secretion was serviceable in lessening
muscular fatigue and in accelerating coagulation
(clotting) of the blood. It was pointed out that
excitement, pain and asphyxia were conditions
which in natural existence would commonly be as-
sociated with struggle, and the adrenal secretion,
which accompanies these three states, would be
useful in great muscular effort."

Cannon criticized l>y Professors Stewart and
Gley. — Stewart, of Western Eeserve University,
Cleveland (working in conjunction with his chief
assistant, Dr. Eogoff), and Gley, of the College de
France, Paris, have seriously questioned Cannon's
interpretations. From his own work Stewart
draws three conclusions, each one of which helps
to explain a discrepancy, and all three of which
tend to throw confusion into the camps of Cannon's

THE NERVOUS SYSTEM 163

followers: In the first place, the discharge of
adrenaline is continuous; secondly, the amount of
this substance in any animal is approximately con-
stant ; thirdly, the supposed variation is dependent
on the rate at which the blood flows through the
veins. Keeping these views in mind, Stewart finds
that neither in pain, nor in asphyxia, nor in emo-
tional excitement, can any increased secretion of
adrenaline be detected.

An experiment ~by Professor Cannon. — Segments
of rabbit intestine were placed in cylinders and
these filled with samples of blood taken from the
lumbo- (pertaining to the loins) adrenal veins.
The blood was taken before and after stimulation
of the central end of the sciatic nerve. "Normal
blood removed before stimulation of the central end
of the sciatic nerve caused no inhibition of the
rhythmically contracting intestinal segment,
whereas that removed afterwards produced a
marked relaxation.1 The conclusion was drawn

aln the chapter on the adrenal glands we stated that there
were two accepted methods for the estimation of adrenaline, —
the one a physiological, and the other a chemical method. The
physiological method is the more sensitive, and for the extremely
minute quantities of the substance with which we are here deal-
ing, the physiological method is, at present, the only one that
yields results. The principle employed is one -which depends
upon the fact that a portion of an organ, such as the uterus or
the intestine, when bathed in blood or in Ringer's solution —
containing a mixture of inorganic salts of a concentration similar
to that found in blood — will produce rhythmic contractions that
can be made to record on a slowly revolving drum; when, how-
ever, adrenaline even in the proportion of on»part in one million

164 GLANDS IN HEALTH AND DISEASE ,

that the adrenal glands are affected through ner-
vous channels when a sensory trunk (the main
stem of the nerve) is strongly excited, and that
they then pour their secretion into the blood
stream.1

It must be remarked that the inhibitory influ-
ence on the beating intestinal strip is shown by
adrenaline, which of course suggests that the in-
hibition described in this experiment is the result
of an increased activity of the adrenals, with a
consequent increased production of adrenaline.
This adrenaline is discharged into the blood. If

is added to the solution, or when blood containing a quantity of
adrenaline above the trace that is probably found normally, then
the tracings on the drum show a sudden jump. For details we
must refer the reader to any standard textbook of physiology.
Stewart's includes a number of interesting practical exercises.

1 For the benefit of some readers who may desire more detailed
information, the following additional points in Cannon's pro-
cedure are appended: The segments of rabbit intestine were sus-
pended lengthwise in a glass cylinder through which oxygen waa
passed. The segment, when not surrounded by the blood to be
tested, was bathed in Ringer's solution (see above). The test
blood, the cylinder and the fresh Ringer's solution were all kept
at body temperature in a common bath. The blood to be tested
was taken before and after the experimental procedures by pass-
ing a catheter (a tubular surgical instrument for discharging
fluid from a cavity of the body) through an incision in the
femoral vein (referring to the thigh) into the iliac (the haunch-
bone or the flank) and thence into the inferior vena cava an-
terior to the entrance of the lumbo-adrenal veins. A thread tied
tightly around the catheter marked the point to which it was
inserted and permitted reinsertion to the same point in subse-
quent sampling of the blood. The position of the catheter open-
ing, which was at one side, was kept constant by attention to the
position of the knot in the thread. Thus both the control blood
and the blood after stimulation were taken as -exactly as possible
from the same region.

THE NERVOUS SYSTEM 165

Professor Cannon's theory is correct there ought
to be more adrenaline in the blood after stimula-
tion— in the above experiment the stimulation was
sensory — than before stimulation. His experiment
tends to show that such is actually the case.

In a similar manner Cannon has shown that
asphyxia "causes a change in the blood producing
the same effect as adrenaline on the beating in-
testinal strip, namely, inhibition" ; and that emo-
tional excitement gives rise to a similar phenome-
non. Hence the conclusion that stimulation of the
type described — whether sensory,! as in pain,
whether of the nature of emotional excitement, or
of the nature of asphyxia — increases the secretion
of adrenaline.

Stewart and Rogoff's criticism. — As we shall
again refer to Professor Stewart's work, we need
only mention here one or two points that bear
directly on the technique employed. In a critical
review of Cannon's catheter method, Stewart and
Kogoff point out that the results obtained by it are
only valid if the blood flow is assumed to be con-
stant during the whole experimental period, and
the method does not permit any judgment on that
point. If in the course of an experiment the rate
of blood flow over a particular region varies, then
the samples taken at various intervals are not
strictly comparable. They maintain that the secre-
tion of adrenaline is not influenced by reflex stimu-

166 GLANDS IN HEALTH AND DISEASE

lation, and that the only way in which the experi-
ment would indicate an increased concentration of
adrenaline in the blood is if the blood flow through
the adrenal vessels were retarded.

The denervated heart as an indicator of adrenal
secretion. — In this method instead of removing
blood from the body, the denervated heart is used
to demonstrate an increase of adrenaline in the
blood. "In a cat under urethane, with vagi (nerves
of sensation and motion) cut and stellate ganglia
(referring to nervous matter) excised, stimulation
of the central end of the cut sciatic will cause the
heart rate to increase in some instances as much as
50 beats per minute. . . . The completely dener-
vated heart can be used as an indicator of adrenal
secretion in testing the influence of emotional ex-
citement quite as well as in testing the influence of
sensory stimulation and asphyxia.1 The results
obtained with the isolated heart used as an indi-
cator of adrenal secretion thus confirm in every

1 Again for the benefit of some readers certain details should
be added. To denervate the heart the stellate ganglia are first
removed under ether with aseptic precautions; later the right
vagus nerve is severed below the recurrent laryngeal branch; and
still later the left vagus nerve is cut in the neck. The heart is
thus wholly disconnected from the central nervous system, and
any agency causing an increase in the heart rate must exert its
influence through the blood stream. With the adrenal glands
normally innervated the rate was 217 per minute when the animal
was calm, and 255 when excited. After the adrenal glands were
removed the rate when calm was 217 and when excited 221, — an
inappreciable difference.

THE NEEVOUS SYSTEM 167

respect the results obtained eight years ago (1911)
by the catheter method." (Cannon.)

Professor Stewart objects again. — One would ex-
pect an increased rate of the denervated heart,
writes Professor Stewart, when the central end of
the sciatic or the peripheral of the splanchnic nerve
is stimulated, for "it is obviously dependent upon
the better flow through the coronary vessels'' ; and
the increased rate of blood flow through the de-
nervated heart increases the amount of adrenaline
passing a given area in unit time. He objects to
the use of any organ in the body as an indicator of
adrenal secretion when asphyxia is employed as
a stimulus, "because asphyxia may be expected to
alter the reactivity of the test object to adrenaline,
making it, for example, more sensitive." "We never
supposed/' he continues, "that it was possible to
use in one observation an asphyxiated test object
and in the comparison observation the same object
with unobstructed respiration, or to assume that
if there was any difference in reactions, it must be
due to a difference in the rate of output of adrena-
line; the conditions of the test object itself being
of no moment."

When two such redoubtable adversaries as Can-
non and Stewart appear in the field, it is not to be
expected that either the one or the other can hope
for a quick, decisive victory. Both are masters in

168 GLANDS IN HEALTH AND DISEASE

the field of experimental physiology, and both are
thinkers untrammelled by any standardized meth-
ods of thought. For every "no" of Stewart, Cannon
finds a "yes." To-day as little as ever before is
Cannon disposed to agree with his colleague that
the adrenal effects may be accounted for on the
basis of greater flow, or of altered distribution of
the blood. Cannon hits back with the same weap-
ons that Stewart employs: he does not question
the results but he does question the methods. "The
work of Stewart and Kogoff was admirably quanti-
tative in character, but it was done under experi-
mental conditions which could not afford informa-
tion regarding the normal secretion of the adrenal
glands or the natural conditions which affect that
secretion. This conclusion applies to all inferences
as to the nature of adrenal activity which they
have based upon the employment of the pocket

method.1

t

JThe "pocket" refers to a pocket in the inferior vena cava.
The pocket was made by opening the abdominal cavity, clamping
the vena cava immediately above the iliacs, then clamping the
renal veins, emptying the cava segments by stripping it upwards,
and placing a clamp on the vessel above the entrance of the
lumbo-adrenal veins. Any small branches of the cava segment
were tied. The pocket thus formed was allowed to fill with
blood from the adrenal veins, and the blood was either allowed
to pass into the general circulation by removal of the clamp of
the inferior vena cava, or was withdrawn and tested outside the
body on preparations of rabbit uterus and intestine.

Professor Cannon's comment is characteristic: "Either be-
cause the opening of the abdomen produces a secretion unsur-
passable by reflex stimulation, or because that operation abolishes
abdominal reflexes, the influence of sensory stimulation on the

THE NERVOUS SYSTEM 169

Professor Cannon's views as to the function of
adrenaline. — This brings us to Cannon's "emer-
gency theory." In times of stress — as when a per-
son suffers pain, or is in an agitated state of mind
— a chemical factor, in the shape of adrenaline,
cooperates with nervous factors in an attempt to
meet the emergency and not be overcome by it.
That is why, according to Cannon, we find an in-
creased output of adrenaline in times of stress.

But we must be careful not to misinterpret this
view of Cannon's. "The concept of an emotion
may be expressed either in psychological terms of
subjective experience or in physiological terms of
bodily change. Adrenal secretion is not essential
to the subjective experience of strong emotion.
Adrenaline has its effect peripherally, on outlying
viscera. An assumption that subjective feeling de-
pends on circulating adrenaline involves support-
ing the view that emotion as a psychological state
is the consequence of visceral changes. I have, in
fact, definitely argued against this view. If the
critics of the emergency theory conceive emotion
as bodily change, they will find in Cannon's con-
sideration of the interrelations of emotions the
point emphasized that it is the sympathetic division

adrenal glands is not manifested. There is little wonder, there-
fore, that Stewart and Rogoff, who alone have employed the
pocket method, with its attendant severe abdominal operation
and repeated manipulation of the abdominal contents, failed to
obtain the positive results which have been obtained by all other
observers."

170 GLANDS IN HEALTH AND DISEASE

of the autonomic system which is the primary
'agency in mobilizing the bodily forces in times of
great fear or rage. . . . These suggestions imply
coordination of chemical and nervous factors, but
not a dependence of the nervous factors on the
chemical."

Professor Cannon's book. — Under "Bibliography"
towards the end of the book I shall include suffi-
cient references to Cannon's papers so that the
reader who desires it may get inspiration from the
original source; but I cannot resist the temptation
of dwelling, if only for a minute or two, on his
book, "Bodily Changes in Pain, Hunger, Fear and
Kage," a sequel to an earlier and no less celebrated
volume, "The Mechanical Factors in Digestion."
It is a record of an attempt to investigate certain
psychological reactions — some of which have al-
ready been discussed in these pages — by means of
recognized methods in experimental physiology.
The writer is strongly convinced that the great ad-
vances in psychology are not to be expected so
much from the psychologist who is an arm-chair
philosopher or who dabbles in "efficiency" tests, as
from those men whose training has been in the ex-
perimental sciences primarily, — in chemistry,
physics and biology. I do not of course mean that
the philosopher has no contribution to make ; I do
not belong to the ultra-scientific school which takes
it for granted that it, and it alone, can lay claim to

THE NEKVOUS SYSTEM 171

the mantle of glory and achievement; but, com-
paratively speaking, I think that the physiologist
who investigates psychological phenomena has
more to offer us than the metaphysical speculator
who turns psychologist.

In the early portion of the book we are intro-
duced to the physiological methods for determining
adrenaline, and are then shown that emotional
excitement gives rise to adrenaline in the blood in
amounts sufficient to be detected, though the
amounts may be less than a few parts per million.
One of the experiments dealing with emotional
excitement is to bring a dog and cat near one an-
other. The cat exposed to the barks of the dog
shows an increased adrenaline output.

The fact that injection of adrenaline into the
body of an animal gives rise to a glycosuria, or an
increase of sugar in the urine (a form of what is
commonly called "diabetes"), and the fact that
emotional excitement induces an increased output
of adrenaline, leads directly to the next step : can
glycosuria be called forth by emotional excite-
ment? Cannon finds that it can. One experiment
is of exceptional interest. Of 25 members of the
Harvard University football squad whose urine
was examined immediately after a most exciting
contest during the season of 1913, 12 showed sugar.
After a day or two, — after a complete rest, that is —
the sugar disappeared completely.

GLANDS IN HEALTH AND DISEASE

Of what value are the sugar and the adrenaline
that are poured into the blood during emotional
excitement? We have already indicated the an-
swer in several portions of the book. Let Professor
Cannon speak. "The adrenaline plays an essential
r61e in calling forth stored carbohydrate from the
liver, thus flooding the blood with sugar. . . .
Since the fear emotion and the anger emotion are,
in wild life, likely to be followed by activities (run-
ning or fighting) which require contraction of
great muscular masses in supreme and prolonged
struggle, a mobilization of sugar in the blood might
be of signal service to the laboring muscles. . . .
Adrenaline helps in distributing the blood to the
heart, lungs, central nervous system and limbs,
while taking it away from the inhibited organs of
the abdomen; it quickly abolishes the effects of
muscular fatigue; and it renders the blood more
readily coagulable. These remarkable facts are,
furthermore, associated with some of the most
primitive experiences in the life of the higher or-
ganisms, experiences common to all, both man and
beast — the elemental experiences of pain and fear
and rage that come suddenly in critical emergen-
cies."

In connection with these investigations, Cannon
discusses and connects the excitements and ener-
gies of competitive sport; the frenzy and endurance

THE NERVOUS SYSTEM 173

in ceremonial and other dances ; and the fierce emo-
tions and struggles in battle.

The latter portion of the book is devoted to the
nature of hunger, which has roots similar to those
of fear and anger. Hunger is shown to be the direct
result of contractions of the alimentary canal, a
fact amply verified by the elaborate researches of
.Professor Carlson, of the University of Chicago.
That in fever hunger should be absent seems logical
because "infection, with systemic involvement, is
accompanied by a total cessation of all movements
of the alimentary canal. Boldireff observed that
when his dogs were fatigued the rhythmic contrac-
tions failed to appear. Being 'too tired to eatf is
therefore given a rational explanation."

The closing chapter of the book pleads for moral
substitutes for warfare. The key to Cannon's
views is presented through the medium of William
James who, in proposing a moral equivalent for
war, wrote: "We must make new energies and
hardihoods continue the manliness to which the
military mind so faithfully clings. Martial virtues
must be the enduring cement; intrepidity, con-
tempt of softness, surrender of private interest,
obedience to command, must still remain the rock
upon which states are built. . . . The martial type
of character can be bred without war. Strenuous
honor and disinterestedness abound elsewhere.

174 GLANDS IN HEALTH AND DISEASE

Priests and medical men are in a fashion educated
to it, and we should all feel some degree of it im-
perative if we were conscious of our work as an
obligatory service to the state. We should be
owned, as soldiers are by the army, and our pride
would rise accordingly. We could be poor, then,
without humiliation, as army officers now are.
The only thing needed henceforth is to inflame the
civic temper as past history has inflamed the mili-
tary temper."

It is ten years since James wrote these words,
and during those years much has happened to make
this advice even more imperative. Neither the vic-
torious Peace of Versailles, nor yet the Washington
Conference for the Limitation of Armaments, holds
out immediate relief from military dominance.
One wonders what kind of calamity the gods can
send us so that we may be awakened before the
Great Flood sweeps us forever from off this globe.

Dr. Crile's researches. — Dr. Crile, the famous
Cleveland surgeon, has advanced a theory regarding
shock and exhaustion which deserves treatment in
this chapter for two reasons: first, because in his
theory the adrenals play an active part; and sec-
ondly because of the success he has had in the clini-
cal application of his theory.

Shock — of which the varieties of shell-shock de-
scribed during the late war are types — is character-
ized by a loss, to a large extent, of deliberate ac-

THE NERVOUS SYSTEM 175

tion. "The man in acute shock or exhaustion,"
writes Crile, "is able to see danger, but lacks the
normal muscular power to escape from it ; his tem-
perature may be subnormal but he lacks the nor-
mal power to create heat ; he understands words but
lacks the normal power of response." He cannot
transform potential into kinetic energy. Herein
lies the key to the situation. We also see why Crile
talks of the "kinetic theory of shock."

Let us dwell on this "kinetic theory" for a min-
ute. Various stimuli arouse various associations;
the latter may be of the nod or injurious type, or
the bene or beneficial type. "All of life is made up
of bene- and noci-associations, and the constant
effort of the race and the individual is to increase
the former and decrease the latter, to develop an
environment which shall be as free as possible from
noci-associations, — to reach a state of anoci-associa-
tion" Anoci-associaMon is the title given to one
of Dr. Crile' s very suggestive books. In it he shows
how the percentage of successful surgical cases
may be increased by a treatment which applies the
principles of anoci-association before, during and
after the operation.

"The difference between normal processes and
shock is that of intensity, not of kind. From these
premises it becomes obvious that the exclusion of
both traumatic and emotional stimuli will wholly
prevent the shock of surgical operations." To ac-

176 GLANDS IN HEALTH AND DISEASE

complish the desired result, the conditions which
produced the shock are ameliorated or eliminated,
and the circulation is supported. For the details
the reader must be referred to the book. One fur-
ther quotation must suffice. "By an assuring pre-
operative treatment; by the definite dulling of the
nerves through the administration of a narcotic;
by a non-suffocating odorless anesthetic ; by a local
anesthetic to cut off all afferent impulses during
the course of the operation ; by a second local anes-
thetic of lasting effect to protect the patient during
the painful postoperative hours ; by gentle manipu-
lation and sharp dissection, — by the combination of
all these methods — the patient is protected from
damage from every factor excepting those which
exist in the diseased condition from which relief
is sought." *

*How successful this method is may be gauged from the fact
that Dr. Crile can operate on a patient suffering from exophthal-
mic goiter without materially increasing his pulse rate. "It was
in large measure the study of the preoperative and postoperative
course of cases of Graves's disease which led to the enunciation
of the kinetic theory of shock and the development of the shock-
less operation. ... By the extension of employment of anocia-
tion and asepsis, the mortality in the last 6,261 operations at
Lakeside Hospital (Cleveland) has been reduced to 1.6 per cent.
Our series have included 58 colostomies and resections of the
rectum and large intestine for cancer, with one death, and 70
resections of the stomach and gastro-enterostomies for cancer
and ulcer of the stomach, with one death. Anociation and
asepsis have made possible a series of 227 consecutive thyroid-
ectomies and 180 consecutive ligations, that is, 407 conseci5tive
thyroid operations for hyperthyroidism without a death. These
are not selected cases. No patient was rejected and many were
dying. Among the last 500 thyroidectomies, there have been five

THE NERVOUS SYSTEM 177

Man is surrounded by noci-associations, and he
is forever attempting to reach a state of anoci-asso-
ciation. An example of this is the attempt made by
a body when infected to produce an anti-toxin.
Under certain conditions — as a result of fear,
worry, physical injury, infection, hemorrhage, ex-
cessive muscular exertion, starvation, insomnia —
an excessive amount of energy, stored in the form
of potential energy, is discharged; this "excessive
conversion of potential into kinetic energy in re-
sponse to adequate stimuli" leads to shock. Such
is the "kinetic theory of shock," which further
states that the lesions of shock are to be found in
the cells of the brain, in the liver, and — what inter-
ests us most in this chapter — in the adrenals.

"In our laboratory," writes Dr. Crile, "we found
cytologic changes in the adrenals in exhaustion
from any cause, including insomnia ; these changes
being more marked in the cortex than in the me-
dulla. Apparently adrenaline alone can cause the
brain greatly to increase its work. By cross-circu-
lation experiments, we have found that adrenaline
causes increased activity of the central vasomoter
mechanism. Not only can adrenaline, as Cannon
has shown, cause all the basic phenomena of exer-
tion, emotion, infection, etc., but it also causes
brain cell lesions identical with those produced by

deaths, a mortality rate of one per cent., and among the last 500
ligations, two deaths."

178 GLANDS IN HEALTH AND DISEASE

exertion, emotion, infection, etc. . . . The injection
of adrenaline causes an immediate increase in the
conductivity of the brain to above normal, followed
by a later decrease to below the normal; more-
over, adrenaline causes an immediate increase in
the temperature of the brain, as evidenced by
thermo-couple measurements."

The work of Drs. Steivart and Rogoff. — In dis-
cussing Dr. Cannon's work we have also referred,
a number of times, to that of Drs. Stewart and
Rogoff, if only because the latter two are equally
eminent authorities, and mainly because they com-
bat much of what Cannon has to say. The nature
of this work and the limitations of space will pre-
vent us from giving details, but the reader who is
interested may refer to the list of references to their
work that is included in the bibliography.

Adrenaline is the big theme. Is there or is there
not an increase of this substance when an animal is
emotionally aroused? We have already suggested
that Stewart's answer is in the negative, and that
he explains Cannon's positive results by finding
fault with the method employed, and with the way
in which the results were interpreted.

It will also be remembered that Cannon makes
much of the fact that not only does adrenaline give
rise to a hyperglycemia, but — what might be ex-
pected if what Cannon asserts is true — so do the
emotions when aroused sufficiently; for, according

THE NERVOUS SYSTEM 179

to Cannon, the emotions arouse the adrenals to
particular activity, an increased quantity of adrena-
line then appears in the blood, and this in turn
interferes with normal carbohydrate metabolism
to such an extent that an abnormal quantity of
sugar finds its way into the blood, giving rise to
hyperglycemia.

"We have recently," write Drs. Stewart and
Kogoff, "studied the question whether adrenaline
secretion of the adrenals is indispensable for the
production of certain experimental hyperglycemias.
The majority of previous investigations have suf-
fered from the defect that they were carried out,
if not on practically moribund animals, at least on
animals still under the effects of a serious opera-
tion. This undoubtedly is the chief reason for the
astonishing lack of uniformity in the results.
Working with animals (cats) in which the adrena-
line secretion was abolished or reduced to an in-
significant fraction of the normal by removal of
one adrenal and section of the nerves of the other
(an operation which does not preclude the contin-
ued life of the animal in good health), we were
able to show that two forms of experimental hyper-
glycemia— that produced by ether and that pro-
duced by asphyxia — are as readily obtained in the
absence of adrenaline secretion as when the adre-
nals have not been interfered with." What, then,
have the adrenals got to do with hyperglycemia?

180 GLANDS IN HEALTH AND DISEASE

Neither have Drs. Stewart and Kogoff less sharp
criticism to offer with regard to the alleged con-
nection of adrenaline with the condition known as
"shock," a subject we have discussed in the last few
pages. "A large though quite undeserved place has
been occupied in clinical literature of shock and
allied conditions by adrenal insufficiency, or one
or other of its aliases. There is no evidence that
any notable change occurs in the adrenaline output
in either direction." The experimental methods of
producing shock in dogs and cats — by exposing and
manipulating the intestines, by partial occlusion of
the inferior vena cava, by hemorrhage and by "pep-
tone" injection — led to a permanent lowering of
blood pressure ; but the rate of output of adrenaline
after the blood pressure had been permanently
lowered was found to be the same as before the
lowering of the blood pressure, "within the limits
of error of the methods used for assaying the
adrenaline."

Professor Stewart's caustic pen hits at the
"clinical endocrinologist" even more than at the
experimental physiologist. He writes : "In reading
the papers by 'clinical endocrinologists/ especially
the French and Italians, the physiologist can
scarcely escape the feeling that here he has broken
through into an uncanny fourth dimension of medi-
cine, where the familiar canons and methods of
scientific criticism are become foolishness, where

THE NERVOUS SYSTEM 181

fact and hypothesis are habitually confounded,
and 'nothing is but what is not.' ?

Such criticisms, coming from a critic whose aim
is to create rather than to destroy, are of the utmost
value to the progress of the science. It deserves
prominent place in a book such as this, where the
attempt is made never to confound fact with
fancy.1

The sexual glands and the nervous system. — That
the sexual glands and the nervous system are
closely related is only too obvious from the many
studies on the sex problem, and by the more direct
method of castration in animals and men. Much
of all this has already been discussed in another
chapter (page 94). Less pronounced connections
between the glands and the nervous mechanism are
noticeable in diseases of the pituitary and the para-
thyroids.

*I have just (December, 1921) returned from the annual meet-
ing of the Federation of American Societies for Experimental
Biology, held this year at Yale University. These meetings were
much enlivened by papers by Stewart and Cannon. Both are not
only first-class scholars but excellent debaters, and their annual
tilts are eagerly looked forward to. This eagerness on the part
of the onlookers to enjoy the fun brought forward this remark
from Dr. Stewart: "We are not waiting for Dr. Cannon to say
something and then to jump at him; we merely seek the truth,
just as I know he does." This but brought laughter and knowing
looks. Dr. Carlson, the Chicago physiologist, whose sympathies
are evidently more with Stewart than with Cannon, brought
down the house with this remark: "I am glad to find that
Cannon no longer pins his faith to the adrenals alone; for that
he and the Society are to be congratulated on a return to
'normalcy.' "

182 GLANDS IN HEALTH AND DISEASE

Psycho-analysis. — It would be strange that in
the treatment of those most complex of phenomena
that group themselves under mental disorders, con-
flicts should not arise between the enthusiastic en-
docrinologist and the Freudian disciple; the one
with his eye to the ductless glands as the source of
much evil, and the other with his emphasis on the
repression of the emotions. Professor Gushing, in
an article on "Psychic disturbances associated with
disorders of the ductless glands," leans towards
the former school, though he is not blind to the
merits of psycho-analysis. He writes : "The vari-
ous neuroses (nerve diseases) and asthenias (loss
of strength) may result primarily as the result of
some disturbance of internal secretion which paves
the way for the dreams, symbolisms and other
manifestations dissected by the psycho-analyst.
... It is quite probable that the psycho-pathology
of every-day life hinges largely upon the effect of
ductless gland discharges upon the nervous system.
This is particularly worthy of consideration in the
study of child psychology in its relation to puberty
and adolescence, especially in those individuals in
which there is some underlying, possibly inherited,
/ functional deviation in the chemistry of the inter-
nal secretion. . . ."

Shell-shoclc.-^-This brings us to the last phase
of our subject, that of shell-shock. ( The reader is
advised to re-read Dr. Crile's views on shock, page

THE NERVOUS SYSTEM 183

174.) We may perhaps preface our remarks by
saying that the strenuous life led by the individual
in the city, especially by the "hustler/' and espe-
cially by the "hustler" with a weak resistive ca-
pacity, may cause a nervous breakdown which is
not far removed from shell-shock. Again we must
refer the reader to Dr. Crile.

Shell-shock

I _

I I. I

Transitory symptoms Concussions Psycho-neuroses

Death Organic affection Functional affection

I I I

Hysteria Psychasthenia Neurasthenia

Ductless glandular disturbance

I I I

Hyper-adrenalism Disfunction of sex glands Hyperthyroidism

Shell-shock has been defined as "the condition
which follows exposure to the forces generated by
the explosion of powerful shells in the absence of
any visible injury to the head or spine." It may
result in a speedy recovery, in a definite concussion,
or in the appearance of symptoms of the psycho-

184 GLANDS IN HEALTH AND DISEASE

it
nettroses. If either of the latter two symptoms

makes its appearance, it may be in connection
with a disturbance of one or more of the ductless
glands.1 Dr. Cobb has drawn up an attractive
classification which is given above.

The classification of nervous disorders is due to
Beard, Charcot, Mobius and Janet. Janet divided
psycho-neuroses as shown in the table. "Hysteria"
represents a typical mental disintegration, whereby
there is a splitting of mental processes, so that two
separate and unconnected streams exist in the mind
(for example, anesthenia, amnesia [loss of mem-
ory], paralysis) ; "psychasthenia" refers to cases
characterized by phobias (persistent insane dread
or fear), hesitations, doubts, anxieties; while
"neurasthenia" refers to cases showing a prepon-
derance of symptoms referable to physical exhaus-
tion (fatigue, indigestion, disturbances of excre-
tion, etc.).

1Clemence Dane, the author of "A Bill of Divorcement," now
playing in New York, has drawn a powerful and moving picture
of the shell-shocked soldier. Allan Pollock, who interprets the
part, was himself through this living hell. The interpretation is
a triumph of the actor's skill.

CHAPTER XIII

ORGANOTHERAPY

The treatment of ductless glandular diseases by
means of extracts of appropriate glands dates back
to Brown-Sequard's investigations in 1889, and
Brown-Sequard merely revived the old "humoral"
view of disease. Hippocrates advocated the efficacy
of various organs, and Hahnemann, the originator
of homeopathy, built up a subdivision of the sub-
ject, isopathy, which dealt with diseased organs,
and with their cure by the administration of fresh
organs. Is your liver out of joint? Then we will
prescribe the liver of a wolf. Have you a tremor?
The brain of a hare will put you on your feet again.
Are you a sufferer from dyspepsia? Take the lung
of a fox and you will get well. Is your stomach
misbehaving? Take rennin.

The "humoral" philosophy throve, made many
converts, did some good and very much mischief,
and gradually died out. Brown-Sequard brought it
to light again; but, let us add, in quite a modern
form, and with reasons for its revival drawn from
the knowledge of the nineteenth and not the ninth

185

7?

186 GLANDS IN HEALTH AND DISEASE

century. One may truly say of him that he is the
founder of the conception of ductless glandular
function as we understand it to-day.

Poor Brown-Sequard! In glorious company
with other ill-received or unrecognized geniuses, he
became the laughing-stock of scientific Paris. He
described to his audience how he had administered
to himself testicular extracts, and how, as a result
of this administration, his vigor and youthful de-
sires and appetites had returned. (In 1889 when
this announcement was made Brown-Sequard was
70 years old.) The Academy laughed, and Paris
and the other capitals of Europe made the most of
a sensational piece of news.

Was there any foundation for Brown- Sequard's
claim? From what we know to-day, not very much.
Not even the most enthusiastic exponents of "reju-
venation" by means of the sexual glands advocate
such a procedure.

If the use of testicular extract proved discourag-
ing, it did not prevent the use of extracts from
other glands that produce an internal secretion.
And then came the truly remarkable discovery that
in myxedema and cretinism, examples of hypothy-
roidism, the administration of thyroid extracts
brought cures — cures that lasted, to be sure, only
so long as treatment with the extract was contin-
ued. This discovery made those who had scoffed
at Brown-Sequard revise their opinion of that illus-

OEGANOTHEEAPY 187

trious Frenchman. A new impetus was given the
subject, and glandular treatment became the hope
of a world full of maladies.

Despite an enormous amount of work, it cannot
be said that we have accomplished much with glan-
dular extracts beyond their use in thyroid disease.
Pituitary extracts have had a measure of success
in pituitary disorders, but not comparable to the
corresponding extract from the thyroid when ap-
plied to cases of hypo-thyroidism.

With a persistence worthy of some admiration,
glandular advocates, failing to get results with any
one extract, tried each one of the others in turn.
Still without result, they adopted pluriglandular
treatment — that is to say, treatment by the use of
extracts from several glands. It cannot be said
that these methods yielded any better results.

Now the question may very naturally be asked,
why should thyroid extract be of service in hypo-
thyroidism, and why should extracts from other
glands be of so little service in other diseases due
to glandular insufficiency? We do not know,
though we can speculate as to the cause. Are we
to assume that only the thyroid hormone is resistive
enough to escape all dangers and reach its desti-
nation safely, whereas other hormones are de-
stroyed on the way? 1 This is not a likely hypothe-

1 "No assumption is needed in this case any longer, because we
now know that thyroxin is of a very different nature from any

188 GLANDS IN HEALTH AND DISEASE

sis, for even injecting directly into the blood —
the path along which the hormones travel — does not
materially improve matters. Or perhaps extracts
other than the thyroid contain substances in addi-
tion to the liormones that are in themselves inju-
rious to the system. Unfortunately for this theory,
we know that adrenaline, 100 per cent, pure, repre-
senting the adrenal hormone, does not cure Addi-
son's disease, a disease of the adrenals. Of course
it may be said with much force that adrenaline is
the hormone of but one portion of the adrenals, the
medulla, and that the hormone of the cortex of the
gland has not yet been isolated ; so that until this

other of the constituents of the ductless glands. We know that
it does not vary in its amount in the tissues except in a minor
degree, that it is constantly supplied and that any single portion
of it functions for as long as seven weeks after administration
or after the gland manufactures it ; that is, it acts as a catalyst,
and it does not come under your definition of a hormone. It
acts in a manner to increase the rate of oxidation within the
tissues, and we can now picture the chemical changes occurring
which permit thyroxin to function as a catalytic agent. None of
the active constituents of the other ductless glands acts in this
way in respect to time. Adrenaline does undoubtedly act as a
catalyst, increasing the rate of oxidation within the cells, but it
functions for a very short period of time. That, to my mind,
is the explanation of why the adrenal and the hypophysis are so
closely related to the nervous system. They are strictly emer-
gency glands and their output must be increased and decreased
on demand. They function for a brief interval and that is why
it is impossible to administer them successfully, because only
relatively massive doses are given, interspersed with periods of
zero administration. Thyroxin is just the reverse of this. It
does not function immediately and lasts for as long as five to
seven weeks, so that it is not only unique among the glands for
therapeutic purposes, but it is unique in its chemical proper-
ties." (E. C. Kendall.)

ORGANOTHERAPY

is done, and until the pure hormones from both
parts of the gland are used, it would be premature
to draw any conclusions.

Perhaps the .most plausible suggestion so far ad-
vanced is that in the preparation of a glandular
extract, involving physical and chemical processes,
the chemical configuration of the hormone is pos-
sibly altered, and hence its physiological action be-
comes lost. To point to the thyroid extract as dis-
proving this hypothesis does not hold, for the an-
swer may be made that there is no reason to sup-
pose that all the hormones have the same degree
of resistive power. The antiscorbutic vitamine is
more easily destroyed than the antirachitic ; why
may this not be true of hormones as well? Why
may not one hormone fall a prey to chemical
agents more quickly than another?

Unquestionably the next step in our forward
march will be the isolation, in a pure form, of the
hormones from the pituitary, the cortex of the adre-
nals, the sexual glands, etc. Until this is done we
can hope little more from glandular treatment than
what has already been accomplished.1

»At the recent (Dec., 1921) meeting of the Physiological So-
ciety, held in New Haven, Professor Macleod, of the University
of Toronto, read a paper on the value of pancreatic extracts, in
which he pointed out that the blood sugar of a depancreatized
dog could be lowered by injecting a pancreatic extract, and that
neither an extract of the liver nor one of the spleen had that
effect. Though preliminary in character, the investigation i&
important and suggestive.

CHAPTER XIV

PLANT HORMONES

The work of Professor Bottomley, of the Uni-
versity of London, has made it very probable that
vitamines play an important part in the plant, as
well as in the animal kingdom. He has even pre-
sented some very good evidence to show that the
vitamines found in the animal world can 'be traced
to vegetable sources; that though the animal needs
vitamine, yet it cannot synthesize it, but must rely
on this synthesis being accomplished by plant cells.
This work of Bottomley's has been amply confirmed
in many quarters.

Similar problems present themselves when deal-
ing with hormones. In the first place, are there
plant hormones that are activators in the sense
that the animal hormones are? And is it possible
that the hormones in our body are synthesized in
the plant, rather than in the animal kingdom?

The second question will be disposed of first.
We know that glands are factory centers of the
body. We know that the gland has the power of
taking various materials from the blood, and con-

190

PLANT HORMONES 191

verting them into an entirely new product, or prod-
ucts. The essential product of a ductless gland is
its hormone — at least, that is the supposition — and
this is probably manufactured by the gland. The
indirect proof we have for this statement is that
under normal conditions the hormones in the
body are sufficient in amount, or sufficiently active,
to perform their specific functions; and it is only
when a pathological condition sets in that the
hormonic function is disturbed.

You may say that this is not very convincing.
You may claim that under normal conditions the
gland has the power of removing the hormone from
the blood, and that it no longer has such power
under pathological conditions. This objection can,
I think, be met with in this way: If we examine
the constitutional formula for adrenaline, a hor-
mone in the adrenals, or of thyroxin, a hormone
in the thyroid gland, we shall see that no food
we eat contains any such substance. We do,
however, find that their formulas show them to be
closely related to certain substances that are in-
cluded in our diet — or at least, are formed in the
digestive tract as a result of the food we eat. For
example, the amino-acid tryptophane1 shows cer-
tain resemblances to thyroxin; hence the opinion
that one of the possible reasons why tryptophane is

1 See the chapter on Amino-Acids in the author's book on
Vitamines.

192 GLANDS IN HEALTH AND DISEASE

an essential acid is that the body needs it for the
manufacture of thyroxin; though so far as I know
no one has as yet shown that an increase of trypto-
phane in our diet increases the quantity of thyroxin
in the body.

Now as to the next question: are there plant
hormones? And if so, do they play a part in the
plant kingdom analogous to that played by hor-
mones in the animal kingdom? Let us quote Pro-
fessor Bayliss on this point:

"Although there is no such effective way of
chemical interchange in plants as there is in the
circulating blood of animals, there is distinct evi-
dence that chemical products of one part are able
to influence the activities of other parts. The lat-
eral roots, which normally grow horizontally, can
be made to grow vertically downwards if the main
root is removed. Errera investigated, in pines, the
corresponding change of direction of growth of a
branch into a vertical stem when the apical bud
of the main stem is removed. He suggested that
the apical bud of the main stem forms some kind
of internal secretion, which prevents the upward
growth of the lateral shoots as long as this apical
bud is present.

"Keeble considers that such 'chemical stimu-
lators' play a part in the transfer of activity of
localized cambium cells to others in their neighbor-

PLANT HOEMONES 193

hood. In the case of Convoluta, Roscoffensis, the
signal for the commencement of the later phases
of development owes its origin to the presence of the
green algal cells, without whose concurrence, prob-
ably by the production of a hormone, no kind of
artificial feeding has been found effective.

"Mention may also be made of the substance ex-
tracted by rain from grass, which has been shown
by Pickering to be injurious to apple trees. They
should not, in fact, be surrounded by growing grass,
as is common in orchards."

We know that a number of ethereal salts, or, as
the chemist calls them, "esters," act as accelerators,
in the sense of hastening the flowering of plants and
the ripening of fruits ; and we know further that the
essential oils present in plants are largely made up
of such "esters." As to whether these essential
oils are manufactured by glands similar to those
existing in the animal kingdom, and as to whether
there is any interrelationship between such glands,
cannot, at present, be answered. It is supposed
that these "esters," and substances other than
"esters" that act like accelerators, stimulate en-
zyme (ferment) action in the plant, particularly in
the later stages of its development. On this basis
the many color changes that take place during the
ripening period, the autumnal color of leaves, and
the dropping of the leaves from the stem of the

194 GLANDS IN HEALTH AND DISEASE

plant, have been explained ; but all this is, at pres-
ent, largely fancy and little more.1

1 Mention may here be made of a more direct experiment by
Dr. Budington, of Oberlin College. He experimented with sound
onion bulbs which were placed in a nutrient solution to which
small quantities of glandular extracts — from the thyroid, the
adrenal and the pituitary — were added. A certain amount of
"retardation" in the growth of root tips when thyroid extract
was used, and marked modifications of growth when iodine in
the form of potassium iodide was used, were obtained. "While
no general conclusion can be based on experiments limited to a
single form, the indication is that thyroid constituents — and it
will be remembered that iodine is such a constituent — may in-
fluence the role of protoplasmic action in cells other than those
of animal tissues."

REFERENCES

REFERENCES

GENERAL. There are a number of books dealing with
the glands of internal secretion. A standard work is that
by A. Biedl: The Interned Secretory Organs (William
Wood & Co., New York) . More than 100 of the 600 pages
are devoted to references to the original literature. An-
other excellent work is S. Vincent's Internal Secretion and
the Ductless Glands (Edward Arnold, London). C. E.
de M. Sajous' The Internal Secretions and the Principles
of Medicine (F. A. Davies Co., Philadelphia) is an am-
bitious work in two volumes. E. A. Schafer, the Edin-
burgh physiologist, is the author of The Endocrine Organs
(Longmans, Green & Co., London), which emphasizes the
physiological rather than the clinical point of view. On
the other hand, W. Falta's The Ductless Glandular Dis-
eases (P. Blakiston's Son & Co., Philadelphia) is wholly
clinical. D. Noel Paton in The Nervous and Chemical
Regulators of the Body (Macmillan & Co., London) em-
phasizes chemical factors. For those having a reading
knowledge of German, A. Weil's Die Innere SeTcretiori
(Julius Springer, Berlin) may be recommended, since it
is both authoritative and up-to-date. A very good histori-
cal development is given by E. Gley in The Internal Secre-
tions (Paul B. Hoeber, New York; translated from the
French by Maurice Fishberg). A more recent book by
the same author, who is professor of physiology at the

197

198 GLANDS IN HEALTH AND DISEASE

College de France, may be suggested to those possessing
a working knowledge of the French language ; it is entitled
Quatre Legons des Secretions Internes (J. B. Balliere et
Fils, Paris). Other books dealing with internal secretions
are I. G. Cobb : The Organs of Internal Secretion (William
Wood & Co., New York) ; S. W. Bandler: The Endocrirws
(W. B. Saunders Co., Philadelphia); L. Berman: The
Glands Regulating Personality (Macmillan & Co.) ; and
H. R. Harrower: The Internal Secretions in Practical
Medicine (Chicago Medical Book Co., Chicago).

Among medical encyclopedias that include articles on
internal secretions, two may be mentioned because they
are recent productions. An article on ductless glands will
be found in volume 3 of The Oxford Medicine (Oxford
University Press, London), and another, in volume 3 of
The Nelson Loose-Leaf Living Medicine (Nelson & Co.,
New York).

Books dealing with various phases of medicine include
chapters on the ductless glands. Some of these are J. J. R.
Macleod: Physiology and Biochemistry in Modern Medi-
cine (C. V. Mosby, St. Louis) ; R. Burton-Opitz : A Text-
Book of Physiology (W. B. Saunders & Co., Philadelphia) ;
A. P. Mathews: Physiological Chemistry (William Wood
& Co., New York) ; L. Luciani: Human Physiology, vol-
ume 2 (Macmillan & Co., London) ; W. M. Bayliss: The
Principles of General Physiology (Longmans, Green & Co.,
London); W. H. Howell: A Text-Book of Physiology
.(W. B. Saunders & Co., Philadelphia) ; W. G. MacCallum:
'A Text-Book of Pathology (W. B. Saunders & Co., Phila-
delphia) ; W. Osier : The Principles and Practice of Medi-
cine (D. Appleton & Co., New York) ; E. H. Starling:

REFERENCES 199

Principles of Humari Physiology (Lea & Febiger, Phila-
delphia) ; G. N. Stewart : A Manual of Physiology (Wil-
liam Wood & Co., New York) ; M. Kahn : Functional
Diagnosis (W. F. Prior Co., Hagerstown, Maryland) ; and
H. G. Wells: Chemical Pathology (W. B. Saunders & Co.,
Philadelphia).

VITAMIKES Ain) HORMONES. The possible relationship
or identity of these two substances has been urged, more
particularly, by Voegtlen and Myers, and by Butcher
(American Journal of Physiology, volume 49, page 124,
1919; Journal of Pharmacology and Experimental Thera-
peutics, volume 13, page 301, 1919; and Journal of Bio-
logical Chemistry, volume 39, page 63, 1919). This the-
ory has met with opposition; see, for example, Anrep and
Drummond's paper on "The Supposed Identity of the
Water-Soluble Vitamine B and Secretin" (Journal of
Physiology, volume 54, page 249, 1921). A possible con-
nection between vitamine B and adrenaline has been sug-
gested by MacCarrison (see the Indian Journal of Medical
Research, volume 6, pages 275 and 550, 1919, and the
Proceedings of the Royal Society, section B, volume 91,
page 103, 1920). Kellaway's paper on "The Effect of
Certain Dietary Deficiencies on the Suprarenal Glands"
(Proceedings of the Royal Society, section B, volume 92,
page 6, 1921) should also be consulted.

THE THYROID. (See also the "general" references
above.) A number of books dealing more specifically with
this gland have been published. R. McCarrison's The
Thyroid in Health and Disease (Balliere, Tindall & Cox,

200 GLANDS IN HEALTH AND DISEASE

London) may be especially recommended. A. Crotti fe the
author of the Thyroid and the Thymus (Lea and Febiger,
Philadelphia). Other books are H. J. Ochsner: Surgery
and Pathology of the Thyroid and Parathyroid Glands
(C. V. Mosby, St. Louis) ; and H. Eichardson: The Thy-
roid and Parathyroid Glands (P. Blakiston's Son & Co.,
Philadelphia).

Kendall's work on the "Isolation of the Iodine Com-
pound Which Occurs in the Thyroid" will be found in the
Journal of Biological Chemistry, volume 39, page 125, and
volume 40, page 265, 1919. His lecture before the Harvey
Society ("The Chemistry of the Thyroid Secretion," the
Harvey Lectures, 1919-1920, published by J. B. Lippincott
Co., Philadelphia) was a fine historical review of the entire
work.

The subject of hyper-thyroidism has received consider-
able attention lately. In this connection the reader will
find in W. M. Boothby's article, "Adenoma of the Thyroid
with Hyper-thyroidism" (Endocrinology, volume 5, page 1,
1921), a very thorough discussion of the types of thyroid
disease, with references to the latest literature. H. R.
Harrower's booklet, Hyperthyroidism (Glendale, Califor-
nia), suffers from an over-enthusiastic treatment. The
favorable effects of surgical treatment coupled with
"physiologic rest" are advocated by C. W. Crile in "Surgery
Versus Roentgen Ray in the Treatment of Hyperthyroid-
ism" (Journal of the American Medical Association, vol-
ume 77, page 1324, 1921).

With regard to the subject of metamorphosis, a very
exhaustive review, with references to the original literature,
is given by J. F. Fulton in his article, "The Controlling

REFERENCES 201

Factors in Amphibian Metamorphosis" (Endocrinology,
volume 5, page 67, 1921). A shorter review is that by
L. T. Hogben (Science Progress, volume 15, page 303,
1920). Jacques Loeb's "Natural Death and the Duration
of Life," an article included in B. Harrow's Contemporary
Science (Boni & Liveright, New York), suggests many
fascinating possibilities.

How the determination of the basal metabolic rate helps
to diagnose the various types of thyroid disease is dis-
cussed by a number of physicians in a forthcoming volume,
Basal Metabolism (Sanborn Co., Boston). There are any
number of individual articles dealing with basal metab-
olism; only a few of these can be mentioned here. See, for
example, F. G. Benedict, Journal of the American Medical
Association, volume 77, page 247, 1921; J. H. Means,
Journal of the American Medical Association, volume 77,
page 347, 1921 ; W. M. Boothby, Journal of the American
Medical Association, volume 77, page 252, 1921; F. H.
Lahey, Boston Medical and Surgical Journal, volume 184>
page 348, 1921; J. R. Murlin, Science, volume 54, page
196, 1921; C. W. McCarthy, Journal of the American
Medical Association., volume 76, page 978, 1921. In vol-
ume 1 of the Oxford Loose-Leaf Medicine (Oxford Uni-
versity Press, London) will be found Du Bois' article on
"Clinical Calorimetry Methods of Study of Metabolism."

With regard to the prevention of simple goiter in man,
Marine, and his co-worker Kimball, are widely known for
such studies. Some of their papers are to be found in the
Journal of the American Medical Association., volume 77,
page 1068, 1921, and volume 73, page 1874, 1919 ; Ohio
State Journal, October, 1920 ; Archives of Internal Medi-

202 GLANDS IN HEALTH AND DISEASE

cinef volume 22, page 41, 1918, and volume 25, page 661,
1920; and Journal of Laboratory and Clinical Medicine,
volume 3, page 40, 1917. A suggestive article by E. K.
Hayhurst, entitled "The Present-Day Sources of Common
Salt In Kelation to Health and Especially to Iodine Scar-
city and Goiter'5 (Journal of the American Medical Asso-
ciation, volume 78, page 18, 1922), wherein it is urged that
"common salt for dietary purposes should include not only
sodium chloride but also sodium iodide," should be con-
sulted.

THE PARATHYROIDS. (See also the "general" references
above.) Two books that deal with the parathyroids as well
as with the thyroid have already been mentioned: H. J.
Ochsner: Surgery and Pathology of the Thyroid and Para-
thyroid Glands (C. V. Mosby, St. Louis), and H. Rich-
ardson: The Thyroid and Parathyroid Glands (P. Blakis-
ton's Son & Co., Philadelphia). An exhaustive account of
these glands, accompanied by a very complete bibliography,
may be found in W. M. Boothb/s "The Parathyroid
Glands" (Endocrinology, volume 5, page 403, 1921).
MacCallum and Voegtlin (Journal of Experimental Medi-
cine, volume 11, page 118, 1909) take up the question of
the relation of tetany to the parathyroid glands and to
calcium metabolism.

THE PITUITARY GLAND. (See also the "general" refer-
ences above.) The classical work in English is Harvey
Cushing's The Pituitary Body and Its Disorders (J. B.
Lippincott & Co., Philadelphia). W. Blair Bell is also the
author of a book on the pituitary (William Wood & Co.,

REFERENCES 203

New York). T. B. Robertson's work on the isolation of a
substance from the anterior lobe of the pituitary is set
forth in an article in Endocrinology (volume 1, page 24,
1917).

THE ADRENAL GLANDS. (See the "general" references
above, as well as the references listed under "the nervous
system and the ductless glands.") Fine critical articles are
those by Stewart and by Barker (Endocrinology, volume 5,
page 283, 1921, and volume 3, page 253, 1919). An ac-
count of the chemistry of adrenaline is given by Abel
(Johns Hopkins Hospital Bulletin, volume 9, page 215,
1898, and volume 12, page 80, 1901), Takamine (Ameri-
can Journal of Pharmacy, volume 73, page 523, 1901;
Journal of Physiology, volume 27, page xxix, 1901) and
Friedmann (Beitrdge zur chemische Physiologic, volume 8,
page 95, 1906). Bargees volume, The Simple Natural
Bases (Longmans, Green & Co., London) should also be
consulted.

THE ORGANS OF REPRODUCTION. (See also the "gen-
eral" references above.) A standard work is Marshall's
Physiology of Sex Reproduction (Longmans, Green &
Co., London). Steinach's book, Verjungung (Julius
Springer, Berlin), gives an excellent summary of the
author's researches. Phases of Steinach's work are
discussed in the Journal of the American Medical Asso-
ciation for Jan. 29, 1921 (page 348), Aug. 14, 1920
(page 490), Aug. 28, 1920 (page 617), Sept. 11, 1920
(page 755), and Dec. 25, 1920 (page 1811). Readers
with a knowledge of German may be referred to Stieve's

204 GLANDS IN HEALTH AND DISEASE

Entwicklung , Bau and Bedeutung der Keimdruesen-
zwischenzellen (development, structure and significance of
the interstitial cells of the gonads) (J. F. Bergman,
Munich) . Voronoff gives an account of his experiments in
the book entitled Life (E. P. Dutton & Co., New York).
An analysis of the behavior of organs after transplantation
is discussed by L. Loeb (Journal of Medical Research,
volume 39, page 189, 1918). An editorial in the Journal
of the American Medical Association (volume 75, page
1070, 1920) should also be consulted. J. S. Horsley is
the author of an instructive article on the "Suturing of
Blood Vessels" (Journal of the American Medical Asso-
ciation, volume 77, page 117, 1921).

THE PANCREAS AND THE LIVER. ( See also the "general"
references above.) There is a mass of literature on these
organs; we can refer to but one or two recent articles.
See, for example, E. P. Joslin: Diabetes Mellitus (Lea &
Febiger, Philadelphia); F. M. Allen: Diabetes Mellitus
(Physiatric Institute, Morristown, N. J.) ; E. P. Joslin:
"The Prevention of Diabetes Mellitus" (Journal of the
American Medical Association, volume 76, page 8, 1921),
wherein we find the cry that diabetes is a penalty for
obesity; J. J. E. Macleod: "The Sugars of the Blood"
(Physiological Reviews, volume 1, page 208, 1921), a
comprehensive review of the significance of blood sugar;
and E. Langfeld's series of articles on the significance of
a physico-chemical factor, the hydrogen ion content, in the
regulation of blood sugar (Journal of Biological Chem-
istry, volume 46, pages 381, 393, 403, 1921).

REFERENCES 205

THE INTESTINAL HORMONE. (See also the "general"
references above.) Two of the papers by Bayliss and Star-
ling are "The Mechanism of Pancreatic Secretion"
(Journal of Physiology, volume 28, page 325, 1902) and
"The Chemical Regulation of the Secretory Process"
(Proceedings of the Royal Society, section B, volume 73,
page 310, 1904). The books on physiology by Bayliss and
by Starling, referred to under "general" references, give
good accounts of the discovery and action of eecretin.

THE THYMUS, SPLEEN, MAMMARY GLAND, PINEAL AND
KIDNEY. (See the "general" references above.) Quite a
number of investigators are busying themselves with the
problem of the function of the thymus. See, for example,
J. A. Hammar (Endocrinology, volume 5, page 543, 1921),
E. Uhlenhuth (Endocrinology, volume 3, page 284, 1919),
and M. B. Gordon (Endocrinology, volume 2, page 405,
1919). "Is there a thymic hormone?" asks Hoskins (En-
docrinology, volume 2, page 241, 1918) ; he is inclined to
answer in the negative. See, also, Crotti's book, The
Thyroid and the Thy mm (Lea and Febiger, Philadelphia),
and an editorial in the Journal of the American Medical
Association (volume 77, page 2063, 1921).

N. B. Eddy (Endocrinology, volume 5, page 461, 1921)
reviews the functions of the spleen. Sir Berkeley Moyni-
ham (W. B. Saunders Co., Philadelphia), and Pearce,
Krumbhaar and Frazier (J. B. Lippincott Co., Philadel-
phia) are authors of books dealing with the spleen.

Two articles on the pineal, that also include the litera-
ture, are Horrax's "Studies on the Pineal Gland" (Ar-

206 GLANDS IN HEALTH AND DISEASE

chives of Internal Medicine, volume 17, page 607, 1916)1
and Bailly and Jeliffe's "Tumors of the Pineal Gland"
(Archives of Internal Medicine, volume 8, page 851, 1911).
See, also, W. E. Dandy's "The Treatment of Brain Tu-
mors" (Journal of the American Medical Association,
volume 77, page 1853, 1921). Tilney and Kiley's The
Form and Functions of the Central Nervous System
(P. B. Hoeber, New York) contains a mass of valuable
material.

THE KELATION OP THE DUCTLESS GLANI>S TO ONE
ANOTHER. (See also the "general" references above. )
Certain angles of this problem are taken up by Stewart
and Rogoff (American Journal of Physiology, volume 46,
page 90, 1918), and Anon. (Endocrinology, volume 1,
page 404, 1917).

THE INFLUENCE OF THE DUCTLESS GLANDS ON GROWTH
AND METABOLISM. (See the "general" references above.)'
Biedl discusses this question in an article entitled "The
Significance of the Internal Secretions in Disturbances of
Metabolism and Digestion" (Endocrinology, volume 5,
page 523, 1921).

THE NERVOUS SYSTEM: AND THE DUCTLESS GLANDS.
(See also the "general" references above.) A mass of
literature, much of it of a pseudo-scientific nature, has
accumulated on this phase of the subject. Only a few of
the books and pamphlets will be referred to. See, for ex-
ample, M. Laignel-Lavastine : The Internal Secretions and
the Nervous System (Nervous and Mental Disease Pub-

REFERENCES 207

lishing Co., New York) ; W. Langdon Brown: The Sympa-
thetic Nervous System in Disease (Oxford University
Press, London) ; W. B. Cannon : Bodily Changes in Pain,
Hunger, Fear and Rage (D. Appleton & Co., New York) ;
G-. W. Crile : A Physical Interpretation, of Shock, Exhaus-
tion and Restoration (W. B. Saunders Co., Philadelphia) ;
G. W. Crile: Anoci-Association (W. B. Saunders Co.,
Philadelphia) ; F. W. Mott: War Neuroses (Oxford Uni-
versity Press, London); W. Harris: Nerve Injuries and
Shock (Oxford University Press, London) ; T. R. Elliot:
"Ductless Glands and the Nervous System" (Brain, vol-
ume 35, page 306, 1913); N. Pende: "Endocrinopathic
Contributions to Pathology" (Endocrinology, volume 3,
page 329, 1919) ; Y. Henderson, H. W. Haggard and R. C.
Coburn: "The Acapnia Theory, Now" (Journal of the
'American Medical Association, volume 77, page 424,
1921); C. W. Crile: "The Mechanism of Shock and Ex-
haustion" (Journal of the American Medical Association,
volume 76, page 149, 1921); H. H. Dale: "The Nature
and Cause of Wound Shock" (Harvey Lectures, 1919-
1920, page 26; J. B. Lippincott Co., Philadelphia, pub-
lishers) ; F. X. Dereum: Clinical Manual of Mental Dis-
eases (W. B. Saunders Co., Philadelphia).

An article by Cannon that reviews much of his work on
the adrenals may be found in the American Journal of
Physiology, volume 50, page 399, 1919; literature is ap-
pended. For articles by Stewart and Rogoff see, among
others, the American Journal of Physiology, volume 46,
page 89, 1918, volume 48, pages 22 and 397, 1919 ; Journal
of Pharmacology and Experimental Therapeutics, volume
13, pages 95, 167, 183, 361, and 397, 1919, and volume

208 GLANDS IN HEALTH AND DISEASE

14, page 343, 1919; American Journal of Physiology, vol-
ume 51, page 366, 1920, and volume 52, page 304, 1920;
Journal of Pharmacology and Experimental Therapeutics,
volume 16, page 71, 1920, and volume 17, page 227, 1921 ;
and the review by Stewart, "Adrenal Insufficiency" (En-
docrinology, volume 5, page 283, 1921), which includes
many references.

ORGANOTHERAPY. Consult Osborne's Therapeutics (W.
B. Saunders Co., Philadelphia), and H. K. Harrower's
Practical Hormone Therapy (P. B. Hoeber, New York).
The Wilson Laboratories, Chicago, 111., publish a quarterly,
The Autacoid and Suture, which includes articles on the
subject. The dangers involved in the use of glandular
extracts is pointed out by M. P. Rucker and C. C. Haskell
(Journal of the American Medical Association, volume 76,
page 1390, 1921).

PLANT HORMONES. The literature on the subject is
very meager. See, for example, J. Loeb: "Hormones in
Bryophyllum" (Science, volume 44, page 210, 1916) ; E. J.
Eussell: Soil Conditions and Plant Growth (Longmans,
Green & Co., London) ; E. W. Thatcher: The Chemistry
of Plant Life (McGraw-Hill, New York).

A FEW CLASSICAL BOOKS AND PAPERS

Johannes Miiller: Lehrbuch der Physiologie, volume 1

(Koblenz, 1844).

"Miiller points out that the process of secretion consists
of two phases, — the production of certain materials, and
the casting out of these materials upon a surface either in

REFERENCES 209

the interior or upon the exterior of the body. The first
phase he called 'secretion/ the second, 'excretion.' ):

A. A. Berthold: "Transplantation der Hoden" (Archiv
fur Anatomie und Physiologic, page 42, 1849).
Berthold removed the testicles from cocks and grafted
them to other parts of the body. He observed that "the
animals retained their male characteristics in regard to
voice, reproductive instinct, fighting spirit, and growth
of comb and wattles."

Thomas Addison : On, the Constitutional and Local Effects
of the Disease of the Suprarenal Bodies (London, 1855).
An account of the now well-known "Addison's Disease."

Claude Bernard: Legons sur les proprietes physiologiques
et les alterations pathologiques des liquides de I'organ-
isme (Bailliere et Fils, Paris, 1859).
Here we find the first clear accounts of glandular or-
gans that distribute their products by means of the blood
stream. The very name "internal secretion" is due to
this illustrious Frenchman.

Theodore Kocher: "Ueber Kropfexstirpation und ihre
Folgen" (Archiv fur Iclinische Chirurgie, volume 29,
1883).
Myxedema is due to the loss of the functional activities

of the thyroid gland.

M. Schiff: "Bericht iiber eine Versuchsreihe betr. die
Wirkungen d. Exstirpation der Schildriise" (Archiv
•fur experiment elle Pathologic und Pharmakologie,
volume 18, 1884).

210 GLANDS IN HEALTH AND DISEASE

Epoch-making experiments on the effects of the removal
of the thyroid.

P. J. Mobius: Schildruse theorie (Schmidts Jahrbiicher,

volume 210, page 237, 1886).

The opinion is expressed that Basedow's disease depends
on an abnormally increased activity of a ductless gland.

P. Marie: "Sur deux cas d'acromegalie, hypertrophie sin-
guliere non congenitale des extremites superieures, in-
ferieures et cephaliques (Revue de mededne, page 298,
1886).
The discovery that acromegaly is a disease due to the

pituitary.

Brown-Sequard : "Des effets produits chez 1'homme par des
injections sous-eutanees d'un liquide retire des testi-
cules frais de cobaye et de chien" (Comptes rendus de
la societe de biologie, volume 41, page 415, 1889).
"Brown- Sequard injected the juice of the testicle sub-
cutaneously into his own body and observed an increase in
corporeal and mental powers that he attributed to the
influence of these injections." The beginning of modern
organotherapy, or treatment by means of glandular ex-
tracts.

J. von Mering and 0. Minkovski : "Diabetes mellitus nach
Pankreas exstirpation" (Archiv fur experimentelle
Pathologie, volume 26, page 371, 1889).
The complete removal of the pancreas results in severe

diabetes.

REFERENCES 211

E. Gley: "Sur les effets de Pextirpation du corps thy-
roide" (Comptes rendus de la societe de biolotfie, page

843, 1891).
Tetany is due to the removal of the parathyroids.

G. Oliver and E. A. Schafer : "The Physiological Effects of
Extracts of the Suprarenal Capsules" (Journal of
Physiology, volume 18, page 230, 1895).
An injection of an extract of the adrenal glands in-
creases the blood pressure.

E. Baumann : "Ueber das normale Vorkommen von Jod im
Tierkorper" (Z eitschrift fur physiologische Chemie>
volume 21, page 319, 1896). ,

The discovery that the element iodine is a normal con-
stituent of the body.

J. Takamine: "The Isolation of the Active Principle of
the Suprarenal Gland" (Proceedings of the Physiologi-
cal Society, in the Journal of Physiology, volume 27,
page xxix, 1901).
An account of the isolation of adrenaline.

A. Frohlich: "Fall von Tumor der Hypophysis cerebri
ohne Akromegalie" (Wiener Jclinische Rundschau,
1901).
A disease is described which is the reverse of acrome-

galy — that is, it is due to a diminished activity of the

pituitary.

W. M. Bayliss and E. H. Starling; "The Mechanism of
Pancreatic Secretion" (Journal of Physiology, volume
28, page 325, 1902).
The hormone, secretin, is described.

212 GLANDS IN HEALTH AND DISEASE

J. S. Edkins : "The Chemical Mechanism of Gastric Secre-
tion" (Journal of Physiology, volume 34, page 133,
1906).
Extracts of the lining of the stomach cause an increased

formation of gastric juice.

H. Gushing: The Pituitary Body and Its Disorders (J. B.
Lippincott Co., Philadelphia, 1912).
A classic on the subject.

E. C. Kendall: "The Isolation of the Iodine Compound
Which Occurs in the Thyroid" (Journal of Biological
Chemistry , volume 39, page 125, 1919).
The isolation of "thyroxin," the active principle of the

thyroid gland.

INDEX

Alel, 56, 81, 203
AUlard, 93
Acromegaly, 48, 62

— case of, 65

— cure in, 63

— symptoms in, 62
Addison's disease, 73
Adrenal extract, effect of, 75
Adrenal glands, 10, 70-88

— cortex of, 77

— description of, 70

— history, 70

— in shock, 177

— medulla of the, 79

— removal of, 71

— summary of function, 88

— vitamine B and, 10. See Ad-

dison's disease ; Adrenal
extract; Adrenaline; Graft-
ing; Hyperadrenalism ;
Nervous system and the
ductless glands; Sympa-
thetic nervous system
Adrenaline, 78, 79

— blood and, 85

— chemistry of, 79

— derived from tyrosine, 79

— determination of, 85, 163

— emotional excitement, pain,

asphyxia and, 162

— function of, 169, 178, 188

— preparation of, 81

— properties of, 82

— sugar metabolism and, 86
— •sympathetic nervous svstem

and, 87, 161

— uses of, 83. See Adrenal

glands ; Nervous system
and the ductless glands

Allen, 19, 125, 204
Amnesia, 183
Anoci-association, 175
— operations and, 176
Anrep, 199
Atwater, 37

Bailty, 206

Bandler, 198

Basedow's disease, 15, 31. See

Exophthalmic goiter
Barger, 203
Barker, 203
Baumann, 211
Basal metabolism, 39, 41
Bayliss, 4, 127, 129, 132, 133,

144, 192, 198, 205, 211
Beard, 183
Bell, 202
Benedict, 37, 201
Berman, 198
Bernard, Claude, 118, 119, 120,

209

Berthold, 209

Biedl, 78, 97, 141, 146, 197, 206
Bile, 116

Boothby, 41, 200, 201, 202
Bottomley, 190
Braun, 84
Broum, 207
Brou-n-Sequard, 72, 91-92, 97,

98, 102, 114, 185, 186, 210
Budington, 194
Burton-Opitz, 198

Carbohydrate metabolism, 116
Carbon dioxide, 119
Carlson, 173, 181
Cassan, 70

213

214

INDEX

Castration, 93

— effects of, 93

— mental development and, 94

— sex characteristics and, 95
Catalysts, 12

Charcot, 183

Clark, 61

Cobb, 159, 183, 198

Cretinism, 15, 18, 22

Crile, 83, 158, 174, 182 183, 200

207

Crotti, 200, 205
Gushing, 48, 49, 51, 57, 64, 65,

66, 182, 202, 212

Dale, 207
Dandy, 206
Dane, 183
Darwin, 69
de la Paz, 161
Dementia precox, 84
Dercum, 207
Descartes, 100
Diabetes, 7, 120, 121

— Allen treatment for, 125
Doege, 146
Drummond, 199

Du Bois, 39, 201
Ductless glands, 2, 3, 4

— influence of, on growth and

metabolism, 156

— nervous system and, 158

— relation of, to one another,

147. See Endocrine
glands; Glands, of inter-
nal secretion

Dutcher, 9, 28, 199

Dyspituitarism, 64

Eddy, 140, 205
Edkins, 133, 134, 212
Eidelsberg, 74
Elliot, 207
Endemic goiter, 27
Endocrine glands, 3, 4. See

also Ductless glands
Enriquez, 131

Enzymes, 3, 11
Epiphysis. See Pineal
Eppinger, 148, 150
Errera, 192
Eunachoids, 95
Eustachius^ 70
Exophthalmic goiter, 15, 31
-—symptoms in, 31

— treatment of, 33

Falta, 18, 93, 148, 160, 197

Ferments. See Enzymes

Finney, 141

FisKberg, 197

Foa, 141

FoUn, 86

Frazier, 205

Friedmann, 81, 203

Frotich, 211

Fulbert, 93

Fulton, 200

Funk, 9

Furth, 81

Gastric secretion, 133
Gigantism, 63
Glands, 2, 3
Glandular extracts, 187

— conflicting results with, 187.

See Organotherapy
Glands, of internal secretion,

3, 6. See Ductless glands;

Endocrine glands
G-ley, 43, 47, 151, 162, 197, 211
Glucose, 117
Glycogen 117
Ooetsch, 152
Goiter. See Endemic goiter;

Exophthalmic goiter
Gordon, 205
Grafting, 76, 97, 108. See

Transplantation of tissues
Graves's disease, 15, 31, 158.

See Exophthalmic goiter
Growth, influence of ductless

glands on, 156

INDEX

215

Gruber, 161

Gudernatsch, 19, 20, 137
Gull, 16

Haber, 12
Hahnemann, 185
Hallion, 131
Hammar, 205
Hammond, 145
-Harris, 207
Harrow, 9, 201
Harrower, 198, 200
Haskell, 208
Hayliurst, 202
Heloise, 93
Henderson, 119, 207
Herter, 51
Hertzler, 159
Hippocrates, 185
Histidine, 56
Hogben, 201
Hopkms, 136
Hormones, 5, 6

— composition of, 8

— in plant, 190

— relation of vitamines to, 8-

11

— relation of amino-acida to,

11

Horraao, 141, 205
Horsley, 204
Howell, 54, 198
Hunger, nature of, 173
Hyper-adrenalism, 77
Hyperpituitarism, 56, 61

— and giants, 64
Hyperthyroidism, 15, 159. See

Exophthalmic goiter
Hypophysis cerebri, 47. See Pit-
uitary
Hypopituitarism, 50

— and the dwarf, 51
Hypothyroidism, 15, 160

— symptoms of, 17. See Myxe-

dema; Cretinism
Hysteria, 183

Intestinal hormone, 127-134

— influences flow of pancreatic

juice, 128. See Secretin
Intestine, small, digestion in,

127

Islands of Langerhans and dia-
betes, 121

Interstitial cells, 90, 97, 102,
103, 104

— old age and, 98
Iodine, in the thyroid, 25

— an essential element of the

body, 29

Jaboulay, 77
James, 173
Janet, 183
Jeliff e, 206
Joslin, 204

Kahn, 72, 199

Keeble, 192

Kellaway, 199

Kendall, 8, 24, 25, 26, 27, 28,

188, 200, 212
Kidney, internal secretion of,

146

Kimball, 29, 201
Klinger, 30
Koch, 45

Kocher, 16, 34, 209
Kolber, 107
Krumbhaar, 205

Latey, 201

Laignel-Lavastine, 206
Langfeldt, 124, 204
Lavoisier, 36
Le Page, 130
Lichtenstem, 107
Liver, 116

— a ductless gland, 118

— carbohydrate metabolism

and, 116

— glycogen and, 117. See

Claude Bernard; Dia-
betes ; Pancreas ; Urea

216 INDEX

Loeb, J., 19, 201, 208
Loeb, L., 204
Lovand, 112
Luciani, 132, 198
Lusk, 39
Lyman, 161

MacCalUm, 198, 202

MacCarrivon, 10, 199

MacCarthy, 201

Mackenzie, 145

¥o,cioe<Z, 55, 189, 198, 204

Magnums-Levy, 160

Mammary Gland, 144-145

Marie, 48, 61, 210

Marine, 29, 201

Marshall, 203

Mathews, 73, 198

lf<M/o brothers, 25

Mat/o, (7., 34

Means, 201

MecfceZ, 71

Meltzer, 86, 161

Mendel, 51

Mendenhall, 161

<y. Mering, 116, 120, 210

Metabolism, definition of, 36

— in thyroid disease, 40

— influence of ductless glands

on, 156. See Basal meta-
bolism; Surface area

Minkowski, 116, 120, 125, 210

MoUus, 183, 210

Monkey Glands, 111

Mott, 207

Moyniham, 205

Miiller, 208

Murlin, 201

Myers, 199

Myxedema? 15, 23

— symptoms in, 23

— treatment of, 23

Ttagel, 111

Nervous system and the duct-
less glands, 158-184

Nervous system, sexual glands
and, 181. See Adrenaline;
Adrenal glands; Cannon;
Crile; Stewart

Xioe, 161

t?. Noorden, 125

OeJisner, 200, 202
Old age, 98, 102, 105

— the Steinach operation and,

106

— the Voronoff operation and,

109

— Brown-Sequard's experi-

ments, 186
Oliver, 53, 80, 211
Ord, 16
Organotherapy, 185-189. See

Glandular extracts
Organs of reproduction, 7, 89-

114

— proof of internal secretion,

89

— two types of secretion, 90.

See also Brown-Sequard;
Castration; Eunachoids;
Grafting; Interstitial

cells; Monkey glands ; Old
age; pubertas precox; Re-
juvenation; Steinach; Vas
deferens; Voronofi

Osborne, 0. T., 208

Osborne, T. B., 51

Osgood, 161

Osier, 198

Pancreas, 7, 115

— blood sugar and, 122-124

— internal secretion of, 115,

120, 121. See Diabetes;

Islands of Langerhans;

Liver

Pancreatic extract, 189
Parathyroids, 43-46. See Tet-

any

Paton, 197
Pavlov, 128, 133, 139

INDEX

217

Pearce, 205
Pende, 207
Pettenkofer, 37
Pickering, 193
Pineal, 140-144

— a case of disease of, 142

— clinical features of disease

of 144

— effect of extract of, 141

— evidence in favor of hor-

mone in, 141

— removal of, 141
Pituitary, 47-69

— description of, 47

— difficulty in interpreting

data, 56, 57

— function of, 52, 53

— removal of, 49. See also

Acromegaly; Dwarf; Dys-
pituitarism; Hyperpitui-
tarism; Hypopituitar-
ism; pituitary extract;
Pituitrin; Tethelin

Pituitary extract, use of, 58,
60, 145

Pituitrin, 54, 55

Plant hormones, 190

Polk, 68

Pollock, 183

Popielski, 132

Psychasthenia, 184

Psycho-analysis, 182

Ptyalin, 3

Pubertas precox, 113

Quackery in medicine, 59

Rejuvenation, 107, 110. See Old
age

Relation of ductless glands to
one another, 147-155

Reproductive organs. See Or-
gans of reproduction

Richardson, 200, 202

Ril&y, 206

Robertson, 52, 53, 152, 203

Rogoff, 162, 165, 168, 169, 178,

179, 180, 206, 207
Rosa, 37
Rubner, 37
Rucker, 208
Rudinger, 148
Russell, 208

Sacchi, 114

Sajous, 206

Schafer, 53, 71, 78, 80. 197, 211

Schiff, 15, 16, 17, 209'

Sciplades, 137

Secretin, 6, 127-134

— how discovered, 129-131

— objections to Bayliss and

Starling's work on, 132

— origin of name, 131. See

Bayliss; Intestinal hor-
mone; Pavlov; Starling

Sexual glands. See Organs of
reproduction

Shell-shock, 182. See Shock

Shock, 174

— kinetic theory of, 175, 177.

See Shell-shock
Shohl, 161

Skin, internal secretion of, 146
Spleen, 138-140

— extirpation of, 139

— function of, 138

— gives rise to internal secre-

tion, 140
Starling, 4, 127, 129, 132, 134,

198, 205, 211
Steinach 92, 99, 101-107, 108,

111, 112, 203
Stewart, 151, 154, 162, 165,

167, 168, 169, 178, 179, 180,

181, 199, 203, 206, 207,

208

Sti-eve, 203
Surface area and metabolism,

38

Sweetbread. See Pancreas
Swingle, 137
Sympathetic nervous system, 82

218

INDEX

Tdkamine, 81, 211

Tandler, 96

Temperature, constancy of

body, 37

Testicular extracts, use of, 186
Tetany, 43
Tethelin, 53, 152
Thatcher, 208
Thymic asthma, 138
Thymus, 135-138

— effect of extract, 138

— function of, 136. See Thy-

mic asthma

Thyroid, 14-42. See Basal me-
tabolism; Cretinism; Ex-
ophthalmic goiter; Hyper-

thyroidism; Hypothyroid-

ism; Iodine; Kendall;

Myxedema; Thyroxin
Thyroid feeding, 19, 20, 23
Thyroid gland transplantation,

21
Thyroid hormone, isolation of,

25

Thyroidectomy, 15
Thyroxin, 26-28, 187, 188
TUney, 141, 206
Transplantation of tissues, 99,

104. See Grafting
Tucker, 207

Uhlenhuth, 136, 156, 206
Underhill, 154
Urea, 118

Vas deferens, 90, 103, 104

— operative technique, 105
Vincent, 80, 197
Vitamines, 9

— secretin, and, 134
Voegtlm, 134, 199, 202
Voit, 37

Foronof, 77, 92, 98, 99, 105,
107-112, 204

War, moral substitutes for, 173

Washbum, 161

Weil, 197

Wells, H. G., (the novelist),

128
Wells, H. G., (the pathologist),

199

Wertheimer, 130
Wright, 161

X-rays and the organs of re-
production, 96, 104, 106

Zandren, 141
Zuelzer, 123
Zunz, 37

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