INTERNAL SECRETION AND THE
DUCTLESS GLANDS

INTERNAL SECRETION

AND THE

DUCTLESS GLANDS

BY

SWALE VINCENT

LL.D., D.Sc., M.D., M.R.C.S., L.R.C.P., F.R.S. (EDIN.),
F.R.S. (CAN.), F.Z.S.

PROFESSOR OF ^PHYSIOLOGY IN THE UNIVERSITY OF LONDON; FORMERLY PROFESSOR OF

PHYSIOLOGY IN THE UNIVERSITY OF MANITOBA J ASSISTANT PROFESSOR OF PHYSIOLOGY,

UNIVERSITY COLLEGE, LONDON J INGLEB Y LECTURER (UNIVERSITY OF BIRMINGHAM! ,

1921 ; ARRIS AND GALE LECTURER (ROYAL COLLEGE OF SURGEONS), IQ22

ILLUSTRATED

SECOND EDITION

LONDON,

EDWARD ARNOLD & CO.
1922

[All rights reserved']

PREFACE

THE first edition, issued in 1912, has been out of print since
1914, but for various reasons the publication of the second
edition has been delayed. During this time many aspects of
the subject of internal secretion have undergone material
changes. These I hope will find adequate expression in the
new version of the book. If I have not been so optimistic
and expansive in the treatment of certain topics as other
writers on the same subjects, it is because I am convinced
that a surer road to sound knowledge lies in the direction of
rigid criticism and a reasoned scepticism.

After much doubt and hesitation I have decided to omit the
bibliography. The objections to such a course are obvious,
but I found that to review the whole of the literature has
become impossible, and to make a selection involves a task so
invidious and delicate and at the same time laborious that I
have not had the courage to attempt it. The omission of the
references to literature will, however, have the advantage of
making the book easier to read, and for a large number of
students and practitioners will, I hope, not constitute a serious
drawback. Investigators who have access to the first edition
will find no difficulty in completing a survey of the literature
up to the present time. The papers since 1917 are abstracted
in Endocrinology, and since 1915 in Physiological Abstracts.
Names are still mentioned freely in the text for the reasons that
this arrangement involves less re-writing, and that it leaves the
responsibi'ity in the hands of the original author on numerous
topics in which I have had no opportunity of gaining first-
hand information.

The present edition contains much new matter, but, by
re-arrangement and some curtailment of historical and con-
troversial sections, it has been possible to avoid increasing the
size of the book. The number of illustrations has been
increased from 93 to 105. The portions dealing with clinical

VI

PREFACE

subjects have been increased very considerably and this, it is
hoped, will make the book more useful to students and
practitioners. Many of the new illustrations are photographs
of patients suffering from diseases of the organs of internal
secretion.

The nucleus of the book was an article in the Ergebnisse der
Physiologic, and I have to thank the Editor, Professor Asher,
of Bern, and the publisher, for their courtesy in allowing me to
use the material as the basis of the present work.

Many of the illustrations are derived from papers contributed
to various journals from time to time, either by myself, or by
or in conjunction with pupils and others working under my
direction. A large number have been drawn for me by the
late Mrs. F. D. Thompson, of the University of Manitoba.
The figures specially drawn by her for the present work are
Nos. 13, 13a, 29, 56, 91, 92, 93, 95, 104 and 105, while Nos. 9,
10, 11, 57, 77, 79, 80 and 81 were drawn by her to illustrate her
paper in the Phil. Trans., 1910.

Most of the tracings have been taken from papers by myself
or conjointly produced in the Journal of Physiology and
Endocrinology, and I have to thank Professor Langley for
supplying cliches of blocks of many of those published in the
former journal. Some of the tracings have, however, been
taken from the records of class demonstrations (Figs. 39-43)
or from unpublished work in my laboratory (Fig. 46). Figs.
58 and 59 were drawn by Mr. Carmichael from sketches kindly
furnished by Professor Evatt.

Diagrams A and B of Figs. 82 and 90 are taken from a paper
by Dr. Kohn, of Prag. Figs. 20, 23, 24 and 26 are taken from
papers by Giacomini, Fig. 21 from Diamare, and Fig. 22 from
Kohn. Figs. 83-86 are borrowed from Murray (Diseases of the
Thyroid Gland. London, H. K. Lewis, 1900). Fig. 87 from
Adami (Text-book of Pathology. Lea and Febiger). Figs. 88
and 89 are taken from a paper by Sutherland Simpson. Fig.
98 is a photograph kindly supplied by Dr. Harvey Gushing,
while Figs. 99, 100, 101, 102 and 103 are taken from Cushing's
book on the Pituitary. l For all these I beg to express my best
thanks, to both author and publish IT.

I have to thank Professors A. T. Cameron and Charles H.
O'Donoghue of the University of Manitoba for much assistance,
1 The Pituitary Body and Us Disorders, 1912. Lippincott Phila.

PREFACE vii

Dr. Cramer, of the Imperial Cancer Research Laboratory, for
criticism in the chemical portions of the book, and Dr. Leonard
Kidd for references to literature. To Mr. Samson Wright I
am deeply indebted for his services in the revision of the whole
book, and to Mr. J. W. Brown for assistance in the preparation
of the index.

I owe a debt of gratitude to Sir Edward Sharpey Schafer for
his kindly encouragement and advice on various matters
extending over a period of many years. From the time when
I had the privilege of acting as his assistant in University
College, London, he has always been ready to place the services
of his laboratory at my disposal and to assist me in numerous
other ways.

SWALE VINCENT.
MIDDLESEX HOSPITAL
MEDICAL SCHOOL,
February, 1922.

CONTENTS

CHAPTER I

PAGES

J INTRODUCTORY — SECRETION AND INTERNAL SECRETION . . 1 — 11

Definition of secretion . . . . . . ... 1

Ductless glands . . . . . .,',-* . 4

Internal secretion . . . . . .... 5

Organo- therapy ......... 6

Nature of internal secretion . . . . . . . 7

Limitation of the term "internal secretion" . . . .9

Internal secretion and pathology ...... 9

CHAPTER II

« DEFINITION AND LIMITATION OF THE TERM " INTERNAL SECRETION " 12 — 19

" Negative internal secretion " . . . . . .16

" Hormones " . .16

CHAPTER III

GENERAL METHODS OF INVESTIGATION AND THE VALUE OF THE RESULTS

WHICH MAY BE OBTAINED BY SUCH METHODS . . 20 34

Pathological methods ........ 20

Experimental pathology . . . . . . . .21

Extirpation experiments . . . . . . . .21

Grafting 22

Feeding 22

Subcutaneous injections ........ 22

Intravenous injections . . . . . . • .22

Depressor substances ........ 25

Pressor substances ......... 25

Observations upon frog's mesentery . . . . . .31

Cytotoxic sera ...... . . 33

" Vividiftusion " 33

CHAPTER IV

J THE NATURE, MODE OF ACTION, AND ORIGIN OF HORMONES . 35 — 37
Augmentory and inhibitory hormones ... .35

ix

I CONTENTS

CHAPTER V

"PAGES

THE INTERNAL SECRETION OF THE LIVER .... 38 39

Glycogenic function of the liver ...... 38

Negative internal secretion . . . . . . .38

Toxicity of liver extracts ..... ;{<)

CHAPTER VI

TIIK IXTKKXAL SECRETION OF THE PANCREAS .... 40 51

Extirpation of the pancreas 40

The islets of Langerhans ..... 41

A and T* cells of islets ..... 47

Glycosuria ....... 48

Diabetes mellitus ...... 48

Polyglandular theories .49

Acidosis ........ -)<(

Medicinal use of pancreatic extracts. . -,1

CHAPTER VII

THK INTERNAL SECRETION OF THE KIDNEY . . 52 56

Effects of kidney extracts 52

Extirpation of kidneys ..... 53

Uraemia and Cheyne-Stokes respiration . . 53

Treatment of nephritis with kidney extracts . r,r,

(Edema in nephritis ..... 55

Influence of the kidney on metabolism . 56

Therapeutic uses of kidney extracts . . ^

CHAPTER VIII

THE INTERNAL SECRETION OF THE INTESTINAL Mucous MEMBRANE

AND THE NORMAL MECHANISM OF THE SECRETION OF THE

PANCREATIC JUICE 57—64

State of knowledge in 1889 . . r)7

Theory of nervous action ... 58

Chemical mechanism

Secretion .

Excitants of the pancreatic juice

Secretion in disease.

CHAPTER IX

8ECRJ7ION OP ™ GASTRI° Mucous MEMBRANE AND
NORMAL MECHANISM OF THE SECRETION OF THE GASTBIC

• . . «ir,-66

Nervous influences .

^tricsecretin" or "Gastric Hormone" .' ' '

-»cU of gastric mucous membrane in 'treated nf di

66
66

CONTENTS xi

CHAPTER X

PAGES

THE INTERNAL SECRETION OF THE REPRODUCTIVE ORGANS . . 07 — 92

A. The internal secretion of the testis .... 67 — 74

Subcutaneous injections of extracts of testis ... 67
Poehl's " spermin " . . . . . .67

Effects of castration . . . . . . .68

Male sopranos ... ..... 68

Effects of tying the vasa defereritia . . . .70

Interstitial cells .... .... 70

Transplantation of the testis . . . . .71

Therapeutic uses of extracts of testis . . . . 74

B. The Internal secretion of the prostate gland . . . 74 — 75

Extirpation of the prostate . . . . . .74

Administration of extracts of prostate . . . .75

C. The internal secretion of the ovary and the corpus luteum . 75 — 89

Structure of the ovary . . . . . .75

Cyclical changes in the ovary and in the uterus ... 75
Extirpation of the ovaries before puberty. ... 76

Extirpation after puberty . . . . . .76

Effects of ovariotomy . . . . . . .77

Ovarian transplantation . . . . . .78

Classification of sex characters ..... 80

Structure of the corpus luteum ... .81

Mode of formation of the corpus luteum . . . .81

Chemistry of the corpus luteum ..... 83

Effects of corpus luteum extracts . .84

Ovarian extracts ...... .85

Changes in the uterine mucosa produced by the corpus

luteum ..... 86

Function of the corpus luteum ... .88

Interstitial cells . . . . . . . • .88

" Femininity ".......• 89

U. Ovarian medication ....... 90 — 91

E. Osteomalacia . . • • • „ 92

CHAPTER XI

THE INTERNAL SECRETION or THE ADRENAL BODIES (THE CORTEX OF

THE ADRENAL AND THE CHROMAPHIL TISSUES) . . . 93 — 249

A. Introductory ....•••••

Early history of the subject.

B. Comparative anatomy of the adrenal bodies .

1. Introductory ... ....

2. Invertebrata '• . •

3. Anamnia .....•••

Cyclostomata ....

Elasmobranchii

Teleostei .

Ganoidei

Dipnoi ...

Amphibia. . .109

Anura

Urodela ll°

.

CONTENTS

Amniota .

Reptilia ..... .112

Aves .... 112

Manunalia

Accessory adrenal bodies . 114

Accessory cortical bodies . . ll(i

Accessory " medullary " bodies (chromaphil
bodies) .... .116

r». Tabular statement of chief facts in the comparative

anatomy of the adrenal bodies . .126

C. Development of the adrenal bodies.

D. Addison's disease and the pathology of the adrenal bodies.

1. Introductory and historical

2. Symptoms

(1) Pigmentation

(2) Asthenia . . .129

(3) Other symptoms . 130
The " white line " of Sergent

3. ^Etiology and onset . .

4. Metabolism in Addison's disease

5. Morbid anatomy of Addison's disease

6. Pathogeny of Addison's disease . .134

7. Course and event of the disease — diagnosis, prognosis,

and treatment ... ... 137

8. Other conditions involving adrenal insufficiency . .138

9. Excessive adrenal function . . . . .138
10. Adrenal tumours ... . 139

A. Tumours of the adrenal medulla (chromaphil

tissue) . ... 139

B. Tumours of the adrenal cortex . . .140

E. Extirpation experiments in mammals . . .140

F. The question as to accessory adrenal bodies in relation to extir-

pation experiments in mammals . . . . .147

G. Extirpation of the adrenal bodies in the lower vertebrata . .149
H. The question as to the relative importance to life of cortex and

medulla .... ..... 152

I. Changes found post-mortem after extirpation of the adrenal

bodies .......... 154

J. Compensatory hypertrophy of the adrenal bodies . . .154
K. Transplantation of the adrenal bodies . . . . .156

L. The pharmacodynamics of extracts of adrenal medulla (chroma-

phil tissues) and of adrenin . . . . . .158

1. The general physiological effects of chromaphil tissue

acts and adrenin ...... 158

2. The special physiological effects of chromaphil tissue

extracts and of adrenin . . . . .165

(1) The effects upon the heart and arteries . . 165

(2) The effects on other structures, and the mode

and seat of action of adrenin . . .177
M. The chemical nature of the active substance of the adrenal

ilia and otli«-r rlin.maphil tissues . .... 185

rnal secretion of adn-niii . . . . .199

N. The origin of adrenin in the body ...... 200

MC mode of disposal of adrenin in the body . . . L'ol

CONTENTS xiii

PAGES

P. The proteins, lipoids, etc., of the adrenal bodies . . . 202
Q. The medical and surgical employment of adrenal preparations . 204
Surgical employment of adrenin alone or combined with
other drugs ........ 204

Application of adrenal preparations to the conjunctiva and
mucous surfaces ....... 205

Use of adrenal preparations in diseases of the bladder . . 206
Use of adrenal preparation and of adrenin in haemorrhage s. 206
Adrenin in cardio-vascular conditions .... 208

Adrenal preparations in Addison's disease . . . 209

Various applications of adrenal preparations and of adrenin 211

Mode of administration of adrenal preparations . .211

R. Theories as to the function or functions of the adrenal bodies . 212

Introductory . . . . . .212

1. Theories as to the function of the medulla . . .216

Stimulation of the splanchnic nerve . . . 224

Discharge of adrenin into the circulation . . 233
Histological evidence. ..... 235

Emotional discharge of adrenin .... 236

2. Theories as to the function of the adrenal cortex . .238

Tumours of adrenal cortex . . . .241

Adrenal hypernephromata .... 242

Functional variations ..... 243
Effects of administration of adrenal preparations

upon growth of body and testes . . . 245
S. Summary of views as to the probable functions of the adrenal

bodies . 248

CHAPTER XII

THE CAROTID AND COCCYGEAL BODIES ..... 250 — 254

A, The carotid body 250

Historical ". • 250

Comparative anatomy and embryology . .251

Microscopical structure ... . 252

B. The coccygeal body 254

CHAPTER XIII

THE FUNCTIONS OF THE THYROID AND PARATHYROIDS . . 255 — 324

A. Introductory : The organs derived from the region of the

pharynx and gill-clefts ..... • 255

B.

The comparative anatomy and histology
parathyroid bodies ....
1. Cephalochorda and cylostomata
2. Elasmobranchs .
3. Teleosts ....
4. Urodela .
5. Anura .....
6. Reptilia ....

of the thyroid and

255
255
256
256
257
258
260

XIV

.7. Aves

CONTENTS

PAGES

260
262

8. Mammalia

(a) General

(6) Man .

(c) Monkey ,

(e) Cat . •

(/) Rabbit . .
(f/) Guinea-pig .
(/,) Rat . .

(i) Wolf and badger.

(?) Pig

(ft) Hone . . • -268

(i) Sheep and goat .

C. Histology of the thyroid in man and mammals.

D. The intervesicular cellular tissue of the thyroid

E. Structure of the parathyroids

F. Development of the thyroid

G. Development of the parathyroids and some other branchial cleft

organs . . . • • . • • • • • 279
H. Diseases of the thyroid gland ...... 282

1. Goitre . . . . .... 282

2. Endemic cretinism ...

3. Myxoedema

(a) Symptomology . • .

(6) Morbid anatomy .....

(c) Pathogeny .

4. Cachexia strumipriva ....

5. Graves' disease ....... 290

Symptoms

Pathogeny 291

Treatment

6. Other conditions due to thyroid disorder

" Petite insuffisance thyroidiemie "

Mongolism ..... • 294

Progeria 294

Foetal and maternal athyrosis .
I. Diseases of the parathyroid glandules ..... 295

Tetany 295

I'arulj'sis agitans ........ 296

Endemic tetany .297

J. Early views as to the functions of the thyroid .... 297
K. Kxtirpation experiments upon mammals .... 300
L. The mechanism of the thyroid secretion ..... 307

M. The chemistry of the thyroid 308

N. Physiological actions of the thyroid secretion . . . .314

O. The effects of thyroid gland and preparations made from it,

upon metabolism ........ 316

I Transplantation of the thyroid gland . . . . .317

Q. The relationships between the thyroid gland and the repro-
ductive functions . . . . . . . .318

I: The functions of the thyroid gland . ..... 318

upon ihr parathyroid L'liiiidul' . 319

fictions of the parathyroid glandules . . . .323

CONTENTS xv

CHAPTER XIV

PAGES

THE FUNCTION OF THE THYMUS . . . . . . 325 — 337

A. Comparative anatomy and development of the thymus . . 325

B. Structure of the thymus ....... 329

C. Extirpation of the thymus ....... 333

D. A probable relation between the thymus and the reproductive

organs .......... 335

E. Physiological effects of extracts of thymus . • . . 336

F. Pathology of the thymus . . . . . . .337

CHAPTER XV

\/ THE FUNCTION OF THE PITUITARY BOBY .... 338 — 384

' A. Comparative anatomy of the pituitary body .... 338

1. The mammalian pituitary body . . . .338

2. The pituitary body of birds and lower vertebrates . . 343
1 B. Development of the pituitary body ..... 344
' C. Old views as to the functions of the pituitary body . . . 346

D. Physiological action of extracts of the pituitary body . . 347

• 1. Effects on the heart and blood-vessels . . . 347

2. Effects on the vaso-motor reflexes .... 350

3. Effects on the respiration. . . . . .351

4. Effects on involuntary muscles other than those of the

vascular system . . . . . .351

(a) The uterus 351

(b) The bladder . . . . . .352

(c) The intestine 352

(d) The stomach ...... 353

(e) The pupil 353

X 5. Effects on the secretion of certain glands . . .353

(a) The mammary gland ..... 353

(6) The kidney 355

(c) The stomach ... .355

6. General physiological effects (subcutaneous and intra-
venous injections) ....... 356

' E. The question as to which elements of the pituitary body furnish
the active substance or substances. — Functions of the different

parts of the pituitary body ...... 356

F. Feeding and metabolism experiments . . . 357
' G. Grafting experiments . . . . . • • .359

' H. Stimulation of the pituitary in situ ..... 360

v I. Extirpation experiments .... . 361

J. The question as to a functional relationship between the

pituitary and the thyroid bodies ..... 366

K. Pituitary insufficiency and a pituitary antiserum or cytotoxin ' . 367

• L. Chemistry of the pituitary body" ..... 368

' M. The comparative physiology of the pituitary body .
" N. Diseases of the pituitary body .

1. Introductory ..... • 370

2. Acromegaly . . . • • • • .371

(1) Introductory ....

(2) Symptoms .

(3) ^Etiology and onset « 373

xvi CONTENTS

PAGES

- (4) Metabolism in acromegaly .
. (5) Morbid anatomy .

(6) Pathogeny .

(7) Course and event of the disease — diagnosis,

prognosis and treatment . . . .375

(8) Other conditions involving pituitary hyper-

function .

J 3. Conditions involving hyposecretion of the pituitary . 378
Dystrophia adiposo-genitalis
Infantilism
Progeria

Classification of " infantilisms " .
Achondroplasia

Carbohydrate tolerance in pituitary disorder.
Diabetes insipidus

O. The use of pituitary extracts in medicine, surgery, and
gynaecology .

CHAPTER XVI
THE FUNCTION OF THE PINEAL BODY . • 385 — 394

Anatomy and development of the pineal body
Uistological structure of the pineal body
Physiological experiments upon the pineal body .

1. Injection of extracts of the pineal body

2. Direct stimulation of the pineal body .

3. Attempts to destroy the pineal body by means of the

•iQO

cautery .......•• •iyi

4. Extirpation of the pineal body

5. Effects of castration upon the pineal body .

6. Feeding experiments ....

Pathological anatomy and clinical pathology . . • 392

CHAPTER XVII

•/ THE INTERRELATIONS OF THE ORGANS OF INTERNAL SECRETION . 395 — 409

Introductory 395

A. Interrelationships involving the thyroid gland . . . 398

Action of the thyroid upon the adrenal bodies . . . 398

Relations between the thyroid and pituitary bodies . . 399
Relations between the thyroid and the reproductive organs 400
Action of the thyroid on the thymus . . . .401
Action of the thyroid on the pancreas . . . .401
H. I ' i-l lips involving the pituitary body . . . 402

Action of the pituitary b<»<!\ upon the thyroid . . . 402

Action of tin- pituitary body upon the repnxlurt ive organs . 402
ii <>f th«- pituitary body upon the adrenal bodies. . 404
Action of the pituitary body upon th. pan. Teas. . . 404

CONTENTS xvii

PAGES

C. Interrelationships involving the adrenal bodies (chromaphil

tissues and the adrenal cortex) ...... 405

Action of the adrenal bodies upon the gonads . . 405

Action of the adrenal bodies upon the thymus . . 405

Action of the adrenal bodies upon the pituitary . . 405

Action of the adrenal bodies upon the thyroid . . 405

Action of the adrenal bodies upon the pancreas . . 405

D. Interrelationships involving the organs of reproduction . . 406

Action of the reproductive organs upon the pituitary

body . . . 406

Action of the reproductive organs on the thymus . . 406

Action of the reproductive organs on the adrenal bodies 407

Action of the reproductive organs upon the thyroid . . 407

E. Interrelationships involving the thymus. .... 407

F. Other interrelationships ....... 407

The " pluriglandular syndrome " . . . . . 407

Pubertas praecox ........ 408

Dercum's disease (adiposis dolorosa) .... 408

Arachnodactyly ........ 409

LIST OF ILLUSTRATIONS

no. I'A1'1:

1. Tracing showing the effect of intravenous injection of brain extract . 26

2. Tracing showing the effect of intravenous injection of an extract of

spinal cord ...••••••• 27

3. Tracing showing the effect of intravenous injection of an extract of

brain as compared with that of injection of choline in a dog after
administration of atropine .

4. Tracing showing the effect of intravenous injection of an extract of

brain as compared with that of injection of choline in a cat after
atropine

5. Tracing showing the effect of brain extract and choline in a rabbit

after atropine

6. Tracing showing the effect of injection of a " protein " extract of

striped muscle . ...... 29

7. Tracing showing the effect of an injection of a saline decoction of

striped muscle ......... 29

8. Tracing showing the effect of injection of an alcoholic extract of

brain .... . .... 30

9. Islet of Langerhans from the splenic end of the pancreas of a dog . 43

10. Section through the splenic end of the pancreas of a normal pigeon . 44

11. Section through the splenic end of the pancreas of a pigeon after a

few days' inanition . ...... 45

12. Photograph of a series of uteri showing the effect of ovariotomy on

the uterus . . . . ... . . .78

13. Section through the ovary of Dattyurus viverrinus, showing Graafian

follicles and corpus luteum ......

13a. Portion of corpus luteum of Dazyurus viverrinus, showing the

glandular nature of the cells ...... 83

14. Dissection of Scyllium canicula, giving a ventral view of " pi'.in-d

suprarenals" (chromaphil bodies) and the interrenal (cortical body) 1 00

15. Ventral view of kidneys and adrenal representatives of Raja batis . 101

16. Tracing showing the effect of injection of an extract made from t he

" paired supfarenal bodies " of Scyllium canicula . . .102

17. Tracing showing the effect of injection of extract of interrenal body

of ScyUium canicula . . . . . . . .103

18. Kidneys and posterior cortical adrenal bodies (" corpuscles of

Stannius ") of Pagelluf) centrodontus . . . . .104

19. Kidneys and posterior cortical adrenal bodies (" corpuscles of

Stannius ") of Oadus morrhua . . . . . .104

20. Semi -diagrammatic figure showing the kidneys and their relations

with the cardinal veins and the cortical and chromaphil tissues

in Conger vulgaris ........ 105

L'l. ' Pransverse section of the interrenal body of Trigon violaceus. . 106
22. Transverse section through one of the paired bodies of Torpedo . 1 <»7
J i. Transverse section of a " corpuscle of Stannius " (" posterior

interrenal ") of Salmo fario ....... 108

24. Section of "bean of Salmo fario, showing an islet of

cortical adrenal tissue ("anterior int* in nul"). . . . 109

xviii

LIST OF ILLUSTRATIONS xix

FIG. PAGE

25. Section through a cortical body (" corpuscle of Stannius ") of the

sturgeon (Acipenser sturio) . . . . . . .110

26. Section through suprarenal body of Bufo vulgaris. . . .111

27. Small portion of the adrenal body of Uromastix Hardwic-kii . . 113

28. Section of the adrenal body of Meleaqris Gallopavo . . .114

29. Section through the adrenal bodv of the dog . . . .115

30. Sketch of the abdominal chromaphil body of the dog . . .117

31. Sketch of the abdominal chromaphil body of the cat . . .118

32. Sketch of the abdominal chromaphil body of the rabbit . . .118

33. Transverse section through the abdominal chromaphil body of a dog 119

34. Section through a small portion of the medullary part of the

adrenal body of the dog . . . . . . .120

35. Section through a group of chromaphil cells in the inferior cervical

ganglion of a dog ........ 121

36. Tracing showing the effect on blood-pressure of injection of an

extract of the abdominal chromaphil body of the dog . .122

37. Diagram of the adrenal representatives in elasmobranch\

fishes [ 124, 125

38. Diagram of the adrenal representatives in mammals . . J

39. Tracing showing the effect of injection of adrenal extract into the

vein of a dog . . . . . » . . . 167

40. Tracing showing the effect of injection of nicotine into a vein of a

dog ... 169

41. Tracing showing the effect of injection of adrenal extract after the

administration of atropine . . . . . .170

42. Tracing showing the effect of injection of adrenal extract after the

administration of nicotine . . . . . • . .171

43. Tracing showing the paralysing effect of adrenal injection upon the

vagus nerve . . . . . . . . .173

44. Diagram of the adrenal representatives in elasmobranch fishes ]_ ~, „

45. Diagram of the adrenal representatives in mammals . . j

46. Tracing showing the rise of blood-pressure on release of the adrenal

veins which have been compressed for some time . . . 223

47. Tracing showing the effect of stimulation of the splanchnic nerve

in a dog .......... 226

48. Tracing showing the effect of stimulation of the splanchnic nerve

in a dog after the administration of morphine .... 227

49. Tracing showing the effect of stimulation of the splanchnic nerve

before and after clamping the adrenal veins .... 228

50. Tracing showing effect of stimulation of the splanchnic and the

effect of tying of the adrenal body . . . . . • 228

51. Tracing showing the effect of stimulation of the splanchnic nerve

before and after clamping the adrenal veins . . . . 229

52. Tracing showing the effect (on blood-pressure and on a denervated

limb) of stimulation of the splanchnic nerve . 229

53. Tracing showing the effect (on blood-pressure and on volume of a

denervated limb) of stimulation of the splanchnic nerve after
clamping both adrenal veins ....... 230

54. Tracing showing the effect (on blood-pressure and on the volume of

a denervated limb) of stimulation of the central end of the right
sciatic nerve . . . . . . . « .231

55. Tracing showing the effects of stimulation of sciatic after tying off

the adrenal bodies on both sides ..... 232

56. Section through the carotid body of a. cat . 253

xx

LIST OF ILLUSTRATIONS

no. M«

57. Section through the parathyroid and the post- branchial body of

the pigeon ... .261

58. Semi-diagrammatic sketch showing the position of the parathyroids

in the human subject. Front view. Parathyroids projected on

to the surface .... . 2<>3

59. Semi-diagrammatic sketch showing the position of the parathyroids

in the human subject. Posterior view . . 263
60-65. Semi -diagrammatic sketches showing the position of the thyroid

and parathyroids in the dog ...... 265

66. Thyroid and parathyroids in the cat . ... 266

67-71. Thyroid and parathyroids in the rabbit .... 267

72-76. Thyroid and parathyroids in the guinea-pig .... 268

77. Section through the thyroid of a normal dog .... 269

78. Section of a normal parathyroid of a dog ..... 275

79. Drawing, as seen under a simple lens of a portion of the thyroid and

a parathyroid (human) ....... 276

80. Section through a portion of a human thyroid and adjoining para-

thyroid .......... 276

81. Section through a small portion of the parathyroid of preceding

figure ...... . . . . .277

82a. Diagram illustrating the development of the branchial cleft organs

of mammals ......... 281

826. Diagram showing the relations of the branchial cleft organs in

the adult mammal . . . . . . . . 281

83. Photograph of a cretin before treatment ..... 284

84. Photograph of a cretin after treatment ..... 285

85. Photograph of man with myxoedema . . . . .287

86. Photograph of same man after treatment with thyroid extract . 287

87. Photograph of a patient suffering from Graves's disease . . 292

88. Photograph of a group of thyroidectomized sheep taken five months

after the operation ........ 305

89. Photograph of " cretin " lamb . ... 305
90a. Diagram illustrating the development of the branchial cleft organs

of mammals ....... 326

90fr. Diagram showing the relations of the branchial cleft organs in the

adult mammal ......... 326

91. Section through a portion of the thymus gland of a monkey . . 330

92. HassaU's corpuscle from the thymus of a cat .... 332

93. Hassairs corpuscle from the human thymus .... I}:})}

94. Diagram showing the relations of the principal parts of the pitui t }. .-. v

body . ...... *. 340

95. Section through a portion of the pituitary body of a dog . . 341

96. Tracing showing the effect upon the arterial pressure and intesl inn I

volume of intravenous injection of decoction of infundibular body

(posterior lobe of pituitary body). ..... 34!)

97. Tracing showing the effect upon the arterial pressure of two

•«wive doses of extract of posterior lobe of pituitary . . 350

98. Photograph showing typical acromegalic profile . . . ,371

99. Photograph showing characteristic hand of acromegaly . . . 372

graph showing hyp«rpttmt«ram with gianl ovcr-n.wth . 377

!- PJl< 'imvinu hypopitiiitarism with marked adiposit \ . 37S

al case of infantilism of the Lorain type . 370

M- Section , al gland of the sheep ..... :>,x7

105. A small portion of the pineal gland of th- cat . 388

INTERNAL SECRETION AND THE
DUCTLESS GLANDS

CHAPTER I

INTRODUCTORY-^SECRETION AND INTERNAL SECRETION

DURING the last quarter of a century a vast amount of
investigation has been carried out upon the subject of internal
secretion, and very numerous facts have been accumulated
and various theories put forward. Our knowledge of the
subject is still in many directions very indefinite, and it will
be my duty to adopt a somewhat more sceptical and less
optimistic attitude in regard to certain branches of the subject
than that adopted by some modern writers. It is desirable,
at any rate, that the material should be collected and critically
examined, though the task is rendered difficult from the fact
that many of the contributions are to be found in obscure and
even inaccessible publications.

Before passing on to the discussion of internal secretion,
it will be well to define as accurately as possible our conception
of secretion in the most general sense of the word. In plants
as well as animals, in unicellular as well as in multicellular
organisms, various substances are formed as a result of
the metabolic activities of the living protoplasm. In the
unicellular organisms these substances help in the absorption
of food material, or serve some other purpose in the economy
of the cell, or they are cast away as waste materials into the
medium in which the creature lives. In multicellular organisms
the materials may be utilized either in the cell itself or in some
other part of the body. In the latter case they may be of
service to minister either to the proper function of some special
apparatus (such, for example, as the digestive tract), or to the

l 1

•2 INTERNAL SECRETION

rity of the entire organism. On the other hand, they may
be of no further use in the economy, and may be cast out as
\\a-te products.

By the term " secretion," applied in its most general sense,
is, or has been, understood the separation out of a substance
or of substances from or by the agency of the living protoplasm.
Tli is. the original conception of the process, has long been
< \t< nded to include also the preliminary preparation, or a
more or less complete elaboration of the materials which are
supplied by the processes of osmosis and diffusion, and in the
case of the multicellular organisms by the blood circulating
through the organ or tissue.

Johannes Miiller pointed out that the whole process of
secretion consists of two phases — the production of certain
materials and the casting out of these materials upon a surface
either in the interior or upon the exterior of the body. The
first phase he called " secretion," the second " excretion." In
some cases the material eliminated might be found in the
blood-stream, and was simply separated by the cells of the
organ and passed out. This applied to the urea of the urine,
which was looked upon by Miiller as a pure case of " excretion."
The distinction thus set up has, however, not been maintained
by physiologists. The term " excretion " has been, and is at
the present time, applied sometimes in a vague kind of way,
sometimes more definitely and specifically, to denote the
process of elimination of waste products from the body. This
process is frequently of the nature of secretion. Thus the
elimination of urea by the kidney is referred to as a " secretion,"
although the product itself is an " excretion." This is due to
Mic fact, now well established, that, although urea is present
in the Mood supplied to the kidneys, yet it is not simply filtered'
out of the blood, but is got rid of by a definite " secretory "
activity of the cells of the tubules. It can be shown that the
cell- arc capable of performing a definite chemical synthesis,
and t hi> is regarded as a sign, or one of the signs, of a " secre-
tory " activity; so that the term "secretion" includes
"ii. When the products of metabolism are of no
SWTviofl in the economy, they are called "excretions."

Among the Iic-t known of the secretions are the enzymes
and analogous products (such as will be referred to later as the
products of the "internal" secretions). But many skeletal

INTRODUCTORY 3

substances are often included in the same category ; such are
the calcareous shells of the Foraminifera, the chitinous cases
of insects, cell membranes, etc. Many authors would include
also certain intercellular substances, such as are found in the
fibrillar connective tissue, cartilage, and bone. Where, how-
ever, definite morphological structures are formed, it will be
well not to employ the term " secretion." Thus, the products
of the reproductive organs — the ova and spermatozoa — are
not to be included in this category.1

The term " secretion " in higher animals is ordinarily meant
to apply to the liquid or semiliquid products formed by the
glandular organs, or to the process of manufacture and setting
free of such products. The idea of secretion has, from the
earliest period of physiology, been associated with what are
called " glandular " organs. The term " gland " was applied
in the early days of anatomy to a very varied group of struc-
tures which resembled each other only in certain general
external characters.2 Thus, in the same general category
were included not only such typical glands as the pancreas,
submaxillary glands, and kidneys, but also the liver, spleen,
lymph nodules, reproductive organs, and, as they were dis-
covered, the thyroid body, the suprarenal capsule, the thymus,
and so on.

There is no need to describe a " gland " in any detail. We
may define a gland as a structure made up of one or more
cells of a special epithelial character which forms a product,
the secretion, which is discharged upon an epithelial surface,
such as the skin or a mucous membrane. This is the definition
of an ordinary or externally secreting gland.

The simplest type of a gland consists merely of a layer of
epithelial cells placed upon a basement membrane, while

1 The seminal fluid as a whole is, of course, to be looked upon as a secretion
coming partly from the testes, but chiefly from the accessory sexual glands.
The secretion itself is to be regarded as a vehicle for the transportation of
the spermatozoa, and possibly also for their nutrition. But whether or no
we view the testis as a gland having an external secretion, we shall see reasons
later for considering it to be a gland with an internal secretion.

2 " Die Classe der Driisen ist eine derjenigen welche eine Wissenschaft in
ihrer ersten Jugend leichtsinnig schaff t, und welche zu begrenzen und recht-
fertigen ihr in Zeiten der Reife grosse Sorgen und Miihe kostet. Mannhatte
anfangs nur die aiissere Form in Augeund nannte jedes weiche, rundliche,
gefassreiche und daher rothliche oder rothe Organ eine Druse, und das Gewebe
solcher Organe driisig (Henle).

4 INTERNAL SECRETION

ith tlu» nu'inbruiK' are found blood capillaries and lymph
spaces. When such a layer of epithelial cells becomes
invaginated, we have a tubule or saccule possessing a lumen,
and forming a simple tubular or saccular gland. Such glands
may be coiled, as in the case of the sweat glands, or the secretory
portions of the glands may divide, forming branched tubular
glands. This branching may occur again and again, until a
complicated structure is produced (compound tubular and
compound saccular for racemose] glands). In these glands
the terminal portion of the tubes or " alveoli " are the secre-
tory portions, while the tubes leading to the exterior are the
" ducts." The gland cell varies in its microscopic appearance,
according to its functional condition. In the submaxillary
gland and in the pancreas the variations are well known and
easily observed — the discharge of the zymogen granules and
the resulting changes in the appearance of the secreting cells.
Similar functional changes may be observed in the epithelium
of the intestine.

But it was discovered that some of these glands possessed no
duct, and they were therefore called " ductless glands," or in
German more usually " Blutgefassdriisen," or " Blutdriisen."
The latter names are, however, rapidly falling into disuse, and
the terms, " ductless glands," or " glands with an internal
secretion," are replacing them. The assumption was at once
made that, since these structures had the characters of glands,
they must " secrete." But since there was no communication
with a free surface, the hypothesis soon arose that in these
cases the specific secretion is passed into the blood-stream,
and both the process and the product were termed " internal
secretion." Thus a new conception in regard to the
physiological nature of secretion sprang into existence, and
tin- definition of a gland was extended so as to apply to any
structure made up of one or more cells of a special epithelial
character which form a produci^the secretion— which is

urged upon a free epithelial surface, such as the skin or
mucous membrane, or upon the closed epithelial surface of the
blood cavities. In some cases the material secreted by the
ductless glands has been supposed to be passed away not
directly into the blood-stream, but indirectly by means of the

fiatics. This was formerly believed to apply to the
specific secretion of the thyroid gland (see, however, p. 307).

INTRODUCTORY 5

In the case of the pituitary it has been supposed that the
secretion passes out into the cerebro- spinal fluid.

The "consensus partium " of the older medical writers was
supposed by Cuvier to depend on the activity of the nervous
system, and upon this alone ; but in 1775 Borden put forward
the doctrine that each organ has its " humeur particuliere "
which is necessary to the body as a whole.1

The first experimental demonstration of internal secretion
was undoubtedly that of Berthold in 1849. This writer
describes how he removed the testes from young cockerels and
transplanted them to the surface of the intestine, and found
that when this was done the young cockerel did not develop
in the way that castrated animals usually did, but that they
grew into normal cocks. Berthold concluded that the " con-
sensus partium " depends on the fact that the testes affect
the blood and the blood affects the whole animal.

The term " internal secretion " was, so far as I can ascertain,
first used in 1855 by Cl. Bernard, who described the glycogenic
function of the liver as the " secretion interne," while he
referred to the preparation of the bile as the " secretion
externe."2

The glycogenic function of the liver is not at the present
time usually treated among the internal secretions. It is
a special kind of arrangement for the storing of food material.
The glycogenic function of the liver is, however, intimately
related to certain internal secretions — notably those of the
pancreas and the adrenal body. Moreover, there are reasons,
as we shall see, for attributing to the liver other kinds of in-
ternally secreting activities.

. Since the time of Cl. Bernard there has been much loose
thinking and loose writing upon the whole subject of internal
secretion. A great tendency has often been manifested to
reach premature and unwarrantable conclusions. In mor-
phology and comparative anatomy ill-understood organs or

1 According to Gley, Borden does not express himself quite so definitely
as some writers have alleged.

2 " Chez les animaux la secretion glycogenique est une secretion interne,
parce qu'elle se diverse directement dans le sang. J'ai considere le foie, tel
qu'il se present chez les animaux vertebres eleves comme un organe secreteur
double. II semble reunir, en effet, deux elements secretaires distincts et il
represent deux secretions : 1'une externe qui coule dans 1'intestin, la secretion
biliare ; 1'autre interne, qui se verse dans le sang, la secretion glycogenique.

6 INTERNAL SECRETION

parts of organs have sometimes been hastily and incorrectly
assigned to the group of ductless glands, and in physiology
many processes which were imperfectly understood have been
prematurely classed among the internal secretions. In the
realm of clinical medicine this tendency has been even more
marked.

The study of the efficacy of various organs as remedial agents
arose in the time of Hippocrates, and Celsus and Dioscorides
recommended the use of various animal organs for the relief of
those symptoms in man which were considered to be due to
defective action of the same organ ; hence the use of the
pigeon's or wolf's liver in cases of hepatic disease, the brain of
the hare for tremors, the lung of the fox for dyspnoea, and the
use of rennet for disorders of the stomach and intestines. Pliny
recommended the use of the testicles of the donkey and of the
stag as aphrodisiacs ; and even at the present time there
remains the practice of employing castoreum for menstrual
disorder.1

> Much interest was aroused by the work of Brown-Sequard
in 1889 upon testicular extracts. This author put forward the
theory that all tissues give off something or other to the blood
which is characteristic or specific, and which is of importance
to the nutrition of the body generally. This may be regarded
as the real beginning of the modern doctrine of internal secre-
tion, and represents the actual view of many modern writers,
particularly in France. It will be seen that the view of internal
secretion which we shall advocate is modified from this, inas-
much as secretion is only to be attributed to certain special cells,
and not to all elements in the body.

Brown-Sequard's theory led to a revival of the old humoral
physiology, a partial dethronement of the nervous system, and
a return to the therapeutic methods called " opotherapy."
The "humours" of to-day are, however, very different con-
ceptions from those of the blood, the yellow bile, the black bile,
and the phlegm of Hippocrates and Galen. The modern con-
ceptions, indeed, could only have arisen with the growth of
modern chemistry. Both physiology and pathology are
becoming more and more chemical.

We shall see hereafter how very minute may be the quantities
of substances which come into play in physiological actio

se examples are quoted from Batty Shaw.

.

INTRODUCTORY 7

The phenomena of chemotaxis, of anaphylaxis, and of the
activities of ferments and toxins, all illustrate the importance
of the " chemistry of imponderables." Richet lays stress on
the significance of individual humoral differences. " Every
illness, every intoxication, has caused the formation, perhaps
the destruction, of a certain substance in the blood, and has left
its natural trace — a trace which is not effaced by years. Just
as there is a psychological memory — facts which are present
to the consciousness — so there is a humoral memory of all
preceding injections. As these injections differ in each person
in intensity, quantity, and duration, it follows that each
person differs from every other in the chemical properties of his
blood."

The irritability which rules the functions of the nervous
system is in itself a chemical phenomenon. Richet says :
' ' The living being is a chemical mechanism, and perhaps it is
nothing more." Such a sentence by an eminent modern
physiologist illustrates the trend of present-day physiology.
The attitude is reminiscent of that which became prevalent in
the earlier days of Huxley's work. The modern view of
" protoplasm "is, however, very different from the original one,
and the chemical attitude, critically restrained, may possibly
do more to explain the processes of life than all the painstaking
anatomical, microscopical, and mechanical investigation of the
past fifty years.

The theoretical basis for opotherapy and the practical value
of this method of treatment has varied very considerably in
different cases. Some flagrant examples of uncritical applica-
tion of the method are the treatment of heart disease by extracts
made from heart muscle, subcutaneous injections of extracts of
ciliary bodies in iritis, and of synovial membranes in diseases
of the joints.

Long ago the conception was formulated that "each single
part of the body, in respect of its nutrition, stands to the
whole body in the relation of an excreting organ."" The
term "excreting " was here used in Johannes Miiller's sense
(vide supra, p. 2), and is practically synonymous with the
modern " secretion." It is certain that the organs of the body
produce effects upon one another in many different ways by,
means of the products of their metabolic activity. Conveyed
in the blood-strearn to different parts of the body, these pro-

8 INTERNAL SECRETION

duet* may act as agents of augmentation, or possibly inhibition,
in regard to the special activities of various organs and tissues.
One of the best examples of this is the excitation of the respira-
tory centre produced during asphyxia by the circulation in the
blood of decomposition products normally eliminated in the
expired air. Again, when a large amount of protein is absorbed
and digested, the products formed probably stimulate an in-
creased metabolism in the body generally. When this occurs,
urea is formed by the liver in larger amount, and stimulates the
kidneys to increased activity.

In a certain sense, and in the direction just indicated, it is
evident that all the tissues and organs of the body form internal
secretions, for they all pass into the blood materials which have
been formed as products of their metabolism. Everything
which an organ or tissue absorbs from the blood and lymph it
gives out to them again in some form or other, except in so far
as it forms or separates a secretion which passes away by special
ducts. It is obvious that in this, the broadest sense of the
expression "internal secretion," nothing further is implied
than that the blood which leaves by the veins coming from an
organ or tissue contains different chemical substances from that
which enters by the arteries. A distinction might possibly be
made in some cases between katabolic products such as are
formed by all tissues, and synthetic products which are only
formed by some, and the term " internal secretion " might be
reserved for the latter. But this distinction could not be
maintained systematically, for it is quite conceivable that a
definite specific and powerful internal secretion might be
formed by a katabolic process. Some authors have included
intracellular enzymes among the internal secretions. These
are still more " internal " than the secretions usually so-called,
for they are not passed out of the cell in which they are pro-
duced. They differ from the exo-enzymes such as are found
in the secretions by reason of the fact that they are bound up
in the protoplasm of the cells, and, so long as the cells are alive,
can only exert their action intracellularly. When the cells die
tin- protoplasm breaks up, and the enzymes may pass into
solution. It is supposed that these enzymes are elaborate < 1 by
and used during the life of the protoplasm. It is possible that
in starvation they may bring about the solution of the tissue
protein-, and that the autolytic processes which take place

INTRODUCTORY 9

after death are due to their activity. It has been suggested
that life is nothing more than the sum-total of the activities of
the enzymes contained within the living matter. A theory
related to this has been suggested in a tentative form by Bayliss
and Starling. In a paper on the mechanism of pancreatic
secretion (a subject which will be referred to again later on,
vide infra, p. 59), these authors tested the hypothesis that the
products of metabolism of certain tissues would be found to act
as vasodilators only for certain tissues in functional relation to
those in which they arise, or, at all events, would act to a
greater degree on these tissues than on the rest of the body in
general. Results were obtained which tended to confirm their
view. Vincent and Sheen, however, obtained different results,
and suggested that the subject may be complicated by the
existence not only of specific vasodilators, but also of specific
vasoconstrictor substances, whose effects might be looked for
on those occasions when the injection of a tissue extract pro-
duces a rise of blood-pressure. This line of work has, however,
not led to any definite conclusions.

In some modern textbooks the conception of internal secre-
tion is extended beyond the limits which appear reasonable.
Thus, it is stated that the lymphatic glands "form an internal
secretion which consists of lymph cells, and these furnish the
blood with a supply of certain kinds of colourless corpuscles."
It has already been mentioned (supra, p. 3) that definite
morphological elements should be excluded from the category
of the secretions. Thus, the ova and spermatozoa are not
included among the external secretions, and the cells manu-
factured by the spleen, lymph glands, and bone-marrow must
be excluded from the group of internal secretions.

The conception of internal secretion has had far-reaching
effects in the realms of both physiology and pathology. Patho-
logists are now able to recognize the existence of new forms of
stimuli which influence growth and metabolism, and this either
in a positive or in a negative direction — that is to say, either in
the direction of augmentation or inhibition. Thus, to mention
one example, dwarfism and gigantism may be explained by
reference to certain internal secretions, or, at any rate, a plaus-
ible hypothesis may be furnished by such reference. It is
further to be noted that the function of each particular internally
secreting gland may be conceived as varying, or capable of

10 INTERNAL SECRETION

varying, from the normal in the sense either of hypersecretion or
h \ | '», * (ivt i» >n. In the former case the amount of augmentation
or inhibition may be greater than the normal ; in the latter
case the amount of augmentation or inhibition will be less than
the normal.

Various older pathological conceptions are now expressed in
trims of the modern "internal secretion." The "consensus
partium " of the early writers may be regarded as the prime
function of the internal secretions. The " formative stimuli "
controlling the " vegetative processes " of the body and the
" sympathetic " relationships between different parts of the
organism are now frequently regarded as depending upon the
integrity of the ductless glands or " correlative organs."

An interesting pathological development may be mentioned
in this place. Not only in various forms of physiological
hypertrophy are we to suppose there is a hypersecretion of a
ductless gland, but the same may happen in definite patho-
logical overgrowth ; so that it is even believed that in tumours
of the internally secreting organs — thyroid, pituitary, pan-
creas, adrenal — there may be actually a hypersecretion — that
is to say, that the tumour cells may secrete in a specific
manner.

Some evidence has been put forward for the existence of what
is described as " endocrinopathic inheritance," and the rela-
tion of such to the Mendelian theory has been considered.
But there is not sufficient evidence before us to lead to any very
definite conclusions.

There is a gradually increasing tendency to attribute many
cases of mental disease and many kinds of neuroses to changes
in the ductless glands. Certain writers have attached con-
siderable importance to a relation between endocrine dis-
turbances and the dental apparatus.

It must be confessed that we do not know the functions of
any one of the ductless glands in the same definite way in which
we know the functions of, for example, the lungs or the pan-
creas. Owing to the lack of boundaries and the absenc3 of
precise exploration in many regions, the territory of internal
secretion has been invaded by some irresponsible exploiters.
The tii in- ha- arrived for us to take our bearings and ascertain
our pnri-r po-ition with regard to the subject. In doing this,
< Hdi t \\ ill IM iimdi' to avoid dogmatism, even at the risk

INTRODUCTORY 11

of losing, or hesitating to accept, some tempting and plausible
theories.

In the following pages, after a chapter upon the definition
and limitation of the term "internal secretion," it will be
desirable to treat first of the general methods of investigation
of the subject of internal secretion and the validity of the con-
clusions which may be drawn from results obtained by such
methods. Afterwards the internal secretion of glands which
have also an external secretion will be dealt with. These are
the liver, the pancreas, the kidney, the intestinal glands, and
the gastric glands. Following these, the internal secretion of
the testis and ovary (with its corpus luteum l) will be described.
Then will follow in due order treatment of the function of the
" ductless glands " — namely, the adrenal body, consisting of
"cortex" and "medulla"; the thyroid body; the para-
thyroid bodies ; the pituitary body, consisting of the " infundi-
bular " or " nervous " portion and the " glandular : portion ;
the thymus gland ; and the pineal body.

Finally will be found a chapter dealing with the relation-
ships which exist between the various internally secreting
organs.

1 The corpus luteum may be looked upon as a " ductless gland," but it
will obviously be convenient to treat of it along with the ovary (see p. 75).

CHAPTER II

DEFINITION AND LIMITATION OF THE TERM "INTERNAL
SECRETION "

IT is obvious at the outset that the term " internal secretion "
ought to be employed in such a way that it corresponds as
far as possible to the term " external secretion," or secretion
by means of ducts. Secretion, as we have seen, is the prepara-
tion and setting free of certain substances, the raw material
for which is supplied by the circulating blood. Such secretion
is the function of certain specially differentiated cells — the
secretory cells.

It has already been mentioned that several authors, relying
upon the fact that the different organs and tissues of the body
have different functions, and therefore pour out into the blood
different metabolic products, have insisted that all these have
an internal secretion, and that this secretion is in each case a
specific one. But this, as pointed out by Kohn, is simply a
misuse of the term " secretion." Just as we have certain
tissues — namely muscle and nerve — highly specialized and
set apart for the functions of motility and conduction of
irritability, so we have certain other tissues also highly differ-
entiated and set apart for the purposes of secretion, and it is
only to these that we can with propriety ascribe the function.
Such are secretory cells and their accumulations, called
" glands." The secretory cells are in their origin and in their
character epithelial Secretory cells are highly specialized
epithelial cells. It is not necessary to insist on this criterion
in the case of externally secreting glands, because here it is
generally recognized ; but it is just as important in regard to
internal secretion if the term is to be defined with anything
approaching accuracy. The morphological sign of special
differentiation in gland cells is the presence of granules which
undergo periodical changes in number and position, according

12

DEFINITION OF "INTERNAL SECRETION" 13

to the stage of activity of the gland. It is not, perhaps,
possible to insist on the recognition of granules as definite as
those in the pancreatic cells before we admit a structure into
the category of internally secreting glands, but it is essential
that the constituent cells should have the general character
of glandular — i.e., secretory — cells. This is in some instances
not altogether an easy matter to determine, and, as we shall
see later on, there is still some discussion as to whether such a
tissue as the chromaphil may reasonably be supposed to have
a secretory function. That a discussion of this kind should
arise in connection with a structure generally supposed to be
internally secretory shows how little we know about the actual
act of secretion in such a case (see p. 216 et ff.).

We conclude, then, that secretion (internal or external)
represents a highly specialized grade of metabolic activity,
and should be distinguished as rigorously from general meta-
bolism as the contraction of muscle from general motility
(Kohn).

Kohn gives a very excellent illustration of the two processes,
external secretion and internal secretion. The manufacture
of the bile and its conveyance into the duodenum is a secretion
in the ordinary sense of the word — an " external" secretion.
When we obstruct the bile ducts, the secretion goes on just
the same ; but now the bile is conducted into the blood-stream,
and we get an " internal secretion " of bile. This shows that
the products of secretion can, under certain circumstances,
pass into the circulation. And we can be tolerably certain
that this process can in some tissues occur normally. As we
have seen, it is sometimes difficult to decide whether a given
tissue is glandular or not, and therefore whether we ought to
ascribe to it a secretory function. Thus, Kohn admits the
"cortex" only of the adrenal among the glands, while he
insists that the " medulla " consists of " chromaphil cells,"
which are not secretory, not epithelial, and therefore cannot
secrete. This point will be referred to later and more fully
under the head of the adrenal body (see p. 216 et ff.). It may
be well, however, to remark in passing that it is from the
medulla, and not the cortex, that the active principle is
obtained.

We are now in a position to define internal secretion. The
process consists in the preparation and setting freq of certain.

14 INTERNAL SECRETION

substances of physiological utility (the raw materials for which
are supplied by the circulating blood), by certain cells of a glandular
type ; the substances set free are not passed out on to a free surface,
but into the blood -stream.

According to this definition, the products of ordinary meta-
bolism, and even the special products of metabolism arising
in such kinds of highly specialized tissues as muscle and nerve,
are excluded from the internal secretions.

We have seen that externally secreting glands sometimes
manufacture and pour out substances which are waste products,
and are no longer of any use in the economy. These are
''excretions." It is possible that some of the substances
elaborated by the internally secreting glands may also have
to be placed in the category of " excretions." They would
then be " internal excretions " (see p. 38).

The terms " ductless gland " and " Blutgefassdriise " were
originally applied to a very varied group of structures, including
the thyroids and parathyroids, the adrenal bodies, the thymus
gland, the pituitary body, the spleen, and the lymphatic glands.
But some of these — the spleen and the lymphatic glands —
have not a "glandular" structure; that is to say, they do
not consist of epithelial " secreting " cells, and belong to quite
a different category of organs, namely, the " haemolymph "
series. The structures usually included at the present time
under the title of " ductless glands " are the thyroid gland ;
the parathyroid glands ; the adrenal body, consisting of
" cortex " and " medulla " ; chromaphil cells and bodies in
different regions ; the pituitary body, consisting of the " in-
fundibular " or " nervous " and the " glandular " portion ;
the thymus gland; and the corpus luteum.1 The thymus
originates as an epithelial structure, but subsequently appears
to become largely converted into a lymphoid organ.2 Its
morphological characters are therefore unique.

It is believed that these " ductless glands " manufacture
and pour, directly or indirectly, into the blood-stream some
robfltanoe <>r -ubstances which are of service in the economy,
< -it her by supplying a need or by destroying other substances
which arc needless or positively harmful. This last function

1 It 'm |.ossil,|.- that w. may have to add to the list the " Glandula insularis

of N. Peii'l-'.
* See, however, discussion on p. 329.

DEFINITION OF "INTERNAL SECRETION" 15

—that of " Entgiftung," an "antitoxic" function — is fre-
quently ascribed to the thyroid, though in this, as in other
cases, the two conceptions are not necessarily antagonistic.
We can readily imagine that a gland may manufacture a
definite internal secretion whose active principle may be
competent to destroy poisonous products in the blood-stream
or in some part of the body.

It is, perhaps, desirable to point out at this stage that the
term "internal secretion" has been used too generally and
too confidently in many cases. Our knowledge of internal
secretion is not to be compared in accuracy and definiteness
with our knowledge of "external" or ordinary glandular
secretion. Thus, in the case of the submaxillary glands, we
can observe the various conditions, loaded or unloaded, of
the gland cells. We can watch the flow of the secretion,
and regulate it by stimulation of nerves. We can note changes
in the volume and blood-supply of the gland concomitantly
with the act of secretion. Finally, we can recognize an
" enzyme " in the fluid secreted, and are familiar with its
chemical action on the food as a process of digestion. Very
different is the case, for example, of the medulla of the adrenal
body and of the chromaphil tissues generally. Here com-
paratively little is known of changes in the cells indicative of
the act of secretion,1 and the very fact that any secretion is
poured into the blood-stream can only be shown, if shown at
all, by laborious and indirect methods. It must be confessed,
as a matter of fact, that some of our conceptions in regard to
internal secretion are worthy to rank little higher than plausible
hypotheses.

But a typical gland having a duct and performing " external
secretion" may possess also, according to modern views, the
function of "internal secretion." This applies to the liver, the
pancreas, the kidney, as well as the intestinal and gastric glands.
The liver has, besides the formation of the bile and the gly-
cogenic function (which, owing to its highly special character,
is usually not treated along with the internal secretions),
the still further duty to render innocuous the end-products of
protein metabolism. One of these end-products is ammonia ;
this is converted in the liver into urea. So that the distinctly
poisonous ammonia is transformed in the liver into the com-

1 See, however, pp. 235, 237.

16 INTERNAL SECRETION

paratively harmless urea. This is an example of what Biedl
calls " negative internal secretion." Since the process is a stage
in the elimination of waste material, it might be called " internal
excretion " (vide supra, p. 38).

INrently discovered and extremely interesting examples
of internal secretion are furnished by the mechanisms of pan-
creatic and gastric secretions (vide infra, pp. 59 and 65).

There is considerable reason for ascribing an internally
secreting function to the testis and to the ovary (vide infra,
pp. 66 and 75). Though these are not glands in the usual
acceptation of the term, yet many of their constituent cells
are of the "glandular," "secretory" type.

Lane-Clay pon and Starling reported that injections of
extract of foetus into a virgin rabbit causes growth of the
mammary glands. Starling suggested the name " Hormone "
(from 6p pa to = I excite or arouse) for these various substances
which act as chemical messengers, and the name has in recent
years become generally adopted. Foa finds that injection of
extract of foetal calf causes some mammary growth in rabbits.
It is concluded, therefore, that the effects described by Lane-
Claypon and Starling are not specific for only one kind of
animal.

Heape points out that it is well known that virgin animals
sometimes produce milk. So that it seems clear that the
beginning of the development of the gland dates from some
point of time prior to or during pro-oestrum or oestrus, and
occurs normally quite apart from pregnancy, and that since
the full functional development of the gland may be experienced
by virgin animals, this must occur without any stimulus from
a foetus. Heape believes that the source of the stimulus which
excites the development of the mammary glands is to be found
in what he calls " gonadin," secreted by the ovary at that
time, if not in the "generative ferment," which, he holds,
governs the activity of the generative glands.

There is now some considerable evidence that the stimulus
to growth of the mammary gland arises from the corpus
luteum. This will be referred to again and more fully under
the head of " The Internal Secretion of the Ovary and the
Corpus Luteum " (vide infra, Chapter IX., Sect. C., p. 75).

Arguing from the mammary gland experiments, and from
those upon the mechanism of pancreatic secretion (vide infra,

DEFINITION OF " INTERNAL SECRETION" 17

p. 59) performed in conjunction with Bayliss, Starling has
made some interesting generalizations upon this type of
mechanism. He points out that in the normal life of the higher
animals, looked at as a series of reactions to environmental
change, the nervous system plays such a predominant part
that we are in danger of overlooking more primitive means of
co-ordination between different parts of the body. Starling
further points out that in the lowest animals, before the appear-
ance of a central nervous system, it is by chemical means that
co-adaptation of function is achieved. As examples he
mentions the movement of phagocytic cells towards an irritant,
the chase for food, the escape from noxious environment, or
the approach of sexual cells. In these cases the mechanism is
chemotaxis. The process of action of these stimuli must be
slow, and the development of a blood-circulation is necessary
in order to quicken it. But before this development occurs,
the need for quick reactions has determined the setting apart
of special reactive cells ; we see, in fact, the rudiments of the
nervous system. The whole history of the evolution of man
and the higher animals centres about this nervous system.

But in some cases still, where there is no necessity for a
specially rapid reaction, as, for example, in the adaptation
of the activities of the digestive glands to the presence of food
in the alimentary canal, one might expect to find, as Bayliss
and Starling actually found, that chemical means of stimula-
tion are employed. Among the various hormones Starling
enumerates the gastric. and pancreatic hormones, as well as
similar bodies which determine the secretory activity both of
the liver and the intestinal glands, adrenin, thyroiodin, and
the substance secreted by the foetus during pregnancy. He
prophesies that with increasing knowledge the list of these
messenger substances will be largely extended, he points out
that they are comparable in many respects to the alkaloids,
and he intimates that the practice of drugging would therefore
seem to be not an unnatural device of man, but the normal
method by which a number of the ordinary physiological
processes of the organism are carried out.

How far this attitude may be justified by future discoveries
must at present remain doubtful, but it certainly represents
the view of a large number of modern workers upon the subject
of internal secretion. The nervous system is no longer the

2

18 INTERNAL SECRETION

only controlling influence to be reckoned with in explaining
the bodily functions, and especially is this the case with the
co-ordination and interactions of many of the chief functions
of the body. It is even possible that the nervous system itself
may be controlled by chemical stimuli.

Leyton has performed some experiments to test the hor-
mone theory of the causation of new growths. The work
of Starling and Claypon upon the internal secretion of the
foetus in relation to the mammary gland suggested that
perversion of internal secretion might have some relation
to the formation of new growths. Such a hypothesis
presupposes the existence within the organism of separate
substances which stimulate the normal growth and repair
of the several organs and tissues, and that each substance
is secreted either by its own special organ, or by another organ
or tissue. Under the former supposition, so the authors
imagine, malignant growth of such tissue would be very
unlikely. Under the latter the result might be brought about
either by hypersecretion of the substance or by insufficient
absorption thereof, whereby in either case the still absorbing
tissues would receive an excess. Given an excess of hormone
in the organism, together with a lesion or irritation of the tissue
complementary to the hormone, unlimited growth might
result. It is further conceivable that a real hypersecretion
acting on otherwise normal tissue might lead to the formation
of a quickly increasing growth, while the relative hypersecretion
resulting from diminished absorption from an atrophied senile
membrane might account for slow-growing tumours.

The author inoculated previously refractory rats with
pieces of glandular organs from known susceptible animals,
along with sarcoma. The results in two experiments seemed
to show that parotid gland is able to assist sarcoma growth
in rats otherwise insusceptible. He further excised the
parotid along with inoculation with sarcoma to see if the
growth of the tumour was inhibited. The results were not
very definite.

Ehrlich thinks that there may be substances circulating in
the organ i> in which may stimulate the body cells to resist the
athreptie influence of cancer cells. Askanazy believes that
certain hvperpla>ias in the genital organs subsequently to the
formation of tumours in the ovary, testis, or pineal body, may

DEFINITION OF " INTERNAL SECRETION " 19

be due to the influence of embryonic tissue formed by the
tumour.

The object of the present chapter has been to define as
accurately as possible what we mean by internal secretion.
The point of greatest importance is to limit our conception
of internal secretion so as to include only those processes which
are comparable to ordinary or external secretion. We must
only allow of the hypothesis of internal secretion in cells which
are of a glandular type, and we must diligently search for all
signs of cellular activity indicative of secretion. We must
further strive to study the process of secretion itself, to discover
the products of secretion, to trace them out into the blood-
stream, to follow them to their place of activity, and to find
their ultimate destination.

In the next chapter we shall study some of the methods of
such investigations.

CHAPTER III

GENERAL METHODS OF INVESTIGATION AND THE VALUE
OF THE RESULTS WHICH MAY BE OBTAINED
BY SUCH METHODS

IN the investigation of a subject of such wide physiological
import as internal secretion, it is natural that all methods
employed in general physiological research should be utilized
as occasion demands. The usual methods of experimental
physiology, recording devices, and all the appurtenances
belonging to the graphic method, are in regular requisition.
Physiological chemistry is no longer a mere handmaiden, but
is rapidly becoming mistress of the situation. No attempt
will be made to pass in review all these details of scientific
biological technique. A few of the more important methods
which have been of especial service in the development of the
subject of internal secretion will be briefly referred to, and an
opportunity will at the same time be seized to deal with a few
side issues which could not conveniently be treated in any other
chapter.

The subject of internal secretion is, of course, a physiological
one, but we shall again and again have occasion to make
reference to pathological methods and pathological data. This
is perhaps more emphatically the case than in any other chapter
in physiology, because such a large proportion of our knowledge
of internal secretion is derived from the realm of pathology,
not only from human pathology, but also from experimental
pathology, the result of experiments upon animals.

The fact discovered by Addison in 1855 that the symptoms
nf what is nn\\ known as Addison's disease are due to a lesion
of t he adrenal bodies is still one of the most important pieces of
Information we possess about these structures. The association
of <l<-fr( -t ivr thyroid development or atrophy with cretinoid and
myxo2dematous conditions is still the sheet anchor of our

30

METHODS OF INVESTIGATION 21

knowledge of the thyroid apparatus. The same may be said
of the pituitary body and acromegaly, and doubtful as may
be the connection between enlarged thymus and sudden death
in infants, yet this is almost the only allegation which points
to the organ having any definite function.

Experimental pathology in the form of extirpation experi- •
ments has been largely employed in the attempt to elucidate
the functions of the glands with an internal secretion. The
method has undoubtedly brought to light many important
new facts. It has revealed, for example, the fact that certain
of these glands, such as the adrenal and the pituitary, are
essential for life, and that removal of the thyroid apparatus
entails in most animals very serious results. It has taught
us, further, that extirpation of the thymus is without obvious
effects. But the results obtained by different observers have
often been very contradictory, and the method of complete
extirpation has several drawbacks. In the first place the
technical difficulties are always very considerable, and are
often wellnigh insurmountable. This applies especially to the
pituitary body, though modern surgical skill seems at last to
have triumphed (see p. 361). It is very frequently impossible
to remove just the organ one wishes to remove without doing
considerable damage to other tissues. Thus the extirpation
of the adrenal bodies and the thyroids must always involve
considerable injury to nervous structures and bloodvessels.
This consideration must largely account for the contradictory
results obtained by different observers. The difficulty of
removing the parathyroids without considerable injury to
the thyroids can scarcely be overcome, and the successful
removal of the pituitary cannot have been performed by more
than a very few observers.

Again, we must remember that complete removal of an
organ, even if successful from a surgical standpoint, is, owing
to its suddenness, an event which can never happen in nature,
and can never happen in pathology, and we must be cautious
in interpreting the results. The method, however, under
modern surgical conditions, is capable of fruitful results, for
animals do not appear to suffer to any considerable degree
from surgical shock.

Extirpation experiments performed in a series of steps at
successive operations are more valuable than when the whole

22 INTERNAL SECRETION

of an organ (or both organs in the case of bilateral structures)
is removed at once. Better still and more fruitful of results
are operations in which the organs are crushed, damaged, or
infected artificially with the germs of disease, or inoculated
with toxins, or partially destroyed by chemical poisons, or in
which the blood-supply is interfered with to a more or less
complete degree.

Further, extirpation experiments, as usually performed,
are only likely to give us useful information in cases where the
organ or tissue extirpated normally provides an internal
secretion which is needful for the body as a whole. If we
remove the submaxillary glands, for example, we find that the
animal is apparently unaffected, and the same applies to the
mammary and gastric glands. But we are not justified in
concluding from these experiments that the glands in question
have no internal secretion, but merely that if there be such a
secretion, it cannot be regarded as essential to the body as a
whole. As a matter of fact, it is now believed that the gastric
mucous membrane secretes a specific hormone (vide infra, p.
65), and the same has been alleged to be the case with the
salivary glands.

Proceedings of a reverse character, such as grafting, feeding,
and subcutaneous and intravenous injections, have also been
extensively employed in the search for the functions of the
ductless and other glands supposed to possess an internal
secretion. Experiments in grafting have been chiefly carried
out in connection with the thyroid and parathyroid glands,
and the reproductive organs. Some work in the same direction
has also been done with the adrenals. The object of these
experiments has been to replace the extirpated tissue by freshly
implanted tissue of the same kind, either in the original
situation or in some other part of the body. The earlier
attempts were not very successful, and the effects were of a
temporary character. The graft became absorbed, and so the
final result was no more than that of the administration of a
certain dose of the substance of the gland. Some recent
experiments, however, have been more successful, and have
yielded interesting and important results. An account of
these grafting experiments will be given in their appropriate
place under the heads of Thyr^d, Adrenal, and Reproductive
Organs.

METHODS OF INVESTIGATION 23

/ Feeding with fresh tissues, or with tissue extracts prepared
in various ways, has been very extensively employed. The
therapeutic method called " opotherapy " is based upon the
principle that the active substance, the " hormone," or the
" internal secretion," is absorbed unaltered into the circulation.
This is apparently a matter for discussion in some cases, as,
for example, in the case of the adrenals (vide infra, p. 211). On
the other hand, feeding with thyroid glands or thyroid extracts
(or even with the so-called active principle, iodothyrin or
thyroiodin or thyroxin [Kendall]) has proved a most valuable
mode of treatment in cases of cretinism and of myxcedema,
and has, besides, been used by physiologists for experimental
purposes. But our knowledge of the functions and internal
secretions of most of the glands, and especially of their true and
intimate relationships to morbid processes and pathological
conditions, is still so limited and inexact that it can hardly be
expected to furnish guidance in treatment. More especially
is this true in regard to the pituitary body, the thymus, and
even the pancreas. Among the tissues which have been con-
sidered from the standpoint of opotherapy or organotherapy
are, in addition to the thyroid apparatus and the adrenals,
the glands of the alimentary tract, the ovary, the testis, the
pituitary body, the thymus, the spleen, the bone-marrow, the
lymphatic glands, muscle, nerve, and the placenta.

In feeding experiments the effects produced upon metabolism
have been carefully studied in many cases. Thus the addition
of thyroid substance to the normal dietary of growing rats
causes a great increase of food consumption, with alteration of
growth and retention of nitrogen in the body. At the same
time the nitrogenous metabolism is greatly increased.

Gudernatsch has carried out a very interesting series of
experiments showing that certain mammalian ductless glands,
when given as food, can exert a decided influence on the growth
^ and differentiation of amphibian embryos, the thyroid stimu-
lates differentiation, but it lacks the power to cause growth.
The thymus and spleen stimulate growth, but are wanting in
power to excite differentiation.

A word of caution is necessary in respect to the mode of
preparation of commercial gland substances. In order to
obtain a clean, easily manipulated product, it is usual to re-
move all fatty matters before desiccation. It is possible,

24 INTERNAL SECRETION

<-]x c ially in the case of the adrenal cortex, that some useful
principles may thus be removed (see under Adrenal Bodies,
p. 203).

S/ilx-tilaneous injections of extracts (either fresh or after
various modes of extraction and preparation) was the method
which first aroused modern interest in the subject of internal
S<H ivtion. The work of Brown-Sequard in 1889, upon testi-
cular extracts was, perhaps, open to some criticism, but it
served to stimulate research in various directions, and led
directly or indirectly to very valuable results. Subcutaneous
or iniraperitoneal injection of all other tissues and glands has
since been carried out, and the results will be referred to in
their proper place. By far the most striking are those obtained
by the injection of extracts of the adrenal bodies (vide infra,
p. 158).

Hypodermic injection of the non-coagulable portion of
aqueous extracts of thyroid, parathyroid, thymus, spleen,
and liver increases both gastric secretion and the movements of
the stomach, while those prepared from the pituitary body
and the adrenal inhibit the flow. Pancreatic extract increases
the flow of gastric juice. The same kind of extract made from
liver causes a marked flow of pancreatic juice. Extracts of
thyroid and thymus act less powerfully in the same direction,
while those of the pituitary, the parathyroid, spleen, and
pancreas are inert. Adrenal extract inhibits the flow. There
is not sufficient evidence to warrant us in regarding these
effects as manifestations of internal secretion.

Intravenous injection does not appear to have been much
IIM-'| in the study of internal secretions until the publication
by Oliver and Schafer of the extraordinary effects upon the
heart and circulation produced by the injection of adrenal
extracts, or in more modern phraseology, by extracts made
from the chromaphil tissue included in the adrenal (see p. 165
and Figs. 16, 36, 39-43). Since that time, however, the
method has been used perhaps to a greater extent than any
other. Numerous observers have tested the effects of every
imaginable organ and tissue in the hope of finding some remark-
able substance in the extracts comparable in its effects with
adrenin from chromaphil tissues. Briefly, the results have
been as follows. One other tissue besides the chromaphil—
n inicly, the nervous portion of the pituitary— has been found

METHODS OF INVESTIGATION 25

to contain a pressor substance. All other organs and tissues,
but especially nervous tissues, contain a depressor substance,
or depressor substances (see Figs. 1-8).

The subject of intravenous injection of tissue extracts has
played such a large part in connection with internal secretion
that it must be dealt with in some detail. Considerable
naivete has been displayed by many observers, both as to
details of method and as to the interpretation of the results
obtained. Thus, for example, it has too often been assumed
that a slight rise or fall of the blood-pressure obtained after
injection of a fluid into the circulation is in reality due to some
specific action of the extract, and not due, as it very likely is,
to its effects qua fluid, or to its temperature, or to the rate of
injection, or to some other adventitious circumstance. Again,
it has been rashly concluded in many cases that because an
extract of a certain tissue or organ produces a certain effect,
for example, on the blood-pressure, that this is evidence of an
internal secretion on the part of the tissue or organ in question.
This unjustifiable attitude is being continually maintained.
Thus, Livon divides the glands of the body into two groups,
"hypertensive" and " hypotensive," according as their
extracts when injected into the circulation of an animal cause
a rise or a fall of the blood-pressure. The adrenals, the
pituitary, the spleen, the kidney,1 and the parotid, are placed
in the former group ; the liver, lung, pancreas, thymus, ovary,
and testis in the latter.

As we have seen, the remarkable discovery of Oliver and
Schafer stimulated numerous observations upon the special
physiological effects of extracts made from different organs
and tissues. These authors noted, in addition to the effects
of adrenal extracts, that pituitary preparations also produce
a rise of blood-pressure. And we may state at the present
time, with some degree of certainty, that these are the only
two tissues in the body an extract of which produces pressor
effects.

Professor Schafer also, working in conjunction with the
present writer, found that a depressor substance is also present
in pituitary extracts, and noted " a certain similarity of physio-

1 It is doubtful in any case whether the spleen and kidney would be in-
cluded in the pressor group. (In regard to the kidney, see p. 52.)

26

INTERNAL SECRETION

logical action between nervous matter and the infundibular
part of the pituitary." A striking result in some of our experi-
ments was the causation of very extensive irregularities in the
blood-pressure curve after injection of brain extracts. Schafer
and Moore had previously noted a lowering of blood-pressure
on injection of brain extracts, but they did not lay any stress
on the observation. Professor Osborne and the author worked
out fully the effects of nervous-tissue extracts, and found that
extracts made from all parts of the nervous system produce a

marked temporary fall
of arterial blood-pres-
sure, which can be ob-
tained after section of
both vagi and after
administration of suf-
ficient atropin to abol-
ish vagus action (see
Figs. 1 to 5). We came
to the conclusion (con-
trary to that of Mott
and Halliburton) that,
although choline was
present in small
amounts in the ex-
tracts, the depressor
effect was not due to
the presence of that
substance. The reason
for this view was that,
whereas after the ad-
ministration of atropin

to an animal, choline always produces a rise of blood-pres-
sure, these extracts, on the contrary, always produced a fall
(see Figs. 3-5).

Figs. 1 and 2 show the effects of extracts of brain and spinal
cord upon the blood -pressure, the volume of the intestinal wall,
the volume of the hind-limb, and upon the contraction of the
auricle and the ventricle of the heart.

Figs. 3, 4, and r> show the difference in action between

nervous-ti— in extracts and choline in an atropinized animal.

Vine. 'hi and Shern found that a depressor substance can be

Fio. 1. — Dog. A. C.E., morphine, curare, arti-
ficial respiration. Loop of intestine in air
plethysmograph. Injection of 1-5 c.c. de-
coction cat's brain (Osborne and Vincent).

METHODS OF INVESTIGATION

27

extracted, not only from nervous tissues, but also from all kinds

of muscular tissue, kidney, liver, spleen, testis, pancreas, ovary,

and lung. They note, also, that other observers have extracted

a depressor substance

from thyroid, thymus,

adrenal, and pituitary

body.

Figs. 6 and 7 show the
effect of injection of ex-
tracts of muscle. Fig. 8
shows the effect of brain
extract for the purpose
of comparison.

By this time it had
become tolerably clear to
the present writer that all
animal tissues impart to
watery or saline extracts
a substance or substances
which, when injected into
the circulation of a living

animal, affect the arterial

blood-pressure. The effect

produced by these sub-
stances is depressor, with

the exception of the

medulla of the adrenal

[ ' ' paraganglion supra-

renale " (Kohn)], other

groups of chromaphil

cells, and the infundi-

FIG. 2. Dog. A.C.E., morphine, curare,

artificial respiration. Hind -limb
plethysmograph. Hooks in auricle
and ventricle. Injection of 2 c.c.
saline decoction spinal cord (Osborne
and Vincent).

bular portion of the
pituitary body. It had
also been rendered prob-
able that these depressor
effects of an extract are
not to be regarded as an indication of an internal secretion on
the part of the tissues in question. This seems now to be
generally recognized, and the view is adopted in the majority
of textbooks.

It is naturally of some interest and importance to ascertain

INTERNAL SECRETION

FIG. 3. — Dog. A.C.E., morphine, curare, artificial respiration, atropin.
The first injection = choline. The second = saline decoction of brain.
(Osborne and Vincent).

FIG. 4. — Cat. A.C.E., morphine, atropin. First injection = 1 c.c. of 0-2
per cent, choline. The second = 1 c.c. brain decoction (Osborne and
Vincent).

FIG. 6.— Rabbit. A.C.E.,
The second =

morphine, atropin.
brain decoction (Osborne and Vincent).

First injection = choline.

METHODS OF INVESTIGATION

29

as far as possible how far the
active substances are identical
in different tissues. The pre-
sent writer, working in con-
junction with Dr. Cramer,
found that there are two groups
of substances in watery ex-
tracts of nervous tissues, which,
when injected into the veins of
an animal, lower the blood-
pressure. Both of these groups

FIG. 7. — Dog. A.C.E., morphine, curare, arti-
ficial respiration. Upper curve = intestine ;
middle'curve — limb ; lower curve = carotid
blood-pressure. Injection of 5 c.c. saline
decoction striped muscle of rabbit (Vincent
and Sheen) .

FIG. 6. — Dog. A.C.E., mor-
phine. Injection of 5 c.c.
" protein " extract of
striped muscle (Vincent
and Sheen).

are soluble in water.
One group is easily
soluble in absolute
alcohol, and the other
scarcely soluble in this
fluid. The alcoholic
solution contains two
depressor substances ;
one of them has its
effect abolished by
atropin, the other has
not. The latter is
the more powerful,
but rather the less
soluble in alcohol.
The alcoholic solution
gives an abundant
precipitate with plati-
num chloride. Only a
small part o'f this is
readily soluble in
water, and on purify-
ing gives octahedra
and prismatic crys-
tals. The greater part
of the precipitate

30

INTERNAL SECRETION

consists of the platinum chlorides of potassium and ammonium.
The octahedra are the ammonium salt. Since the prisms have
a percentage of 32' 8 — i.e., 1'2 per cent, higher than would
correspond to the platinum salt of choline — and since the free
base has a physiological action slightly different from that of
choline, it would follow that the base is not choline, but a
choline-like body, perhaps a di-choline anhydride.

Fio. 8. — Dog. A.C.E., morphine, curare, artificial respiration. Upper curve =
limb volume ; middle curve = intestine ; lower curve = carotid blood-
pressure. Effect of injection of 5 c.c. alcoholic extract of rabbit's brain
(Vincent and Sheen).

Apart from this choline-like body, we did not find any choline
as such in brain extracts, and we fully confirmed the view of
Osborne and Vincent, and Vincent and Sheen, that the de-
pressor effects of nervous-tissue extracts are not due to choline.
We stated that the chemical and physiological tests recom-
mended for tin- -u I stance in pathological blood cannot be
n -lied upon : indeed, normal blood gives both the octahedral
crystals and the depressor effect on the blood-pressure,

METHODS OF INVESTIGATION 31

In regard to the chemical nature of the depressor substance
in tissue extracts, nothing positive has yet been discovered.
It has been suggested that it may be histamine (ft — Iminazol-
ylethylamine) but more recent investigations have rendered
this hypothesis untenable.

It is doubtful whether the presence of these depressor sub-
stances in tissue extracts has any physiological significance.
Recent literature supplies many contributions from authors
who become impressed by the fact that some organ (such as a
lymphatic gland) yields a depressor substance to extracts, and
therefrom rashly assume that it is the function or one of the
functions of the organ in question to pour out this depressor
substance as. an internal secretion to minister to the needs of
the economy.

Abelous and Bardier find in normal urine a substance which
raises the blood-pressure. This substance they call " uro-
hypertensin," but it is satisfactory that so far there has been
no suggestion that this is any kind of * ' hormone ' ' or evidence
of an "internal secretion."

The physiological activity of the amines which are formed
when carbon dioxide is split off from amino-acids, as, for
example, by putrefaction, ought perhaps to be referred to
here. ABelous first noted the presence of pressor principles in
putrid meat. These have since been identified by Barger and
Walpole as isoamylamine, phenyl-ethylamine, and p. hydroxy-
phenylethylamine .

But, of course, the effects upon the blood-pressure are not
the only actions of tissue extracts which have been studied.
The influences which such extracts exert upon the heart are
studied by recording directly the heart movements either in
the body or isolated in the lower vertebrata, and in mammals,
and various forms of tonometers and plethysmographs have
been employed for registering changes in the volume of the
heart. The muscle-nerve preparation may be used to demon-
strate the action of the extracts upon muscle and upon nerve.
The volume of organs, the rate of flow of secretions, and the
movements of muscular tissues, are also observed. In fact, all
the modern methods of observing and recording changes in
physiological conditions are constantly employed for the study
of the action of tissue extracts.

An interesting method of studying the action of animal

32 INTERNAL SECRETION

extracts on the peripheral vessels was employed by Oliver.
The vessels of the frog's mesentery were observed before and
after the application of a drop of normal saline (as a control)
and of normal saline containing 1 per cent, of the organ dried at
38° c. — the simple saline and the saline extract being exactly
of the same temperature (16° C.). Throughout each observa-
tion the micrometer scale was kept in situ over exactly the same
portion of an artery and its companion vein ; and when any
change of calibre was observed to follow the application of the
saline extract its duration and degree were noted until the
calibre was restored, and it was accepted as the effect of the
extract when it exceeded the normal variations and when it was
practically immediate, was invariable, and when it lasted a
certain uniform time, and was succeeded by restoration of the
calibre. There was not much effect except in the case of
adrenal extracts. This constricting effect of adrenal extract
on the peripheral vessels may likewise be observed by the
unaided eye by setting up inflammation of the conjunctiva in a
rabbit (as by touching the eyeball with a glass rod dipped in
acetic acid) and then dropping the extract on the injected
surface, when the redness quickly vanishes, and remains absent
for about half an hour.

But even if, on injection of an extract of an organ, we get
several different effects on the organism, it is obvious that we
have no right to assume on these grounds alone that the organ
yields an " internal secretion." This may be suspected when
the extract yields a substance having very special physiological
actions, but can be definitely stated only when the organ con-
sists of glandular " secreting " cells which show histological
signs of activity (granules, etc.), and when the blood which
leaves the organs by its veins can be found to contain the same
active principle as the organ itself. To make the evidence for
internal secretion complete, it ought to be possible to recognize
in the symptoms produced by extirpation of the organ the
direct and reasonable effects of absence of the active principle,
the internal secretion, and to remove these symptoms by re-
placing the organ in some other part of the body or by admin-
istering the active principle in some form or other.

Isolated organs and tissues are now employed frequently in
nnlrr to tr-t the effects upon them of extracts of the various
organs. Thus a strip of uterine wall or of different portions of

METHODS OF INVESTIGATION 33

the intestine may be suspended from the short arm of a writing
lever in a cylinder containing Locke's fluid at the proper
temperature. Then the fluid may be replaced by any other
(such as an organ extract) whose action it is desired to record.
Various organs yield extracts which will produce distinct
effects upon such muscle preparations. Many of these have
been shown not to be specific. The more important of them
will be referred to again under adrenal bodies, pituitary, etc.
This method is one of extreme delicacy, and great care should
be taken that proper control experiments are carried out. The
preparations are very susceptible to slight changes of tem-
perature, slight accidental mechanical stimuli, and in all
probability the rate of change of dosage of the active substance
makes a great difference to the result. Distinct effects are
reported to be noticed by this method when adrenin in dilutions
of 1 : 500 millions is employed.

The electrical response as an index of glandular activity has
been employed to study the activity of the thyroid gland. By
preliminary experiments with the submaxillary it appeared
that the electrical change is a manifestation of the secretory
process and not of anything else. The results of these
experiments will be described in the chapter on the thyroid
(p. 308).

Abel has recently introduced a method which he calls
" vividiffusion," which seems likely to be of great service in
the study of the internal secretions. An artery or vein is
connected by a cannula to an apparatus made of celloidin in
the form of tubes immersed in a saline solution, and providing
for the return of the blood to the animal's body by another
cannula attached to a vein. The tubes and cannulse are filled
with saline solution. This is displaced into the body by the
inflow of blood when the circulation in the apparatus is estab-
lished. The blood leaving the artery flows through a perfectly
closed system and returns to the body within a minute or two,
while the diffusible substances which it contains can pass out
through the walls of the tubes. Coagulation of the blood is
prevented by means of hirudin. If, then, the hormones are
diffusible substances they may be separated from the circulating
blood by this method.

The employment of cytoioxic sera as a means of investigating
the tissues concerned in internal secretion has so far not yielded

3

34 INTERNAL SECRETION

any results of importance. The antibodies obtained are not
specific for any particular organ or tissue.

It seems to the present writer that one of the methods which
will yield the most valuable results in the near future is the
oldest of all — namely, careful study of clinical conditions and a
patient investigation of pathological anatomical findings. Now
that the microscopical structure and the comparative anatomy
has been worked out with some completeness, and the results
of extirpation experiments and the action of organ extracts
fairly well known, pathologists may return to the problems
with a better foundation of knowledge and fresh hopes for
future discovery.

CHAPTER IV

THE NATURE, MODE OF ACTION, AND ORIGIN OF HORMONES

HORMONES may conceivably be of two kinds — namely,
augmentary and inhibitory — analogous in their action to the
two well-known kinds of nerve fibres. But it would seem
probable that the inhibitory is in many cases the only active
influence exerted. This may be regarded as a putting on of
the brake, while the augmentary influence is simply a case of
removing the brake. In other words, the organs have a
superabundance of stored energy, and are constantly tending
to over-activity. The normal degree of activity is determined
by inhibitory influences. These influences may be nervous, or,
as we have seen, they may be chemical.

But there seem to be some definite examples of augmentary
hormones, as, for example, secretin and adrenin. The two
groups are sometimes called " assimilation " and " dissimila-
tion " hormones.

Sir E. Sharpey Schafer suggests the name " autocoid sub-
stance " instead of " hormone," and restricts the term " hor-
mones " to the excitatory autocoid substances, while those
whose actions are inhibitory are called " chalones." Matthews
has recently introduced the term " cryptorhetic tissues " as
applied to those furnishing an internal secretion. These organs
and tissues are also often referred to as " endocrine " or
" endocrinous," and the subject as " endocrinology."

Nothing definite can be stated about the origin of hormones
in general. In the case of some of the individual hormones,
the matter may be discussed in its proper place.

The hormones which have so far been described are secretin,
the gastric hormone, the hormones of the liver, pancreas,
kidney, testis, ovary, and corpus luteum, as well as adrenin
and the active substances of the thyroid apparatus and the
pituitary body.

35

36 INTERNAL SECRETION

Zuelzer, Dorhn and Marxer (in a series of communications
dating from the year 1908) have described the property which
extracts of certain tissues (gastric and duodenal mucous
membrane, and the spleen) have of exciting intestinal peri-
stalsis. This property they refer to "peristaltic hormone."
A substance called " hormonal," said to contain a solution
of the hormone, has been recently put upon the market.
If used for therapeutic purposes, the peristaltic hormone
must be introduced intravenously or intramuscularly. It has
been strongly recommended for atonic constipation. The
hormone is probably developed in the gastric mucous mem-
brane and stored in the spleen. It is pointed out by Starling
that the hormones must not be of such a character as to pro-
duce antibodies, that if they are to pass easily through the
walls of the blood-vessels, they must have a comparatively
low molecular weight, and that they should be susceptible of
easy destruction in the fluids of the body. It is said that
they are destroyed by ultra-violet rays.

Our knowledge of the chemical nature of the hormones is at
present confined to adrenin and possibly to the recently dis-
covered thyroxin ot Kendall. (See Chap. XI.)

In 1911 Eppinger and Hess enunciated a complicated theory
that not only is the whole sympathetic controlled by adrenin,
but that the autonomic fibres other than those of the sympa-
thetic proper are dependent on the beneficent influence of a
hypothetical hormone — autonomin. This is sometimes called
" Hormone X." There are no sound reasons for believing that
any such hormone exists.

Gley has recently suggested a classification of endocrine
substances based upon their general physiological actions.
Substances which regulate chemical processes and functions
he calls " Harmozones " ("p/zo?"*, I regulate). Under this head
he includes the substance which controls the production of
sugar, adrenin (in so far as it is concerned in the mobilization of
sugar), and antithrombin. Starling's term " hormone " Gley
proposes to restrict to specific functional excitants such as
secretin, thyroid substance, and adrenin, while he introduces
the term " Parhormones " to include products of metabolic
activity which have a physiological role such as carbon dioxide.
\Vhcn we consider how little we know about the internal
secretions, we are tempted to regret that the nomenclature

NATURE AND ORIGIN OF HORMONES 37

has already become so abstruse and complicated. In the
opinion of the present writer the term " internal secretion "
is sufficient to satisfy all the working requirements of the
subject.

CHAPTER V

THE INTERNAL SECRETION OF THE LIVER

As stated in a preliminary manner above, the liver has, in
addition to the formation of the bile, several important meta-
bolic duties. The chief of these, the glycogenic function, has
already been alluded to, and although to it was first applied
the name " internal secretion," we shall not treat of the subject
any further, for the reasons that the process is a highly special
one, and that it would occupy too much space to treat of the
enormous literature of the subject.

It is possible that some of the ductless glands which are
usually supposed to act only on the pancreas may act on the
liver by means of the sympathetic nerves.

A word or two ought to be said about the duty of the liver
in rendering innocuous the end-products of protein metabolism.
There are many facts which point to the significance of
the liver in the production of urea. In the dog, when the
arterial blood -supply is completely cut off from the organ,
the ratio of the urea to the total nitrogen of the urine falls
considerably. The liver can manufacture urea not only out
of NH3, but also from other nitrogenous bodies. So far as
the production of urea from ammonia compounds is con-
cerned, the process involves an antitoxic action, the dis-
tinctly poisonous ammonia being transformed into the com-
paratively harmless urea. This is what Biedl calls a " negative
internal secretion," and what has already been referred to as
"internal excretion" (pp. 14, 16). There are, however,
probably several sources of urea in the body, and several
distinct places of origin.

The liver is stated to be antitoxic also for other poisons, such
as strychnine and nicotine, but not for atropine and curare.
According to Charrin, the protective action of the liver in

38

THE LIVER 39

certain intoxications is probably due to its action on the
coagulability of the blood.

According to some authors, extracts of the liver are toxic.
Mairet and Vires find that injection of a watery extract of
rabbit's liver into the veins of another rabbit causes various
severe affections of the respiration, heart's action, and the
nervous system, and a dose of 60 grammes per kilogramme of
body weight is fatal. The efficiency disappears on heating the
extract. Of course, these are enormous doses. It is probable
that in corresponding doses other animal extracts prepared in
the same way would be equally injurious.

Liver extracts have been administered therapeutically in
several affections. The value of cod-liver oil has been sup-
posed to be due to its containing some of the internal secretions
of the liver. Hepatic opotherapy is recommended in digestive
disorders, hepatic insufficiency, hepatic cirrhosis, haemorrhages
due to liver disorders, phlebitis, icterus, hepatic diabetes, gout,
ansemia, and tuberculosis. It is in cases of hepatic diabetes
that liver extracts might be tried with the best prospects of
success, but it cannot be guaranteed that any good results will
certainly accrue.

CHAPTER VI

THE INTERNAL SECRETION OF THE PANCREAS

THE most usually quoted example of a gland which has both
an internal and an external secretion is the pancreas. A
relation between diseases of the pancreas and diabetes has long
bean suspected, but Minkowski and Mehring first definitely
showed that complete removal of the pancreas in the dog, cat,
and pig is followed by diabetes having the usual symptoms of
that disease in man. That this is caused by the absence of an
internal secretion is proved by the facts that it does not occur
if the gland be left in situ and the duct tied, nor does it occur
if a portion of the pancreas be grafted in some situation remote
from its normal position (e.g., underneath the skin or in the
peritoneum).

It is interesting to note that a dog dying from pancreatic
diabetes eats ravenously because of increased intensity of the
gastric hunger contractions.

It has been observed that complete pancreatectomy in
pregnant bitches near term does not result in diabetes, although
there is serious general disturbance.

How the internal secretion of the pancreas normally prevents
glycosuria is not olear. We can only say that it exerts some
influence upon the carbohydrate metabolism, either by favour-
ing the formation of glycogen in the liver from the glucose
taken to it by the portal vein, or by furthering the oxidation
of glucose in the tissues generally.

Pfliiger confirmed the observation of Marcuse that extirpa-
tion of the pancreas in the frog produces the same symptoms
as in mammals. He also makes the further statement that
extirpation of the duodenum or separation of the duodenum
from the pancreas — the blood-supply of the gland being left
intact— has the same effect. Pfluger criticizes the ordinary

40

THE PANCREAS 41

internal secretion theory of the pancreas, and substitutes for
it a theory according to which there exist nerve centres,
stimulation of which determine the production of sugar, and
other centres of an antagonistic nature determining an internal
secretion of the pancreas, which internal secretion hinders the
production of sugar. In removing the pancreas these centres
are necessarily damaged, and the same happens in extirpation
of the duodenum or separation of the duodenum from the
pancreas.

Herlitzka, working with frogs, agrees that the ganglia in the
wall of the duodenum are necessary for the normal internal
secretion of the pancreas, and agrees with the doctrine of
Pfluger that the correlation between duodenum and pancreas
is due to the action of these ganglia.

Vahlen points out that it is usually believed that there is in
the pancreas a material which promotes the destruction of
sugar in the organism, and that this unknown substance splits
up the sugar in some way and thereby makes oxidation easier.
The author referred to has tried to isolate such a substance,
with entirely negative results, but he thinks he has obtained a
constituent of the pancreas which acts in a purely catalytic
manner on the vital destruction of sugar.

Pancreatic extracts exercise an inhibitory influence on the
production of lactic acid in surviving muscle.

The Islets of Langerhans

By perhaps the majority of authors the pancreas is considered
to consist of two separate and distinct kinds of tissue, the
secreting alveoli, and the islets of Langerhans. The question,
however, as to the morphology and physiology of the islets of
Langerhans needs a little discussion. Modern writers may be
divided into two chief groups according to their views as to the
morphological significance of the islets. The first of these
believe that the islets are essentially of the same embryological
and morphological nature as the zymogenous tubules, and are
not to be looked upon as, in any sense, organs sui generis. The
second group of observers regard the structures in question as
definite and distinct organs, analogous to the cortex of the
adrenal, the epithelial part of the pituitary body, and the
parathyroids, and consider that they have no connection

42 INTERNAL SECRETION

(except a community of embryonic origin) with the secreting
tubules of the pancreas.

Some among the first group of writers even consider there
may be no difference in function between the two structures.
Thus Harris and Gow thought that the islets might take part
in the external secretion, probably forming one of the ferments.
Some authors look upon the islets as exhausted secreting
cavities, and believe that after a period of repose they may
again take on their secretory function. Others, on the con-
trary, look upon the islets as exhausted acini which are unable
to return to their former state.

In most vertebrates there are no lumina in the islets of
Langerhans, but such have been described occasionally in
amphibians and reptiles.

Laguesse refuses to admit that the islets are simply exhausted
masses of acini, or that they are in their nature simply secreting
tubes modified by inanition, and he urges against either of these
theories the abundance of the granules of secretion in the islets,
the permanent juxtasplenic islet of the Ophidians, and the fact
that islets are found in every functional state of the pancreas.
The presence of lumina in the islets of reptiles is a strong indi-
cation that their origin is from alveoli. The same author, in
his numerous contributions on the subject, has laid stress on
the anatomical details above referred to, and inclines strongly
to the view that the islets of Langerhans are portions of the
secreting tubules temporarily modified for the purpose of
supplying an internal secretion.

Dale employed a new method for investigation of the sub-
ject, using secretin to exhaust the gland. He concluded that
the islets of Langerhans are not independent structures, but
are formed by certain changes in the cells of the secreting tissue
of the pancreas. The change from the secreting to the " islet "
condition may be accelerated by the administration of secretin
and as a result of inanition.

The authors belonging to the second chief group all believe
in the internal-secretion theory of the islets, and, indeed, so
convinced are many of them that this is the correct theory, that
they do not accept the statements of the first group, who
i be changes in the islet in exhaustion and inanition, and
the t mi i -it inn tmins from one kind of tissue to the other.
According to Diaman -. tin- i>l< -ts are "epithelial bodies" in

THE PANCREAS

43

Kohn's sense. They are constant and invariable, and are a
form of " epithelial body " derived from the pancreas (for he
admits, of course, the common embryonic origin of pancreas
and islets). The adult islets, in his view, have no relation to
the surrounding tissue, except that of contiguity, and he denies
that the islets ever possess lumina, even in reptiles. He denies
the continuity of the islets with the exocrine gland and all

bid. c.

c.c.a.
zym.

FIG. 9. — Islet of Langerhans, from the splenic end of the pancreas of a
normal dog, showing the alveolar form of the islet tissue. The tissue of
the islet is seen to consist of solid branching columns of cells, for the most
part two deep, separated by wide capillary bloodvessels (Vincent and
Thompson). (Drawn by Mrs. F. D. Thompson.)

Lettering common to Figs. 10, 11, and 12. — bld.c., red blood-corpuscles;
c.a.c., centro-acinar cells ; cap., blood-capillaries ; i., islet of Langerhans ;
£., lumen ; trans. c., transitional cells ; zym., zymogenous tissue.

forms of physiological variation. Rennie, in his work' on the
teleostean fishes, describes the fairly constant occurrence of an
encapsuled islet (" principal islet ") of large size, whose relation
to the pancreatic tissue is frequently extremely slight'. He
considers the islets to be " blood-glands " which have entered
into a secondary relation to the pancreas. This author finds
no sign of any transitional forms.

44 INTERNAL SECRETION

The present writer, as the result of investigations carried out
in conjunction with Mrs. Thompson, considers that the em-
bryological work of Laguesse and the experimental researches
of Dale are confirmed in all essential points.

Fig. 9 represents an islet of Langerhans from the splenic
end of the pancreas of a normal dog, showing the " alveolar "
form of the islet tissue. The islet is seen to consist of solid,
branching columns of cells, for the most part two deep, sepa-
rated by wide capillary blood vessels. In some places the
zymogenous tissue shows transitions towards islet. Pig. 10

•.

zym.

FIG. 10. — From the splenic end of the pancreas of a normal pigeon. The
section shows the islets and the zymogenous tissue. Compare this with
the next figure (Vincent and Thompson). (Drawn by Mrs. F. D. Thomp-
son.) Lettering same as for Fig. 9.

is a section taken from the splenic end of the pancreas of a
normal pigeon. The section shows the islets and the zymo-
genous tissue. Compare this with Fig. 11, which shows the
splenic end of the pancreas of a pigeon after a few days'
inanition. The increase in the amount of islet tissue is very
striking.

If a pancreas from an animal in inanition is examined, a
very remarkable increase in islet tissue is noted1 (see Figs.

1 It must be admitted that this does not occur with complete regularity,
'.bably depends upon the state of nutrition of the animal at th«- time
ion is begun.

THE PANCREAS 45

10 and 11), but if after such a period the animal is restored to
its normal state of nutrition, the usual proportion of islet tissue
is found. The most obvious explanation of this is that the
alveoli are reformed from the islet tissue. There is, however,
another possibility — namely, that the islet tissue formed from
alveoli, as a result of changed physiological conditions, is not
reconverted into secreting tubules, but, having reached the
last stage of its career, degenerates and disappears. If this

trans, c..

zym.

trans, c.

FIG. 11. — Splenic end of the pancreas of a pigeon after a few days' inanition.
The increase in the amount of islet tissue is very marked (Vincent and
Thompson). C/. with Fig. 10. (Drawn by Mrs. F. D. Thompson.)

Lettering same as for Fig. 9.

be the case, we must assume that new alveoli are formed from
the existing tubules, and occupy the space recently occupied
by islets. On this hypothesis the more solid islets might be
regarded as nothing more than worn-out alveoli about to
disappear. Of the two possible views here put forward, the
present writer is inclined to support the former.

Feeding dogs upon a purely carbohydrate diet also increases
the amount of islet tissue, and removal of the spleen from frogs
has a similar effect.

46 INTERNAL SECRETION

Experiments involving ligature of the pancreatic duct
have given contradictory results in the hands of various
observers. Many writers have alleged that if a portion of
the pancreas is separated from the rest of the gland and its
duct tied it atrophies and leaves a tissue containing enlarged
islets.

Schafer was the first to suggest that the islets of Langer-
hans are the part of the pancreatic tissue concerned with
carbohydrate metabolism. A number of more recent observers
have found in cases of diabetes mellitus that the islets are
affected by a hyaline degeneration, atrophy, or inflammatory
changes ; but others have been unable to confirm these results.
Notwithstanding the conflicting nature of the evidence upon
this point, a large number of pathologists have — at any rate,
until quite recently — appeared to favour the view that the
islets of Langerhans constitute a tissue &ui generis, whose
function it is to control, by means of some kind of internal
secretion, the metabolism of sugar in the body.

Diamare has, indeed, put forward some experimental work
in support of this definite view as to the function of the islets.
He finds that the amylolytic ferment occurs only in the ordinary
pancreatic cells, while it is absent in the islets of Langerhans.
He states that the islets possess the power of inverting grape-
sugar, and is of opinion that these structures are intimately
concerned in the economy of glucose in the body. The
glycolytic action of the islets in vitro is very weak, and he
looks upon the tissue as furnishing an endocrine zymoplastic
secretion. Hyperglycaemia and diabetes are in this view the
result of functional insufficiency of the islets. This observer
further records certain modifications occurring in the islets
of Motelkt tricirrata as the result of the injection of glucose
into the abdominal vein.

As we have seen, the present writer was the first to prove
experimentally that the islets of Langerhans actually pass
through a structural cycle, corresponding to a cycle of changes
in physiological conditions. We were able to provoke ex-
perimentally the formation of new islets at the expense of the
exocrine parenchyma, and then to induce their disappear-
ance by a new transformation into acini.

Laguesse, working with the pigeon, has been able to confirm
our results. He has performed a very large number of expert

THE PANCREAS 47

merits, and his results are carefully tabulated. He gives,
moreover, a careful account of the anatomy of the pancreas
in the pigeon. He states his conclusions as follows : " Chez
les animaux soumis a Finanition pendant quelques jours, le
nombre des ilots double presque, pour retomber a son taux
normal chez les pigeons renourris." " Nos observations,
completant . et elargissant celles de Swale Vincent et Thomp-
son, nous paraissent fournir une preuve experimentale tres
demonstrative du balancement."

The results of recent investigations have not been very
concordant. M. Labbe and P. Thaon have reported an in-
crease in amount of islet tissue in guinea-pigs when fed on
animal food. This result may possibly be attributed to inani-
tion.

Bensley, as the result of very painstaking work, finds
himself unable to agree with Vincent and Thompson. He has
used Lane's methods for the study of the cell granules and has
adopted the classification into A and B cells, according as
the granules are fixed respectively by alcoholic or watery
solutions. In order to test the question as to alterations in
islet tissue under different conditions, this author employed
the neutral red method for staining the islets and for their
enumeration. He has taken no account of the size of the
islets. He believes that the structures in question are con-
stant and do not change under different physiological
conditions.

Von Hansemann confesses that he has been forced to change
his opinion as to the significance of the islets of Langerhans.
He now regards them as varieties of the parenchyma of the
organ and not as separate structures. He finds that in dia-
betes the changes in the islets correspond exactly to those in
the rest of the organ.

Pratt and Murphy have observed that pancreatic tissue
implanted in the spleen and separated from its original vascular
and nervous connections can live and functionate for months.
A small nodule of pancreas composed of acini without demon-
strable islets prevented the development of diabetes. This
shows that the islets are not the only portions of the pancreas
which furnish an internal secretion. Other experiments of
the same nature and with similar results have been
recorded.

48 INTERNAL SECRETION

Adami affirms that he has encountered appearances in the
human subject which would be difficult to explain, except on
the hypothesis that the islands are not separate organs ; that
they vary in number according to the state of nutrition and
activity of the gland, becoming converted into active acini, and
vice versa. As Adami justly points out, these observations do
not wholly negative the contention that the islands bear some
intimate relationship to a certain order of cases of diabetes ;
they suggest, however, that degenerative changes seen in
them are an indication of other changes occurring in the
intimately connected pancreatic tissue proper.

Whatever may be subsequently discovered to be the true
function of the islets of Langerhans, their intimate anatomical
relationship with the zymogenous tubules, the numerous
transition forms in all groups of vertebrates, and the transforma-
tion of alveolus into islet, and vice versa, all appear to prove
conclusively that the islets are not organs sui generis, but are
an integral part of the pancreatic tissue. As to whether the
temporary structural modification of alveolus into islet tissue
corresponds to a specialization of function, the evidence is at
present inconclusive.

A prolonged discussion of the pathology of glycosuria and
speculations as to the precise manner in which the internal
secretion of the pancreas normally prevents such a condition,
would serve no useful purpose. It is, however, of supreme
importance to bear in mind that a certain order of cases of
diabetes mellitus are, in all probability, due to insufficiency
of the internal secretion of the pancreas. But we must bear
in mind the possible influence of disturbances in certain others
of the endocrine glands which are concerned with carbohydrate
metabolism, as, for example, the adrenal and the thyroid.
In disease of the pancreas the limit of assimilation for carbo-
hydrate may be greatly lowered even when spontaneous
glycosuria does not occur.

The symptoms of diabetes as observed in the human subject
are well known, and need only be referred to briefly. The
cases are described as acute and chronic, the former usually
occurring in children, the latter usually in older people. There
are mild and severe cases, and there are the fat or emaciated
cases. Many other subdivisions and classifications have been
suggested. Polyuria, thirst, increased appetite, dry ness of

THE PANCREAS 49

the skin, constipation, loss of sexual power, are among the
most prominent symptoms. The diagnosis, when these symp-
toms are present, is based upon the finding of sugar in the urine.
The percentage varies from 3 to 5 per cent, or over. In the
acute cases the course is rapid and the disease is almost inevit-
ably fatal. In the chronic cases the condition is not so serious
and the patients may live for many years. Among the
complications the commonest is pulmonary tuberculosis, the
most serious diabetic coma. The presence of ft — oxybutyric
acid or diacetic acid in the urine is relied upon as a sign of
approaching coma. The commonest form is the dyspnosic.
The condition may be introduced by lassitude, headache,
etc., followed by restlessness. Speech becomes incoherent,
and the patient lapses into coma.

Although physicians have been warned repeatedly against
confusing glycosuria with diabetes, a clear distinction between
the two is by no means generally made. The " poly glandular "
theories of the. Viennese school take no account of the dis-
tinction between, for example, adrenin intoxication and true
diabetes.

The work of Mehring and Minkowski referred to above led
to a great deal of investigation and to much controversy. Many
authors stated that diabetes did not always occur when the
pancreas was removed. But this was supposed by the sup-
porters of Minkowski to be due to incomplete removal. Pan-
creatic feeding seemed useless in diabetes and it was not always
possible to find any lesion of the pancreas in cases of diabetes.
Considerable stress was laid, moreover, upon the differences
between diabetes in the human subject and the condition
induced in animals by extirpation of the pancreas. But more
recently it has been found that diabetes may be induced
artificially in a dog if a sufficient portion of the pancreas be
removed, leaving the remainder with its normal blood supply
and its normal connection with the duct. In such cases the
progress of the disease is hastened by carbohydrate feeding.
Changes in the islets have been described in such cases.

The chief differences which are alleged to exist between
clinical and experimental diabetes are as follows. The dextrose
— nitrogen ratio is said to be 3' 65 in severe human diabetes,
while in the dog after extirpation of the pancreas it is not more
than 2' 8. The increase of total metabolism in the depan-

50 INTERNAL SECRETION

ereatized dog is said to be greater and more frequent than in
human subjects with diabetes. The changes found in the
islets of Langerhans in human diabetes are not so striking as
in dogs after removal of large portions of the pancreas. Finally,
dogs with experimental diabetes rarely die of coma, while
this is notoriously a common ending in the case of human
beings with diabetes. Allen, who has carried out a great
amount of painstaking work on this subject, points out that
dogs have much less tendency to ketonuria than man, and
believes that experiments upon animals of other species may
give a result more nearly approaching human diabetes. He
is inclined to believe that explanations may be found for the
other differences enumerated.

Nothing is certainly known about the nature and origin of the
acidosis and the diabetic intoxication which gives rise to coma.
It is generally believed, however, that ketones are formed as
a result of an incomplete destruction of fat, due to an imperfect
consumption of carbohydrates. The ketones become oxidized
to acetoacetic and /? — oxybutyric acids. The condition is
often referred to as ketosis. The intoxication seems largely
due to the increased acidity, an increased H — ion concen-
tration,

After extirpation of the pancreas in dogs and cats, Loewi
produced dilatation of the pupil by the installation of adrenin.
He attributes the dilatation to an increased excitability of
the sympathetic nervous system. The reaction has been used
as a test for pancreatic deficiency in the human subject, but
does not appear to be very reliable.

Organotherapy — treatment with pancreas or extracts made
from it — appears to be useless. The most modern form of
treatment and, so far as can be judged from the clinical
evidence available, the most successful form, is by fasting,
combined with vigorous exercise. These measures, at any
rate, prolong the life of the patient and render him useful
and comfortable, even if they do not cure. As Allen points
out, what is required is some means of strengthening the
weakened function as well as giving it a rest. There can,
however, be little hope for this till we are quite clear about
the pathogenesis of the condition.

A functional relationship between the islets of Langerhans
and the reproductive organs is claimed by some observers

THE PANCREAS 51

and a similar relationship between the spleen and the pancreas
has been suggested by certain authors.

An important function of the pancreas appears to be to
increase the resistance of the body towards bacterial in-
fection.

Extracts of pancreas are employed medicinally in gangrene and
tuberculosis, as well as in pancreatic diabetes. The use of such
extracts with the object of increasing the resistance to infection
is of recent date, but is deserving of further practical
study.

CHAPTER VII

THE INTERNAL SECRETION OF THE KIDNEY

A BELIEF in some kind of internal secretion on the part of
the kidney has existed since the period when interest in the
subject was stirred by the researches of Brown-Sequard. We
have already seen (p. 25) that some writers have described
pressor effects as the result of the injection into animals of
extracts made from the kidney. Lewandowsky, however,
found that with 5 to 6 centimetres of the blood from the renal
vein no more positive result upon the blood-pressure was
obtained than with a similar amount of blood taken from any
other vein in the body. He concludes that no specific pressor
substance is poured out from the kidney by the renal vein.
The present writer has frequently tested the effects of different
kinds of kidney extracts upon the blood-pressure. Sometimes
there is a slight rise of pressure, sometimes there is no rise,
or there may be a fall. The rise is never very marked, and
only occurs with unboiled ''protein" extracts. The same
result may frequently be obtained from extracts made from
other organs and tissues, and it may probably be concluded
that, so far as the question of internal secretion is concerned,
the results are not of any great importance. Further, it may
be stated as probable that the high blood-pressure and hyper-
trophy of the heart in nephritis bear no relation to the presence
of a pressor substance in kidney extracts.

But arguments based upon experimental work of a different
character and upon clinical and therapeutical observations
have been urged in favour of the view that the kidneys furnish
an internal secretion. Brown-Sequard in 1869, had expressed
the opinion that the phenomena of uraemia were not entirely
due to the accumulation of urinary constituents in the blood,
but to the absence of the normal internal secretion, or, as he
expressed it, due to " 1'existence de changements chimiques

THE KIDNEY 53

morbides du sang rempla9ant la secretion interne normale."
This view was partly based upon clinical observations in which
in spite of long-continued anuria the symptoms of uraemia were
practically absent. Later, in 1892, Brown-Sequard and d'Ar-
sonval stated that " le rein a une secretion interne d'une grande
utilite. ' ' They removed both kidneys from rabbits and guinea-
pigs, and found that death occurred much earlier than after
ligature of both ureters, although, of course, in both cases
there was an accumulation of urinary substances in the blood.
Then they administered to some of these by subcutaneous
injection diluted juice of kidney from a normal animal of the
same species, while they left others untouched as controls.
They found that those animals which had received the injection
survived one or two days longer than the controls ; the duration
of life in the injected animals was, in fact, equal to or longer
than that of animals which had undergone ligature of both
ureters. The phenomena of ursemia were of slower develop-
ment in those animals which survived the longer, owing to
treatment with kidney extract.

Some observations of Lepine seemed to point to the fact
that the kidney blood contains peculiar substances. Working
with rabbits, this observer found that tying both ureters induced
death after fall of temperature, vomiting, and diarrhoea. But
if the flow through the ureter were checked by connecting
it with a vessel containing normal saline at a higher pressure
than that in the ureter, then the symptoms induced were quite
different. Instead of a fall of temperature there was a rise,
and in addition one observed increased rate of respiration and
convulsions. A watery extract of kidney injected into the
circulation produces, according to Lepine, a rise of temperature
and dyspnoea. He concludes that the kidney substance con-
tains materials inducing these effects, and suggests the possi-
bility of auto -intoxications of renal origin.

E. Meyer, a pupil of Brown-Sequard, found that while the
blood of ursemic animals produces no definite effects upon
normal animals, when injected into nephrectomized animals,
it induces dyspnoea and slowing of respiration. The same
observer further found that injections of kidney extract, or
normal blood, or of renal venous blood from a normal animal,
have the immediate effect of checking the Cheyne -Stokes
respiration which is such a striking symptom of ursemia.

54 INTERNAL SECRETION

Vitzou found that in rabbits and dogs the injection subcu-
taneously and intravenously of defibrinated blood from the
renal vein of a normal animal prolonged the life of a nephrec-
tomized animal in a very striking manner. Thus in one rabbit
the survival was forty -two and a half hours longer than was
the case with the control, which had, like the first, undergone
double nephrectomy. Vitzou concludes that the kidney has
an important internal secretion, the absence of which plays
an important part in the causation of uraemia.

Many experiments of a similar character have been per-
formed. Some of these have been in favour of the views ex-
pressed by Meyer and Vitzou, some have been opposed to them.
The results obtained have been in fact very contradictory.
Thus Chatin and Guinard investigated the question as to
whether, by injection of blood from the renal vein of normal
dogs into nephrectomized animals, there was any lengthening
of life, or a diminution of the ursemic symptoms. The results
were completely negative — that is to say, the animals treated
with the serum died on the whole sooner than those not treated.
Chatin and Guinard do not, however, definitely deny an internal
secretion on the part of the kidney, for which they think there
is a certain amount of clinical evidence.

It is doubtful if much importance can be attached to the
results obtained by Vitzou. His work has been severely
criticized by Lewandowsky, who points out that as a matter
of fact animals can live from three to five days after double
nephrectomy ; whereas Vitzou states that he succeeded by his
treatment in causing them to live sixty to sixty-nine hours
instead of thirty-four ! As pointed out by Biedl, the duration
of life of nephrectomized animals is extremely variable. Accord-
ing to his own experience in some cases dogs and rabbits
may survive as long as five or six days after extirpation of
both kidneys, while in other cases they may die in thirty-six
hours. Again, the incidence and course of the symptoms of
uraemia in such animals is no criterion of their actual condition.
It frequently happens that nephrectomized animals show no
characteristic symptoms for two, three, or even four days,
and then suddenly succumb. Others, on the other hand, on
the day after the operation, suffer from vomiting and dyspnoea,
then cither recover or remain in a chronic condition of urn in ia
evera] days, Su< -h experiments are of little value as

THE KIDNEY 55

demonstrating an internal secretion on the part of the kidney,
and still less as pointing to the treatment of nephritis in man
by means of kidney extracts. Notwithstanding this certain
writers report good results in cases of chronic nephritis after
treatment with kidney extracts by the mouth.

Lindemann found that guinea-pigs, after having received
injections of rabbit-kidney emulsions, furnished a serum which
was very toxic to rabbits, giving rise to albuminuria and uraemia.
The injection of this nephrolytic serum provokes symptoms
precisely similar to those induced by true kidney poisons.
Here we have the formation of certain specific substances
formed in the blood under the influences of the processes of
absorption of the renal substance injected, and these are the
substances which affect the kidney. Schiiltze could not observe
the nephrotoxic effect of the serum of rabbits into which he
had injected an emulsion of guinea-pig kidney. This observer
also could not confirm the hepatolytic effect of the sera of
animals which had been injected with liver emulsion, although
Delezenne and Deutsch affirm that animals into which one
injects liver emulsions furnish a serum which possesses powerful
hepatotoxic properties.

Nefedieff believes firmly in a specific nephrotoxic serum in
Lindemann's sense. He states further that this serum is also
ha3molytic. The serum is analogous to the cytotoxins in
general. Under the influence of hypodermic injections of
kidney emulsion from healthy animals there appear in the
blood of rabbits and guinea-pigs certain substances which
exercise an injurious effect on the kidneys of the species of
animal whose organs have been used in the preparation of the
emulsion. Nefedieff found also that the serum of rabbits in
which one of the ureters had been tied soon acquires powerful
nephrotoxic properties. He suggests that in this case substances
pass from the kidneys into the blood just as they do when an
emulsion of the kidney has been injected.

Arguments of an analogous kind have also been used to
explain the causation of oedema in nephritis. Kast observed
that the blood of nephritics with oedema contains a lymphagogue
substance of great strength, which also passes out into the
dropsical fluid. Blanck noted, in investigating the serum of
animals with uranium nephritis and uranium oedema, and of
rabbits with chromium or aloin nephritis (which does not give

56 INTERNAL SECRETION

rise to oedema), that if one injects rabbits with serum or cedema-
tous fluid from a rabbit affected with uranium nephritis, one
gets oedema in this case also. Timofeen, from a review of the
work of previous experimenters and on the basis of his own
investigations, believes that the cause of the oedema in neph-
ritis is the passing into the blood of certain lymphagogue
substances, the source of which is a substance he calls " nephro-
blaptin " arising in the diseased kidney.

A discussion of this question would not be complete without
a reference to the work which has been carried out upon the
influence of the kidney on metabolism. Sir J. Rose Bradford
removed portions of the kidney from animals, and subse-
quently studied their metabolism. He obtained results which
suggested that when the amount of available kidney substance
is greatly reduced the tissues of the body, and more especially
the muscles, rapidly break down and liberate urea. But he
states that he has no observations to show whether this is
dependent upon the cessation of the action of an internal
secretion supplied normally by the kidney.

Biedl performed a series of experiments of a similar nature
upon dogs. He excised wedge-shaped pieces of the kidney,
removing about a quarter of a kidney, and sometimes removed
the whole of the other kidney in addition. It was found that
after such operations the quantity of urine secreted was notably
increased, even up to two, three, four, or five times the original
amount. At the same time the total nitrogen excreted was
much increased. V. Haberer also reports polyuria after ex-
cision of portions of the kidney substance. It is not possible
to state whether these changes are really due to a deficiency
in a normal process of internal secretion on the part of the
kidney.

Notwithstanding the conflicting nature of the evidence as
to an internally secreting function of the kidney, many authors
insist that renal hormone therapy is of considerable value in
many cases. Many French writers recommend kidney extracts
in nephritis, but it is usually advised to persist in ordinary
measures of treatment and to employ the renal extracts as
adjunct remedies.

CHAPTER VIII

THE INTERNAL SECRETION OF THE INTESTINAL

MUCOUS MEMBRANE AND THE NORMAL MECHANISM OF THE

SECRETION OF THE PANCREATIC JUICE

IT was first observed by Claude Bernard that the secretion of
the pancreatic juice is dependent on the passage of food into
the duodenum, and it has long been known that in the dog the
flow of pancreatic juice, although it begins immediately after
food has been taken, does not reach its maximum till either the
first or the second hour, but more commonly is not reached
until the third or fourth hour. It is to be noted that this is at
a time when the greatest quantity of food from the stomach
contents is passing into the duodenum. There has been much
laborious investigation and a continued keen controversy
as to the causal relationship existing between the passage
of food through the pylorus and the secretion of pancreatic
juice.

It will be interesting to glance at the state of knowledge
on this subject in the year 1889. This can be conveniently
done by recalling the exposition in a standard textbook of
the period. M. Foster says : " Stimulation of the medulla
oblongata or of the spinal cord will call forth secretion in a
quiescent gland, or increase a secretion already going on.
From this we may infer the existence of a reflex mechanism,
though we cannot as yet trace out satisfactorily the exact path
of either the afferent or the efferent impulses ; all we can say is
that the latter do not reach the pancreas by the vagus, since
stimulation of the medulla is effective after the section of both
vagi.

' ' A secretion already going on may be arrested by stimula-
tion of the central end of the vagus, and the stoppage of the
secretion which has been observed as occurring during and
after vomiting is probably brought about in this way. This

57

58 INTERNAL SECRETION

effect, which, however, is not confined to the vagus, stimulation
of other afferent nerves, such as the sciatic, producing the same
effect, may be regarded (in the absence of any proof that the
result is due to reflex constriction of the pancreatic and local
vessels unduly checking the blood-supply) as an inhibition of
a reflex mechanism at its centre in the medulla or in some other
part of the central nervous system, much in the same way as
fear inhibits at the central nervous system the secretion of
saliva following food in the mouth. But if so, then we must
regard the secretion of pancreatic juice as closely resembling
that of saliva, inasmuch as it is called forth by a reflex act. Yet
it is stated that, unlike the case of saliva, the secretion of
pancreatic juice continues after all the nerves going to the gland
have been divided, an operation which would do away with the
possibility of reflex action. Such an experiment, however,
cannot be regarded as decisive, since it is almost impossible to
be sure of dividing all the nerves."

It is interesting to note how the one single observation
(secretion after severance of all nerves), which at this period
had to be opposed to the theory of reflex stimulation, was dealt
with by Michael Foster. At this date, then, and for some time
later the prevailing view was that the flow occurring when the
acid chyme passed into the duodenum is due to the action of a
reflex arc ; but the observations of Bernard, Heidenhain and
Pavlov, incorporated in the above account by Foster, were
inconclusive, and the results obtained in different experiments
were by no means constant. In more recent years Pavlov and
his pupils have multiplied ingenious experiments and developed
a wonderful technique, have struggled hard to reconcile the
conflicting statements of different observers, and with infinite
ingenuity have sought to establish on a firm basis the theory of
nervous action. In searching for the channels of the reflex,
Pavlov showed that, if certain precautions be taken, one can
bring about a flow of pancreatic juice by stimulating the vagus
HI splanchnics.

A great step in advance was made by Popielski and by
Wertheimer and Le Page. These observers proved conclu-
sively that introduction of acid into the duodenum still excites
pancreatic secretion after section of both vagi and both
splanchnic nerves or destruction of the spinal cord, or even
after ri.inplete extirpation of the solar plexus. Thus it was

THE INTESTINE 59

clear that ordinary reflex action was out of the question.
Popielski concluded, therefore, that the secretion is due to a
local, a peripheral, reflex action, the centres for which are
situated in the scattered ganglia found throughout the
pancreas.

Wertheimer and Le Page, however, made a very interesting
discovery — namely, that secretion of the pancreatic juice
could also be induced by the injection of acid into the lower
portions of the small intestine, the effect, however, gradually
diminishing as the injection was made nearer and nearer the
lower end of the small intestine, so that no effect at all was
produced from the lower two feet of the ileum. Secretion could
be excited from a loop of jejunum entirely isolated from the
duodenum. They concluded that, in this latter case, the reflex
centres are situated in the ganglia of the solar plexus, but they
did not perform the obvious control experiment of injecting
acid into an isolated loop of jejunum after extirpation of these
ganglia.

About this time Bayliss and Starling were engaged upon
investigations into the local nervous reflexes concerned with
movements of the intestine. These observers made numerous
experiments to test the validity of a hypothesis such as that of
Wertheimer and Le Page, but soon found that in the case of
the pancreatic secretion they were dealing with an entirely
different order of phenomena, and that the secretion of the
pancreas is normally called into play, not by nervous channels
at all, but by a chemical substance which is formed in the
mucous membrane of the upper parts of the small intestine
under the influence of acid, and is carried thence by the blood-
stream to the gland cells of the pancreas.

The experiments of Bayliss and Starling confirmed those of
previous observers in so far as they found that, after exclusion
of all nerve centres except those in the pancreas, a secretion of
pancreatic juice is obtained by the introduction of acid into the
duodenum. But, as pointed out above, the experimentum
crucis of taking an isolated loop of intestine, dividing the
mesenteric nerves supplying it, and then injecting acid into it,
had not been performed.

Bayliss and Starling found that when this was carried out a
well-marked flow of pancreatic juice was brought about. They
next cut out the loop of jejunum, scraped off the mucous

60 INTERNAL SECRETION

membrane, rubbed it up with sand and 04 per cent. HC1 in a
mortar, filtered and injected into a vein. The first effect was a
considerable fall of blood-pressure, and, after a latent period of
about twenty seconds, a flow of pancreatic juice at more than
twice the rate produced at the beginning of the experiment by
introduction of acid into the duodenum.

Bayliss and Starling suggest the name " secretin " for the
active substance present in the intestinal extract, and the
term has been adopted by subsequent workers. Secretin is
probably produced by a process of hydrolysis from a pre-
cursor " prosecretin " present in the intestinal cells. It is
not a ferment, nor is it of the nature of an alkaloid or
diamino-acid.

The results obtained by Bayliss and Starling were confirmed
by Camus and Gley and others, and Wertheimer demonstrated
the presence of secretin in the blood flowing from a loop of
intestine into which acid has been introduced.

In a later communication Bayliss and Starling announced
that secretin can be prepared from the upper part of the in-
testine of any animal belonging to the class of vertebrata by
scraping off the mucous membrane, pounding it up, and boiling
with dilute hydrochloric acid.

The experimental evidence which is clearly put before us by
Bayliss and Starling justifies the view that the normal sequence
of events in the secretion of juice by the pancreas is as follows :
The acid of the gastric juice upon reaching the duodenum
converts the prosecretin manufactured by the epithelial cells
into secretin ; this secretin is then absorbed into the blood-
stream, carried to the cells of the pancreas, and stimulates the
organ to secretory activity. The external secretion of the
pancreas is the result of the internal secretion of itie duodenal
mucous membrane.

The formation of prosecretin in the duodenum does not
appear to take place as a response to the stimulus of ingestion
of food. Pringle has quite recently found that secretin
prepared from newly-born kittens, before suckling, gives
a fairly active flow of juice when tested on a dog. When
foetuses of different periods were examined, it was found
that some showed the presence of an active secretin, some
did not.

In tli is most important discovery of Bayliss and Starling is

THE INTESTINE 61

involved an important modification of our conception as to the
empire of the nervous system. The production of secretin is,
in fact, the best authenticated examjple of internal secretion
which can be quoted. The hitherto most oft-cited examples,
such as those of the adrenal body and the thyroid gland,
are, in the opinion of the present writer, more distinctly
hypothetical.

Beyond all doubt secretin is a powerful excitant of the
pancreatic secretion, but its specific nature is denied by some
authors. Bayliss and Starling admit that secretin acts to a
small degree on the secretion of bile, and other authors state
that it acts on the secretion of saliva and the gastric and
intestinal juices. Again, while Bayliss and Starling affirm
that secretin can only be obtained from the upper part of the
small intestine, others assert that they have found this sub-
stance, though only in small amount, in other parts of the
intestinal tract, and even in lymphatic glands.

Although Bayliss and Starling showed that the depressor
substance in extracts of the intestinal mucous membrane is
independent of secretin, and that a secretin solution can be
obtained free from the depressor substance, yet this has not
hindered Popielski and others from urging that the flow of
pancreatic juice after injection of intestinal extracts is due to
the lowering of the blood-pressure and consequent anaemic
stimulation of nerve centres.

Meig shows that secretin does not produce its effects by
acting on the nerve endings in the intestinal epithelium, and
the last-named author, as well as Wertheimer and Le Page,
state that they obtained a secretion of pancreatic juice by
injecting acid into an isolated loop of jejunum whose nerve
communications were intact, and even when the venous blood
of this loop is diverted, and the thoracic duct is tied off. Fleig
concludes that the mechanism of secretion of pancreatic juice
after the injection of acid into the upper part of the small
intestine is, under normal conditions, of a double character :
(1) Secretin calls forth secretion of pancreatic juice by direct
action on the cells of the pancreas. (2) Acids, independently
of the formation of secretin, cause a secretion of pancreatic
juice by reflex nervous action.

These two secretions are said by Sawitsch to present quite
different characters. The latter is thick, opalescent, rich in

I;L> INTERNAL SECRETION

enzymes and proteins but poor in alkalies. The chemical
secretion, on the contrary, is thin and watery, contains little
enzyme or protein, and js rich in alkali.

Gley has recently given the accompanying classification of
substances which excite the flow of pancreatic juice (p. 63).

Gley points out that the part played by the acid of the gastric
juice as an excitant of the flow of pancreatic juice is altogether
special, since it acts at the same time through the chemical
mechanism in liberating secretin, and by means of a nervous
mechanism, that is to say, by reflex excitation of the secretory
nerves to the pancreas.

V. Fiirth and Schwarz believe that secretin is not a
definite, single substance, but a mixture of several gland-
stimulating substances, of which choline can be recognized
as one.

With regard to the mechanism of the secretion of the intes-
tinal juice, nothing definite is yet known. We know that the
juice when it is formed is essential for the activation of the
pancreatic juice by means of the enterokinase. The tryp-
sinogen is only converted into the proteolytic ferment trypsin
after the action of the enterokinase. According to Pavlov, the
secretion of the succus entericus depends upon two factors :
(1) The mechanical distension of the alimentary canal; (2)
the presence of the pancreatic juice. Bayliss and Starling
consider it probable that the secretion of succus entericus is
called forth by the chemical action of the pancreatic juice upon
the glands in the intestinal wall. Delezenne and Frouin
report that the intravenous injection of secretin provokes an
immediate and abundant secretion of succus entericus.

It has been suggested that the increase in red and white cells
in the blood after a meal is due to the stimulation of the bone-
marrow by secretin.

According to Lombroso the prime factor in the secretion of
the intestinal juice is the action of chemical substances which
are produced during normal digestion, and act on the nerve
endings of the mucous membrane of the intestine.

It has been suggested that secretin may be useful as a drug
with the object of increasing the pancreatic flow. But it must
be noted that it is absent from some commercial preparations
supposed to contain it, and even if it is present it would be
• I'-troyed quickly by the gastric juice and the trypsin. It

THE INTESTINE

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64

INTERNAL SECRETION

might perhaps be administered subcutaneously, but the results
of such administration have been negative in cases where it has
been tested.

At the present time there is little or no sound physiological
basis, as there is no certain clinical evidence, for the value of
secretin in treatment of disease.

CHAPTER IX

THE INTERNAL SECRETION OF THE GASTRIC

MUCOUS MEMBRANE AND THE NORMAL MECHANISM OF

THE SECRETION OF THE GASTRIC JUICE

IT has been shown by Pavlov that psychical secretion, as well
as the results of a sham meal, are entirely abolished by division
of both vagi, and, further, that stimulation of the peripheral end
of the cut vagus (after its cardio-inhibitory fibres have been
allowed to degenerate) calls forth a steady secretion of gastric
juice. These experiments show conclusively that an important
—probably the most important — part of the gastric secretion
is determined by a nervous mechanism.

On the other hand, Ducceschi finds that dogs and cats whose
stomachs have been severed from any nervous connections
either with the central nervous system or with the semilunar
ganglion, show no particular disturbances.

However important the nervous influences may be, it is
possible that the nervous secretion does not account for the
whole of the gastric juice obtained as the result of a meal.

The question as to the existence of some specific hormone in
relation to gastric secretion analogous to secretin was put to
the test by Edkins. This observer found that extracts made
of the pyloric mucous membrane in boiling water or HC1 04
per cent, contain an active substance, which, on injection into
the bloodvessels of an animal, leads to a secretion of gastric
juice. Extracts made in cold water, peptone, glucose, or
glycerin also contain variable amounts of this substance.

Extracts of the fundus mucous membrane, however made,
do not contain this substance. The inactive condition of some
extracts is due to the substance being present in an undeveloped
state ; boiling the substance or treating with acid will lead to
the complete development. This is, however, only the case
with extracts made from the pyloric or true cardiac mucous

65 5

66 INTERNAL SECRETION

membrane, but not the fundus mucous membrane. Atropine
does not diminish the reaction of an animal to this excitant.
The substance is not a ferment, as boiling an extract leads to an
increase rather than a diminution of its properties.

From these experiments it would seem that we are justified
in concluding that the first products of digestion act on the
pyloric mucous membrane, and produce in this membrane a
substance which is absorbed into the blood-stream and carried
to all the glands of the stomach, where it acts as a specific
excitant of their secretory activity. This substance may be
called the gastric secretin, or gastric hormone. It exists in
the mucous membrane in the form of a precursor (progasfrine)
which is activated by the boiling water or the hydrochloric
acid.

In the normal secretion of gastric juice there is a nervous
secretion due to the secretory fibres in the vagus, and a chemical
secretion due to the chemical stimulation of the secretogogues
or of the hormones produced by them.

The investigations carried out in Pavlov's laboratory seem
to indicate that the quantity as well as the properties of the
secretion vary with the character of the food.

Many physicians believe that preparations of the gastric
mucous membrane have a therapeutic influence, probably due
to their hormone content. Some of these extracts are employed
in place of pepsin.

CHAPTER X

THE INTERNAL SECRETION OF THE REPRODUCTIVE ORGANS

A. The Internal Secretion of the Testis

SOME of the effects due to the absence of the internal secretion
of the testis have been known from the remotest times. The
transformation of the bull into the ox and the cock into the
capon are examples which will occur at once to the reader.

Brown-Sequard found that subcutaneous injections of
extracts of testis exercised considerable influence upon the
general health, as well as the muscular power and mental
activity. The experiments were performed upon himself when
he was seventy-two years of age, and he describes very marked
rejuvenating effects. It is probable that some at least of
Brown-Sequard's personal benefit under this treatment is to
be attributed to suggestion.

More recently Poehl asserts that he has prepared a substance,
spermin, to which he assigns the formula C5H14N2, which has
a very beneficial effect upon the metabolism of the body. He
believes that this spermin is the substance which gives to the
testicular extracts prepared by Brown-Sequard their stimulat-
ing effect. He claims for this substance an extraordinary
action as a physiological tonic. It is recommended that
testicular preparations be employed in cases of deficiency of
testicular substance, or in old age, when the testes lose their
functional capacity. Zoth and Pregel seem to have obtained
definite proof, by means of ergographic records, of the stimulat-
ing action of the testicular extracts upon the muscle-nerve
apparatus in man. They find that injection of such extracts
not only causes an increase in the amount of muscular work
which can be accomplished, but lessens the subjective fatigue
sensations.

The chemical composition and physiological action of Poehl's
spermin and other orchitic extracts have also been investigated

67

68 INTERNAL SECRETION

by Dixon. He finds that the preparations contain a very
large amount of nucleo -protein and other proteins, some
organic substances unaltered by boiling, and inorganic salts.
Injection into the circulation caused a fall of blood-pressure,
but this we now know is an action common to all tissue extracts.
Walker is doubtful of the efficacy of testicular medication,
stating that the injection of fluid extract into castrated dogs
had no effect in arresting the atrophy of the prostate gland.

It is exceedingly doubtful how far the effects of subcutaneous
injection of orchitic extracts are to be regarded as specific.
Fresh (unboiled) extracts of various organs and tissues of the
body have a distinct stimulating effect when administered
subcutaneously to dogs, cats, and other laboratory animals.

There are, however, reasons of quite another kind for thinking
that the testis pours into the blood-stream certain materials
which are essential for the proper development of the body
and the maintenance of normal health and vigour. The
condition of persons or animals in whom the testes have not
descended, or from whom the testes have been removed, is
strong evidence that, besides the function of the preparation
of the specific reproductive elements, the organs have other
important duties to perform. There seems to be no doubt
that the secondary sexual characters in the male are due to
an internal secretion on the part of the testis. Castration
before the age of puberty in man is well known toyprevent
the growth of hair on the face, to arrest ythe growth of the
thorax, and pelvis, and the larynx (and so preserve the voice
of childhood). It is stated that the practice of castrating
boys for the cathedral choirs in Rome was carried out until
1878. Male sopranos or " sopranists " were formerly a leading
feature of musical life. " A peculiarly soft and full quality
of tone seems to have been the characteristic of these evirati,
who, as a class, disappeared from the operatic stage with Vel-
luti, who retired about 1829, and died as late as 1861." 1 The
effect on the larynx is noticed also in horses and cattle when
the testes are extirpated in early life. There is in many
eunuchs a tendency to a certain form of gigantism, and the
mental characteristics are peculiar.

The first result of castration before the age of puberty is the
hind ranee' to further development of the reproductive appara-
1 Oxford History of Music, Vol. IV., F. Maitland, 1902.

THE REPRODUCTIVE ORGANS 69

tus. The vesiculse seminales and the prostate are small and
atrophied. The penis does not share in the atrophy, so that
in Eastern countries it is frequently considered necessary to
remove this as well as the testes. The atrophy of the vesiculse
seminales and the prostate after castration can also be noted
experimentally in animals ; and, further, if castration be
performed in quite young animals, the operation prevents the
development of the prostate, whereas division of the vas and
the abolition of the production of semen have no arresting
influence. The atrophy of the prostate after castration led
to the introduction of this operation as a method of treating
prostatic enlargement. Castration on one side produces no
effect, the retention of a single testis being sufficient to main-
tain the functional integrity of the prostate. It is stated,
also, that Cowper's glands atrophy after castration. It is
generally assumed that the growth and integrity of the prostate
are determined by a hormone furnished by the testis. On this
hypothesis we might explain hypertrophy of the prostate as
due to a hypersecretion of the hormone. This would not be
inconceivable if we make the further hypothesis that the
internal secretion proceeds from the interstitial cells of the
testis, and these might still be active, or even of increased
activity at a time when the seminiferous tubules are in process
of degeneration.

So much for the influence exerted by the testis, in all proba-
bility by means of an internal secretion, upon the growth and
development of the other generative organs. We have now to
consider the influence of the testis in developing and main-
taining the secondary sexual characters. It is, perhaps, well
to point out that castration never induces a condition in any/
respects resembling the female type ; the condition is infantile,
and not female. The effects in man are well known, and have
already been briefly referred to. The relation between testis
and secondary sexual characters is, however, closer in those
animals in which we find increased testicular activity in the
breeding season associated with a periodic development of other
sexual characters. An example is given by Marshall. In the
male elephant the glands on the side of the face emit a musky
secretion during rut.

If the testes are extirpated from quite young stags, the
antlers never develop ; if the operation is performed at the

TO INTERNAL SECRETION

period when the antlers have just begun to grow, these remain
covered by skin, forming the " peruke " antlers. If castration
be carried out after complete development of the antlers, these
are shed prematurely, and replaced by imperfect structures.
Analogous results are recorded in the fallow deer and prong-
buck (Antilocapra americana). As pointed out by Marshall, it
is of interest to note that in the eland and in horned cattle,
where both sexes possess horns, the growth and development
of these structures are not affected by castration.

Changes in the bodily conformation as a result of castration
in quite young animals also occur in sheep, guinea-pigs, oxen,
and other animals. In the case of the cock, it is well known
that castration arrests the development of the comb and spurs.

Experiments of a somewhat different nature must now be
referred to. Bouin and Ancel tied the vasa deferentia in
different animals. The result of this operation was that the
seminiferous tubules atrophied, while the interstitial cells were
unaffected. These authors were the first to point out the
distinctly glandular appearance of these interstitial cells.
They suggest that it is owing to the presence of the interstitial
tissue that the secondary sexual characters become developed,
and that this is due to the activity of a definite internal secre-
tion on the part of the interstitial cells. Bouin and Ancel
report further that subcutaneous injection of extract of the
interstitial tissue in guinea-pigs diminishes the effects of
castration, and tends to promote growth. In a still further
communication, these authors state that the development of
the interstitial glandular-looking tissue coincides with the first
occurrence of spermatogenesis. Other authors also lay great
stress upon the importance of the interstitial cells of the
testis.

Shattock and Seligmann have also studied the effect of the
occlusion of the vasa deferentia in sheep and fowl, and find that
this does not hinder the full development of the secondary
male characters. Since castration does hinder this develop-
ment, it follows that the metabolic results arising from the
functions of the testis must be attributed to the elaboration of
an internal secretion and its absorption into the general
circulation. These authors agree with Bouin and Ancel that
the interstitial cells of the stroma have characters so unmis-
takably glandular that some secreting function must be

THE REPRODUCTIVE ORGANS 71

assigned to them, and they may possibly be responsible for the
internal secretion just referred to.

There is an important difference in the result obtained when
the whole cord is ligatured from that obtained when the vas
only is tied. In the former case all sexual activity comes to
an end ; in the latter, after a short interval of time, the animal
remains just in the same condition as the control, although, of
course, reproduction is impossible in both cases. After ligature
of the vas the interstitial cells remain unaltered, although the
spermatogenic tissue degenerates. These results, pointing
distinctly to an internal secretion on the part of the interstitial
cells of the testis, have been furnished to me by Dr. Copeman.
His results are generally in agreement with those of Bouin and
Ancel.

^ Foges in 1899 could not be sure that transplantation of the
testis had any influence on the secondary sexual characters.
In a later paper he states a different conclusion. The experi-
ment he performed was to remove the testes of fowls and
transplant them to abnormal positions in the body cavity. In
these later experiments — at any rate, in those which were
successful, the transplanted testes had a similar influence upon
the development of the secondary sexual characters to that of
Jbhe normally placed testes, and the comb and spurs were
developed just as in uncastrated cocks. From these experi-
ments Foges draws the conclusion that the testes are organs
furnishing an internal secretion which controls the develop-
ment of the male characters.

Shattock and Seligmann have also performed some experi-
ments upon testicular transplantation in fowls. They report
that the secondary sexual characters develop to a varying
extent, which seem to depend on the amount of testicular
substance left behind.

It has been alleged that the development of male characters
followed the injection of extracts of testis. The injections
were made into hens, and the combs and wattles grew in size,
and became more brightly coloured. These experiments
require confirmation.

Very important indeed, as bearing on the question of the
internal secretion of the testes, are the experiments of Nuss-
baum. At the approach of the breeding season there is formed
in the male frog a thickened pad of skin on the first digit of each

72 INTERNAL SECRETION

limb, associated with an increased muscular development
in the forearm. This modification is preparatory to the act of
copulation, when the male frog uses its arms in embracing the
female, and so assists in pressing out the eggs from the oviduct.
If the male frog be castrated, the pad is not formed, and the
muscles do not develop. Nussbaum found that when pieces of
testis were introduced into the dorsal lymph sac of a castrated
frog, the swelling on the thumb and hypertrophy of the muscles
of the leg took place just as though the frog had not been
castrated. This development of a secondary sexual
characteristic must have been due to the absorption of sub-
stances (internal secretions) derived from the testicular tissue,
since there was no nervous connection. If, however, the nerves
supplying the muscle of the forearm were severed (in an entire
frog) the enlargement did not occur. A similar result was
brought about on transsecting the nerve supplying the glands
and papillae of the thumb -swelling. Nussbaum concludes,
therefore, that the internal secretion provided by the testis acts
through the medium of the nerves. It has, however, been
pointed out that in similar cases it has been shown that the
apparent effect of the transsection of nerves is due to the loss
of sensibility in the parts concerned, in consequence of which
the tissues are not guarded from injury.

Transplantation of the testis was carried out by Hunter and
by Berthold, and, apparently, with complete success. In cocks
Berthold found that the secondary sexual characters were
retained after transplantation, and the author puts forward
what is practically the modern view of internal secretion,
except that he considers the nervous system to play an impor-
tant part.

A subject of peculiar interest is the influence of the testis
upon growth in general, and upon the growth of bone in parti-
cular. There has long been a belief in a definite antagonism
between growth and sexual activity. It was laid down as a
general biological principle by Carpenter, Spencer, and others,
that the functions of nutrition and reproduction are essentially
opposed to one another, because reproduction makes such a
demand upon the parent for material that the supply for
nutrition and growth of the parent is lessened. This philoso-
phical generalization has been vigorously combated by Mi not,
Morgan, and others. However this may be, abundant evidence

THE REPRODUCTIVE ORGANS 73

^ has now been accumulated that the absence of the functional
testis brings about abnormal growth of bony tissues. But this,
according to modern views, is not due to the fact that the
testis is not acting as an organ of reproduction, but to the fact
that the normal internal secretion from the organ is not avail-
able for the controlling of the growth of bone in the body.

Poncet in 1897 reported a series of experiments upon rabbits,
in which he found that castration has a very definite effect upon
the development of the skeleton. The bones of the castrated
' animals were stronger, but especially longer, than those of the
controls. The increase in length was particularly noticeable
in the femur, the tibia, and the fibula. The whole skeleton of
the castrated rabbit was, however, somewhat larger than that
of the control. The fact that the presence of a functional
testis is inimical to bone growth is also emphasized by Lortet
and by Pirsche. The work of Pirsche firmly established the

^ fact that castration in youth is followed by abnormal growth
of the long bones. Geddes has recently reinvestigated several
points in connection with the matter. He reports that males
whose testicles are functionless are found to possess unduly
long limbs. This undue length affects the radius and tibia
more than the humerus and the femur. The process of

+~ ossification is unduly prolonged. He finds, also, that in animals
which have been castrated there is an increase in the length

^ and weight of the bones, and a delay in the obliteration of the

^epiphysial cartilages. In eunuchs there is delay in the com-
pletion of the process of endochondral ossification. Further,
the long bones of the appendicular skeleton are unduly long.
This excess of length is particularly remarkable in the more
distal segments of the limbs. The bones are thin, smooth, and
slender. Geddes is inclined to look upon these results as
occasioned by the setting free for general use of foodstuffs
which would otherwise have been used to provide for the drain
of sperm atogenesis. In other words, the activity of the sexual
glands is opposed to body- growth. Apparently there are no
experiments to determine whether simple vasotomy or ligature
of the cord itself will induce these bony changes. If simply
abolishing the spermatogenesis will bring about these changes,
it is obvious that the theory of internal secretion would have
to be abandoned.

Loisel believes that one of the functions of the internal

74 INTERNAL SECRETION

secretion of the testis is to destroy fat in the body. For this
reason men are thinner than women, and castrated men
become fat.

The view that the internal secretion of the testis which is
responsible for the secondary sexual characters is derived from
the interstitial cells of Leydig is strongly supported by the
facts that these cells have the characters of secretory cells (fatty
granules and mitochondria), that the animal remains normal
even when there is atrophy of the seminiferous tubules (after
tying of vas deferens), and that it is only when we remove the
atrophic testis with the Leydig's cells then in good condition,
that we produce the changes that are noted after castration.
(Massaglia. )

It is stated (Wheelon and Shipley) that castration causes a
depression of the vaso -motor irritability and that transplanta-
tion partially reinstates normal activity.

In the human subject Lichtenstern reports that after loss of
both testes, transplantation of a testis from another man
restores the previous physical and psychical condition.

Brown-Sequard's work has already been referred to, and a
summary of the alleged beneficial results from the use of
Poehl's spermin has been given. Orchitic extracts have also
been recommended in certain toxic dermatoses, and even in
psoriasis, with the idea that they have an antitoxic action. In
asthenia and nervous irritability it is stated that the extracts
of testis are useful and far-reaching in their results.

B. The Internal Secretion of the Prostate Gland

It has been reported that after prostatectomy in dogs the
testicles gradually lose; their functional activity, ejaculation
ceases to occur, the formation of spermatozoa is stopped, and
the other generative secretions are no longer formed. On the
other hand, the administration of glycerin extract of prostate
to dogs so operated upon prevents the atrophic changes ;
ejaculation continues, the spermatozoa do not disappear, the
preputial glands secrete. It is inferred, therefore, that the
functional activity of the testis and other generative organs is
dependent upon an internal prostatic secretion.

Walker had previously obtained contrary results with white
mice. As Mai -hall very justly points out, the most obvious

THE REPRODUCTIVE ORGANS 75

criticism of the theory of prostatic internal secretions is that
it is unlikely on phylogenetic grounds, that the functional
activity of the essential organ of reproduction should depend
on the presence of an accessory gland of comparatively recent
evolutionary development. Further, Dr. Halpenny, working
in my laboratory, has repeated the experiment upon dogs.
In these there was certainly no appreciable effect upon the
testes.

There are several reports of cases of prostatic enlargement
in which good results are said to have followed the administra-
tion of extract of prostate. Such extracts are also affirmed to
be of value in increasing the contractions of the bladder.

C. The Internal Secretion of the Ovary and the Corpus

Luteum

The ovary in mammalia consists of a connective tissue
stroma, with bloodvessels, lymphatics, and nerves, enclosing
the Graafian follicles with the ova. At certain periods there
are corpora lutea and atretic follicles, and in certain species
the "interstitial gland."

Cyclical changes occur both in the ovary and in the uterus.
In the ovary these consist of ripening of the follicle, ovulation,
and formation of the corpus lute'jm. In the uterus we have to
deal with the structural changes which accompany the cestrous
cycle, consisting of growth of the mucous membrane with
increased glandular activity, followed by regression and period
of rest.

The quiescent period is called the " ancestrum." The
" pro-oestrum " is distinguished by increased vascularization
of the reproductive organs, which reaches a climax at the
period of "oestrus" or "heat," during which only in the
majority of animals the female will admit the male. In the
human subject and the primates generally menstruation
corresponds to pro-oestrum in the lower animals.

If conception occurs, oestrus is followed by gestation, lacta-
tion, and finally succeeded by another ancestrum. But if
conception does not take place, oestrus is followed by metoes-
trum, during which there is a return to the normal on the part
of the whole system.

The following scheme is given by Hill and O'Donoghue —

76 INTERNAL SECRETION

An oestrum

Pro -oestrum (uterine degeneration)

I

(Estrus (ovulation)

Pregnancy

| Metoestrum

Nursing period

Anoestrum

In males, as we have seen, interference with the discharge of
the seminal fluid has no effect on the secondary sexual charac-
ters, while removal of the testis has a very marked effect.
Similarly in the female, any operation which abolishes the
normal passage of the ova down the Fallopian tubes into the
uterus has no influence on the secondary characters, while re-
moval of the ovary results in the changes about to be described.

Our knowledge of the effects of extirpation of the ovaries
before the age of puberty in the human subject is very limited.
A fairly large number of operations must have been performed
in which female children were deprived of both ovaries at an
early age, but there seems to be no systematic account of them.
Marshall states that such extirpation, if the operation be
carried out before puberty, besides preventing the onset of
puberty and the occurrence of menstruation, produces notice-
able effects on the general form and appearances. He instances
the case of certain adult women in semi-barbarous parts of
Asia, where the natives perform this operation upon young
girls. Such women are said to be devoid of many of the
characteristics of their sex, and in certain cases to present
resemblances to men. This account seems to be derived from
the observations of Roberts in the East Indies. According to
Biedl, however, there is no ovariotomy among such people,
but simply a mutilation of the external organs of generation.
Indeed, it seems incredible that savages could successfully
perform double ovariotomy.

When extirpation of both ovaries is carried out in the human
female after the age of puberty, the most marked effect is the
cessation of menstruation. There is also in some cases an
atrophy of the uterus, vagina, and external genitals. The
effects on the breasts vary in different cases. Sometimes these

THE REPRODUCTIVE ORGANS 77

atrophy, while in other cases they appear to increase in size.
This latter result, when it occurs, may be attributed to obesity,
which is the usual result of the operation. It is difficult to
obtain information as to the effects on sexual desire, It
appears, however, that it may not be much affected for some
time after the operation.

After extirpation of the ovaries it is stated that the hair
becomes more luxuriant and the skin lighter in colour. The
nipples become smaller and the pigmentation of the areolse
becomes less marked.

The metabolic results have not yet been fully worked out.
In the human subject extirpation leads to a series of symptoms
which are usually attributed to excitation of the autonomic
nervous system. These consist of emotional disturbances,
headache, fainting, intestinal disturbances, and feelings of heat
and cold.

In some female animals removal of the ovary has been stated
to lead to the appearance of male characters. Cases are
recorded in which female deer possessed horns. In these the
ovaries were abnormal or the animals were old. Similar cases
are not uncommon in birds. Such cases are difficult to explain
on any other hypothesis than that the secondary male charac-
ters are normally present in a latent form in the female, and
that the ovaries exert an inhibitory influence over their
development. As we have seen above (p. 69), castration in
the male never induces a condition in any respects resembling
the female type.

Carmichael and Marshall have furnished some further details
of the effects of ovariotomy in rabbits. The degree of uterine
degeneration was proportional to the time after the operation
(see fig. 12.) After six months the organ was fibrosedand the
glands had disappeared. The epithelium was greatly thinned
and the muscle fibres disintegrated. The Fallopian tubes had
undergone atrophy. When the operation was performed upon
very young rabbits the uteri remained infantile. The same was
the case with the Fallopian tubes. In dogs ovarian extirpation
results in a marked increase in the vaso-motor response to a
standard dose of nicotine. This phenomenon is interpreted as
indicating overexcitability of the sympathetic nervous system
(Hoskins and Wheelon). These effects are very similar
to those observed after ovariotomy in the huma.n subject.

78

INTERNAL SECRETION

All the foregoing fact's show that the ovary, just like the
testis, has a far-reaching influence on the metabolism of the
body, this influence manifesting itself in helping to develop
and maintain the secondary sexual characters. Until recently
this influence has generally been supposed to be nervous. As
we shall see below, the evidence as to one or several kinds of
internal secretion is now tolerably conclusive.

Considerable attention has been paid to the subject of
ovarian transplantation. Unfortunately there has been some
confusion in the terminology. In the present section the term
" autoplastic " will be used in cases where the organ is trans-

Group I

ill

IV

Normal

FIG. 12. — The effect of double ovariotomy on the growth of the uterus in
young rabbits. The first five are the uteri from rabbits who had both
ovaries removed on March 2, 1921, and were kept alive till June 7.
Number 6 is a normal control. Note the effect of ovariotomy on the
size of the uterus. No. 3 was a month older than the others. (Photo
by Sutherland Simpson, from a class experiment carried out by students
at Cornell University).

planted into some part of the body of the same individual. A
" homoplastic " transplantation will refer to a graft made from
one individual to another belonging to the same species, while
" heteroplastic " will be the term applied to a graft from one
animal to a second belonging to a different species.

In human beings ovarian transplantation has been carried out
on many occasions, with varying degrees of success. Morris

THE REPRODUCTIVE ORGANS 79

reports a successful case of transplantation of the homoplastic
variety. The ovaries from one woman were grafted into a
second, and the latter gave birth to a child four years later.

Knauer was apparently the first to report successful auto-
plastic transplantation in animals. The ovaries were detached
from their normal position and grafted upon the mesometrium
or into the abdominal wall. A certain part of the grafted organ
degenerated ; the rest of it gave rise to ova which were capable
of fertilization. Atrophy of the uterus, an invariable result of
castration, was prevented if successful transplantation of an
ovary had been effected. Several other authors have obtained
similar results. Some writers have reported that the offspring
resulting from fertilization of ova from grafted ovaries indicate
a " foster-mother " influence. Thus ovaries have been trans-
planted from hen to hen. Such fowls laid eggs which were
duly hatched, and the chicks partook of certain of the foster-
mother's characters.

Transplanted ovaries remain normal for a time, except that
the germinal epithelium becomes absorbed. Sometimes
degeneration occurs and the stroma may remain normal while
the follicles disappear or are replaced by corpora lutea.
Transplanted ovaries show the same cyclical changes as normal
organs, i.e., ovulation occurs in them. Autoplastic trans-
plantation is more easily carried out than homoplastic, and the
most successful cases are those in which two animals from the
same litter are employed.

But ovarian grafts and their effects on the uterus are not
permanent. Sooner or later degeneration takes place in the
grafted organ and atrophy of the uterus takes place. Accord-
ing to A. Louise M'llroy, the rate of degeneration varies with
the site of implantation, the more vascular the site, the longer
the persistence of the graft. The corpora lutea first undergo
a hyaline change and infiltration of leucocytes. Cystic
degeneration overtakes the follicles, though the interstitial
cells may persist for some time longer. Professor 'M'llroy
considers that it is the interstitial cells which control the
nutrition of the uterus, since atrophy occurs only when they
are degenerated. The experiments so far carried out indicate
that a grafted ovary may remain functional for a year or more.

Experiments carried out by Steinach show that if ovaries
are grafted into young male guinea-pigs, the mammary gland

80 INTERNAL SECRETION

may develop and secrete milk. It seems likely that the
interstitial cells are responsible for this effect.

Lipschiitz concludes that the secretion of the gonads acts in
a " sex specific " manner, that is, the male gland aids the
development of male sexual characters only while it inhibits
the female characters, whereas the female gland promotes the
growth of female sexual characteristics, at the same time
inhibiting male characters. In birds the development of the
male plumage and the spurs does not depend on the male
sexual gland, while the ovary converts a male plumage into a
female one and inhibits the growth of spurs. The male
plumage and the spurs are evolved out of the characters of the
hypothetical non-sexual embryonic form, without any influ-
ence of the sexual glands. (See however p. 68.) The plumage
and spurs become male sexual characters, not because of any
action of the male gland on the non-sexual soma, but because
the development of these non-sexual characters is influenced
in the female by the internal secretion of the ovary. Accor-
dingly Lipschiitz classifies the sex characters as follows :—

1. Those non-dependent on the " puberty gland " (Steinach)
or " interstitial gland."

2. Those dependent on the puberty gland, which calls forth
the characters by acting on the non-sexual embryonic form in
the direction of augmentation or inhibition.

Sand asserts that, by simultaneous transplantation of both
ovary and testis into a castrated animal, he has succeeded in
obtaining a true experimental hermaphroditism (somatic and
psychic).

The results of ovarian transplantation in the human subject
with the object of reducing the symptoms of the artificial
menopause after ovariotomy seem to be encouraging. But
if the uterus has also been removed, the retention of ovarian
tissue is of little benefit.

Extracts of ovary do not contain any substance of special
clirinical or physiological interest. The pharmacodynamical
effects of ovarian extracts are found to be the same as those of
i '\ tracts from organs and tissues generally, viz., a temporary
depression of the arterial blood-pressure brought about by
dilatation of arterioles throughout the body. The substance
nr -ubstances which produce this effect are not known. They
are soluble in alcohol and in ether, as well as water. It has

THE REPRODUCTIVE ORGANS 81

been stated that there is a considerable difference in the
activities of extracts from different animals. It is said that
extracts of ovary raise the metabolism in castrated animals,
and have a stimulating action on uterine contraction. It is
doubtful whether these effects are specific.

A considerable amount of work has been carried out upon
the structure and functions of the corpus luteum. This body
in its fully formed state consists of columns of large cells
(luteal cells) containing a yellowish pigment. The columns
are separated by intervening trabeculse, composed of fibrous
tissue containing numerous bloodvessels. These trabeculae
converge inwards from the surrounding ovarian stroma to a
central strand or plug of connective tissue, in which there are
no luteal cells, occupying the axis of the nodule (see Fig. 13).
The columns of cells are not unlike those of the cortex of the
adrenal (see Figs. 13 and 13a). The fully developed corpus
luteum is a highly vascular structure.

The fullest and most complete account both of the develop-
ment and of the histology of the fully formed corpus luteum is
given by Sobotta. In the mouse the epithelial cells are large
and polygonal in shape, measuring 20 p or more in diameter.
The cells contain fat, which is mostly disposed excentrically,
but it may almost fill the entire cell. The peripheral cells are for
the most part free from fat, while those in the centre contain
the largest amount. Generally speaking, the older a corpus
luteum is the more fat does it contain. The nucleus is rounded.
The connective tissue is in the form of spindle-shaped anasto-
mosing cells. They surround groups of four to five epithelial
cells by anastomoses of their processes. Their nuclei closely
resemble those of the capillary walls. The connective tissue
of the central plug consists of stellate elements. In some
animals the fully formed luteal cells are rounded or spindle-
shaped, and may show signs of degeneration.

The mode of formation of the corpus luteum is still under
discussion. Former investigators were not able to agree as
to whether the body is a connective-tissue structure, or whether
the luteal cells are formed by the hypertrophy of the epithelial
cells of the undischarged Graafian follicle. The former theory
is that of v. Baer, the latter that of Bischoff. The investiga-
tions of Sobotta upon the mouse and the guinea-pig confirm
Bischoff 's view, but there have been several investigators

a

82

INTERNAL SECRETION

who could not adopt this theory. There is no need to enumerate
the authors who have held one or the other view on this ques-
tion. There is a tendency towards a compromise in some of
the recent papers. Thus, van der Stricht found that, whereas
the majority of the luteal cells are derived from the follicular
epithelium, a certain number are developed out of interstitial

FIG. 13. — Section through the ovary of Dasyurus viverrinus, showing Graafian
follicles and corpus luteum. (Drawn by Mrs. F. D. Thompson from
material supplied by Prof. Charles O'Donoghue.)

( ( IU in the inner theca of the connective-tissue sheath. As
pointed out by Marshall, this is of special interest in view of
the statement made by Miss Lane-Claypon that the follicle
and interstitial cells have an identical origin, since both are
d» ii\rd limn the germinal epithelium, and pass through a
similar si-rirs of changes. The majority of recent investigators

THE REPRODUCTIVE ORGANS 83

are, however, in favour of the view that the luteal cells are
derived from the follicular cells.

The glandular nature of the organ is admirably shown in
the corpus luteum oiDasyuru3 (see Figs. 13 and 13a,).

The yellow pigment of the corpus luteum belongs to the
group of lipochromes. These are found in several organs and
tissues and are related to similar vegetable pigments. The
lutein from egg-yolk has a molecular weight of 624 and the
formu'a given is C40H56C)2. It is isomeric with xanthophyll,

FIG. 13a. — Portion of corpus luteum of Dasyurus under a high power, showing
the glandular nature of the constituent cells. (Drawn by Mrs. F. D.
Thompson from material supplied by Prof. Charles O'Donoghue.)

obtained as a by-product in the preparation of chlorophyl.
The precise chemical nature of lutein has not yet been made
out, but it has been suggested that it is an oxidation product
of carotin (obtained from carrots), or again, that it is an oxida-
tion product of the esters of cholesterol with unsaturated
acids.

Different " active principles " have been isolated from corpora
lutea by means of different solvents. Thus some of these are
extracted by ether, others by acetone. If these are to be

84 INTERNAL SECRETION

tested medicinally there is great need for more uniform methods
in the preparation of extracts. The only definite physiological
effects alleged to be produced by luteal extracts are changes
in the contractions of the uterus and smooth muscle of other
regions, and an effect on the flow of milk. For example,
Itagaki states that luteal extracts usually increase the tone
of the surviving uterus of the rat, rabbit, dog, and guinea-
pig, though occasionally the result is in the opposite direction.
He believes that the different results are due to the effects
of two separate principles, having antagonistic actions on the
uterus. The inhibitory substance is soluble in alcohol, while
the augmentory principle is insoluble in alcohol, but soluble
in water. The evidence for the existence of two opposing
active principles cannot be regarded as very convincing.
Chauffard urges that the yellow body is a centre for the pro-
duction of cholesterin. He points out that this substance
is present in the corpus luteum during pregnancy, and that
cholesterinaemia occurs at this time. But the corpus luteum
is not the only centre for the production of cholesterin. Ex-
tracts of the corpus luteum are said to stimulate the contrac-
tions of the vas deferens and the seminal vesicles, but this must
be an accidental and not a specific reaction. One cannot
avoid the suspicion that in such experiments no adequate
regard is paid to control experiments carried out with extracts
from other organs and tissues.

Ott and Scott (1910) reported that extracts of pituitary,
thymus, pineal, and corpus luteum act as galactagogues.
So far as the pituitary and luteal extracts are concerned, the
result was confirmed by Schafer and MacKenzie. It is now
generally considered that galactagogue principles can be
extracted from pituitary, corpus luteum, pineal, mammary
gland, and the involuting uterus. It is very probable that
the list will be extended, but there is little reason to regard all
these organs as furnishing " hormones " for the purpose of
stimulating milk secretion.

Corpus luteum extracts are now frequently employed by
medical men in cases of deficient milk secretion in women.

Attempts to replace the internal secretion of the corpus
luteum by means of injection of extracts have not given very
satisfactory results. Several years ago the present writer,
in conjunction with Dr. F. H. A. Marshall, performed a s< -ri< •>

THE REPRODUCTIVE ORGANS 85

of experiments designed to test the theory that the cestrous
cycle is determined by an internal secretion on the part of the
ovary. Extracts were made from ovaries in a pro-cestrous or
cestrous condition and injected subcutaneously into a bitch
at a period as remote as possible from the cestrous one. In
some of these experiments a swelling of the vulva and other
slight signs of the cestrous condition were induced, but the
results were not decisive enough to warrant publication.
Since then, however, Marshall and Jolly have reported that
" heat," or a transient condition resembling it, can be produced
by the injection of extracts of cestrous ovaries. It is possible
that in some of these experiments the extracted ovaries con-
tained corpora lutea and that the effects observed (chiefly
consisting of hyperaemia of the external genitals) were due to
active substances derived from the yellow bodies. Recent
experiments have confirmed the fact that injection of extracts
of ovary cause hypersemia and swelling of the reproductive
organs. It is not clear from these experiments how far the
results are due to corpus luteum and how far to other parts
of the ovary. The changes induced do not seem to be tr,ue
cyclic growth processes, but simply transient circulatory
effects. Pearl and Surface have recently shown that the
desiccated fat free substance of the corpus luteum of the cow,
when injected in suspension into an actively laying fowl,
immediately inhibits ovulation. After the bird begins ovula-
ting again, the laying goes on as before. The substance
which produces the effect is rendered inactive by boiling.

In future researches upon the pharmacodynamics of ovarian
extracts great attention should be paid to the chemistry of
the products obtained, and very careful control experiments
should be carried out.

Prenant, in 1898, thought that the corpus luteum, through
an internal secretion, influences the general metabolism of
the body and prevents ovulation during pregnancy anpl between
the cestrous periods. As a result of the investigations of
Loeb and others, this theory seems now to be firmly established.
Loeb found in sixty-six guinea-pigs that spontaneous ovulation
rarely occurs within sixteen to eighteen days after a preceding
ovulation. In twenty -five animals all the yellow bodies were
removed and 92 per cent, of these all ovulated within 12-
days after coitus, showing a marked shortening of the

86 INTERNAL SECRETION

interval between ovulations. It is known that pregnancy
will not in itself inhibit ovulation. We have seen above that
the injection of luteal extracts into fowls will prevent ovulation.
It is clear that the ovulation can only be accelerated up to a
certain degree by removal of the luteal substance. The
succeeding ovulation has to await the maturation of follicles.
Without the presence of follicles in a state of maturity,
renewed ovulation is impossible, even after extirpation of the
corpora lutea.

The idea that the corpus luteum might be an organ with
an internal secretion was first conceived by Gustav Born, who
suggested that the function of the internal secretion was to
subserve the fixation and development of the impregnated
ovum in the uterus. Born did not publish his views, but
bequeathed the idea to Fraenkel to work out. It was found
by this and subsequent authors that ovariotomy (involving
removal of corpora lutea) caused discontinuance of pregnancy
in animals. As pointed out by Marshall, there is no evidence
that the corpus luteum governs the fixation of the embryo
otherwise than by stimulating the uterine mucous membrane
to hypertrophy.

In rabbits spontaneous ovulation and subsequent production
of corpora lutea do not occur. The additional stimulus of
coition is necessary. Ancel and Bouin observed that, if the
follicles be ruptured artificially, corpora lutea are formed and
a growth of the mammary glands supervenes. But O'Donoghue
found that rupture of the follicles was not always succeeded
by the formation of corpora lutea, and when such formation
did not occur, there was no growth of the mammary glands
(vide infra, p. 88).

The changes in the uterine mucosa produced by the corpus
luteum, and which help in the fixation of the foetus, were studied
in greater detail and by a new method by Loeb. It occurred
to this observer that the influence exerted by the corpus
luteum might be explained if experiments were conducted in
which the changes in the uterus could be studied directly,
without the interference of a fertilized ovum. Accordingly
Loeb excluded the chance of pregnancy by tying the Fallopian
tubes immediately after the occurrence of coition. Ordinary
foreign bodies and various mechanical stimuli were applied
to the uterine mucous membrane. It was found that when

THE REPRODUCTIVE ORGANS 87

this latter had been sensitized by the internal secretion of the
corpus luteum, the mechanical stimulation gave rise to a
maternal placenta — an artificial deciduoma — at the point of
stimulation. The mechanical stimulus has the same or a
very similar effect to that of the ovum. Even apart from
special mechanical stimuli, the uterine mucosa frequently
shows some slight deciduomatous growth, due in all probability
to some ill-defined stimuli occurring in normal life and rendered
effective by the internal secretion of the corpus luteum.
O'Donoghue finds that in marsupials, in which the yellow
body is persistent in the non-pregnant animal, the uterine
overgrowth is specially marked. He suggests that the effect
of the mechanical irritation is chiefly to localize the over-
growth, and thus produce definite deciduomata.

Loeb's observations have been confirmed by several
authors.

It seems clear, then, that the internal secretion of the corpus
luteum sensitizes the uterine mucous membrane and renders
it capable of reacting to mechanical stimulation. There is a
relation between the quantity of the internal secretion poured
out by the corpus luteum and the degree of response which
can be elicited by mechanical irritation. The .response can
only be obtained when an amount of secretion sufficient to
sensitize the mucous membrane has been poured out. If the
stimulus be applied when the body is just beginning to secrete,
little effect may be produced. But if the stimulation is
carried out later on, at a time when the uterine mucous mem-
brane has become completely sensitized, the secretion of
the substance goes on for a few more days and increases the
reaction. The ovum becomes attached at about the time when
the greatest sensitization of the mucosa has been obtained.
The substance secreted by the yellow body is not specific, that
is to say, the substance secreted by one individual will cause
growth in the sensitized uterus of a second individual of the
same species. The effect, however, is less pronounced than
in the organism to which it belonged. This difference is
supposed to be due to the presence of " homoiotoxins " in
the second individual. The artificial deciduomata in any
particular species have the structure of the normal maternal
placenta. In some animals these are confined to the uterus,
but in women deciduomata can be produced in the Fallopian

88 INTERNAL SECRETION

tubes, as in cases of tubal pregnancy. The readiness with
which extra-uterine pregnancy may develop in any species
depends, in part at least, upon the readiness with which the
stroma of the host responds with the production of a decidua
favourable for the development of the embryo.

It is probable, then, that the corpus luteum aids in the fixa-
tion of the embryo by favouring the growth of the deciduoma
in response to the stimulus of the ovum. But recent investi-
gations point strongly to the view that the yellow body has an
important function related to the mammary gland.

It was suggested by Hildebrandt that during pregnancy an
impulse is exerted by the ovum on the mammary glands, which
stimulates them to growth. Lane-Claypon and Starling re-
ported that extracts of foetus stimulate the growth of mammary
gland. But virgin animals sometimes produce milk. Hence
it is clear that the source of the stimulus which normally
calls forth the development of the mammary gland must be
sought elsewhere than in the developing foetus. Frank
V. linger and O'Donoghue have definitely urged that this
source is to be found in the corpus luteum. The last-named
author, working upon Dasyurus, has found that the enlarge-
ment of the mamma begins quite apart from fertilization,
and is continued when there is no fertilized ovum present to
produce an internal secretion. He gives tables and curves to
show that as soon as the corpus luteum has begun to be formed,
the growth of the mammary gland commences, and this
growth is notably increased after the corpus luteum is fully
formed. As we have seen above (p. 86) O'Donoghue observed
that, if follicular rupture is not followed by formation of cor-
pora lutea, there is no growth of the mammary glands. The
conclusion can scarcely be avoided that the hormone causing
the growth of the mammary gland is produced in and secreted
by the corpora lutea.

Reference has already been made to the " interstitial cells "
or the "interstitial gland" ("puberty gland" of Steinach).
The tissue is so often referred to in the literature, that it is
astonishing how little can be definitely stated about it. It
is not known certainly whether the tissue is epithelial or whether
it is of connective tissue origin. It is not even known whether
it is constantly present. In fact, out of more than one hundred
species so far examined, 50 per cent, are said to possess none.

THE REPRODUCTIVE ORGANS 89

It has been supposed that the cells undergo periodic changes
of such a character that at certain times they may be more,
at others less, abundant or conspicuous. For example, they
are stated to reach their greatest development during preg-
nancy and lactation.

The cells have a typically glandular appearance. They
have an abundant blood supply and contain granules. These
are of various kinds, as indicated by their staining reactions.
There is an abundant chondrioma and enclosures of a lipoid
character, siderophil protoplasm, and distinctly polychromatic,
large, round nuclei. The chondrioma is made up of chon-
drioconta and mitochondria. It undergoes important modi-
fications in the course of the evolution of the cell. The
granulations, at first few, increase in number in the later
stages ; the fatty products are the result of a chemical change
in the mitochondrial substance. The lipoid enclosures prob-
ably represent the products of secretion (Athias).

When the theory of internal secretion on the part of the
ovary had once become generally accepted, and when the
organ was found to contain, in addition to the follicles, certain
other cells of a glandular appearance, it was natural that
these last should be charged with the function of internal
secretion. But so far no hypothesis in regard to them has been
put forward which has much direct evidence in its favour.
Perhaps the best accredited of such hypotheses is that the
interstitial cells preside over the nutrition of the reproductive
organs (e.g., the uterus) and are responsible for the appearance
of the secondary sexual characters.

In birds there seems to be some doubt whether the " inter-
stitial " cells can be regarded as secretory elements. They
appear to contain hsemopceetic centres.

Bell urges that " femininity " is dependent, not only on
influences arising from the ovary, but on all the various
internal secretions. The relations of the thyroid gland and
the adrenal to the female reproductive system are treated in
other chapters (pp. 241, 400). The pineal is alleged to have
an influence on sexual precocity (p. 390). It is believed that
the pituitary and the thymus influence the metabolic functions,
determining the onset of puberty. The question is rendered
complicated by the influence of the various internally secreting
organs upon each other (p. 395).

90 INTERNAL SECRETION

D. Ovarian Medication.

Brown-Sequard in a first communication to the Societe de
Biologic, in June, 1889, expressed the opinion that the ovaries
of animals might furnish a juice which would have a beneficial
effect upon women similar to that obtained in the case of men
by the employment of testicular extracts. In 1890 he reports
that a Parisian midwife had injected herself with a liquid
made from the ovaries of guinea-pigs, and had benefited thereby.
He further calls attention to a report of Villeneuve, who made
injections of ovarian extract into three individuals — two women
and one man. One of the women, who had undergone double
ovariotomy, was very considerably benefited. Finally, he
gives an account of the work of an American lady doctor, Mme.
Augusta Brown, who " avec un grand courage " had observed
good results by injection of extracts made from the ovaries
of rabbits. The injections were mostly subcutaneous, but
the application was sometimes made on to the skin after
blistering, and in one case the juice was applied directly to
the uterus (in the case of prolapse).

Brown-Sequard does not seem to regard these reports as
of much value, for he concludes that it is the testicular juice
which ought always to be given " comme agent dynamo-
genique " in women as well as in men. He states that the
ovarian extracts are less powerful than the testicular, and
their action is not specific.

Mainzer obtained good results in the treatment of heats,
sweating, headache, etc., after double ovariotomy, and also
in the vasomotor troubles of the menopause.

Bestion de Camboulas gives many interesting references
showing how completely persuaded were many physicians
of the period that the ovary is a gland with an internal secre-
tion. The evidence at their disposal was, however, very meagre.
They seem to have been led to their belief chiefly by Brown-
Sequard's famous dictum that all glands, whether or not they
possess a duct, pour into the blood useful principles, whose
absence makes itself felt after their extirpation or their destruc-
tion by disease.1

Bestion de Camboulas gives an account of the various

1 Bestion de Camboulas says naively : " The ovary, being a gland, ought
not to escaf tli is law.''

THE REPRODUCTIVE ORGANS 91

modes of preparing ovarian extracts. He employed (1) fresh
gland, (2) dried gland, (3) ovarian juice or fluid extract. This
last was watery or alcoholic, or a glycerin extract. He recom-
mended the employment for medical purposes of the ovaries of
the sow.

This author performed a series of experiments upon animals
in order to investigate the toxicity of the ovarian extracts,
and found that the glycerin or watery preparation is much
more toxic for the male than for the female. After large doses
males died with pyrexia, hsematuria, and other disturbances.
With non-toxic doses the males lost weight, the females gained
weight. The resistance of pregnant females was much less
than that of non-pregnant.

Clinically, his results were as follows : Troubles of the
menopause, natural or after castration, are considerably
relieved by ovarian extract without other medication. There
is constant amelioration in cases of amenorrhcea and chlorosis,
and there is a real improvement in the mental troubles
which accompany genital lesions, or which occur after cas-
tration. Improvement in the general condition is marked
in all cases. The extract should never be given to preg-
nant women.

Andrews speaks very cautiously as to the benefit accruing
from the administration of ovarian extracts, while Cohn
finds that the results are nearly always disappointing.

Batty Shaw says that the special value of ovarian substance
is shown in cases in which the ovaries are ill-developed, or have
become atrophied as at the menopause, or have been removed
by operation.

There are numerous other papers on the subject of ovarian
medication. Much of the work has been very uncritical.
No due regard has ever yet been taken even in experiments on
animals as to the condition of the ovary from which the
extract is made, and it seems clear that the corpus luteum will
in the future have to be considered separately both experi-
mentally and clinically.1

1 Bouin and Ancel now believe that the corpus luteum secretes a hormone
which excites the mammary gland to growth, but that the hormone which
excites to secretion is derived from a gland which they claim to have discovered
in the muscular layer of the uterus, and to which they have given the name
" myometrial gland." Recent work has thrown considerable doubt upon
the existence of any such " gland " in the uterine wall.

92 INTERNAL SECRETION

E. Osteomalacia

Perhaps this is the most suitable place in which to refer to
the disease known as osteomalacia. The theory which connects
this condition with hyperfunction of the ovaries has found
most adherents. The argument in favour of this view is
largely based upon the fact that the condition is benefited
both by removal of the ovaries and by artificially induced
labour.

CHAPTER XI

THE INTERNAL SECRETION OF THE ADRENAL BODIES

(The Cortex of the Adrenal and the Chromaphil Tissues)

A. Introductory

WHEN we consider the extraordinarily voluminous literature
devoted to the adrenal bodies, and the immense amount of
time and patience which has been expended by physiologists,
pathologists, and comparative anatomists, in the attempt to
elucidate their function, it is regrettable to have to admit
that we are still unable to give a satisfactory answer to the
question, " What is the function of these bodies ? " We have,
perhaps, a fairly reasonable suggestion to offer as to the service
in the economy rendered by the chromaphil tissues (including
what in mammals is called the " medulla " of the adrenal), but
of the physiology of the " cortex " we still know very little.

There are two important discoveries which stand out among
all others as epoch-making. The first is the observation by
Addison in 1849 that certain cases of disease characterized by
pigmentation of the skin, languor, and other symptoms, are
associated with destructive lesions — usually tubercular — of
the adrenal bodies. The second is the discovery in 1894 by
Oliver and Schafer of the blood-pressure-raising activity of
extracts of the medullary portion of the gland. We are, how-
ever, by no means clear, as will be seen in the sequel, what is
the precise relationship between the facts revealed in these
two discoveries.

A third very important step in our progress ought to be
referred to in this place. This is the isolation in crystalline
form of the active principle of the medulla of the gland (i.e., of
the chromaphil tissues) by Takamine and Aldrich independently
in the year 1901.

The first definite account of the adrenals with illustrations

93

94 THE DUCTLESS GLANDS

is given by Eustachius in 1563. For a long time the discovery
was unnoticed, or the existence of the new organ was denied !
It is indeed remarkable, as pointed out by Biedl, that Vesalius
in 1642, Fallopius in 1606, and Fabricius in 1738 make no refer-
ence to the bodies discovered by Eustachius. However, they
began to be referred to even before the end of the sixteenth
century in the medical books as the " glandulse " or the " cap-
sulae renales Eustachii."

The story of Montesquieu's participation in the history of
our subject is so interesting that, although it has now been told
several times, it will well bear repeating.

In the year 1716 the Academy of Sciences of Bordeaux
offered as the subject of a prize essay, " What is the Use of
the Suprarenal Glands ? " The essays submitted were placed
in the hands of Montesquieu, the famous author of the Esprit
des Lois, who acted as j udge . His report is of especial interest,
not only because of the personal fame of the author, but because
it gives an admirable critical account of the older views upon
the adrenal bodies. The style is satirical, but it is probable
that it was not intended to be so satirical as it appears to us at
this date, when every theory mentioned in 1716 appears to us
positively absurd. Montesquieu briefly discusses the older
views that the glands, serve to hold up the stomach and
strengthen the nervous plexus which touches them, or that
" black bile " is preserved within their cavity (Bartholin), or
that they serve to collect the humidities which leak out of the
great vessels in the neighbourhood. He then criticizes the
essays which were presented to the Bordeaux Academy.

"We have found one author who declares that there are
two kinds of bile : one grosser, which is separated out in the
liver ; the other more subtle, secreted in the kidneys by the
assistance of the ferment which flows from the suprarenal
capsules by ducts of which we are ignorant, and of which,"
comments Montesquieu, " we are menaced with perpetual
ignorance."

" Another describes to us two small canals which carry the
liquids from the cavity of the capsule into the vein belonging
to it ; this humour, which many experiments lead us to con-
sider alkaline, serves to give fluidity to the blood returning
from the kidneys after it has been deprived of serosity in the
formation of the urine.

THE ADRENAL BODIES 95

" Another essayist, who gives a difference between conglobate
and conglomerate glands, has placed the suprarenal glands
among the conglobate. In his opinion they are nothing but a
continuity of bloodvessels within which, just as in filters, the
blood becomes more subtle. ... In these glands, as in all the
conglobate glands, no excretory duct exists, because there is
no question of the secretion of liquids, but only of making them
more subtle."

In conclusion, Montesquieu announces that the Academy
will not award its prize this year, since the object of the offer
has not been achieved. He ventures his own opinion that
" le hasard fera peut-etre quelque jour ce que tous ses soins
n'ont pu faire," and he is polite enough to state ! " Mais ces
efforts impuissants sont plutot une preuve de 1'obscurite de la
matiere que de la sterilite de ceux qui 1'ont traitee." l

In attempting to assign a function to the adrenal bodies, it is
essential to bear in mind their dual nature. As we shall see
later, the adrenal body of the higher animals has been
derived from two separate and distinct kinds of tissue in lower
vertebrates ; and although there is a more or less gradually
increasing tendency for the two tissues to become united as we
ascend the scale, yet it is only in mammals that the terms
"adrenal cortex" and adrenal medulla" are strictly appro-
priate.

It is essential that, before dealing with the physiology of
the adrenals, we should give some account of their comparative
anatomy and development.

B. Comparative Anatomy of the Adrenal Bodies

1. Introductory

It is only in the Amniota that we find a definite organ whose
parenchyma is divided into two distinct portions, whose
cellular constituents are quite different in character from
each other.

In the Anamnia we have the organ represented by a number
of small bodies. The Amphibians in some respects occupy an
intermediate position. In Pisces and Cyclostomata we find
two distinct categories of bodies each consisting of a special

1 The above account is largely taken from Biedl,

96 THE DUCTLESS GLANDS

form of cell, which categories are homologous with the two
constituents of the adrenals of higher vertebrates.

In Amphioxus nothing corresponding to the adrenals has so
far been discovered, and in the Invertebrata the matter may
perhaps be considered somewhat doubtful.

2. Invertebrata

Leydig discusses the possibility of the existence in some
Invertebrata of the equivalents of the adrenal bodies.

Some years ago the present writer had considered the possi-
bility of the existence of the representatives of cortex and
medulla of the adrenal bodies in the Invertebrata, but had not
succeeded in finding any organs or tissues which seemed at all
likely to correspond to them. But just previously to that time
physiological research had rendered it possible to test any
unknown organ or tissue to see if it should be homologous with
adrenal medulla. An extract made from the medulla of the
adrenal or from any (chromaphil) tissue of the same nature
possesses powerful pressor properties.

Accordingly an extract from certain tissues (including the
cells which Leydig thought might correspond to the adrenal
bodies of vertebrates) of Paludina vivipara was prepared and
injected into the venous system of a cat. The result was
negative, possibly because the material necessarily contained
so much nervpus tissue which would tend to lower the blood-
pressure. Cleghorn finds that glycerin and saline extracts of
sympathetic ganglia produce a fall of blood-pressure, in spite
of the presence in these ganglia of chromaphil cells like those
in the medulla of the adrenal body. l It appears, also, that it
is impossible to obtain any rise of blood-pressure by injecting
extracts of carotid glands into an animal, because there is so
much admixture with various tissues whose extracts have a
depressor effect.

Poll and Summer describe certain cells in the abdominal
ganglia of Hirudo medicinalis which stain a yellowish-brown
with Miiller's fluid. They consider it probable that these are
h<mi< riotous with the chromaphil cells discovered by Stilling.

honi did not ascertain that this result might be obtained from ;my
nervous ti-^u.\ \\ln-tln-r Inain, spinal cord, or peripheral nerve: in t'.-n-t. In-
states that this is not the case.

THE ADRENAL BODIES 97

Such cells were later described in a large number of leeches—
Gnathobdellidse and Rhynchobdellidse — and still later Poll
gives a description and some very convincing drawings of these
chromaphil cells in Nephtkys scolopendroides. As regards the
yellow cells of Pontobdella described by Leydig, these appear
to be of a different nature. As pointed out by Poll, we are
sadly in need of another micro-chemical test for adrenin-
containing tissues. If the ferric -chloride reaction could be
used for histological purposes, it would clear up many doubtful
points.

Roaf and Nierenstein have expressed their belief that there
is a substance in the hypobranchial gland of Purpura lapillus
which is allied chemically and physiologically to adrenin. But
the identity of the substance with adrenin has been denied.
Roaf has recently returned to the subject and finds that in
Purpura lapillus there are associated (1) a pressor substance
in the strip of tissue adjacent to the so-called rectal gland ;
(2) a purple -forming material in the same area ; (3) a collec-
tion of bichromate-reacting granules also in the same situa-
tion. The .inference is that these, if not identical, are at
least functionally associated.

It is curious that, so far as I can ascertain, Poll and Roaf
make no reference to each other's work. It is clear that the
structures they respectively describe are quite different from
one another. The tissue described by Roaf is not apparently
connected with the nervous system, while the chromaphil
cells of vertebrates are always intimately related to the
sympathetic. The cells described by Poll are, on the other
hand, within the central nervous system, and, at any rate,
bear a very great resemblance to the cells which are familiar
to us in the vertebrate sympathetic.

Further investigations on the chromaphil tissue of annelids
have been carried out by Biedl and by Gaskell. Both these
authors claim that they have succeeded in bringing about
inhibition of the virgin uterus of the cat by means of an extract
of the ganglia of Hirudo medicinalis. The cells described by
Gaskell are nerve-cells which give a chromaphil reaction and
which he thinks are the common ancestors of both the chroma-
phil and the sympathetic systems of vertebrates. This is not
in accordance with the views of Giacomini.

98 THE DUCTLESS GLANDS

3. Anamnia

In the Clyclostomata, the lowest vertebrates in which adrenal
elements are certainly known to exist, our knowledge is con-
fined to the Petromyzonta and Bdellostoma.

In Petromyzon [Giacomini] there are two distinct series of
bodies. One of these is represented by small, irregular, lobu-
lated structures in the wall of the posterior cardinal veins and
the renal arteries, and of arteries dorsal to the kidney. They
project into the lumen of the vessels, and consist of cylindrical
or polyhedral cells, containing granules which stain black with
osmic acid. These are the cortical or inter-renal bodies. The
other series, or the chromaphil series, extends from the region
of the second gill cleft to the tail of the animal. The bodies
of this series are thin strips of tissue running along the large
arteries and their branches. These bear the same relations to
the veins as the cortical bodies.

This distribution of the chrome staining tissue in P. fluviatilis
has recently been confirmed by J. F. Gaskell. Extracts of the
regions in which this tissue lies, viz. , the walls of the aorta and
cardinal veins and the sinus region of the heart, cause a rise
of blood-pressure in the cat.1

In Bdellostoma the chromaphil cells have been observed,
but not the inter-renal or cortical.

The relationships of the two adrenal representatives in
Elasmobranchs were first suggested by Balfour in 1878. He
called the representative of the cortex the " inter-renal," while
what we now know as the "chromaphil corpuscles" (repre-
senting the medulla of the adrenals of higher vertebrata) he
called " suprarenal bodies." That the paired " suprarenal
bodies " of Balfour really correspond to the medulla of the
mammalian organ was first definitely shown by the present
writer by the physiological test. This was fully confirmed by
the chemical test [Moore and Vincent] ; and that the " inter-
renal " of Balfour is really homologous with the cortex of the
mammalian body was rendered clear from the negative physio-

1The present writer, working in conjunction with Mr. W. E. Collinge,
made an attempt some years ago to find the adrenals in Cyclostomata, but
we considered that there was no satisfactory evidence to show that the
bodies described by Rathke, Miiller, and others had anything to do with the
adrenals.

THE ADKENAL BODIES 99

logical and chemical tests, and from careful histological
comparisons.

The paired "suprarenal bodies" (chromaphil) are situated
on branches of the aorta, segmentally arranged, and extend
on each side of the vertebral column from the front part of the
sinus of Monro to the posterior end of the kidney. The anterior
pair are elongated, and correspond usually to three or four
segments. These bodies are in close relation to the ganglia
of the sympathetic chain, and contain large numbers of chroma-
phil cells, though they appear not to be made up entirely of
them. (Figs. 14, 15 and 22.)

The inter-renal body [Figs. 14 and 15 (i.r.)] is an " ochre-
yellow " rod-shaped structure, paired in the rays, unpaired in
the dogfishes and sharks, lying usually in the region of the
posterior part of the kidney, but sometimes extending as far
forward as the anterior extremity. It bears a striking resem-
blance in its colour, general appearance, and relations to the
kidney, to the adrenals of the Anura, and in the first two of
these features to those of the Reptilia. The body consists of
cells which have the same general appearance and the same
micro-chemical reaction as the " corpuscles of Stannius " (the
cortical adrenals of Teleostean fishes), and the cortex of the
adrenals of higher vertebrates. (See Fig. 21.)

The effect of injection into the venous system of a mammal
extract made from the " paired bodies " of Elasmobranchs is
shown in Fig. 16. It will be seen that there is a very marked
rise of the arterial blood-pressure. In Fig. 17 is seen the effect
of the injection of an extract made from the inter-renal. There
is a certain effect upon the blood-pressure which can be readily
explained as the result of more or less admixture with " medul-
lary glands " in making the extract.

In Teleosts the cortical adrenal bodies are usually paired,
round or oval, pale pink bodies, placed on the spinal or ventral
surface of the kidney. They are near the posterior extremity
of the renal mass, and are either free on its surface or more or
less embedded in its substance (Figs. 18-20). The constituent
cells are of the same character, and have the same arrangement
as those of the inter-renal of Elasmobranchs (Figs. 23, 24) It
is now fully ascertained that these structures (the " corpuscles
of Stannius ") in Teleosts represent the inter-renal of Elasmo-
branchs. It had been erroneously considered by some authors

100

THE DUCTLESS GLANDS

FIG. 14. — Dissection of Scyttium canicula (young female specimen), giving
a ventral view of " paired suprarenals " (chromaphil bodies) and the
inter-renal (cortical body). The parovarium has been dissected away.
This drawing may be taken as a typical representation of the position of
these bodies in Elasmobranchs. The connections with the sympathetic
are indicated to some extent in the anterior part of the figure. The
chromaphil " suprarenals " were displayed by Semper's chromic-acid

THE ADRENAL BODIES

101

FIG. 15. — Ventral view of kidneys,
etc., of Raja batis. This drawing
represents a not unusual condition
in the rays, in which there is
bridge-like communication be-
tween the inter-renals of the two
sides. The sympathetic is shown
to some extent to about the middle
oFthe left kidney.

Lettering common to Figs. 15, 18, 19
— a.a., axillary artery ; a.i.r., an-
terior broken-off portions of the
inter-renal body ; ao., aorta ;
ax.h., anterior pair of suprarenal
bodies ; h.k., head kidney ; i.a.,
intercostal arteries ; i.r., inter-
renal body ; &., kidney ; l.k., lobe
of kidney substance ; ce., O3so-
phagus cut across ; s.r., suprarenal
bodies ; sy., main chain of the
sympathetic ; sy. g., sympathetic
ganglion ; sy. pi., sympathetic
plexus.

that the modified pronephros of Teleosts represents the adrenal
body in these fishes.1

1 Since this view has now been completely abandoned, there is no need to

102

THE DUCTLESS GLANDS

J(/n.^> <rt. (1Hcl3
Morjj/iift, film/ tint .

f'n to/ id fin if

Injected 1c.c.of extract of 'paired segmental
supmrmals (Scyll. can.) 7 in 25. *

FIG. 16. — Effect of injection of 1 c.c. of extract of " paired segmental supra-
renals " (1 in 25) taken from Scyllium canicula. It will be seen that the
rise of blood-pressure is very striking.

A very important discovery has recently been made by
Giacomini, who finds that the corpuscles of Stannius are not

revive the controversy. It was Rathke who first put forward this theory,
which was later revived by Weldon. The view was proved to be untenable
by the present writer in 1895.

THE ADRENAL BODIES

103

the only representatives of cortical adrenal substance in
teleostean fishes. He has worked out the subject especially
in many fishes of the eel tribe, and finds isolated bodies on the
cranial border of the "head kidney," on the anterior and

Carotid ciirrt

Dog, rzK.

Jan.ZJ, 1S97. CHcl3 .

Morphia ( 3 min.of sol. igr, insmin.)

Atropinet 3mm.of 1 % sol.)

Signal.

Tune tracing (seconds).

FIG. 17. — Effect of injections of 1 c.c. of extract of " inter-renal " (1 in 25)
taken from ScyUium canicula. It will be seen that there is a certain
small rise of the arterial blood -pressure. This is not at all comparable
with that produced by an extract of the " paired bodies " (sfee Fig. 16),
and is to be explained by the fact that in extracting the inter-renal from
the body, it is almost impossible to avoid removal also of some of the
" paired bodies."

posterior cardinal veins, which he considers are to be regarded
as of the same general nature as the corpuscles of Stannius,
though they present certain slight differences (Figs. 20 and 24).

104

THE DUCTLESS GLANDS

5 r

•5.r

ST.

sr-

FIG. 18. — Kidneys and cortical ad-
renals (corpuscles of Stannius) of
PagelluA centrodontus. The adrenals
are on the spinal surface, shown by
the dotted lines.

Lettering same as for Fig. 15.

Fio. 19. — Kidneys and cortical ad-
renals (corpuscles of Stannius) of
Qadus morrhua (ventral view). One
body is on the ventral surface, the
other half-way round towards the
spinal surface.

Lettering same as for Fig. 15.

So that in teleostean fishes we have now to consider a " cran-
ial " and a " caudal " cortical body. This is of the greatest

THE ADRENAL BODIES

105

FIG. 20. — Semi-diagrammatic figure show-
ing the kidneys and their relations
with the cardinal veins and the cor-
tical and chromaphil tissues in an
adult Conger vulgaris. The parts
indicated by a series of horizontal
parallel lines show where one finds
cortical and chromaphil tissues inti-
mately associated, a, aorta ; ia +
sc (csd) (red) cortical and chrom-
aphil substance (" suprarenal cap-
sule ") contained in the right head-
kidney ; | -ia, + sc (ess) (res) do. in
left head-kidney ; ia + sc (csd1)
cortical and chromaphil substance
(" suprarenal capsule ") contained in
the cranial portion of the right vena
cardinalis posterior ; ia + sc (ess1)
do. in left side ; ip (cs), posterior cor-
tical body (" corpuscle of stannius ") ;
mu, mis, lymphoid masses right and
left'; ms, caudal active portion of
kidney (mesonephros) ; vcpd, vcps,
post, card, veins R. and L. ; vcad,
vcas, primitive ant. card, veins, R.
and L. (From Giacomini.)

106

THE DUCTLESS GLANDS

importance as bearing upon certain experimental investigations
(vide infra, p. 152).1

To Giacomini also belongs the credit of having discovered
the chromaphil or medullary structures in teleostean fishes.
They consist of cells which stain brown with salts of chromium
in the walls of the cardinal veins, especially on the right side
and towards the cranial end of the body, along the lymphoid

\ol

FIG. 21. — Transverse section of the Inter-renal body of Trigon violaceus

(from Diamare).

tissue of the head kidney. The groups of cells are disposed
between the lobes of the cranial cortical body. These had often
been searched for by previous observers, but in vain.

In Ganoids the cortical representatives were noted by
Stannius in 1846. He describes them as small whitish or
yellowish bodies scattered throughout the substance of the

1 Giacomini has more recently expressed the opinion that the corpuscles
of Stannius are not homologous with the cortical bodies of petromyzon, the
elasmobranchs, and higher vertebrates. Their origin, structure, and func-
tion put them in a separate category.

THE ADRENAL BODIES 107

kidney and forming alveoli, whose cells stain black with osmic
acid (see Fig. 25). Quite recently Giacomini has described
chromaphil elements in the walls of the cardinal veins and the
venae renales revehentes.

The question as to the existence of adrenal bodies in the
Dipnoi has long been under discussion. In Protoptcms

mi^iimmi^^

* <f.>®. : •• *H«?~ , '

'•'••;ff"''-SlS3',

%' \'-r.;--,V:' V
••»•» ^^ **» «*

»" •» V «> »\

I »v*

» » ' v

FIG. 22. — Transverse section through one of the paired bodies of Torpedo

(from Kohn).

annectens Parker describes " around the kidney, but more
particularly along its dorsal and outer sides, masses of brown
cells, which in appearance remind one of the adrenal bodies of
Amphibia," and he suggests the inquiry " whether they or the
lymphoid cells which give rise to them have anything to do
with the adrenals." In 1895 the present writer examined this
point with some care, and came to the conclusion that this

10$

THE DUCTLESS GLANDS

tissue — a large-celled adenoid tissue — has nothing to do with
the adrenal bodies, and this notwithstanding that in some
regions it has a very " epithelial," a very " glandular," appear-
ance.

Giacomini claims to have discovered the true chromaphil
bodies arranged segmentally round the intercostal arteries and

C/L

' •--

FIG. 23. — Transverse section of a " corpuscle of Stannius " (posterior inter-
renal) of Salmo fario (from Giacomini).

in the wall of the cranial part of the posterior cardinal vein and
the vena azygos dextra. He believes that the inter-renal body
(cortical representative of the adrenal) is absent in this species
of the Dipnoi, and renews Parker's suggestion that it may be
replaced functionally by the adenoid tissue.

It seems extraordinary that there should be no representative
of the adrenal cortex in the Dipnoi. The present writer has

THE ADRENAL BODIES

10S

from time to time dissected specimens of Protopterus, and has
examined series of sections of this fish and of Lepidosiren, but
has never been able to detect any organ or tissue which seemed
likely to correspond to adrenal cortex. If the tissue originally
described by Parker is in reality adenoid tissue, we should

FIG. 24. — Section of head kidney of Salmo fario showing an islet of cortical
adrenal tissue (anterior inter-renal) (from Giacomini).

hesitate to ascribe to it any secretory function. The perirenal
tissue is, however, very extraordinary in appearance, and
deserves careful consideration.

It is obvious that the subject of the adrenal bodies in the
Dipnoi demands further investigation.

The adrenals of Amphibians are intermediate in many

110

THE DUCTLESS GLANDS

respects between those of higher and lower vertebrates. In
the Anura the adrenals are golden -yellow streaks on the ventral
surface of the kidney, of about 15 millimetres in length in the
frog to about 28 millimetres in a good-sized toad. Their
width varies in a similar manner from 1 to about 3 millimetres.
But their dimensions vary very considerably according to the
size and development of the particular individual.

In a good specimen the adrenals present a beautiful appear-
ance, forming on each side a series of irregular arcs with their
convexity outwards, and varying in width from place to place.
Their colour is a bright golden yellow, of a somewhat fatty

!&>:>

'. -

• . • •

* • -\y-al. w.

' . • * •

;.-r '.;i

* » \.^Sw *» -^J, - V*l *^^i • '

, -v, *.j :fz y , ^J^^"^— \ * • '

•-.
i

/

FIG. 25. — Section of an adrenal body (corpuscle of Stannius) of the sturgeon
(Acipenser sturio). The " alveolar " arrangement is well seen, and the
cell outlines are distinct.

al. w., walls of " alveoli " ; x., nuclei ; pr., granular protoplasm.

aspect, and their surface is marbled with veins. In both frogs
and toads, although the body reaches nearly to the anterior end
of the kidney, it always ceases at a point anterior to the
posterior fifth of the organ.

In the Urodela the adrenal is broken up into a series of strips
and islets which extend not only the whole length of the kidney,
but also anteriorly to that organ, as far forwards as the origin
of the subclavian artery.

The microscopic structure is practically the same in Anura
and Urodela. The gland is seen at once to consist of two
distinct kinds of structure. The greater part is made up of

THE ADRENAL BODIES

111

cell columns, which are of varying size and shape, and which
interlace in all directions. The cells are of different shapes
but mostly elongated and tapering, and they contain a large
round nucleus, which stains very deeply with haematoxylin.
This structure is the "cortical," which corresponds to the
"inter-renal" of Elasmobranchs, the corpuscles of Stannius
(" cranial " and " caudal " series) of Teleosts and the cortex of
Mammalian adrenal (see Fig. 26 s.c.).

/*

<S^k * -0 *^^V_^E"™*5"

sy -

p

£• Hfk

"^i^* ••;-«BaK^^>*4«^
% ^q^^*f :'~^^£:
- ' MlSr^«ta^^ n^.

* ^^

\^

&7T2.

FIG. 26. — Section through suprarenal body of Bufo vulgaris showing a mass
of medullary substance (chromaphil tissue) surrounded by cortical
substance (from Giacomini).

But in addition to the above-described structure, we get
masses of a different kind of cell. These are often at the
borders or ends of the cell columns, but are otherwise irregularly
distributed. In the islets anterior to the kidney in the Urodela
these masses of cells are more numerous, and some of the islets
are made up entirely of them. This structure is analogous to
the paired suprarenal bodies of the Elasmobranch fishes and

112 THE DUCTLESS GLANDS

the " medulla " of the adrenals of higher vertebrates. It
consists of chromaphil cells. Thus in the Amphibia we have
transition stages between the single adrenal of higher verte-
brates and the total separation of the two constituents in the
Elasmobranch fishes (see Fig. 26 s.m., c.g.s.).

4. Amniota

In reptiles the "cortical" and "medullary" constituents
enter into closer relationship with each other than in lower
vertebrates. In some groups the chromaphil cells are arranged
mostly on the dorsal aspect of the gland, and only penetrate
to a small extent ; in others there is a considerable mixture of
the two elements. In the Crocodilia and the Chelonia, for
example, the relations of " cortex " and " medulla " are often
almost identical with those of birds (q. v.).

A typical representation of the microscopical appearances
of the reptilian adrenal is given in Fig. 27.

Birds show an intimate interlacement of the " Hauptstrange"
(cortical) and the " Zwischenstrange " or " Intermediar-
strange " (medullary), so that the latter occupy the meshes of
the former (see Fig. 28).

Mammals, alone among animals, possess a true cortex and a
true medulla, the latter as a rule completely surrounded by
the former.

The cortex has in all essential points the same structure
as its homologues in the lower vertebrates — viz., the Haupt-
strange of birds, the "cortical" columns of Reptiles and
Amphibians, the corpuscles of Stannius of Teleosts, and the
inter-renal " of Elasmobranchs. It consists of rounded groups
or columns of cells with one or two vesicular nuclei, and con-
taining glistening fat -like granules. These granules become
blackened by osmic acid, and stain deeply with Sudan III.
and Scharlach R. They are dissolved by xylol, chloroform,
etc., and so, when these reagents are used in the preparation
of microscopical specimens, a vacuolated appearance of the
protoplasm results.

The structure of the medulla is not so easy either to discover
or to describe, but we may say in general terms that it consists
of cell columns which are not so distinctly marked as those of
the cortex. The cell outlines are not so distinct as those of
the cortex, and the granules in the protoplasm have a great

THE ADRENAL BODIES

113

affinity for nuclear stains such as hsematoxylin, safranin, etc.
These granules also reduce chloride of gold and become green
in contact with ferric chloride. But their most characteristic
reaction is with chromium salts. In the presence of any of
these, or of chromic acid itself (in many instances, at any rate),

FIG. 27. — Small portion of adrenal of Uromastix Hardwickii. Leitz panta-
chrom. ; 3.0mm. Drawn with Abbe's camera lucida. c., cortex; c.t.,
connective tissue ; g.p., granular protoplasm of medullary cells ; i.,
interspaces between cell columns ; m., medulla ; p., protoplasm of
cortical cells.

the cells become stained so as to assume any tint between a
bright yellow and a dark brown. This reaction was discovered
by Henle in the year 1865. Stilling, who discovered the cells
having the same reaction along the sympathetic and in the
carotid gland of mammals, called them, the corpuscles which
they formed, and the medulla of the adrenal, " chromophil."

S

114 THE DUCTLESS GLANDS

The modification " chromaphil " will be used throughout.1

5. Accessory Adrenals.

Many important points in the comparative anatomy of the
adrenals may be conveniently dealt with under this heading.

co. -blcLc. .rne

FIG. 28. — Section of the adrenal of Meleagri* Gallopavo. The material was
fixed in Miiller's fluid with acetic acid and stained with haematoxylin.
A strand of medullary cells is seen running between the cortical columns.

al. w., walls of " alveoli " ; bld.c., blood corpuscles ; co., cortex ; e.c., elongated
cells ; n., nuclei ; me., medulla.

The arrangement of the inter-renal and the " paired sup-
rarenals " of Elasmobranchs at once suggests the possibility
of outstanding portions of both " cortical " and " medullary "
constituents being found in the higher as well as in the lower

1 Kohn, who repeated Stilling's observations, used the term " ohromaffin,"
and called the bodies " paraganglia." More recently Poll has invented still
another term, " phaeochroim . lh«Te seems to be no need for either of these,

THE ADRENAL BODIES

115

vertebrates. And the same possibility was suspected long ago
from other considerations.

•v &f

*•'•

z.f.

-z. r.

FIG. 29. — Section through portion of the adrenal body of a dog, showing the
various zones of the cortex, and the medulla. (Drawn by Mrs. Thomp-
son.)

c., capsule ; m., medulla ; z.f., zona fasciciilata ; z.g., zona glomerulosa
(zona arcuata) ; z.r., zona reticularis.

The term " accessory adrenal " in mammals has been used
in different senses. We must carefully distinguish between :

116 THE DUCTLESS GLANDS

1. Bodies composed entirely of cortical substance —
"accessory cortical bodies."1

2. Bodies made up exclusively of medullary substance —
" chromaphil bodies."

3. True accessory adrenals composed of both cortex and
medulla.

The accessory cortical bodies represent by far the larger
number of structures which have passed under the name of
" accessory adrenals." They are said to show the three zones
characteristic of the cortex of the adrenal of mammals, but no
chromaphil cells are present — there is no " medulla." The
smallest of these bodies are microscopic ; others may reach a
diameter of a centimetre or more. They are found in the
neighbourhood of the chief adrenal, sometimes embedded in
other organs, in the retroperitoneal space, or in the genital
region, as, for example, in the ligamentum latum, or in the
space between testis and epididymis, where they are known as
" Marchand's adrenals."

The Chromaphil Bodies. — These are found, or may be found,
in any part of the body into which the sympathetic nervous
system extends, and more particularly as groups of cells in
connection with the abdominal sympathetic and its extensions.
In connection with the abdominal sympathetic they were first
noted and described by Ley dig and called ' ' Kernnester ' ' by
Mayer. The observations of both these authors applied to the
Urodela.

But the recognition of the chromaphil cells and corpuscles
in mammals and the characteristic reaction with chromium,
by which they are now designated and homologized with the
medulla of the adrenals, are due to Stilling. This author found
in the abdominal sympathetic small bodies composed of cells
having the same chromaphil reaction as those forming the
medulla of the adrenal. He states that some are nearly a
centimetre in length, while others are only just visible to the
unaided eye. They are round, oval, or elongated in form, and
their thickness is never more than a few millimetres. They
have a tunica propria, small vessels and capillaries. Between
the capillaries are cells which resemble in all respects those of

1 The term " accessory inter-renal bodies " has been sometimes applied to
th. in. hut it seems best to avoid the t»-nn inter-renal " except as applied to
the Elasmobrancha.

THE ADRENAL BODIES

117

* »

/•

the adrenal medulla. The resemblance between the chrcma-
phil corpuscles of the sympathetic and the medulla of the
adrenal is rendered all the greater by the occurrence in the
latter of occasional nerve cells. Stilling found these corpuscles
in the rabbit, the cat, and the dog, and especially in young
animals. He gives details of a method for displaying them.
This extracapsular chromaphil material is still very
imperfectly understood by many writers on the physiology
and pathology of the adrenals. Thus Rolleston refers to
Zuckerkaridl's " parasomata "
the carotid body, the coccygeal,
and " some cells in the pitui-
tary." Now, the coccygeal body
does not contain chromaphil
cells, nor the pituitary, so far as
I am aware. But the writer
omits all reference to a very strik-
ing mass of chromaphil tissue
(the paraganglion aorticum of
Kohn) — the abdominal chroma-
phil body — which is present in
the ordinary laboratory animals.1
This important body can readily
be displayed in the dog, for / \\\"

example, by removing the liver
and alimentary tract from the
abdomen, and placing a piece of
absorbent cotton soaked in a
solution of potassium bichromate
(3 to 5 per cent.) over the
retroperitoneal tissues for six to

twelve hours. On removing the whole of the remaining
tissues and washing in running water for a few hours, the
chromaphil bodies are plainly visible, and still more plainly
if the whole preparation be placed in glycerin. The
" abdominal chromaphil body " is revealed by this method as
a very dark brown wavy streak of irregular diameter, placed

1 It seems possible that the "abdominal chromaphil body" of the dog
may correspond to the " Nebenorgan " of Zuckerkandl. But the general
shape and appearance of the two bodies are quite different, and Zuckerkandl's
body was found only in very young subjects. ]

FIG. r 30. — Abdominal chroma-
phil body of an adult dog.

Lettering common to Figs. 30,
31, and 32. — A., aorta; Ad.,
adrenal ; C., abdominal chro-
maphil" body ; c., smaller
chromaphil bodies.

118

THE DUCTLESS GLANDS

in front of the aorta and extending from the region of the
adrenals in front to the bifurcation of the aorta behind. Other
elongated, oval, or rounded patches or specks of chromaphil
tissue are also visible in different regions.1

Figs. 30, 31 and 32 will give an idea of the arrangement of
the abdominal chromaphil body and other smaller chromaphil
corpuscles in the dog, the cat, and the rabbit respectively.

Numerous irregularly disposed smaller masses of chromaphil
tissue are found in different regions more or less closely related
to the principal chromaphil body [see Figs. 30, 31, and 32 (c) ]

o •

&

\

l C

Fig. 31. — Chromaphil bodies of

adult cat.
Lettering same as for Fig. 30.

Fig. 32. — Abdominal chromaphil
bodies of a rabbit.

Lettering same as for Fig. 30. The
principal body is bifurcated an-
teriorly and posteriorly.

In the cat (Fig. 31) the chromaphil body tends to consist of
long threads of tissue. These threads are stretched along the
sympathetic, and the relationship to the nervous system is
more obvious than either in the dog or the rabbit.

In the rabbit (Fig. 32) there is a distinct tendency for the
principal chromaphil body to be paired, or it may be bifurcated
anteriorly and posteriorly [Fig. 32 (C)]. The threads of

1 1 am indebted to the late Dr. Stilling and to Dr. Kohn for their kindness
in giving me detailed instructions as to how to find these bodies, and to Dr.
Kohn for some specimens which he generously sent me.

THE ADRENAL BODIES

119

chromaphil tissue frequently run close up to, and may even be
continuous with, the medullary substance of the adrenal.

In some animals — viz., monkey, pig, guinea-pig, rat, gopher,
and squirrel — the present writer has been unable to discover
any chromaphil bodies.

In regard to the microscopic structure of the chromaphil
bodies, a detailed description is not necessary. It is, however,
desirable to institute some comparisons between the histological

cbld. c.

end 2

conn. t.

bid. v.
chrom. c.

bid. c.

chrom. c.

conn. t.

FIG. 33. — Transverse section through the abdominal chromaphil body of the
dog. Fixed in corrosive sublimate and stained with hsematoxylin.
Section 10 ^t in thickness. Leitz obj. 6. Drawing ocular.

Lettering common to Figs. 33, and 34, bid. c., blood corpuscles ; bid. v., blood-
vessels ; c., capsule ; chrom. c., chromaphil cells ; col.c., columnar cells of
adrenal medulla ; conn, t., connective tissue ; end., endothelium of blood-
n., nuclei.

appearances of the adrenal chromaphil tissue and this substance
as it occurs in other places, as, for example, in the sympathetic
ganglia and in the abdominal chromaphil bodies. These
comparisons refer to the structures in the dog.

A comparison of Fig. 33 with Fig. 34 will show that the
general resemblance between extra -adrenal chromaphil tissue
and adrenal medulla is very great. Both consist of columns
of cells staining yellow or brown with bichromate of potash.
The cell columns are, however, for the most part much thicker

120

THE DUCTLESS GLANDS

in the adrenal than in the abdominal chromaphil bodies. The
blood spaces are wider, and the whole aspect gives the
impression that the adrenal medulla is more highly organized
[see Fig. 34 (bid. v., col. c.)].

Many of the cells of the adrenal medulla are spherical, as in
the abdominal chromaphil body, and their'dimensions are the
same — viz., about 12 // in diameter. The nuclei, also, are of
the same order of magnitude in the two cases — viz., 5 JJL or 6 /«.
But in many regions, especially where the cell columns are

chrom. c.
col. c.

bid. V.

chrom. c.

col. c.

chrom. c.

Fio. 34. — Section through the medulla of the adrenal of a dog, prepared as

in case of previous figure. Same magnification.

Lettering same as for Fig. 33.

separated by large venous sinuses, the cells are arranged in a
definitely epithelial fashion round the bloodvessels [Fig. 34
(col. c.)]. In this case the cells are columnar in shape, and
may reach a length of 26 ^, and the nuclei are placed at the
end of the cell remote from the bloodvessel.

The protoplasm of the adrenal medulla is more distinctly

granular than that of the abdominal chromaphil body, and

>is, moreover, more delicate in consistence, and therefore shows

more shrinkage in fixation and tearing during the process of

i A utting sections. When the adrenal is fixed in bichromate

THE ADRENAL BODIES 121

solutions, the section shows vacuoles as do those of the chroma-
phil body. These are absent in sublimate and Flemming
preparations.

Thus it seems justifiable to regard the medulla of the adrenal
body as composed of chromaphil cells of the same general
character as those forming the chromaphil bodies. But the
former have undergone specialization, and the structure of
the substance has become elaborated into an organ with more
definitely glandular form.

It is clear from all that has gone before that the extra-adrenal

©

" '-'f^\
I jEr^ •-• 9j ••* . g-r\ ^

FIG. 35. — Section through a group of chromaphil cells in the inferior cervical
ganglion of a dog.

chromaphil tissues contain a substance which gives the same
macro- and micro-chemical reactions as adrenin. It has been
shown by Biedl and Wiesel that the " parasomata " (Neben-
korper) discovered by Zuckerkandl in the human subject
contain adrenin or some substance which has an identical
effect upon the blood-pressure. The present writer has
been able to prove that the abdominal chromaphil bodies
of the dog contain the same or a similar substance. Fig.
36 shows the effect of injecting into the saphenous vein of a
dog an extract from the chromaphil bodies of three dogs. It

122 THE DUCTLESS GLANDS

will be seen that there is a very considerable and very char-
acteristic rise of the blood-pressure.

The investigations of Stilling were confirmed and extended
by Kohn and Rose, who laid stress on the fact that the chroma-
phil cells are common and typical elements of the mammalian
sympathetic system. Kohn's view is that what is ordinarily
called the " cortex " of the adrenal is in reality the only part
which ought to be called adrenal at all, while the medulla is
simply the " paraganglion suprarenale," a group of what he
called " chromaffin " cells, which have become included in the
adrenal. This matter will be referred to again later on.

Fio. 36.— Dog, 8 kilogrammes. November 10, 1909. CHC13, morphine,
atropine. Carotid blood -pressure. Time in seconds. At the point
signalled an extract from the chromaphil bodies of three dogs was injected
into the saphenous vein.

Zuckerkandl in 1901 found in the retroperitoneal space at
the origin of the inferior mesenteric artery a pair of large
chromaphil bodies, which he called " Nebenkorper des
Sympathicus." These he found constantly in the embryo
and in the new-born human subject, and, as we have seen,
Biedl and Wiesel found that the bodies contained a pressor
substance.

True accessory adrenals, containing both cortex and medulla,
like the main gland, are said to occur in the neighbourhood of
the abdominal sympathetic, and in the region of the body where
the cortical elements first arise.

THE ADRENAL BODIES 123

6. Tabular Statement of Chief Facts in Comparative
Anatomy of the Adrenals

The table l on page 126, modified from Poll, will render
clear the chief facts in the comparative anatomy of the
adrenal system.

In concluding this section we would call special attention to
Figs. 37 and 38, which give in a diagrammatic form a com-
parison of the adrenal representatives in Elasmobranch fishes
and in mammals respectively.

C. Development of the Adrenals

Balfour expressed the view that "in Elasmobranch fishes
we thus have (1) a series of paired bodies, derived from the
sympathetic ganglia, and (2) an unpaired body of meso-
blastic origin. In the Amniota these bodies unite to form the
compound suprarenal bodies, the two constituents of which
remain, however, distinct in their development. The meso-
blastic constituent appears to form the cortical part of the
adult suprarenal body, and the nervous constituent the medul-
lary part." This hypothesis has been fully supported, and
the observations leading to it have been completely confirmed
by all subsequent work upon the embryology of the adrenals.
In the various classes of vertebrates there have been numerous
observations, all of them clearly pointing out the totally distinct

1 In the table, the term " cortical system " has been substituted for " inter-
renal system " employed by Poll. Each of the alternative terms has a certain
and a similar disadvantage, inasmuch as it refers to an anatomical arrange-
ment which is not universal throughout vertebrates, but confined to a single
group — the term "inter-renal" being only applicable to Elasmobranchs,
the term " cortical " being only applicable to mammals. But it seems on the
whole preferable to vise the word " cortical," because it refers to the arrange-
ment in mammals which will long continue to serve as the standard of com-
parison in the organology of the adrenal system.

Further, as announced previously, it is proposed to use the term " chroma-
phil " instead of " chromaffin " or " phseochrome." There is no doubt that
in some respects " phaeochrome " is the best word, but " chromaphil " is
only a slight modification of the original " chromophil " employed by Stilling,
and was suggested to me by Sir Edward Sharpey Schafer.

It is a pity that we cannot for the " cortical " cells use some name which
would describe their staining reaction, or the chemical nature of their contents.
But the literature of the comparative anatomy of the adrenals is already
overburdened with a complicated and abtruse nomenclature, so perhaps it
is best to be content with the term "cortex."

124

THE DUCTLESS GLANDS

(VomapA
(paired. Supra-

Sympathetic Ganglia,
'Sympathetic A/ewe.

Sympathetic (ra*Tg//a

Cortical Bodies

Kidney

7

FIG. 37. — Diagram of the adrenal representatives in elasmobranch fishes
showing the cortical gland (inter-renal body) and the medullary glands
(chromaphil bodies, " paired suprarenals ") in relation to the sympathetic
and the kidneys.

THE ADRENAL BODIES

125

Groups of Chromaphil Cells
'c Ganalia

^-Carotid Body
upenor Cervical Ganglia

Inferior Cervical Ganglia
fellaie Ganglia

ympatheiic Nerve

Medulla of Adrena
Kidney

Bodies

Corf ex of Adrenal Body
iMedullaci Adrenal

bdominal Chromaphil Body

ccessory Cortical Body
Tesficle

FIG. 38. — Diagram of the adrenal constituents and outstanding " cortical "
and " medullary " (chromaphil) bodies in the mammal, showing the
adrenal bodies, the chromaphil cells of the sympathetic, the abdominal
chromaphil body (" accessory medullary ") and accessory cortical
adrenals in relation to the sympathetic and the kidneys.

126

THE DUCTLESS GLANDS

3 g f 1 * i 1 = 4

B 8 JllHll*

g <3 " s '-g -a f § * -s

8 5 I A -3 I « 6 s

THE ADRENAL BODIES 127

origin and nature of the cortex and the medulla. It will only
be possible to refer to some of the more important papers.

Mitsukuri worked out the development of the adrenal
body in the rabbit and in the cat. He concluded that the
cortical substance arises from the mesoblast, while the medul-
lary substance is derived from the peripheral part of the sym-
pathetic nervous system, and is at first placed outside of the
cortical substance, becoming transported into the middle of
the adrenal body in the course of development. That the
cortex is derived from the mesoderm and the medulla from the
same blastema as the sympathetic ganglia is now almost
universally conceded.

The cortical substance is developed from the ccelomic
epithelium in a region known as the " adrenal zone." The
extent of this zone varies in differentVertebrates. In mammals
the origin of the cortex appears to be from the ccelomic epithe-
lium on either side of the root of the mesentery or a little caudal-
wards from the cranial end of the primitive kidney, appearing
first as a series of buds which subsequently grow together.

In regard to the development of the medulla of the adrenal
body, it has been ascertained that certain cells derived (along
with the sympathetic generally) from the neural ectoderm, do
not develop into nerve cells, but into chromaphil cells. In the
anamnia below the amphibia, these do not enter into any rela-
tions with the cortical elements, but remain as chromaphil
bodies or corpuscles. In Amphibia and in the Amniota some
of these chromaphil cells grow into the cortical gland and form
its medulla. Ultimately these acquire the chromaphil sub-
stance. It is stated that in man this is not actually found in
them until some little time after birth, but it occurs in the
embryo of the ox and the sheep long before birth.1

D. Addison's Disease and the Pathology of the Adrenal

Bodies

1. Introductory and Historical

The medical practitioner directs his inquiries towards experi-
mental physiology and pathology in order to ascertain how far

1 Bruni in 1912 described the development of the chromaphil tissues in
Rana esculenta. The chief point of importance in this paper is the observation
that the chromaphil substance is not derived from the sympathetic, but only

li's THE DUCTLESS GLANDS

modern research will enable him to understand the clinical
phenomena of Addison's disease, and to treat his patients in a
scientific spirit. On the other hand, the physiologist is eager
to acquire whatever information can be derived from the realms
of clinical pathology and pathological anatomy, as to the func-
tions of the adrenal bodies. The fuller and more accurate is
our knowledge of diseased conditions of the organs, the sounder
will be our progress in both these conditions. Pathology has
taught us something of the adrenals, and physiology has
contributed certain facts of primary importance. It must,
however, be admitted that it is not possible at the present time
to combine the knowledge derived from these two sources in
such a way as to give an intelligent explanation of the functions
of the adrenal bodies, and at the same time to offer a satisfactory
explanation of the symptoms of Addison's disease.

Addison's disease is characterized by the cardinal symptoms
of extreme muscular weakness, nausea and vomiting, and an
exaggeration of the normal pigmentation of the skin.

Addison attempted to elucidate the nature of a malady
which he had styled " idiopathic anaemia," from an inability
to associate it with any exact pathological condition. He was
thus led to the discovery of the diseased state of the adrenal
bodies, and the association between this diseased state and the
train of symptoms which bears his name. The observations
were confirmed but not much extended by Wilks, Trousseau,
and Greenhow. It was Trousseau who first used the term
' ' Addison' s disease . " It must be admitted that comparatively
little has been added to our knowledge of the clinical aspect of
the disease since it was first described.

Addison considered that any lesion of the adrenal bodies
which would interfere sufficiently with their function would
give rise to the disease. Wilks and Greenhow were, however,
of a different opinion — viz., that the true morbus Addisonii
has essential peculiarities of its own, that no other disease or
degeneration of the adrenal bodies is capable of producing the
same associated train of symptoms. The modern view is
entirely in accordance with that first expressed by Addison,
that the symptoms are due to an interruption of , or a deficiency
in, the functional activity of the adrenal bodi< •-.

secondarily comes into contact with this system. The chromaphil cells
appear first in close relation \\iih «h«- walls of (•••ii.iin 1. 1. ..,<!%••

THE ADRENAL BODIES 129

2. Symptoms

1. Pigmentation. — The pigmentation is very variable both
as to its period of onset and as to its intensity. Usually it
first occurs at a later period of the disease than the general
symptoms, such as the muscular prostration. It sometimes
occurs only shortly before death, and in some cases it never
occurs at all. Occasionally, however, the pigmentation has
been stated to precede the general symptoms.

As for the degree or intensity of pigmentation, it may vary
from the dark hue of the negro to a faint sunburn brown. It
is very interesting to note that the pigmentation is an exaggera-
tion of the normal, and occurs most markedly in those parts
which are normally pigmented, such as the dorsal surface of
the forearm, the axillary folds, the areola around the nipples,
the genitals, and the groins. The pigmented regions have
no sharp margins. Friction or pressure induces especially the
increased pigmentation ; thus we find dark patches or streaks
brought about by corset, belt, garters, braces, or collar-stud.

Pigmentation is usually first noticed on the face, neck, and
backs of the hands and fingers, especially over the joints. The
lips may sometimes become pigmented and the tongue occa-
sionally presents stains near the free border. There are also
to be seen in some cases small, well-defined specks, like small
moles, but occasionally of inky blackness. Pigmentation of
the peritoneum and pia mater has been recorded. The hair
may become darker, but the skin of the hairy scalp and other
regions covered by hair does not appreciably change in colour.
The linea alba may become a dark line. Rolleston says that
the palms of the hands and the soles of the feet are very rarely
pigmented, but he has twice seen pigmentation of the palms
with intensification along the various lines.

Microscopically the pigment is found in the cells of the stratum
Malpighii, and the dermis shows a few pigmented. cells —
"carrier cells " —which, it is thought, convey the pigment
from the bloodvessels of the dermis to the stratum Malpighii.

The pigment is iron-free. In some few cases a combination
of Addison's disease with hsemochromatosis has been reported.
Pigmentation occurs in about 75 per cent, of all cases.

2. Asthenia. — Many authors regard the asthenia or muscu-
lar weakness as the most constant and the most significant of

9

130 THE DUCTLESS GLANDS

all the symptoms of Addison's disease. The patient suffers
from an almost complete indisposition for any exertion. He
is very easily tired, and is never able to get properly rested.
There is no corresponding emaciation or neuritis.

Asthenia is almost always the earliest sign of the disease.
Long before one notices any change in the skin the patient
complains of extreme lassitude. He can perhaps make a
short series of movements with some energy, but he is almost
immediately fatigued. Langlois lays great stress on this feature,
and recommends the use of Mosso's ergograph as an instrument
of diagnosis. He states that what characterizes the patient
with Addison's disease is not so much the loss of ability to
perform a single muscular feat, as a more or less complete
disappearance of resistance to fatigue. If one submits under
the same conditions a patient with Addison's disease, and
another patient in a comparable condition (both, for example,
tubercular to the same extent), to the ergographic test, we
find that the fatigue curve is quite different in the two cases.
We find that the simple tubercular patient can carry out a
sustained labour (lift a weight of 1 kilogramme every two
seconds) for a certain time ; but the patient with Addison's
disease, who at first will lift the same weight to the same height,
soon becomes exhausted ; his curve shows a rapid fall.

3. Other Symptoms. — The majority of authors report that in
Addison's disease the blood-pressure is remarkably low. The
heart is feeble in action ; there is a small, soft, almost impercept-
ible pulse. From the evidence before us we are not justified
in stating that a low blood-pressure is constant.

The temperature is usually subnormal.

In regard to the condition of the blood, some authors state
that anaemia is not characteristic, though the patients present
an anaemic appearance. Others affirm that the blood always
shows changes, in the directions of diminution in number of
the red corpuscles and lowered haemoglobin content. The
number of leucocytes is in most cases normal. It has been
stated also that the eosinophilous cells and the large mono-
nuclear cells are increased in number. Status lymphaticus
is not rare, and hyperplasia of the thymus has been observed.
It U stated that there is no very marked emaciation in the
majority of cases.

Vomiting is very common, and there is frequently hiccup

THE ADRENAL BODIES 131

and sometimes diarrhoea. But there may be constipation
from loss of muscular tone.

Sometimes there is an alternation of constipation and diar-
rhoea, which latter frequently occurs without obvious cause.
Towards the end there may be pain with retraction of the
abdomen, and small pulse, the condition strongly suggesting
peritonitis.

Various symptoms referable to the nervous system have
been described. Some of these, such as twitchings and con-
vulsions, point to irritation of the nervous system, but the most
characteristic, such as a diminished or absent knee-jerk, are
indications of depressed activity of the nervous system. Head-
aches and faintness are not uncommon.

Insomnia, loss of memory, noises in the ears, vertigo, pains in
the trunk and limbs, and mental symptoms with hypochondria
are also mentioned.

The "white line" of Sergent has been recommended as a
test for adrenal insufficiency. The method employed is to
outline a square about the umbilicus with a blunt object by
quite superficial stroking without using pressure or scratching.
The patient should be kept still, and after half a minute, a
pale line or band begins to appear which gradually becomes
more distinct and white. It attains its maximum clearness in
about one minute, persists for two or three minutes, and gradu-
ally disappears. The theoretical explanation given by Ser-
gent is not satisfactory. The normal response to light stroking
appears to be a brief vaso-dilation followed by a vaso-constric-
tion. The failure of this normal reaction is stated to be a sign
of adrenal deficiency.

3. Etiology and Onset

The disease is rare. It is doubtful whether one sex is affected
more than the other ; it occurs about the thirtieth year on the
average. The adrenal bodies may become infected in tuber-
cular patients from the mesenteric glands or from disease of
the vertebrae. But the adrenal bodies themselves seem to be
susceptible to primary tuberculosis, and are often the only seat
of tubercular infection in the body.

Strains and injuries to the back or blows on the abdomen
have sometimes been alleged to be the cause of the mischief.
In these cases the trauma might render the gland more liable

132 THE DUCTLESS GLANDS

to infection. Traumatic haemorrhage into the substance of
the gland has been stated to be the starting-point of the lesion
in some cases.

The onset is nearly always insidious and gradual. Gastric
trouble is perhaps one of the commonest causes of the patient's
seeking advicev Very rarely the disease seems to come on
suddenly after a shock or some cause of worry. It may be
congenital.

4. Metabolism in Addison's Disease

Owing to the rarity of Addison's disease, little is known as
to the general (total) metabolism. Nor have we any a priori
grounds for assuming that this would be either increased or
diminished.

According to a brief account given recently by Richter,
the protein metabolism is not appreciably affected. Senator
and Pickardt observed either nitrogenous equilibrium or, with
abundant food, nitrogenous gain. On administration of
adrenal substance to the patient there was no increase of
protein destruction.

There is an increase in the phosphoric acid elimination.
Richter suggests that this has to do with increased destruction
of bone substance, though Senator found the calcium elimina-
tion not raised.

Nothing certain is known of any change in carbohydrate
metabolism. We might expect, since adrenin pharmaco-
dynamically induces glycosuria, that in Addison's disease,
where there is presumably a deficiency of this substance,
we should find a lowering of the sugar content of the blood.
In experiments upon animals after extirpation of the adrenal
bodies, this is actually found to be the case, but the clinical
evidence in the case of the human subject is meagre and con-
flicting, although Bernstein and Falta believe that hypo-
glycaemia is a sign of some diagnostic value.

There seems to be actually a diminution of the urinary
pigments.

5. Morbid Anatomy

In Addison's original paper eleven cases are recorded. In
five of these there was caseous tubercle in both adrenal glands,
and in one case tubercle was only present in one gland. One

THE ADRENAL BODIES 133

case seems to have been an example of cirrhosis and atrophy.
In three cases there were secondary carcinomatous growths
in the adrenals, bilateral in one case, unilateral in the other
two. In one additional case there was a secondary nodule of
carcinoma blocking the right suprarenal vein, and associated
with haemorrhage into the corresponding gland, but there were
no growths in either.

Bittorf states that in all cases there is disease of both adrenals.
This may be (1) simple atrophy, or (2) inflammatory atrophy
(chronic interstitial inflammation) with shrinkage and destruc-
tion of the parenchyma, resembling cirrhosis. According to
this author, there is no special part of the gland which is of
prime importance to life. He considers that the adrenal bodies
are single organs, clearly essential to life, interference with
which causes a definite train of symptoms. From the tone
of this writer it would appear that he does not clearly recognize
the essential and fundamental difference between the cortex
and the medulla, nor does he appear to appreciate fully the
significance of the fact that even if cortex and medulla do
really constitute one physiological structure, there are out-
standing masses of both constituents in different regions of
the body, concerning which it would be out of the question
to make a similar hypothesis. There may yet be discovered
some reason for looking at the adrenal gland (cortex and
medulla taken together) as a functional whole, but Bittorf
appears to have come to this conclusion simply because the
experimental evidence as to the respective importance to life
of cortex and medulla is conflicting, and because pathologists
have never yet been able to determine any difference in those
cases where chiefly cortex or chiefly medulla have been involved.

Winkler gives an account of twenty-four cases of adrenal
tumours. There were thirteen primary growths (ten epithe-
liomata and three sarcomata), and eleven secondary cases.
In only two cases was there any bronzing of the skin. . From
a careful study of these cases the author is quite unable to
decide whether Addison's disease is due to an affection of
the cortex or of the chromaphil tissue and the sympathetic,
or is to be attributed to a lesion of both together.

In cases of Addison's disease a fibro-caseous condition of
tubercular origin is by far the commonest condition found.
In addition, simple atrophy, chronic inflammation, syphilis,

134 THE DUCTLESS GLANDS

malignant disease, and extravasation of blood have been
recorded. The solar plexus and semilunar ganglia as well as
the ganglia and nerves in the adrenals are often the seats of
alterations. They may be atrophied from the pressure of
tumours, affected by tuberculosis by extension or as part of a
widespread invasion, or they may be involved in inflammatory
processes (Dock).

Hyperplasia of lymphoid tissues has been described.

Wiesel has described in six cases of Addison's disease severe
degenerative changes and destruction of the chromaphil cells
not only in the adrenal medulla, but also in the sympathetic.
He reports, further, that in a case of tuberculosis of both
adrenal bodies, where there had been no symptoms of Addison's
disease, not only was there no destruction, but there was a
hyperplasia of the chromaphil tissues. Wiesel then, regards
Addison's disease as due to a primary lesion of the chromaphil
tissues. It is clear that such cases were easily overlooked by
the earlier pathologists, and may account for some of the
reports of Addison's disease without lesion of the adrenals.

6. Paihogeny.

The theories as to the pathogeny of Addison's disease may
be divided into two groups : (1) Nervous, (2) chemical or
glandular.

If we except Addison's original view (which he somewhat
modified later on) and the theory that the adrenals are of no
importance in the economy, most of the early theories were
nervous. The view of Wilks and Greenhow was that the
lesion is special and primary in the adrenals, while the symp-
toms of the disease are due to the secondary effects on the
adjacent sympathetic, the solar plexus, and the semilunar
ganglia. But in many cases of typical Addison's disease no
changes in nervous structures could be found, and on the
other hand there are numerous examples of irritation of
sympathetic ganglia where no symptoms of Addison's disease
have occurred. It may be, however, that the vomiting is of a
nervous nature, and due to some effect upon the autonomic
nervous system.

The chemical or glandular theory is the one now generally
accepted. It is usually subdivided into two : (1) The auto
intoxication theory ; and (2) the theory of internal secretion.

I

THE ADRENAL BODIES 135

According to the latter view, the pathology of Addison's disease
is to be explained on the basis of adrenal inadequacy — i.e.,
an interference with the normal internal secretion of the gland.
According to the former, the symptoms of Addison's disease
are due to the accumulation of poisonous products (e.g., of
muscular activity), to remove which it is the duty of the adrenal
body. It seems clear that the gland does not effect this
removal after the manner of an excretory organ, but there is
nothing to prevent our supporting the hypothesis that the
secretion of the gland has for its function, or one of its functions,
the neutralization of some of the poisonous products of meta-
bolism.

If we admit that one of the functions of the secretion of
the gland is to maintain the tone of muscular structures
generally, then we have at once an explanation of the extra-
ordinary muscular prostration in Addison's disease. But the
effects of adrenin, the secretion of the chromaphil medulla,
are practically confined to the muscular structures under the
control of the sympathetic nervous system. It may be that
the muscular weakness is to be explained on the hypothesis
that the adrenals in some way neutralize the poisonous products
of muscular activity.

But how are we to explain the pigmentation, the bronzing
of the skin, which is, after all, the most striking of all the
symptoms of Addison's disease ? Is this symptom related
to the colour reactions given by the chromaphil cells of the
medulla, and extracts made from them, or is it related to a
destruction of red blood-corpuscles which is stated to occur
in the central portion of the cortex, or is it due to deficiency
in some other function of cortex or medulla ?

It seems difficult or impossible to induce pigmentation by
experiments upon animals (see, however, pp. 141 and 142).

The pigment is disposed for the most part in places which
are exposed to thermal, chemical, and luminous stimuli. From
a teleological standpoint the pigmentation might be regarded
as a protective arrangement against luminous stimuli. Accord-
ing to Bab (in discussing melano-sarcoma of the ovary), pigment
raises the power of resistance of tissues and organs, and is
therefore found in the locus minor is resistentice. In this view
the pigment is a general means of protection against injury.
Eiselt comments that this can scarcely hold as a general theory,

136 THE DUCTLESS GLANDS

for pigment becomes developed in large amount in ganglion
cells only during the process of degeneration.1 Wieting and
Hamdi, discussing melanin-pigmentation, regard the formation
of pigment as a protective arrangement — e.g., it is laid down
in the skin to protect the underlying structures. Solger looks
upon the skin pigment as a protective against ultra-violet light.

The pigments of the body (respiratory, biliary, urinary,
melanins, lipochromes, etc.) may be divided into — (1) iron-
containing pigments ; and (2) fat-containing pigments. The
second group includes the degeneration pigments, the lipo-
chromes, and the melanins. The pigment in Addison's disease
appears to belong to the melanins.

There are various theories as to the mode of formation of
the pigment. It has been suggested that it arises as a result
of over-activity of the cells of the stratum Malpighii, due to
increased nervous stimulation, the result of mechanical irrita-
tion of the nerves round the adrenals. Eiselt believes that in
consequence of the failure of the antitoxic adrenal function
(of the cortex) the accumulated products act autolytically
upon the protein. Then, by the action of tyrosinase upon the
aromatic molecular complexes thus formed, there arises an
accumulation of melanin.

A modification of this theory, but involving the hypothesis
that the medulla is concerned in the pigmentation, based upon
the work of v. Fiirth and Halle has been put forward by Adami.
The melanin appears to be formed by the action of oxidases
upon tyrosin and other aromatic products of protein decom-
position. It seems possible that adrenin is manufactured in a
similar kind of way, so that when the adrenal bodies are
diseased the tyrosin and allied bodies accumulate in the tissues,
and the greater darkening of the superficial parts most exposed
to light and air gains its explanation from the more active
oxidation of those aromatic bodies in these regions.

Pathologists have never until quite recently given due
consideration to the essential difference between the cortex
and medulla of the adrenals. We have seen that these repre-
sent two separate and distinct kinds of tissue, which only come
into relation with each other in the higher vertebrates, and

1 There seems no reason why this pigmentation in degenerating nerve cells
should not be an example of a protective effort (albeit ineffective) on the part
of the cell.

THE ADRENAL BODIES 137

consist of " cortex " and " medulla " only in mammals. It is
possible that pathology may yet throw some light on the
question of the function of the cortex and the question as to a
possible physiological relationship between the two constituents
of the gland.

We must remember that there are undoubted cases of
Addison's disease in which both adrenal bodies are found to
be healthy, and that there are other cases in which clinically
no signs of the disease are present, but which at the autopsy
show destruction of both glands. These facts may possibly
find their explanation in the distribution of cortical and
chromaphil substance outside the adrenal bodies. On the
other hand, it seems not out of the question that we may have
to resuscitate a long-buried hypothesis that the disease may
sometimes be due to affection of the sympathetic nerves or
ganglia. To bear in mind such a possibility is not so unjusti-
fiable when we consider to how small an extent we are able to
explain any of the symptoms of Addison's disease by anything
we have learnt about the functions of the adrenal bodies.

In the meantime pathologists would do well to investigate,
in all cases of probable adrenal disease, not only the adrenals
themselves, but the rest of the cortical and chromaphil tissues
in the body.

7. Course and Event of the Disease — Diagnosis, Prognosis,
and Treatment

The course of the disease is usually progressive, but the mode
of progress is paroxysmal [Greenhow]. All the symptoms are
progressive, but not steadily so. The course of the disease on
the whole is slow and chronic ; but it is subject to alternate
exacerbations and remissions. During the remissions strength
is to some extent recovered, but after each exacerbation the
patient finds himself upon a lower level than during the
previous remission.

In cases where destruction of the glands is produced by
haemorrhages or thromboses death may occur very rapidly
with acute nervous and intestinal symptoms. In these pig-
mentation is absent.

In young subjects the disease may run a latent course —
that is, the constitutional symptoms first appear suddenly in
a fully developed form producing death in a few days.

138 THE DUCTLESS GLANDS

The diagnosis must depend largely on the extraordinary
lack of resistance to fatigue, upon the other constitutional
symptoms, and upon the bronzing of the skin. Where this
last is absent the diagnosis must be difficult and uncertain.

The prognosis is grave, but the patient may live a con-
siderable time, and care should be exercised in foretelling to
what extent life may be prolonged. At least one case is reported
where the symptoms of Addison's disease have completely
disappeared (Treckin).

The treatment will be dealt with under the therapeutic
applications of adrenal substance (p. 204).

8. Other Conditions involving Adrenal Insufficiency

Defective development of the adrenals is not infrequently
associated with imperfect growth of the brain, particularly
in cases of anencephaly and hemicephaly.

Total deficiency of the adrenal medulla has been reported.
Wiesel records a series of cases of what he calls " hypoplasia of
the chromaffin system."

Lavenson, Sergent, and Cooke have described cases of
acute adrenal insufficiency, which may occur with symptoms
resembling an acute poisoning. These are apt to occur in
diphtheria, scarlet fever, typhoid fever, erysipelas, and
chloroform poisoning. Sergent connects certain conditions
which may supervene in typhoid fever with the syndrome of
adrenal insufficiency.

French writers frequently refer to a condition due to adrenal
insufficiency, in which muscular weakness or lack of tone and a
low blood-pressure, along with digestive and nervous troubles
are striking symptoms. They have even attributed the
symptoms of " shell-shock " to adrenal insufficiency.

9. Excessive Adrenal Function

The fact that excessive production and pouring into the
circulation of the thyroid secretion appears to lead to a very
definite train of symptoms, has naturally suggested the
question whether an analogous condition of excessive pro-
duction of the adrenal secretion may be a factor of consideration
in the production of disease.

The most striking effect of the adrenal secretion is a rise
of blood-pressure. As pointed out by Adami, hyperpiesis, or

THE ADRENAL BODIES 139

pronounced and continued rise of blood-pressure, is not an
uncommon condition. Roger and Gouget report hypertrophy
of the adrenals in a case of experimental arterio-sclerosis
induced by lead intoxication, while several authors have noted
a relation between arterio-sclerosis and hypertrophy of the
adrenal medulla.

Three theories have been put forward to account for the
hyperplasia of the adrenal bodies in arterio-sclerosis : (1) The
hyperplasia is not the cause of the hypertension at all, but an
" antitoxic hyperplasia " due to the effects of the accumulated
products of metabolism which possibly also produce the
hypertension ; (2) the hyperplasia is the cause of the hyper-
tension, but is secondary to a renal lesion ; (3) the hyperplasia
is the cause of the hypertension, and is primary and independent
of the kidney mischief.

It is yet too early to state which of these is the correct
view. The French writers insist that the adrenal hyperplasia is
almost constantly associated with chronic interstitial nephritis.
According to Pearce, it may equally be associated with chronic
parenchymatous nephritis.

On the other hand, Mott states that in his experience in
advanced arterio-sclerosis the adrenal medulla is more often
atrophied than hypertrophied.

Several writers have assumed a functional increase of the
chromaphil tissue in certain forms of diabetes mellitus. but
the matter cannot be regarded as definitely settled. The same
applies to the association of interstitial nephritis and hyper-
function of the chromaphil tissue.

10. Adrenal Tumours

Tumours of the adrenal body are perhaps most usually of
interest as bearing upon hyperf unction of the organ. But
since it is conceivable that in some cases the growths may
determine a reduction in activity, it is better to treat of them
in a separate section.

A. Tumours of the Adrenal Medulla (Chromaphil Tissue). —
A few cases of medullary glioma have been described.
Adenomata of the chromaphil tissue, or " paragangliomata "
are also mentioned. The symptoms noted were arterio-
sclerosis, and cardiac hypertrophy as well as disturbances of
nutrition, and other signs of a more general character.

140 THE DUCTLESS GLANDS

Malignant medullary hypernephromata also occur, and,
although the chief interest of these cases depends on the
distribution of the secondary growths, yet it will be advisable
to give a short account of their most striking features. The
syndrome associated with these growths was first described
by Hutchison. Most of the cases occur in children two or
three years old, and in many the earliest characteristic sign is
a hsemorrhagic streak upon one or both upper eyelids. This
is followed by exophthalmos and optic neuritis. The disease
is always fatal, usually within six months. The primary
tumour is believed to arise from the chromaphil tissue of the
medulla of the gland, and consists of round or oval cells with
large nuclei and a granular protoplasm. It is doubtful whether
it is a sarcoma or a carcinoma.

B. Tumours of the Adrenal Cortex. — These may be divided
into two groups. In the first are included the sarcomata,
carcinomata, endotheliomata, and cysts. These for the most
part only give rise to general results such as may be expected
from benign or malignant tumours. In the second group are
included the adenomata and hypernephromata. The clinical
importance of these will be discussed later in connection with
the relations of the adrenal cortex to the genital functions
(p. 241).

E. Extirpation Experiments in Mammals

The earliest extirpations of the adrenals were performed by
Brown-Sequard in 1856. He employed for extirpation of both
glands forty -four rabbits, nine guinea-pigs, two rats, and several
dogs and cats. All these animals died in nine to thirty -seven
hours after the operation. For the unilateral operation this
experimenter used sixteen rabbits, five guinea-pigs, two cats,
and two dogs. All these died in twenty-three to thirty-four
hours. Later he reported that two dogs survived removal of
one gland for eight days. As a rule young animals survived the
operation longer than adults. Brown-Sequard came to the
conclusion that the death after adrenal extirpation was not due
to adventitious lesions connected with the operation, but to a
cessation of the function of the glands. He noted marked
nni-riilar weakness, but not vomiting or pigmentation, and he
supposed that the absence of these two last symptoms is due to
tin- rapidity with which a fatal iv>ult supervenes.

THE ADRENAL BODIES Hi

These views of Brown-Sequard were vigorously combated by
many workers. Gratiolet performed several series of operations
upon guinea-pigs, and came to the conclusion that extirpation
of the right adrenal was just as serious as removal of both.
This was soon disproved by Brown-Sequard, who succeeded in
keeping three guinea-pigs out of seven alive for three weeks
after right-sided extirpation.

Philipeaux succeeded in keeping white mice and also a certain
number of rabbits alive after bilateral extirpation. He con-
cluded that removal of the adrenals does not necessarily lead to
death, and that where death ensues this is due to the operative
proceedings or some circumstance connected with them, such as
peritonitis, and that some animals can survive complete extir-
pation without showing any symptoms — that, in fact, the
adrenals are no more essential to life than is the spleen. This
view he firmly maintained, although three of his operated
animals died in nine, twenty-three, and thirty -four days.

In order to test the matter further, Brown-Sequard per-
formed a further series of experiments upon rabbits, and felt
justified in affirming that the adrenals are more essential to life
than are the kidneys, and thought that the survival of occasional
animals is due to a vicarious assumption of the adrenal function
by the thymus or the thyroid.

Harley employed among other animals the white rat, and
found that this animal may indefinitely survive entire removal
of the adrenals. From this Harley, as well as Philipeaux and
Gratiolet, ascribed the fatal results in other animals to injury to
adjacent nerves and bloodvessels.

The observations of Nothnagel deserve special mention.
This observer, from clinical observations, thought that a
chronic inflammation of the adrenals would be more likely to
induce symptoms resembling those of Addison's disease than
removal of the glands. Accordingly he resorted to the method
of crushing the bodies. He operated upon 153 rabbits, and
found that if the operation were performed upon the two sides
with an interval of three or four weeks between, then the
animals survived and showed no serious symptoms. Among
the 153 bilaterally operated rabbits, Nothnagel observed in
three cases pigment spots on the mucous membrane of the
mouth. These were noticeable one, three, and five months
after the second operation. The author did not, however,

142 THE DUCTLESS GLANDS

attach any particular importance to them. He thought,
indeed, that the disease of the adrenal glands had no immediate
relation to pigmentation.

The statement that removal of both adrenal bodies does not
necessarily lead to death was denied by Tizzoni. This author
came to the conclusion that in rabbits the destruction of one or
both of the adrenals results in death if sufficient time be allowed
to elapse. He obtained similar results with dogs.

The opinion that unilateral extirpation could lead to death
was strenuously opposed by Stilling, who found that young
rabbits from which one adrenal had been removed could develop
quite normally, and live more than a year without showing any
untoward symptoms. In thirty cases investigated Tizzoni
found pigmentary changes in thirteen. These came on at the
earliest two months after the operation, and occurred exclusively
in the mucous membrane of the nose and mouth. They were
of the same character as those found in Addison's disease.
Stilling was unable to confirm these results. Tizzoni con-
sidered that death, which might occur after removal of one
capsule, was due to lesions of the nervous system.

Abelous and Langlois employed various means for experi-
mental lesions upon the adrenals, such as ligature, crushing,
and cauterization, but most frequently the last method was
used. They report that after complete destruction of one
gland some animals suffered a loss of weight and a small pro-
portion died. After complete destruction of both adrenals
most of the animals soon died. The duration of life could be
increased by performing the operation at two sittings with an
interval of several days between them. After destruction of
a fifth part of each gland, with an interval of one or two days
between the two operations, the animals could be kept alive,
but there was considerable emaciation. If an interval of eight
to fifteen days were allowed to elapse between the two opera-
tions, then the animals lived without symptoms. If the half of
each organ were cauterized away, the animals rapidly wasted
and died, but not so quickly as after total destruction. The
animals employed in the experiments were guinea-pigs.

Alezais and Arnaud, in a series of papers entitled " Recherches
Experi men tales et Critiques sur la Toxicite de la Substance
des Capsules Surrenales," conclude that the suprarenal capsule,
though still functioning in the adult, is not indispensable for

THE ADRENAL BODIES 143

life. Its unknown functions may be disturbed without any
other results than a hyperpigmentation of skin and mucous
membranes. But a lesion of the glands frequently induces
death by affection of the nervous system. The pigmentation
was confined to the mouth and nostrils, and the authors do not
appear to be convinced that it was not accidental and indepen-
dent of the lesion of the adrenals.

Hultgren and Andersson in 1899 published the results of a
carefully conducted series of extirpation experiments upon
rabbits, cats, and dogs. The effect varied very considerably
in different animals.

In cats the unilateral operation (extirpation of one adrenal)
never induced death, but, especially in old cats, there was
some temporary disturbance of the general bodily health.
Bilateral extirpation in these animals, whether carried out at
one, two, or three sittings, led to death, without exception, in a
few days. The average duration of survival after extirpation
of both adrenals at one operation was 68 hours (nine cases) ;
at two operations, 134 hours (eleven cases) ; at three opera-
tions, 88 hours (five cases), but in the last instance there were
three cases of infection.

Extirpation of one and amputation of the other gland x in
one sitting was generally very badly borne. Of the nine cats
operated on in this fashion, only two survived any considerable
time ; one died in six hours, probably from the effects of the
anaesthetic, and three in thirty to seventy-two hours. In
these last the adrenal left behind had undergone necrosis. The
three remaining animals died from various diseases within
three weeks after the operation. It appears from these experi-
ments that the removal of a large part of the adrenal tissue
renders the animal more susceptible to infection.

Extirpation and amputation carried out at two sittings is
less dangerous ; out of thirteen animals so treated, two died
from the actual operation, and three from necrosis of the
adrenal left behind. The remaining eight all lived more than
seven days, and of them two died of intercurrent diseases. If
the removal of the glands be carried out at several operations,
the length of time which elapses between the operations makes
no difference to the result.

1 In these " amputation " experiments a small portion only of one gland
was ,left 'behind.

144 THE DUCTLESS GLANDS

Hultgren and Andersson came to the conclusion that the
iv>i ^tance of castrated animals to adrenal extirpation is gener-
ally greater than that of normal animals. While, for example,
normal animals survived complete extirpation at one operation
for 61 hours, the corresponding time for castrated animals
was 121 hours. In this relation the authors call attention to
the striking morphological resemblance between the cells of the
adrenal cortex and the interstitial cells of the testis and ovary.

In rabbits total extirpation of both glands at one operation
is always fatal, and death occurs on the fourth or fifth day. If
the operation is carried out at two sittings, the duration of life
is considerably increased ; and three rabbits in which there was
an interval of nine to fourteen days between the two operations
lived 121 to 125 days, and were then killed while still in per-
fect health.

After extirpation of one and amputation of the other gland
most of the rabbits lived a long time — as long as 320 days. The
authors, immediately after stating this result, say : "Dieses
Ueberleben der totalen Entfernung der Nebennieren beim
Kaninchen is durchaus nicht durch die Anwesenheit wenigstens
makroskopisch nachweisbarer accessorischer Nebennieren
bedingt." Now, these cases were not cases of total removal
of the adrenals, for some tissue of the amputated gland was
always left behind. But perhaps this is meant to refer to the
three cases of the previous paragraph, where the operation was
performed in two sittings with an interval of nine to fourteen
days between them. But apparently these were not cases of
complete removal, for the gland was transplanted into the
musculature.

Unilateral extirpation in rabbits produces no ill effects, and
the same applies to dogs. Hultgren and Andersson only per-
formed one total extirpation upon a dog, which lived six days.

The symptoms after removal of the adrenals were very
characteristic. After the operation the animal recovers in a
few hours, and in the first few days shows no ill effects from the
operation, except some loss of appetite. During the last
twenty -four hours before death, or earlier, the animal becomes
stupid and quiet, and shows (especially is this the case with
cats) wr;iknr>s and uncertainty of movement in the hinder
extremities. During this period, too, the temperature begins
to fall, and the apathy and weakness increase. Then the hind-

THE ADRENAL BODIES

145

limbs become stiff, the animals tire on the slightest exertion,
and show extreme prostration. Finally, with increasing
asthenia, there is dyspnoea, heart- weakness, and death. In
rabbits convulsions are common, but do not occur in cats and
dogs. The authors lay considerable stress upon the loss of
weight which occurs even after the unilateral operation.1 This
symptom is less marked if the operation be carried out upon
castrated animals. Fall of temperature, too, is regarded by
them as a significant symptom. They could detect no change
in the haemoglobin of the blood, nor in the number of red and
white corpuscles. They could detect no change in the electrical
excitability of the nerves, and deny that removal of the adrenals
gives rise to symptoms resembling those of poisoning by curare.
There was no true paralysis, but only weakness and prostration.
The operated animals were very sensitive to bodily movements.
Adrenal extirpation has no effect on the protein metabolism.
This applies, at any rate, to rabbits and cats. The Scandinavian
authors consider it very probable that the adrenals have a
varying functional significance in different classes of animals.2

Strehl and Weiss operated upon 114 animals, and found that
total extirpation always causes death in from four hours to five
days. If the operation was performed at two sittings, the second
gland was always found to be enlarged. Among the symptoms
noted by these writers after extirpation are muscular weakness,
a low temperature, and a low blood-pressure.

Strehl and Weiss give the following tabular statement of
their results :

Species of Animal.

Duration of Survival
in Hours.

Number of
Animals.

Dogs

Doers

22-75
75 138

7
3

Cats

15 28

15

Cats

28-47

2

Rabbits

8 14

26

Guinea-pigs

4-9

20

Rats
Mice
Hedgehog
Weasel

15-19
8-13
14
21

4
10
1
1

Frogs

22-45

25

1 This result was also obtained by Elliott and Tuckett, and has been fre
quently observed by the present writer.

2 This is probably true of all the " ductless glands."

10

146 THE DUCTLESS GLANDS

Biedl performed a series of experiments upon dogs, cats, and
rabbits. These were carried out by a new method. In a
preliminary operation by a lumbar incision the glands were
" dislocated," the vascular connections were not severed, and
the glands were stitched into their new position between the
skin of the back and the dorsal musculature, so that they
remained in a living condition and easily accessible extraperi-
toneally. After three or four days the glands were exposed by
a skin incision, the vessels tied, and thus could extirpation be
performed in the easiest possible manner.

It was found that extirpation of one gland produced no
serious effects, but that after extirpation of both adrenals the
animals died, almost without exception, in two to four days.
Two rabbits which survived sixteen and twenty-eight days
respectively were found to possess accessory adrenals on the
vena cava beneath the renal veins.

As we have seen, Boinet succeeded in keeping rats alive for
a considerable time after double epinephrectomy ; and Harley
many years ago found that the rat is able to withstand removal
of both adrenal bodies. According to Wiesel, this is due to the
fact that the rat normally possesses between the testis and
epididymis accessory adrenals which are found to undergo com-
pensatory hypertrophy after extirpation of the chief organs.
These accessory bodies consist entirely of cortex (see p. 147).

In guinea-pigs a compensatory hypertrophy of accessory
cortical bodies can be shown to occur, but this is never sufficient
to keep the animal alive after complete removal of the main
glands.

The case of the rat and the results of extirpation experiments
upon this animal seem to point strongly towards the cortex
being the part of the adrenal body which is essential to life.
We shall, however, have to return to this subject again.

We see, then, that later work has confirmed in a general way
the statements of Brown-Sequard as to the necessity for life of
the adrenals. We cannot, however, altogether disregard the
very considerable number of exceptions which have been
recorded by various observers. Moore and Purinton report
the survival of a goat for twenty-two days after complete
removal of both adrenal glands, and they state that no accessory
bodies could !><• detected.

According to Mayer, the diabetic puncture is ineffectual in

I

THE ADRENAL BODIES 147

animals from which the adrenals have been removed. Further,
in such animals the glycosuria resulting from extirpation of the
pancreas is much reduced. Frouin states that the pancreatic
diabetes is also much reduced in severity in animals from which
one adrenal and two -thirds of the other have been previously
removed. This matter will be referred to again in connection
with the subject of adrenal glycosuria.

Levin reports that the blood of animals deprived of adrenals,
when injected into another animal, raises its blood-pressure,
but the tracing he gives indicates that the rise is not consider-
able. He hints that the substance which has this action may
be something of a different nature from adrenin.1

F. The Question as to Accessory Adrenal Bodies in
Relation to Extirpation Experiments upon Mammals

It will be seen, from a perusal of the section on the compara-
tive anatomy of the adrenal glands, that not only may acces-
sory adrenals consisting of both portions of the organ be
present, but there may also be some glandules consisting
of cortex only. The presence of chromaphil bodies and cells
in different regions must also be borne in mind (Figs. 30-33).
How far does the existence of these various bodies explain the
discrepancies between the results obtained by different
observers after adrenal extirpation ? We know that some of
the larger masses of chromaphil tissue (such as the parasomata
of Zuckerkandl and the abdominal chromaphil bodies in
various animals) contain adrenin, and this may have the same
physiological purpose as that manufactured by the adrenal
medulla, whatever that may be.

Schafer recently exhibited a white rat operated upon by
Harley some time between 1856 and 1858. This rat had the
spleen and adrenals extirpated when it was only a month old
and quite small. It increased in size after the operation quite

1 According to Gautrelet and Thomas, after extirpation of the adrenals
in dogs the heart contraction becomes weak, and the rhythm quicker, while
the blood-pressure sinks after five hours to 6 centimetres Hg and later to
1 centimetre. The same authors report that in decapsulated dogs excitation
of the splanchnic no longer induces glycosuria, as it does in normal animals.
They further report that dogs and rabbits, after adrenal extirpation, become
poikilothermic in that their body temperature, within certain limits, follows
that of the external air, and that there is reduction of the excitability of the
sympathetic. (See p. 235.)

148 THE DUCTLESS GLANDS

as fast as its fellows which had not been touched. The animal
was killed when five months old, and no discoloration of the
skin or hair could be detected. The lumbar and other
lymphatic glands were found enlarged.1 Commenting upon
this, Sir Edward Schafer says : " The rat happens to be the
one common animal which is able to withstand complete
removal of both suprarenal capsules. The reason for this
was not at the time apparent, although it is now known, for
the rat is exceptional in possessing in various parts of the back
of the abdomen and pelvis numerous small glandular structures
which are composed of cells having the same characteristic
features and functions as the cells of the suprarenal medulla."

But all observers have not been successful in keeping rats
alive after double adrenal extirpation. Thus, H. and A.
Cristiani found that in their experiments, unless a little of the
medullary substance were left behind, the rats always died.
From these experiments we should be justified in concluding
that it is the chromaphil tissue (including the medulla of the
adrenal body) which is essential to life. But, as we have
already seen, Wiesel arrived at a different conclusion — viz., .
that it is the survival of accessory cortical substance which
saves the animal's life. We thus see that the experimental
evidence as to the effects of extirpation of the adrenals in the
rat is somewhat conflicting, and the explanations offered by
different observers as to the occasional or frequent absence
of ill effects after extirpation are also conflicting. Moreover,
it does not appear to be the case that the rat is more richly
endowed with extracapsular chromaphil cells than are other
common animals. The present writer has been so far totally
unable to demonstrate any such tissue by the method of
Stilling and Kohn, and is further informed by Dr. Kohn that
there is, at any rate, no essential difference between the rat
and other animals as regards its chromaphil tissues.

Vassale, who has performed a series of experiments with
full knowledge of the anatomy of the chromaphil cells and
their distribution in different animals, points out that the
" paraganglion abdominale aorticum " is the most important
mass of chromaphil tissue outside the adrenal body, and that

1 This description is taken from the catalogue of the museum of University
College Hospital, whence the specimen was borrowed by Sir Edward Schafer
for the purpose of his lecture.

'

THE ADRENAL BODIES 149

it is always present, though in varying degree in the animals
ordinarily used for experiment (dog, cat, and rabbit). The
removal of one adrenal and the abdominal chromaphil body
causes death in young cats with the same symptoms as those
obtained after bilateral extirpation of medulla only. Vassale
thinks that survival of animals, when it occurs after extirpation
experiments, can be satisfactorily explained by the extra
amount of extra-adrenal chromaphi] substance which happens
to be present in these individuals.

A further discussion of the question as to the relative
importance to life of the cortical substance and the chromaphil
material can only be carried on after the account of extirpation
experiments upon lower vertebrate animals.

According to Biedl, the cortical accessory adrenals occur
very rarely in dogs and cats, in rabbits in about 15 to 20 per
cent, of animals examined, in rats in almost 50 per cent, of
cases, in guinea-pigs not more than 4 per cent, of cases.

G. Extirpation of the Adrenals in the Lower Vertebrata

Perhaps the best-known and most-often-quoted series of
extirpation experiments upon any animal is that carried out
upon the frog by Abelous and Langlois in 1892. This was, of
course, at a period before the discovery of the physiological
effects of adrenal extracts upon the blood-pressure. The
authors employed frogs because these animals, they say, do
not suffer from the shock of operations as do mammals, and,
in general, tolerate operative proceedings very well. Abelous
and Langlois were the first to study the physiology of the
adrenals in the frog.

Destruction by means of the actual cautery was the method
of extirpation employed. A platinum wire brought to a red
heat was applied to the bodies on the anterior surface of the
kidneys. The authors found that male frogs are more suitable
for the operation than female, and summer frogs better than
winter frogs. There was never any post-operative shock.

Total destruction of both capsules always led to death.
Immediately after the operation the animals were normal. It
was only after a certain period that one observed ill-effects
which finally caused death. The duration of survival was
variable. It varied according to the season ; winter frogs

150 THE DUCTLESS GLANDS

might live twelve or thirteen days, but summer frogs never
longer than forty-eight hours. On the other hand, if the
winter frogs were kept at a mean temperature of 22° C., their
period of survival was much diminished, and from twelve to
thirteen days it was reduced to three.

The symptoms which followed destruction of both capsules
consisted essentially in a progressive paralysis beginning in
the hind-limbs, then becoming general and inducing death.
On the day of the operation the animal remained well. It
was as a rule at the end of the twenty-fourth to the thirtieth
hour that symptoms came on. First one noticed a distinct
inco-ordination in the movements of the hind-limbs when the
frog jumped. Also the animals quickly became fatigued, and
asthenia became more pronounced. This paresis affected first
the flexors and adductors, and finally the extensors ; the frog
was finally no longer able to respond even to the strongest
stimulations except by way of the feeblest movements. Then
the fore-limbs became affected, and the animal was completely
inert. The respiration became slower and slower, and with
contracted pupils the animal died.

If the animal were stimulated from time to time so as to
provoke movements, it was found that the paralysis came
on much more quickly, and the duration of survival was
considerably shortened. From these facts the authors con-
cluded that the length of survival was in inverse ratio to the
chemical changes going on in the body. The more active these
changes — as, e.g., in summer frogs — the more quickly did
death supervene.

Destruction of one capsule never induced death. The
animals after such an operation showed no untoward symptoms,
and their attitude and reactions were perfectly normal. Com-
plete destruction of one capsule and destruction of the greater
part of the other generally led to death, but the survival was
always longer than after complete destruction of both. If the
fragment left behind were of any considerable size, the survival
was as long as in the animals in which only one gland had been
destroyed. The insertion under the skin, in the dorsal lymph
sac, of some fragments of kidney with the adrenals attached
taken from a normal frog, prolonged the survival. Animals
so treated might live twice as long as animals not so treated.
The authors record that summer frogs were by this means

THE ADRENAL BODIES 151

enabled to live five or six days. Post mortem it was found
that the grafted capsules had disappeared — i.e., the graft did
not succeed. Injection of a saline extract of healthy glands
only prolonged the survival by about twenty -four hours.

Now we come to some observations by Abelous and Langlois
upon which they themselves laid considerable stress, and which
have played a prominent part in all subsequent discussions on
the functions of the adrenal bodies. They found that intra-
venous or subcutaneous injection of the blood of a frog dying
after extirpation, into a frog recently operated upon induced
rapid paralysis and death. The same injection into a normal
frog only produces slight temporary symptoms. The authors
were convinced that death after extirpation of both capsules
is in reality due to the suppression of essential organs, and not
simply the result of the shock of the operation. They further
proved that the effects were not due to injury to the kidney.
Their theory was that death resulted from the accumulation in
the blood of one or several toxic substances of unknown nature,
and that the suprarenal capsules are capable of the elaboration
of a material which neutralizes the toxic effects of such
substances. The toxic symptoms were stated to be those of
curare-poisoning — paralysis, that is to say, of the connections
between nerve and muscle.

These observations were in the main confirmed by Gourfein,
who, however, could not satisfy himself that there was any
difference between winter and summer frogs as regards the
results of extirpation, and who denied also that the blood of
operated frogs, when injected into others, gives rise to symp-
toms like those of curare-poisoning.

The same author also carried out a series of observations on
pigeons and tritons. The pigeons only survived four to
twenty -four hours if total extirpation had been performed ;
if only one-eighth to one-tenth of the organ remained behind,
the animals lived fifteen days. Unilateral extirpation in
tritons produced no symptoms. If only a speck of one adrenal
remained behind, this was sufficient to keep the animal alive
for from eighteen days to nine weeks.

Pettit was apparently the first to operate upon fishes. He
performed a series of experiments upon the eel, having chosen
this animal because its adrenals are placed on the ventral surface
of the kidneys, a condition which is rare in Teleosts. He did

152 THE DUCTLESS GLANDS

not, however, perform any total extirpations, since he was only
interested in noticing a compensatory hypertrophy of one
gland after removal of the other. This, he says, indicates a
secreting function for the adrenal of the eel. Pettit looks upon
this organ in the eel as the fundamental type of the suprarenal
capsule, but he was apparently unaware that it consisted only
of cortical substance.

Since the corpuscles of Stannius contained no chromaphil
tissue, the Teleostean fishes appeared to offer an admirable
opportunity of testing how far the cortical adrenal glands were
essential to the life of the animal. Accordingly a series of
experiments were performed by the present writer in 1898
upon eels. The results showed that an eel will survive the
operation for a long time. The conclusion drawn was that the
cortex of the adrenal is not essential to the life of the animal,
but the discovery by Giacomini of the cranial cortical adrenal
in Teleosts renders such a conclusion unwarrantable (see p. 103).

Biedl's experiments upon Elasmobranch fishes will be referred
to in the following section.

H. The Question as to the Relative Importance to Life of
Cortex and Medulla

We have seen that the extirpation experiments upon
mammals have not definitely determined the question as to
which constituent of the adrenal is essential to life, or whether,
indeed, it is to the suppression of the compound organ in its
entirety that we must attribute death after extirpation. Sonic
authors believe that there is no special part of the organ which
is of supreme importance in the pathology of Addison's disease,
and consider that the adrenal bodies are single organs clearly
itial to life, interference with which causes definite ill-
results. Some, on the other hand, have concluded from
experiments upon mammals that the medulla is the vitally
essential constituent, although Wiesel came to the conclusion
that the cortex is the part essential to life.

Biedl states that in mammals he has succeeded in removing
the cortex, leaving the medulla behind intact, and that the
operation was followed by the death of the animals. So he
concludes that it is the cortex which is essential to life.

Biedl says that he has succeeded in determining for the

THE ADRENAL BODIES 153

inter-renal of Elasmobranchs that after its extirpation the
animals can live two or three weeks, and then die with symp-
toms of general prostration, just as do mammals after extir-
pation of both dual adrenals. Again, he concludes that
the cortex is the essential part. These experiments upon
Elasmobranchs must be very difficult, but so far they certainly
seem to point to the cortex as the vitally essential tissue.
The validity of these experiments is, of course, based upon
the assumption that there is in Elasmobranchs nothing
corresponding to the cranial cortical body discovered by
Giacomini in Teleosts.

Some recent experiments carried out in my laboratory by
Mr. T. D. Wheeler lend considerable support to the view that
it is the cortex and not the medulla which is essential to life.
Instead of attempting to remove the cortex and leave the
medulla, Wheeler's object was to cauterize out the latter and
leave the former. This was scarcely ever precisely achieved,
but a systematic histological study of the glands after death
showed that entire destruction of the medulla of both glands
gives negative results. The only fatal cases (at any rate
among the animals which could reasonably be supposed to
have died of adrenal insufficiency) were those in which very
considerable damage had been done to the cortex as well as to
the medulla. In some cases the abdominal chromaphil body
was removed as well as the adrenal medulla. Of course in
such experiments groups of sympathetic chromaphil cells, as
well as scattered cortical " accessory " bodies, must have been
left behind. But this fact does not seriously affect the logic of
the argument that it is the cortex which is essential to life.
For, since removal of both adrenal bodies is fatal, and removal
of the medulla is not, it follows that the cortex is the essential
part of the gland so far as the maintenance of life is concerned.
We have seen in a previous section that the cortex is the more
important from a morphological standpoint.

It seems, then, that the symptoms observed in animals after
adrenal extirpation, complete or partial, are by no means
characteristic. The anatomical line which separates full
physiological sufficiency from fatal insufficiency is very
narrow. It has not been possible to produce experimentally
any well characterized symptoms associated with partial
adrenal insufficiency.

154 THE DUCTLESS GLANDS

I. Changes found Post Mortem after Extirpation of
the Adrenals

Reference has already been made to pigmentary changes
after double extirpation (ree pp. 141, 142).

Tizzoni reported severe lesions in the central and peripheral
nervous system. He describes also extensive destruction of
nerve fibres and ganglion cells, with marked congestion,
alterations in the vessel walls, and haemorrhages and leucocytal
infiltration in all parts of the nervous system. But his work
in this respect should be cautiously considered, for it must
be remembered that he records death after removal of one or
both adrenals, and this is opposed to the experience of every
subsequent investigator.

Poll found in some cases among his rats after unilateral
removal and transplantation, numerous reddish-black spots
on the skin, but never on the mucous membranes.

Hyperaemia and haemorrhages of the lungs have been
observed after both the bilateral and the unilateral operation.
Changes in other organs have only been noted by a few
observers. Donetti states that he found changes in the nerve
cells of the central nervous system of guinea-pigs and rabbits,
especially in the medulla oblongata. The nuclei of the cells
became vesicular, eccentric, and granular, and might disappear.
He also noted changes in the nerve-cell body. Acute ulcer
of the stomach has also been recorded.

Moore and Purinton record cardiac thrombosis following
complete removal of the adrenals. The presence of ante-
mortem clots in the heart has been observed on numerous
occasions after adrenal extirpations in the laboratory of the
present writer.

If the veins of both adrenal bodies be tied, the animal will
survive for a much longer period than after double extirpation.
But the operation is always fatal. The delay in fatal issue is
due to a collateral circulation through the kidney.

J. Compensatory Hypertrophy of the Adrenals

Numerous authors have described a compensatory hyper-
trophy of one adrenal after the removal of the other. Thus,

THE ADRENAL BODIES 155

Stilling found in rabbits, after extirpation of one adrenal, a
considerable increase in weight of the one which was left
behind. Pettit describes a similar hypertrophy in the cortical
adrenal (" corpuscle of Stannius ") in the eel, after the removal
of the glandule of the opposite side.

But all observers could not record such hypertrophy. It is
probable that there is a difference in this respect between
different species. Harley among the older workers, and Poll
among the more recent, could not observe any such hypertrophy
in rats. There can be no doubt whatever that such a com-
pensatory hypertrophy may be regularly and easily observed
in the dog.

The compensatory hypertrophy of accessory adrenals in
the rat, which is described by Wiesel, has already been discussed.
This may be related to the absence of hypertrophy on the part
of the chief organ. A similar hypertrophy of the accessory
adrenals which are found along the walls of the vena cava of
the guinea-pig has been described by Velich.

According to some observers, the chromaphil cells, whether
of the adrenal medulla or of the extra-medullary corpuscles,
seem to be incapable of hyperplasia. If this really be the case,
it is interesting to compare the fact with another to be referred
to again later — viz., that in grafting experiments it is only
the cortex which " takes " ; the medulla disappears. It is
possible that this lack of power of growth and of resistance to
absorption is related to the high degree of specialization of the
chromaphil tissues (Vassale).

That the functional capacity of one adrenal left after the
removal of its fellow is not increased is the conclusion drawn
after some experiments by Battelli and Ornstein. These
authors removed one adrenal from dogs and rabbits, and let
them live for from two to seventeen days. After this period
the adrenin contents of the remaining gland were estimated by
Battelli's colorimetric method in order to obtain a measure of
the degree of vicarious function. No increase in the adrenin
of the remaining gland, but rather a decrease, was found.
These experiments, of course, have no bearing on the cortex of
the organ, but only on the chromaphil medulla.

Elliott and Tuckett could not readily produce compensatory
hypertrophy. They found that the English guinea-pig cannot
survive the removal in one operation of a single gland. By

156 THE DUCTLESS GLANDS

piecemeal extirpation a gland was successfully removed ; the
medulla of the gland left behind grew, and the cortex apparently
not. But in a rabbit both cortex and medulla grew. This
does not accord with the observations of Poll and Vassale. -
From some experiments carried out in my laboratory, I am
inclined to believe that in dogs, after a large part of the ad-
renals have been extirpated, there is a notable compensatory
hypertrophy of the abdominal chromaphil body.

K. Transplantation of the Adrenals

Although considerable attention has been devoted to the
subject of transplantation of the thyroid, comparatively little
has been done in this direction with the adrenal bodies.

Canalis appears to be the earliest worker who attempted
adrenal transplantation. He grafted small portions of the
adrenal into the kidney, but they became necrotic and were
absorbed. Only once, fifteen days after the operation, did he
find in the kidney scar the capsule of the adrenal and some of
the cells of the external layer of the cortex.

Boinet transplanted adrenals intraperitoneally into rats.
He observed atrophy and absorption, which, however, was
sometimes delayed. He noted red spots on the transplanted
organs, which he called " hemorrhagies capsulaires."

Gourfein reports that six days after the transplantation of
frog's adrenal into the lymph sac of another frog the organ
became decolorized, and attached by connective tissue to the
muscles. After twenty days the decolorization and adhesions
were more marked, and after forty days the gland was absorbed.
When the adrenals of a guinea-pig were transplanted into the
lymph sac of a frog there were adhesions, leucocytal infiltration
of the gland, and inflammation of the surrounding tissue.

In all these experiments the effect was no more than that of
the administration of a certain amount of adrenal substance
in the form of the gland itself. The effects, if any, were purely
chemical.

Poll was the first to make a systematic macroscopic and
microscopic investigation of the transplanted gland. This
author employed rats for his experiments. He removed the
left adrenal body from behind, and in one series of experiments
transplanted it into the doisal muscles, in another series

THE ADRENAL BODIES 157

beneath the skin of the back. In addition to some changes in
the elements of the capsule, Poll records that the cells of the
zona glomerulosa and the outer part of the zona fasciculata
became changed into large polyhedral, at times pigmented,
structures, which degenerated with the formation of fat
droplets and pigment granules. The cells of the inner part of
the zona fasciculata, the zona reticularis, and the medulla
degenerate within the first week, forming a necrotic focus in the
centre of the adrenal. This is absorbed in the course of the
second week, and in connection with the process of absorption
giant cells arise from the altered cells of the outer part of the
gland. These finally disappear. Into the centre of the adrenal,
at the place where the suprarenal vein leaves the gland, a band
of connective tissue grows and develops, and remains per-
manently. In the course of the third week heaps of cells
occur in the capsule, which resemble cortical cells, but possess
only small compact cell bodies. These heaps fuse together,
and grow into large masses having the form of a segment of a
sphere. In these masses the small cells show signs of an
arrangement like that of the zona fasciculata, In the interior,
progressing outwards, begins a transformation of these cells
into clear, finely reticular elements in all respects like cortical
cells. Intramuscular implantation gives about twice as many
successful results as subcutaneous. Favourable results were
obtained only with young, small, and middle-aged animals.

It seems, then, that in all cases where the adrenals are
transplanted the medulla disappears. This fact is, perhaps,
not without significance as bearing upon the morphological
relationship existing between the two constituents of the gland.
The results of transplantation experiments are also of con-
siderable importance in view of any future attempts to replace
the adrenal function either in the human subject in Addison's
disease or experimentally upon animals after extirpation of
the organ.1

1 Numerous experiments upon transplantation of different organs and
tissues have shown that as a general rule the transplanted portions degenerate
in a few months, even if they have made connection with surrounding tissues,
and have undergone some temporary growth. Among the exceptions are
portions of skin, thyroids, adrenals, and the notable case of Ribbert, who
succeeded in grafting the rudiment of the mammary gland of a young guinea-
pig upon the outside of the ear. The gland not only developed but ultimately
secreted.

158 THE DUCTLESS GLANDS

L. The Pharmacodynamics of Extracts of Adrenal
Medulla (Chromaphil Tissues) and of Adrenin

1. The General Physiological Effects of Chromaphil Tissue
Extracts and of Adrenin

It has already been noted in connection with the account of
extirpation experiments that a few observers have obtained
beneficial results after removal of the gland from adminis-
tration of adrenal substance either in the form of the gland
itself (grafts) or as watery or saline extracts.

In the present section we have to deal with the effects
produced by the administration of the active principle to the
normal animal. In the first instance we shall confine ourselves
to the general effects (toxic) produced upon the animal as a
whole, reserving the special effects upon different systems —
e.g., the hsemodynamics — for a subsequent section.

The earliest important investigations upon the effects of
injecting adrenal extracts into animals are those of Foa and
Pellacani. In their earlier experiments these observers em-
ployed aqueous solutions of fresh animal substances, includ-
ing the adrenal body. They succeeded in causing death in a
dog by injecting subcutaneously the adrenals of a calf in the
form of neutral extract. Similar but more rapidly fatal effects
were obtained in experimenting upon guinea-pigs and rabbits,
but when injected intravenously they obtained like results
from extracts of liver and kidney. So they concluded that the
effect was not a specific one.

In their later work, the Italian observers eliminating the
injurious effects of fibrin ferment in their extracts, found
that the toxic action was specific for the adrenals. They
further determined that the toxicity is not due to the acids
present, for if one separates these out the extracts remain
active. Further, the toxic effects are not due to a ptomaine
which the authors found in the glands, for this is physio-
logically inactive. They conclude that the active principle
of the adrenals paralyses the spinal cord and the medulla
oblongata, destroys completely all motion and sensation,
and kills by paralysis of the respiratory centre. These authors
prepared their extracts by boiling, evaporating to dry ness.

THE ADRENAL BODIES 159

extracting in the cold with alcohol, and redissolving in water.
" After filtering and evaporating the aqueous solution, one
obtains a residue coloured black, of a peculiar odour, of very
acid reaction, and which, in a dose of 1 gramme, kills a healthy
dog." Thus it will be seen that the doses employed corre-
sponded to very large quantities of the fresh gland substance.

These experiments were adversely criticized by Alexander,
who suggested, with considerable justice, that chemical changes
might have taken place in the active principle during the
complicated manipulations employed by the Italian observers.
This or some such opinion has been shared by numerous
observers.

Oliver and Schafer injected subcutaneously comparatively
large doses of aqueous adrenal extracts into the dog, the
guinea-pig, and the cat without obtaining any very obvious
effects. But in the rabbit a large dose of adrenal extract ad-
ministered subcutaneously invariably produced death. Among
the symptoms noted was a very low temperature. In frogs the
symptoms were those of paralysis due to the action of the
poison upon the central nervous system. The animals re-
covered from large doses in a comparatively short time.

Gluzinsky, injecting intravenously, obtained paralysis of
the posterior part of the body, and convulsions in the anterior
part, with acceleration of the respiration and dilatation of
the pupil. The animal succumbed amid progressive dyspnoea
and general paralysis.

Dubois attempts to account for the variations in the effects
obtained by classifying them under three heads : (1) Those
depending upon the animal experimented upon ; (2) those
due to the animals from whose glands the extracts were made ;
and (3) variations conditioned by the mode of obtaining the
extracts. He found that fatigue previous to injection rendered
the animal much more susceptible to the toxic action, that
extracts obtained from the glands of wild animals were more
powerful than those obtained from animals which had been
kept in captivity, and that the medullary region was much
richer in the active poison than the cortex.

The present writer in 1897-98 performed a series of experi-
ments upon rabbits, guinea-pigs, rats, mice, frogs, toads, as
well as upon dogs and cats. The fresh-chopped glands were
boiled, with normal saline solution, and the extract filtered.

160 THE DUCTLESS GLANDS

or the fresh glands were pounded with water or normal salt
solution and sand in a mortar, and the filtrate injected without
boiling. Dried material was also sometimes employed for
the preparation of the extracts. Sometimes cortex and medulla
were carefully separated, and separately used for extracting
and injecting, either by the fresh or the dry method. In
addition to the above, glycerin and alcoholic extracts were
employed.

In most of the experiments the injection was made subcu-
taneously beneath the skin of the back with a hypodermic
needle. In some cases the extract was injected into the pleura
or the peritoneum, and in a few cases into a vein. Numerous
control experiments were performed.

The adrenals employed in the making of the extracts were
obtained mostly from the sheep, but some were taken from the
ox, and occasionally those of smaller animals were used — e.g.,
dog, cat, rabbit, guinea-pig, etc.

The conclusions reached as a result of this series of experi-
ments were as follows : In rabbits, guinea-pigs, rats, mice,
frogs, and toads, after sufficiently large doses of adrenal extract
injected subcutaneously, we get slowed muscular movements,
paresis, and finally paralysis of the limbs (hind-limbs always
becoming affected first), bleeding from the mouth and nostrils,
haematuria (not observed in rabbits), breathing rapid and
shallow at first, finally becoming deep and infrequent, and
occasionally convulsions resembling those of asphyxia pre-
ceding death, before which the temperature often falls very
low. The paralysis is central. The effects are due to the
medulla of the adrenals, the cortex containing no toxic sub-
stance. The effects are specific for the adrenal, and not
common to other glandular extracts. The toxic material is
easily eliminated in some way or other. This accounts for
the large dose required to produce a fatal result, and accounts
also for the ease with which recovery takes place. Idiosyncrasy
plays a large part in the conditions. A partial immunity can
be set up by giving doses not sufficient to kill. This immunity
passes off after a few weeks.

In dogs the first effect of a subcutaneous injection of an
adrenal extract is excitement. There is increased muscular
activity, which passes into a stage of agitation with tremors,
until paresis and finally paralysis come on. Thirst is also a

THE ADRENAL BODIES 161

striking symptom in dogs. There is abundant micturition,
but no hsematuria.

In cats by far the most noticeable result of the injection
was an enormously increased rapidity of the respiratory
movements in the early stage. Thirst and loss of appetite
were recorded, but the paralysis was not so definite as in other
animals. In the cat doses sufficient to kill do not raise the
blood-pressure within half an hour of injection beneath the
skin.

The remote effects noted by Foa and Pellacani, as well as
by Oliver and Schafer, were not noticed in this series of experi-
ments. If the dose were sufficiently large to produce any
effects at all, there were some changes in reaction and disposi-
tion within a few minutes.

After it had been shown by experimental evidence (Vincent)
that the "paired suprarenal bodies " ("medullary " or " chroma -
phil bodies ") and the inter-renal gland of Elasmobranch fishes
correspond respectively to the medulla and the cortex of the
adrenal body of the higher vertebrata, and that the " cor-
puscles of Stannius " of Teleostei consist solely of " cortical "
substance, it appeared to be a matter of some interest to test
the effects of the two kinds of tissue in Elasmobranchs and of
the cortical bodies of Teleosts when extracts of them are
injected subcutaneously into small animals. Naturally, only
very small quantities of material could be obtained for this
purpose, but tfie effects upon mice were quite definite. The
" corpuscles of Stannius " obtained from six specimens of the
codfish (Gadus morrJiua) were found to weigh in a moist state
0*4 gramme. These were extracted by boiling with a normal
saline solution. The filtered extract was then injected beneath
the skin of the back of a mouse. No effects whatever super-
vened. Next, the " paired suprarenals " of Balfour (" chroma-
phil bodies ") from seven specimens of Scyllium canicula were
found to weigh, when moist, 0*3 gramme. These were simi-
larly extracted, and the filtrate administered to the same
mouse (which had remained in perfect health) a few days later.
The animal was immediately and powerfully affected. The
breathing became very rapid, the limbs became weak, the
temperature lowered, and death with convulsions ensued in
less than five minutes. Extracts of the elasmobranch inter-
renal gland produced no effects when injected in the same

11

162 THE DUCTLESS GLANDS

manner. A further experiment with material obtained from
Raja clavaia gave harmonious results.

These experiments gave further positive evidence of the
homology of the "paired bodies" of Elasmobranchs with
the medulla of the mammalian adrenal, and, in conjunction
with the morphological and histological evidence as to the
homology of the "inter-renal" and the "corpuscles of Stan-
nius" with the cortex of the mammalian adrenal (Vincent,
Balfour, Diamare), show that the toxic effects of subcutan-
eous administration of adrenal extracts are obtained only with
chromaphil substance, whether forming the medulla of the
adrenal or the paired chromaphil bodies of Elasmobranch fishes.

An important observation was made by Blum in 1901.
After subcutaneous or intravenous injection of adrenal extracts,
glycosuria occurs, even when the animals injected are being
fed upon a diet free from carbohydrates, or after several days'
inanition, when it is to be supposed that all the glycogen must
have disappeared from the liver.1 The author considers that
the function of the adrenal is to free the organism from the
poisonous products of metabolism.

More recently the purified active principle of the chromaphil
tissues (under various names, perhaps most commonly "adrena-
lin ") has been employed for subcutaneous and other modes of
injection instead of the crude extracts. The results have not
been very different from those obtained when extracts of
adrenal medulla were used.

The immunity first observed by the present writer, working
with adrenal extracts, has been recently recorded by Ssawel-
jew, who employed pure adrenin. Waterman has succeeded
by injecting rabbits with larger and larger doses of r- supra -
renin in bringing the animals into a condition in which they
cannot be rendered glycosuric by means of Z-suprarenin.

Since Blum's original communication numerous papers
upon adrenal glycosuria have appeared, and the majority of
workers have used, not extracts of the adrenal or of chroma-
phil substance, but the pure active substance (adrenin).
Lazarus states that after prolonged administration of adrenin
there is marked hypertrophy of the islets of Langerhans, of
the pancreas, as well as of the adrenal bodies. Herter and

1 More recent observers conclude that the glycosuria lasts until the glycogen
store of the liver becomes exhausted.

THE ADRENAL BODIES 163

Richards, and also Paton, confirmed Blum's observation that,
as with phloridzin and pancreatic diabetes, glycosuria occurs
even when stored carbohydrates have been previously elimin-
ated. Later observers have not held this view. As pointed
out by Schafer, there seem to be connecting links between the
glycosuria set up by pancreatic removal and that due to the
action of adrenalin. Herter and Wakeman found that quite
small amounts (1 c.c. of a 1 in 1,000 solution) of adrenalin
applied to the pancreas provokes marked glycosuria.

According to Mayer and Frouin, as already noted (vide
supra, p. 146), neither the puncture diabetes nor pancreatic
diabetes occur after extirpation of the adrenals. Zuelzer has
gone so far as to assign definitely an adrenal origin to the
pancreatic diabetes of Mehring and Minkowski. He found
that extirpation of the pancreas carried out at the same time
as ligature of the adrenal veins provokes little or no glycosuria.
Injection of certain doses of adrenalin remains without effect
if one injects at the same time a dose of pancreatic extract.
In dogs, if the pancreas and the adrenals are simultaneously
extirpated, there is no glycosuria. Zuelzer also made some
experiments with an artificial circulation through the liver.
He concludes that the adrenal secretion is normally neutralized
by the pancreas, and that pancreatic diabetes is really a
" negative pancreatic diabetes," while it may be regarded
as a "positive adrenal diabetes," the real stimulus to the
genesis of glycosuria being the adrenal secretion.

Similar views are held by other writers. Others again con-
nect the adrenin glycosuria with the functions of the thyroid
and the action of the sympathetic nervous system (Eppinger,
Falta, and Rudinger).

Loewi reports that in diabetes arising after extirpation of
the.pancreas adrenalin produces dilatation of the pupil if applied
to the conjunctiva, whereas it has no influence on the normal
eye. This observation was confirmed by Biedl, and it is stated
that this reaction may be used as a diagnostic sign of pancreatic
diabetes.

In 1898 Biedl discovered a new form of experimental
diabetes. This was induced by tying the thoracic duct or
by leading it to the exterior and allowing the lymph to flow
away. The author considers that the lymph which constantly
flows into the circulation from the lymphatic duct contains a

164 THE DUCTLESS GLANDS

substance which influences directly or indirectly the supply
of sugar in the organism. Biedl and Offer find that in this
form of diabetes also the pupil reacts to adrenalin dropped on
the conjunctiva. They further find that admixture with
lymph or simultaneous injection of lymph from another animal
prevents both the adrenin diabetes and the mydriatic reaction.
In this relation Schafer recalls the observation of Lepine that
in pancreatic diabetes the injection of lymph from a normal
animal produces marked temporary diminution of sugar in
the urine. He suggests that the lymph normally contains a
chemical (glycolytic ?) substance, derived from the islets of the
pancreas, which substance is essential to the due maintenance
of normal carbohydrate metabolism. This whole question has
recently been complicated by Pfluger's announcement of a
" duodenal diabetes " (vide supra, p. 40). It seems possible
that the final solution of the problem may be arrived at by
an accurate knowledge of the interaction between the adrenals
and the pancreas through the mediation of the sympathetic
nervous system.

Meltzer found that subcutaneous injections of adrenalin,
which normally are without effect on the pupil, produce marked
dilation after removal of the superior cervical ganglion.

Underbill and Closson could not find any change in the
nitrogen of the urine in adrenin glycosuria, such as was recorded
by Paton.

It is stated that heat polypncea hinders the onset of adrenin
glycosuria, while warmth alone does not. This result appears
to depend on the destruction of the adrenin by the increased
chemical processes of the body, due to the polypnoea.

Drummond reports that after administration of adrenalin
there occur congestion of organs and histological changes,
indicating that the substance acts as a protoplasmic poison.

Oliver and Schafer suggested that the material obtained
from the adrenal medulla, which produces death, is of a different
nature from that which has such a powerful effect upon the
blood-pressure. The paralysis is due to the action of the
poison upon the central nervous system. The present writer
came to the conclusion that the adrenal body contains an
active principle which acts both centrally and peripherally.
The central action is produced most probably upon the mutm-
centres of the brain, while the peripheral action is shown by

THE ADRENAL BODIES 165

the effect upon blood-pressure when the extract is injected
intravenously. The question naturally arises whether both
these effects are due to one substance or whether there are two
active materials present in adrenal extracts. It seems to be
generally admitted at the present time that the toxic effects,
like those on the blood -pressure, are due to the action of
adrenin. If this be the case, it would seem that this substance
has a central as well as a peripheral action.

Elliott discusses the effects of subcutaneoiis injections of
adrenin, and classifies the possible causes of the symptoms
under three heads : (1) The strain thrown upon the circulatory
system by the great rise of blood-pressure ; (2) a poisoning of
tissues by quantities of adrenin exceeding that sufficient for
physiological stimulation ; (3) the poisonous action of possible
decomposition products of adrenin within the body. The
author considers that the chief cause is No. 2 — i.e., that the
excess of adrenin itself is toxic. He points out that a poisonous
action of adrenin on bioplasm is suggested by its chemical con-
stitution, which displays the — NH.CH3 grouping that resists
chemical alteration in the body with great stubbornness.

Ssaweljew, as we have seen, confirmed the observation of
the present writer that some immunity can be established by
administering doses of adrenin not sufficient to cause death.
But he reports further that he could obtain an immune
serum which was capable of conferring passive immunity
upon a second animal. Stradiotti, employing the " paragang-
liiia Vassale," produced in dogs a serum which could precipi-
tate the " paraganglina " and neutralize its power of vaso-
constriction. Elliott and Durham point out that these results
are not in accordance with expectation, for as yet no instance
has been discovered of the production of an antibody to a
substance of such chemical character as that of adrenin. In
their experiments no trace of an anti-adrenin could be found.

2. The Special Physiological Effects of Chromaphil Tissue
Extracts and of Adrenin

1. The Effects upon the Heart and Arteries. — A new stage
in the history of our subject was reached in the year 1894
by the discovery of Oliver and Schafer that extract of the
medulla of the adrenal bodies produces a very remarkable

166 THE DUCTLESS GLANDS

rise of the blood-pressure on injection into the circulation
of a living animal.

These observers employed glands mainly from the calf,
but also from the sheep, the guinea-pig, the cat, the dog, and
man. The physiological effects noticed were identical in all,
the only difference being in the case of diseased adrenals in
man (Addison's disease), in which case, if the disease were
extensive, no effect whatever was obtained. Extracts of the
glands were prepared with water, with alcohol of various
strengths, with glycerin, with ether, nigroin, and various other
solvents. They were made either by digesting an ascertained
weight of the fresh gland or of the dried gland in these men-
strua, or in addition by boiling the infusion for a few minutes.
The animals experimented upon were chiefly dogs, but some
experiments were also made upon cats, rabbits, and guinea-
pigs, and one upon a monkey. The extracts were usually
administered by intravenous injection, and the effects upon
the arterial system determined by the mercurial kymograph,
various kinds of plethysmographs, and perfusion through the
arterial system of the frog, after the nervous system had been
destroyed.

The chief and fundamental effect noticed was contraction
of the arterioles. This contraction is so great as to produce
(even when concomitant vagus action has caused a great
diminution in the rate and force of the heart's beats) a large
rise of blood-pressure, and, in the case of the frog with its
nervous system destroyed, almost complete cessation of the
flow of circulating fluid through the arterioles.

The usual effect of the injection is to produce constriction
of isolated organs. The limb shrinks (Fig. 39), the kidney
and spleen contract considerably, while the heart and larger
bloodvessels are enormously distended. But sometimes a
limb expands, and in some experiments one limb contracts
while another expands. In the later stages of experimentation
the passive dilatation is more usual. Hoskins, Gunning, and
Berry have recently reported that adrenin causes active
vasodilation of the muscles, while it gives rise to constriction
in the cutaneous vessels. Eemoving the skin from a limb
converts the usual contraction into an expansion. The rise
of blood -pressure is very largely due to constriction of the
splanchnic arterioles. But sometimes the intestine expands

THE ADRENAL BODIES

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(see Fig. 42). In some cases Oliver and Schafer noticed in
organs enclosed by a plethysmograph an apparent struggle
between the diminution in size resulting from contraction of
the arterioles and the expansion due to swelling of the larger
bloodvessels, and some of their curves show a passive dilation
at the beginning of the effect of an injection, followed by a
prolonged diminution in size due to a more marked contraction
of smaller arteries having supervened. The medium -sized
arteries also participate in the dilation.

The contraction of the arterioles occurs in a frog with its
nervous system destroyed, as stated above. It also occurs
after section of the spinal cord and after section of the nerves
going to the limb. Therefore the contraction must be due to
the direct action of the active principle of the adrenal medulla
upon the muscular tissue of the bloodvessels. This question
as to the precise tissues upon which adrenin acts will be referred
to again later on.

The rise of blood-pressure occurs after a certain interval of
latency (twenty seconds in the dog) occupied by the passage
of the extract from the vein into the arteries. The rise takes
place, whether the vagi be cut or not, and whether atropin has
been injected or not. But it is much greater after section of
the vagi or after injection of atropin, because of the concomi-
tant effect of the injection upon the cardiac inhibitory centre
in the medulla (see Fig. 41). The rise is rapid, but only lasts
a few minutes. During the rise the Traube-Hering curves are
abolished, and in the cat and the rabbit the effect of stimula-
tion of the depressor nerve is in abeyance. Sometimes a rise
followed by a fall is obtained, and sometimes a pure fall.
These effects will be referred to again later.

But the rise of blood -pressure is due not only to constriction of
arterioles, but also to increased rate and energy of the heartbeat.

Another striking phenomenon noticed by Oliver and Schafer
was cardiac inhibition through the vagi. Sometimes in the
earlier stages of the action of the extract, the heart, instead of
being augmented and accelerated, is strongly inhibited. When
the vagi are cut or atropin administered, this effect is abolished,
and the constriction of the arterioles, combined with the aug-
mentation of the heart, produces an enormous rise of the blood-
pressure. The cardiac inhibition is of central origin, but the
augmentation is due to the direct action on the heart. Some-

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times the inhibitory effect is shown only after a few minutes.
The effects obtained with the isolated frog ventricle were less
striking than those in mammals.

Finally, it was proved by these authors that extracts of
the cortex of the gland are quite inactive, the active principle
being confined strictly to the medulla. Their general conclusion
was that the medulla of the adrenal secretes a material whose
action is to increase the tone of all muscular tissue, and espec-
ially that of the heart and arteries.

>••'••'•'•"••• • •' "ff< '

FIG. 41. — Tracing showing the effect of adrenalin after previous administra-
tion of a dose of atropin. Dog, 15 kilogrammes. Ether and morphine-
Lower curve is that of the carotid blood-pressure, upper one the volume
of the left hind-limb.

The work of Oliver and Schafer was confirmed in its main
outlines by Cybulski and Szymonowicz. The Polish physio-
logists independently observed many of the same phenomena,
and brought corroboration of many of the observations.
But in some details and upon one important point they
obtained different results ; they considered that the extract
produces its vasoconstriction effects not peripherally, but
centrally upon the medulla. This was, as has been proved
by all subsequent investigations, an erroneous conclusion.

171

172 THE DUCTLESS GLANDS

As we have already seen, the effects can be induced in an
animal from which the central nervous system ha", been
completely removed.

So far as the haemodynamic effects of adrenal extracts are
concerned, the papers of Oliver and Schafer gave an accurate
account of all the fundamental facts, and there is little or
nothing to add to their account up to the present time.

It had been shown by Gourfein and by Cybulski that adrenal
extract in sufficient dose paralyzes the vagus (see Figs. 39 and
43). This was confirmed by Langley. The paralysis is brief.
In the cat 5 to 10 c.c. of 1 per cent, extract of dried adrenal
cause, as a rule, paralysis for from thirty seconds to one or
two minutes. When a dose is given a little short of that
required to make stimulation of the vagus ineffective, the
respiratory curves disappear, and there is a gradual fall of
pressure. This result is probably due to weakening of the
heart-beat without much variation in rate.

According to Oliver and Schafer, injection of extract in the
dog after section of both vagi causes only quickening of the
heart-beat. In the cat Langley found that after section of
the vagi adrenal extract sometimes causes quickening only,
but that sometimes the rate is irregular, and in one case the
heart stopped for three minutes. The slowing, when it occurs,
is, Langley thinks, due to the increased work thrown upon the
heart ; whether the action is entirely direct on the heart muscle
or is partly due to a post-ganglionic axon reflex, there is hardly
sufficient evidence to show, but the slow beats caused by the
extract are fewer or absent after injection of nicotine, although
the rise of blood-pressure is commonly higher.

As pointed out by Oliver and Schafer, the extract does not
act equally on all the arteries ; its effect is perhaps greatest
upon those of the splanchnic area, and its action in general
runs parallel with the action of the sympathetic nerves on the
bloodvessels. Thus, injection of adrenal extract causes great
pallor of the uterus and but little of the bladder. It has a
strong action on all skin arteries and on all medium-sized
arteries in the body. In the abdominal viscera its effect is
great on the main branches of the cceliac and superior
mesenteric arteries.

The primary effect of adrenal extract on the vessels of the
submaxillary gland is constriction. The gland becomes pale

174 THE DUCTLESS GLANDS

and remains so for thirty seconds. Then it becomes flushed,
and the flushing lasts longer than the secretion caused by the
injection. The pallor is not so great as that produced by
stimulating the cervical sympathetic, nor is the flushing so
great as that produced by stimulating the chorda tympani.
Both of these nerves have their usual action on the blood-
flow, if stimulated while the secretion is going on.

In the dog pallor of the bucco -facial region is produced by
adrenal extract. This is the effect produced by weak stimula-
tion of the cervical sympathetic (Langley).

Brodie and Dixon were unable to obtain evidence of con-
striction of the pulmonary vessels on injection of adrenalin,
and thought this was because the pulmonary arterioles possess
no vasomotor nerve-supply. (Adrenalin, they considered, acts
on the nerve endings.) Plumier, using larger doses, succeeded
in getting a positive result — that is to say, he recorded some
constriction of the pulmonary vessels on injection of adrenalin ;
but, according to Schafer, the action is far less than upon the
sympathetically innervated vessels.

It was stated by Spina that the injection of adrenal extract
causes reddening of the brain, so that the peripheral vessels
were not constricted, but Wiggers, using the isolated dog's brain
and perfusion with Locke's fluid containing adrenalin, has
been able to observe a diminution of the outflow of fluid, from
which he concludes that the brain possesses vasomotor nerves,
and that adrenalin acts on the ends of these. As for the
coronary vessels, it is usually stated that adrenin does not
constrict these. Schafer correlates this with the absence of
vaso-constrictors from the cardiac accelerators, and concludes
that, with both forms of excitation, quickening of the flow
through the coronaries was brought about. It may be sup-
posed, however, that heart muscle is dilated by adrenin just
as skeletal muscle is. Elliott suggests that in the beating heart
such an action cannot be dissociated from a possible secondary
dilatation by metabolites from the increased work of the heart
muscle. He states that when perfusing a strip of the cat's
ventricle by a single coronary artery he has seen almost instant
increase of flow after addition of adrenalin to the Locke's
solution used. This occurred with a strip that did not beat,
and therefore independently of muscular metabolites. Langen-
dorff has recently immersed strips of the vascular wall attached

THE ADRENAL BODIES 175

to a lever in adrenalin solution ; he states that whereas strips
from the arteries so tested contract when adrenalin is brought
in contact with them, a strip from a coronary artery will become
relaxed, and he infers from this that adrenin produces inhibi-
tion and therefore vasodilation. Langendorff points out that
from a teleological standpoint this is advantageous ; since
the adrenin increases the force of the heart-beat, it must be
favourable for this action that the calibre of the vessels in the
heart- wall becomes increased. Schafer has, however, not
succeeded in obtaining the result described by Langendorff,
and suggests that possibly there might have been some other
substance than adrenin in the solution used. According to
some recent experimental investigations carried out by Bar-
bour and Prince, adrenin actively dilates the coronary vessels
in the dog, cat, rabbit, ox, sheep, and pig, but constricts them
in man and the monkey.

Moore and Purinton recorded a, fall of blood-pressure instead
of a rise when very small doses of adrenal extract are adminis-
tered. Other authors have from time to time made reference
to a depressor constituent of the adrenal. This is not to be
wondered at when we remember that, as first noted by the
present writer, extracts of tissues generally lower the blood-
pressure ; but the presence of a depressor constituent will not
explain the result obtained by Moore and Purinton, for there is
no apparent reason why the depressor effect should not be
swamped by the pressor with small, just as with larger, doses.
Pari finds that with freshly prepared extracts there is never a
lowering of the blood-pressure, but that with very dilute
solutions, which have been kept for some time, this may
sometimes be observed. He suggests, therefore, that the
depression described by Moore and Purinton was due to chemi-
cal changes in the adrenalin in the dilute solution. Pari
supports the view of Hunt, that the depressor substance is
choline. The matter has recently become of considerable
theoretical importance as bearing upon current theories of the
function of the chromaphil tissue (see p. 216). Sometimes one
obtains, after a preliminary rise, a fall of blood-pressure, even
with moderately large doses of adrenin. This occurs espe-
cially in my experience with certain commercial preparations
when the blood-pressure is high before the adrenin is admin-
istered . The fall of blood-pressure with small doses is admitted

176 THE DUCTLESS GLANDS

by many workers as a regular phenomenon. It is found that
the splanchnic arteries are constricted while the peripheral
are dilated with very small doses. But with such doses the
dilation of the peripheral vessels begins earlier and lasts longer
than the constriction of the splanchnic. The result is that the
splanchnic rise is masked by the peripheral fall (Hartman).

It has been mentioned above that the " paired suprarenal
bodies " of Elasmobranch fishes yield an extract which pro-
duces the same physiological effects as adrenal medulla. In
1898 Langlois showed that the adrenals of the frog (which
contain masses of chromaphil cells) contain an analogous sub-
stance and are functionally homologous with the glands of
higher vertebrates. Biedl and Wiesel proved that the ' ' Neben-
organe " of Zuckerkandl contain the active substance. The
present writer has further shown that the " abdominal chroma-
phil body " of the dog also contains the pressor substance,
and Fulk and Macleod that the retroperitoneal tissue of various
animals contains substances having the same effect on intes-
tinal and uterine muscle as adrenin. Mulon has raised the
blood-pressure of an animal by injection into the circulation
of an extract made from the carotid body of the horse (which
body was shown by Stilling to contain chromaphil cells). It
seems clear, therefore, that all chromaphil tissues, whether
contained in the adrenal or not, yield adrenin, or a substance
having similar chemical and pharmacodynamical properties.1
How far this conclusion may be adduced, in conjunction with
other observations, as evidence of an internal secretion on the
part of all these tissues, is a matter for subsequent considera-
tion (see p. 237).

A pathological effect which has been noted by Josue as a
result of repeated injections of adrenin into the auricular vein
of the rabbit is a degenerated condition of the wall of the larger
arteries, especially of the aorta (arterio-sclerosis). Atheroma,
calcification, and even aneurisms are also described, and the
changes have been recorded in the pulmonary and other
arteries. It is said that these effects are not peculiar to
adrenin, but are produced by other blood-pressure raising

1 Of course, this conclusion is based upon the provisional assumption that
" chromaphil " tissues are specific in their nature, and are everywhere of the
same essential character. It is not out of the question, however, that there
may be some cells which stain brown with bichromate, which are, nevertheless,
of a different character.

THE ADRENAL BODIES 177

substances, such as digitalin and nicotine. According to
Elliott, " mechanical strain is doubtless the cause of the athero-
matous lesions which develop after repeated intravenous injec-
tions. These occur in the coronary arteries which are not
contracted by adrenin, and must, therefore, be widely distended
in the general rise of blood-pressure " (see p. 175). But
Batty Shaw is of a different opinion. He states that if adrenin
is injected with an amount of amyl nitrite which is just capable
of neutralizing its pressor effects, arterial disease identical with
that produced by adrenin alone is manifested — in other words,
adrenin produces its effects not because of its pressor ten-
dency, but from some other much more subtle influence.
" We have no experimental grounds for believing that persist-
ence of any stimulus should at length lead to degeneration
instead of hypertrophy of the middle coat."

Braun described the degenerative changes in the arteries
in considerable detail, but Kaiserling does not attach much
importance to the effects so far as the rabbit's aorta is con-
cerned, because, he says, such changes sometimes occur in
rabbits not treated with adrenin. Etienne and Parisot have
come to the conclusion that elevation of the blood-pressure is
not in itself sufficient to induce atheroma. This effect is of a
toxic nature.

Klotz has recently made the important observation that, by
periodic suspension of rabbits for a few minutes daily by the
hind-legs most advanced aortic lesions can be induced, while
Biedl and Braun record typical degenerative changes in the
aorta and its branches, as a result of repeated compressions
of short duration. The experiments which have been per-
formed up to the present time do not enable us to decide what
is the precise actual cause of the arterial changes after repeated
injections of adrenin. There seems no reason why both the
principal causes alleged — viz., a toxic action and a mechanical
strain — should not both have a share in the production of the
result.

2. The Effects on other Structures, and the Mode and Seat
of Action of Adrenin. — Oliver and Schafer investigated the
effects of adrenal extracts on the respiration of the rabbit and
the dog. Similar results were obtained in both, but the effect
is most marked in the rabbit. It occurs soon after the adminis-
tration of the drug, and may result in arrest of respiratory

12

178 THE DUCTLESS GLANDS

movements for a short time. More commonly, however, there
is produced a shallowing of the respirations, which persists for
a certain period and then gradually passes off. In the dog no
stoppage of respiration was ever obtained, but the respirations,
although proceeding with an ordinary rhythm, were for a
time slightly shallower. Other observers have also noted this
effect of adrenal extracts upon the respiration. It is nearly
always most marked with the first injection ; with repeated
injections the effect as a rule soon becomes trivial, and always
becomes so if the injections are repeated a sufficient number
of times. The subject has been recently investigated by
Langlois and Garrelon. These authors seem to have obtained
very considerable effects in the case of the dog ; they report
that if adrenalin be injected into a dog, expiratory apncea
sets in simultaneously with the beginning of the rise of
blood-pressure. The duration of this apncea is not constant.
In most cases the respiratory movements begin again while
the blood-pressure is still very high, and the respiration has
most frequently returned to its regular type before the blood-
pressure has returned to normal. If the injections are repeated
in rapid succession, the influence disappears. After section
of the vagi, the adrenalin injection has a much less marked
action on the respiration. There is then a slowing of the
movements, but no apnoaa. Air rich in oxygen favours the
occurrence of this apnoea, while an atmosphere with a large
proportion of carbon dioxide hinders it.

Oliver and Schafer discovered that adrenal extracts prolong
the curve of contraction of the skeletal muscles, both in the frog
and in the dog, though the period of latency is not increased.
They were convinced that the curve is not a fatigue curve, but
that it is comparable rather to the effect of a slight dose of
veratrine. This effect has since been noted by many observers.
Boruttau says that the phenomenon occurs in excised curarized
muscle, and reminds one of the first stage of fatigue. Panella
describes an anticuraric action of adrenin (" hemostasine ")
and states that it (" myosthenin," on this occasion) increases
the activity of fatigued striated muscles. Cannon finds that
the improvement of muscular contraction which apparently
results from adrenal secretion (when the blood-pressure is
controlled) is too slight to account for the increased muscular
power observed during excitement. The main source of power

THE ADRENAL BODIES 179

under these conditions is probably to be found in an immensely
augmented activity of the nervous system. Fatigued muscles
may however be prepared by secretion of adrenin for better
responses to the demands of powerful nervous discharges.
Adrenin improves muscular contraction by its specific effect
on the muscle in eliminating fatigue and by improving the
circulation through the muscle by means of its vaso- dilator
action. Notwithstanding all this, it is difficult to demonstrate
that there is in reality any beneficial effect of adrenin on
voluntary muscular contraction.

Lewandowsky found that intravenous injection of adrenal
extracts produces dilatation of the pupil, withdrawal of the
nictitating membrane, protrusion of the eyeball, and slight
opening of the eyelids. The last two symptoms are usually
less marked than the action on the pupil and the nictitating
membrane. The effects produced on the smooth muscle of the
eye and the orbit are, in fact, the same as are called forth by
stimulation of the cervical sympathetic. There is a short
latent period, and the effects usually last some minutes, the
period of duration being prolonged by cooling the animal.
The action is peripheral, although local application to the eye
is without effect. The experiments were performed upon cats.
The same observer also recorded excitation of the arrectores pili
and inhibition of the bladder.

Boruttau confirmed the observation as to the occurrence of
dilatation of the pupil on intravenous injection of adrenal
extract, and observed that in the cat subcutaneous injection
produces no effect upon either the blood-pressure or the pupil.
This writer further recorded that the injection causes inhibition
of intestinal movements.

Lewandowsky pointed out that the extract is still effective
after the superior cervical ganglion has been excised, and the
nerve fibres proceeding from it allowed to degenerate. He
concluded from this that the extract must stimulate the muscle
substance directly, and not by means of the nerve endings.

Langley confirmed this observation of Lewandowsky, and
agrees that the various eye effects are produced by a direct
action of adrenal extract on the unstriated muscle. This
author also found that the extract excites the salivary and
lachrymal glands, the liver, the muscular tissue of the uterus and
vagina, of the vas deferens, the vesiculce seminales3 thedartos, and

180 THE DUCTLESS GLANDS

the muscular coat of the stomach. In the stomach inhibition of the
muscular movements is produced . The effects on the movements
of the intestine appear to differ according to the strength of the
adrenin solution just as do the effects on the uterus and the
pupil, and, as we have seen above, the effects on the blood-
pressure. According to Langley, the effects produced by
adrenal extract in the cat and rabbit may be arranged roughly
in the following order as regards the amount of extract required
per body weight to produce an obvious effect :

Rise of blood- pressure.

Inhibition of the sphincter of the stomach and of the intestine (rabbit).

Inhibition of the bladder.

Dilation of the pupil (cat).

Withdrawal of the nictitating membrane (cat) \ Slightly less readily than the

Separation of the eyelids (cat) J foregoing.

Contraction of the uterus, vas deferens, seminal vesicles, etc. (rabbit).

Salivary and lachrymal secretion.

Inhibition of the stomach.

Inhibition of the gall-bladder and increased bile secretion.

Dilation of pupil (rabbit).

Inhibition of internal anal sphincter (rabbit).

Contraction of internal anal sphincter (cat)

Contraction of

: internal anal sphincter (cat) ) _
internal generative organs (cat) } Effects relatlvely sllght'

Contraction of the muscles of the hairs.

Contraction of tunica dartos of scrotum |NQ certain effecfc
Secretion of sweat

Langley divides the autonomic nervous system into
sympathetic, cranial, sacral, and enteric, and points out that
the effect of adrenal extract in no case corresponds to that
which is produced by stimulation of a cranial autonomic or of
a sacral autonomic nerve. On the other hand, the effects
produced are almost all such as are produced by stimulation by
some one or other sympathetic nerve. Notwithstanding this, he
is inclined provisionally in his paper written in 1901 to favour
the view that adrenin acts directly on muscle fibres and gland
cells, but leaves unanswered the question as to why the action
in the several cases should correspond so closely with that
caused by stimulation of the sympathetic nerves.

Apocodeine abolishes the effects produced by sympathetic
excitation, and was found by Dixon to abolish those produced
by adrenin. He therefore concluded that adrenin acts upon

THE ADRENAL BODIES 181

sympathetic nerve endings. It has been shown that in
Mammalia, if the vagi have first been paralyzed with atropine,
adrenal extract produces an augmented systole and acceleration
of the heart. Both of these effects of adrenin may be abolished
by the injection of large doses of apocodeine. Thus, Dixon
found that in a cat £ c.c. of a 1 in 30,000 solution of adrenin
increased the heart-rate from 92 to 211 per minute. After
the injection of 100 milligrammes of apocodeine the same
injection of adrenin now only increased the rate from 93 to
101 per minute. A further injection of 200 milligrammes of
apocodeine was then administered, and caused the rate of the
heart to diminish to 87 per minute. Adrenin now, even in
large doses, produced no acceleration, and there was no augmen-
tation of the systole. Dixon therefore concludes that the
whole effect of adrenal extract on the heart is a stimulation of
the sympathetic nerve endings. Similarly, the vasomotor
nerve endings are paralyzed by apocodeine, and after the
administration of this drug no vasoconstriction can be induced
by means of adrenin.

The addition of adrenin to any of the ordinary perfusion
fluids enables the heart to maintain its activity over much
longer periods of time. The time may be quadrupled by such
addition (Burridge).

This view, that adrenin acts on nerve endings, is supported
by the observations of Macfie, who found that extracts of the
adrenal and other tissues are without effect upon the embryonic
heart, upon leucocytes, and upon cilia. Again, the work of
Brodie and Dixon, who find that there are no vasomotor nerves
for the pulmonary arterioles, and that adrenin, when perfused
through the pulmonary vessels, produces no constriction, is
decidedly in favour of the theory that the substance acts upon
jierve tissue only.

On the other hand, Boruttau considers that the action is
direct on somatic muscle, since it occurs in curarized muscle,1
and, according to Lewandowsky, the dilation of the pupil and
other eye effects are produced by a direct action of adrenal
extract on the constricted muscle. This was inferred from the
fact, referred to above (p. 179), that the extract is still effective

1 It does not follow, of course, that, because a curarized muscle cannot
be excited through its nerve, therefore the whole of the nerve endings are
paralyzed.

182 THE DUCTLESS GLANDS

after the superior cervical ganglion has been excised and the
nerve fibres from it have degenerated. With regard to somatic
muscle, Langley is inclined to accept Lewandowsky's view,
while in the matter of plain muscle he is content (in the paper
of 1901-02) with the generalization that the effect of adrenin
is the same as the effect of exciting the sympathetic nerves
supplying the particular tissue.

In studies on the action of adrenin on the bloodvessels of
the rabbit's ear Meltzer and Auer showed that section of the
sympathetic has a marked effect on the results of intravenous
injection of the drug. While on the normal side the constric-
tion of the vessels reaches its maximum in a few seconds, on
the side of the section it lasts a very long time, and is very
pronounced. Following up the discovery of Lewandowsky
(confirmed by Boruttau and Langley), that intravenous
injection of adrenin induces a temporary dilation of the pupil,
Meltzer and Auer found that, though subcutaneous injection
and conjunctival instillation produce no effect in the normal
animal or after section of the cervical sympathetic, yet such
administration produces very striking dilation of the pupil
after removal of the superior cervical ganglion — that is to say,
"the paradoxical effect" is marked in the case of adrenal
extract.1

These observations were confirmed and extended by Elliott,
who generalized as follows : " This, then, is true for all the
muscles thrown into contraction by adrenalin, that after
decentralization — i.e., degenerative section of the preganglionic
sympathetic nerves — and still more clearly after denervation
(degenerative section of the post-ganglionic sympathetic
nerves), they contract in the presence of adrenalin alike with
greater irritability and persistence." Elliott concluded as to
the localization of the action of adrenin that the excitation
must be due to some substance within the muscle fibres being
affected by the drug, and suggested that this substance is
present at the " myoneural junction," where it is originally
formed.

1 Meltzer and Auer point out an important difference between mammals
(rabbits and cats) and the frog. In the latter animal in a normal state,
subcutaneous injection or instillation into the conjunctival sac produces in a
few minutes a characteristic dilation of the pupil, which may last for hours,
so that the frog has become a convenient means of testing adrenal extracts.

THE ADRENAL BODIES 183

Schafer adds a further suggestion — viz., that the formation
of this substance, being once started, its amount is also con-
trolled by the sympathetic, and if this control be cut off an
inordinate quantity may accumulate, thus increasing the
excitability of the isolated muscle fibres. The observations
of Macfie (see above, p. 181) prove that the presence of
nerve fibres is essential to the original appearance of such
hypothetical excitable substance.

These different views do not accord very well together, but
the fact that adrenin has functionally a very intimate relation
to the sympathetic nervous system is particularly interesting
when we remember the accepted origin of the chromaphil
tissues.

According to recent observations by Langley, in all cells
two constituents at least must be distinguished : (1) Sub-
stances concerned with carrying out the chief functions of the
cells, such as contraction, secretion, the formation of special
metabolic products ; and (2) receptive substances, especially
liable to change, and capable of setting the chief substance in
action. According to this author, the active substance of the
adrenals produces its effects by combining with the receptive
substance, and not on nerve endings nor the chief substance.
So that in this view the controversy as to whether adrenin
acts on muscle itself or on sympathetic nerve endings is com-
promised by assuming that there is some material in cells
originally under control of the sympathetic, which material is
specially excited by adrenin.

This theory of Langley has not, however, been universally
accepted. There is some evidence which tends to show
that after all adrenin acts directly upon the smooth muscle.

Among the other effects of adrenin which have been noted
are increase of intra-ocular pressure after intravenous injection,
and changes in the structure and function of the kidneys.
Bardier and Frankel record a diminution of secretion of urine
owing to constriction of renal vessels after the administration of
adrenin. Subsequently and more significantly the conditions
are reversed. Adrenin mydriasis has been employed as a
diagnostic sign of increased diffusibility of the cornea. Adrenin
appears to increase the activity of ansesthetics applied locally
to a nerve. It is said that adrenin gives rise to increased flow
from the thoracic duct as long as the blood-pressure is high.

184 THE DUCTLESS GLANDS

It has been stated recently that rhythmic contractions of
arteries occur normally in the rabbit's ear and that adrenin
augments these contractions.

There seems to be considerable difference of opinion as to the
effect of adrenin on the secretion of sweat.

Redfield suggests that the melanophores of the amphibia
are controlled by adrenin in the circulation.

Cats appear to be peculiarly liable to collapse after intra-
venous injection of adrenin under light chloroform anaesthesia.
Full chloroform anaesthesia appears to be absolutely protective.
There is probably some unknown condition of the heart under
the influence of low percentages of chloroform, which renders
it incapable of accommodation to vascular strain.

In the experience of the present writer, also, it has very
frequently happened that dogs have been killed by a dose
of adrenin (administered intravenously) which it was expected
would only be sufficient to produce a moderate rise of blood-
pressure. This has occurred with both adrenal extracts and
the purified adrenin, and it is not clear that it is dependent
on the nature or amount of the anaesthetic employed. The
phenomenon seems to depend upon a peculiar idiosyncrasy in
some animals, and is comparable to what was found in respect
of the general effects produced in various animals by sub-
cutaneous injections (see p. 159).

A large amount of work has been carried out upon the
antagonism between adrenin and various other drugs. In
many respects there appears to be a true antagonistic action
between adrenin and calcium chloride, although the latter
substance does not hinder the production of adrenin arterio-
sclerosis. Adrenin is also stated to act as an antidote to
poisoning by strychnine, aconitine, and belladonna. A
pharmacological antagonism is alleged between adrenin and
secretin, while adrenin exercises no action which can be
regarded as antagonistic to that of albumoses and of pilocarpine
upon the pancreatic and salivary secretions. It is stated
that the chlorides of calcium, barium, magnesium, and potas-
sium can neutralize the mydriatic action of adrenin.

The table on pp. 187-191, taken from Biedl, gives a summary
of the chief actions of adrenin and a comparison between these
actions and those produced by stimulation of nerves belonging
to the sympathetic and autonomic systems.

THE ADRENAL BODIES 185

Notwithstanding the almost universal acceptance of the
view that the action of adrenin is identical and co-terminous
with that of sympathetic nervous action, it is well to bear in
mind that the evidence is in some directions contradictory and
in others rather meagre. As will be seen from the table it is
by no means easy to formulate an absolute parallelism in every
instance, and the difficulty becomes still greater if we take into
consideration the different effects of varying doses of adrenin.
The parallel problem as to the effects of varying degrees of
stimulation upon the sympathetic fibres does not seem to have
been worked out.

M. The Chemical Nature of the Active Substance of
the Adrenal Medulla and other Chromaphil Tissues

It is one of the greatest triumphs of physiological chemistry
that within seven years of the discovery of the powerful effects
of extracts of the adrenal medulla, 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 product can
now be obtained from the manufacturing chemists.

In 1856 Vulpian described a powerfully reducing substance
in the medulla of the adrenal body. This material was found
to give various colour reactions on being oxidized — e.g., with
ferric chloride it gave a dark green or blue colour, and with
chlorine, bromine, or iodine water or caustic alkalies a rose red.
Several authors attempted, but without success, to isolate the
" chromogen " of the gland from a lead precipitate. They all
obtained decomposition products. Krukenberg, however,
established the important fact that the adrenal chromogen, in
regard to certain properties (iron reaction, reducing power,
production of a dark coloration with oxidizing agents), corre-
sponds with pyrocatechin.

Immediately after the publication of the discovery of the
pressor action of adrenal extracts, Moore concluded that the
active substance is identical with the chromogen described by
Vulpian.

Frankel, by treatment of adrenal extracts with alcohol,
acetone, and ether, obtained a syrupy preparation of great
physiological activity. This was the first claimant to the

186 THE DUCTLESS GLANDS

title of the isolated active principle of the medulla of the
adrenal body. It was called " Sphygmogenin." l Frankel was
also able to show that the chromogen furnishes a benzoyl
product insoluble in water, and contains nitrogen in stable
combination. This author was the first to express the opinion
that the pressor substance is a nitrogenous derivative of
orthodihydroxy -benzene. The statement that from it pyro-
catechin could be obtained simply by boiling with hydrochloric
acid was easily refuted. V. Fiirth, on the other hand, showed
that by dry distillation of the chromogen a compound is
obtained which, as regards its reaction towards iron salts
(emerald green coloration, which on the addition of alkali
becomes carmine red) and its solubility (in ether, whether out
of acid or alkaline solution), corresponds with pyrocatechin.

With a view to the isolation of the extraordinarily unstable
and easily oxidizable active substance, v. Fiirth extracted with
alcohol at a low temperature ; then, after getting rid of inactive
substances by means of neutral lead acetate, threw down a
precipitate with ammoniacal lead hydroxide. By decomposing
with sulphuric acid, concentrating the filtrate in vacua and in
a stream of carbonic acid gas, extraction of the residue with
alcohol, and precipitation with ether, the chromogen was
obtained in the form of a slightly pigmented precipitate which
was extremely active physiologically.

Turning to account an observation by Hofmeister that by
reduction of the adrenal extract with zinc dust in acid solution
one could counteract to a certain extent the instability of the
chromogen, v. Fiirth made use of the following improved
process : The adrenals were extracted with dilute zinc sulphate
solution, the extracts freed from protein by heating, and treated
with excess of ammonia, by which means the chromogen was
thrown down as a zinc compound. This was washed, decom-
posed in a mixture of alcohol and sulphuric acid, the acid
filtrate decolorized by means of heating with zinc dust,
neutralized with zinc oxide, filtered hot, freed from zinc salts
by means of alcohol and ether, and finally concentrated. The
process was also varied by using ammoniacal lead hydroxide
instead of the zinc compound. The amorphous pyrocatechin-

1 No chemical criteria of the purity of this substance were given. Frankel
did not show that it possessed a constant percentage composition, and no
attempt was made to establish even an empirical formula for it.

THE ADRENAL BODIES

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like substance obtained by these methods was precipitable
from alcoholic solution by means of ether. In the state of
solution preserved in sealed tubes it showed considerable
stability, and possessed a high degree of physiological activity.
A dose of 0-000025 gramme raised the blood-pressure of a rabbit
to nearly double its original height. At a later date Abel made
a comparison between a preparation obtained by the above
lead process and the crystalline adrenalin obtained by Taka-
mine's process (vide infra). The test was a double one. On
the one hand a colorimetric estimation of the iron compound
was made, and on the other hand the relative effect upon the
blood-pressure was noted, and in neither case was v. Furth's
substance shown to be weaker than that of Takamine.1 Von
Fiirth called his substance " Suprarenin"

Abel and Crawford converted the pyrocatechin-like substance
into a benzoyl compound, and observed after saponification
by addition of alkali a smell like that of coniine or pyridine.
Furthermore, they made the very important observation that,
by distillation of the product with zinc dust in a stream of
hydrogen, pyrrol was obtained, and they arrived finally at the
conclusion that the active principle of the adrenal medulla
belongs to the series of the pyridine bases. This has not been
confirmed by subsequent investigation. Moore came to the
same conclusion, since he observed that if some adrenal extract
be cautiously fused with caustic potash so as to avoid charring,
the peculiar odour of pyridine was at once obtained. But, as
pointed out by Moore in this relation, it is piperidine, and not
pyridine, which has a marked effect upon the blood-pressure.
Moore surmised, therefore, that the active substance is a
piperidine derivative — i.e., that it contains a hydrogenated ring.

V. Ftirth next proceeded to the formation of an iron com-
pound of the active principle. An extract of the glands was
made by boiling with acidulated water with the addition of
zinc dust. The extract was concentrated in vacua, the residue
extracted with methyl alcohol, and the solution, after getting
rid of inactive substances by means of zinc chloride and acetone,
decomposed with chloride of iron and ammonia. The iron
compound of the " suprarenin " separated out in the form of a
carmine-red flocculent precipitate. The substance was then

1 In recognition of this fact the term " suprarenin " is still frequently used,
especially in Germany, for the active principle of the chromaphil tissues,

THE ADRENAL BODIES 193

repeatedly dissolved in dilute ammonia, and precipitated by
means of acetone, and the final product was extremely active
physiologically, though not yet chemically pure. Analysis
indicated that the suprarenin probably contained C 8-9,
H 11-13, 0 3-4 per cent.

Abel came td essentially different conclusions as to the
chemical nature of the active substance. This worker
benzoated adrenal extracts, saponified the purified benzoyl
product in the autoclave at a pressure of 3 to 5 atmospheres
with dilute sulphuric acid, and precipitated with dilute
ammonia or picric acid from the solution so obtained a
substance which he called " Epinephrin," which he considered
was the isolated active principle of the adrenal medulla. It
yields picrates and other salts, and is a substance of an
alkaloidal nature, having the elementary composition
017H15N04. V. Fiirth has shown that Abel's epinephrin is
quite a different substance from his own suprarenin, that the
former possesses in itself no physiological action, and that
whatever physiological effects may be induced by its adminis-
tration are due to admixture with suprarenin. Epinephrin is
also distinguished from suprarenin by its precipitation by
means of precipitants of alkaloids (phosphotungstic acid, picric
acid, tannic acid, etc.), by zinc chloride, by the absence of
reducing power, and the absence of the colour reaction with
perchloride of iron. Its separation from suprarenin can
conveniently be effected by careful neutralization of the acid
solution with very dilute ammonia, by which means the
epinephrin separates out as a dark flocculent precipitate easily
soluble in excess of ammonia.

Abel has since shown that epinephrin is to be looked upon
as a derivative of suprarenin arising as a result of the treat-
ment with acid in the autoclave. The fact that a methylindol
is obtained by fusing epinephrin with potash must be regarded
as of importance in explaining the constitution of suprarenin.
Abel has suggested the possibility that by the autoclave
treatment a portion of the nitrogen is split off from the supra-
renin molecule. This view has been confirmed by v. Fiirth,
Afterwards, however, Abel was inclined to believe that by
treatment of the benzoyl product in the autoclave saponification
was not complete, and the resulting substance was still a
benzoyl product (C17H15N04) ; epinephrin would therefore

13

194 THE DUCTLESS GLANDS

be a monobenzoyl-suprarenin (C6H5CO) C10H10N03; to sup-
rarenin itself must then be allotted the formula CloHnNOg.

The next important step was the production of the active
substance in a crystalline form. This was effected by Taka-
mine and Aldrich independently. The method in both cases
was the same. Very concentrated adrenal extracts were
largely freed from inactive substances by treatment with
alcohol, lead acetate, etc. ; then the active substance was
precipitated in the form of microscopic crystals by the addition
of concentrated ammonia. The precipitate was then purified
by repeatedly dissolving in acid and reprecipitating with
ammonia. The resulting prismatic needles or rhombic plates
were those of the purified and isolated active principle —
adrenalin.

According to v. Fiirth, a careful comparison of the com-
position and physiological action of adrenalin with those of
his suprarenin indicates that they are one and the same sub-
stance. He has decomposed the " suprarenin " iron com-
pound with sulphuric acid and thereby obtained "adrenalin"
in crystalline form.

All the authors quoted have obtained different analytical
results and suggested different formulae. Aldrich suggested
from his analyses the formula C9H13N03, Takamine
C10H15N03, and Abel C10H18N03 + |H20. The empirical
formula of Aldrich is now generally accepted, and from the
combined researches of v. Fiirth, Jowett and Pauly, the con-
stitutional formula is regarded as —
OH

. CH (OH) . CH2 . NHCH3

That is to say, adrenalin is therefore ortho-dioxyphenyl-
ethanol-methylamine and is related to tyrosin — p-oxyphenyl-
amino-proprionic acid.

If adrenalin be oxidized, we get a substance having the

formula :

HO

\—

S

C . CH . NHCH3.

|
o

This substance, adrenalon (methyl-aminoacetylpyrocatechin)
has been prepared synthetically by Friedmann, Stolz, and

THE ADRENAL BODIES 195

Dakin. The reduction product appears to be chemically iden-
tical with adrenalin in all respects except that it is optically
inactive, while the natural body from the adrenal medulla is
laevorotatory (aD = 43°) according to Pauly.

On testing the physiological action of the synthetic (racemic)
adrenalin and comparing it with that of the natural adrenalin,
Cushny found that the latter acts twice as strongly on the
blood-pressure as the former. From this he inferred that
dextro-adrenalin is devoid of any physiological activity.
Adrenalin thus proves analogous to hyoscyamine and hyoscine,
in which the dextrorotatory form is almost devoid of the
specific action of the natural laevorotatory alkaloid on the
peripheral tissues.

Flacher recently succeeded in dividing the racemic suprarenin
or adrenalin into its two optically active components. These
have been subjected to a pharmacological examination by
Cushny. The synthetic ^-adrenalin was first compared with
natural adrenalin isolated from the glands, and was found to
be identical with it in its power of raising the blood-pressure.
The d-adrenalin was next compared with these and found to
possess one-twelfth to one-fifteenth of their action — that is,
twelve to fifteen times as much of ^-adrenalin was required to
raise the blood-pressure to a definite degree. The earlier
statement of Cushny that the laevorotatory alkaloid is twice as
strong as the racemic is thus seen to be practically correct,
these later experiments showing that a closer approximation
would put the relative strengths between 24 : 13 and 30 : 16.
Cushny found further that the doses necessary to cause
glycosuria are similarly in the proportion of 12 to 18 : 1. The
minimal lethal doses as tested by subcutaneous injection appear
to bear the same relation. No evidence was obtained suggest-
ing that adrenalin acts elsewhere than on the receptive
substances of the sympathetic myoneural junction.

We have seen that the terms " epinephrin," ".sphygmo-
genin," " suprarenin," and " adrenalin " have been applied to
the active principle of the chromaphil tissues. Other names
which have been employed are " hemisin," " paraganglin,"
and " myosthenin." Adrenalin is, however, the term most
commonly used ; but it is advisable to adopt a name which
has no commercial attachments, and Schafer suggests
" adrenin." This term has been adopted in the present work,

196 THE DUCTLESS GLANDS

and is used where reference is not made to some particular
preparation.

In the laboratory adrenin may perhaps be prepared most
conveniently by Abel's method, that is to say, by extracting
chromaphil tissues with 3' 5 per cent, trichloracetic acid in
alcohol, filtering, and adding ammonia. Adrenin is precipitated,
filtered off, and washed with water, ether, and alcohol. A
yield of about 2 per cent, is obtained. A further 1 per cent,
can be obtained by extracting the mass a second time with
trichloracetic acid. It is recrystallized by dissolving in alcohol
with acetic acid and precipitated by ammonia.

Nagai gives the following method for the synthesis of
adrenin : (1) Diacetyl-protocatechuic aldehyde prepared by
the reaction of AcCl or Ac.,0 on protocatechuic aldehyde is
condensed with nitromethane in the presence of weak inorganic
or organic bases ; (2) the resulting diacetyl-dihydroxy
phenyl-initroethanol is reduced in the presence of HCHO by
means of Zn dust and HO Ac ; (3) the diacetyl- adrenalin so
formed is hydrolyzed by HC1, given adrenalin hydrochloride.

It is a colourless crystalline substance, having a melting
point of 211-212° C. It is not easily soluble in cold water,
but more readily in hot. It is insoluble in most organic
solvents such as alcohol, ether, or chloroform. It is a strong
base and is soluble in mineral acids and caustic alkalies, while
it is insoluble in carbonates or ammonia. It is not precipitated
by alkaloidal reagents like picric acid, tannic acid, sublimate,
phospho-tungstic acid, etc. As a phenol it forms water-soluble
compounds with fixed caustic alkalies.

Commercial solution of adrenin chloride is the usual starting-
point in making prescriptions. This solution contains one
part in a thousand of adrenin chloride dissolved in normal
saline solution with about 0'5 per cent, of chloretone. The
solution keeps fairly well if air be excluded.

As it will be more fully stated below (p. 204), adrenin is
widely employed as a drug, and numerous preparations have
been placed upon the market, and manufacturing druggists
have extensively advertised many forms of the pure product.
As pointed out by Schultz, the different preparations vary
greatly in physiological activity — some, even, being worthless.
t lii> being due partly to a lack of care in the process of prepara-
tion, and partly to the nature of the container and solvent

THE ADRENAL BODIES 197

used in bottling the extract. Schultz narrates that in one
instance only 6 grammes of pure adrenalin could be obtained
from a sample supposed to contain 19 '4 grammes of natural
I- adrenalin base. He finds that the ratio of physiological
activity of the natural Z-base and the synthetic dZ-product are
to each other as 2 : 3 instead of 1 : 2, according to Cushny.

The physiological activity of all adrenin-like bodies can be
assayed by the blood-pressure method and their efficiency
expressed in terms of pure adrenin base. Hence, if one has
two solutions, a known adrenin solution, 1 c.c. of which contains
a grammes of the base, and an unknown containing a certain
amount, y, of vasoconstrictor exciting substance, they can
readily be checked against each other by the blood-pressure
method. Whichever solution is the stronger can be diluted
until 1 c.c. injections of it cause the same rise of blood-pressure
as the other, and finally their relative activity calculated by
the following equation :

a adrenin base

. . . — r: — r = relative activity.
y vasoconstrictor excitant

Folin, Cannon, and Denis have described a colorimetric
method for the determination of adrenin. Folin and Denis
had previously described a phospho-tungstic acid reagent
which gives a blue colour with uric acid, and also with poly-
phenol compounds. The method applied to adrenin in solution
reveals the presence of one part of adrenin in three millions of
water. Using a solution of uric acid of known strength for
the colour standard and accepting the proved observation that
adrenin has thrice the chromophoric value of uric acid, it
requires but a few minutes to assay a solution of adrenin.

Schultz has investigated a series of specimens of adrenin sold
under different names by various firms. Of the seven different
brands of " epinephrin " examined, only three possessed an
activity that equalled the standard. The other solutions
varied from 3*75 to 71 per cent, of the required activity. Some
of the solutions were worthless, and perhaps even dangerous.
Certain solutions, though showing a high degree of activity
upon opening the original package, quickly deteriorated in
spite of the extra precautions taken to guard against conditions
known to further this process. This author remarks that, on
the other hand, some of the preparations now upon the market
are of the very highest quality.

108 THE DUCTLESS GLANDS

It has recently been shown that the iodine reaction, the
mercuric chloride reaction, and the bi-iodate reaction are due
wholly or in part to oxidation. Potassium persulphate was
found by Ewins to have a similar oxidizing action upon adrenin,
giving a characteristic red colour. This reaction is stated to
have advantages over those mentioned above both in sensitive-
ness and in being readily obtained with crude extracts of
chromaphil tissues. The mercuric chloride reaction appears
to be due to the oxidation of adrenin by such oxidizing agents
as mercuric chloride, silver nitrate, or platinic chloride under
the catalytic influence of salts of metals with " weak " acids
(i.e., salts which are hydrolytically dissociated by water).
The reaction may be compared with the results which have
been obtained in the investigation of certain " laccases." The
characteristic colour reactions of adrenin are given by certain
other closely related bases — namely, by (a) the amino base,
corresponding to adrenin ; (6) dihydroxyphenylethylamine
and the corresponding methyl, ethyl, and propylamino bases ;
(c) amino-aceto pyrogallol. The bases of the type amino-aceto
catechol do not give these reactions (Ewins).

The physiological action of adrenin, an action simulating
that of the true sympathetic nervous system, is possessed also
by a large series of amines, the simplest being primary fatty
amines. Barger and Dale describe all such amines and their
action as " sympathomimetic." They find, as the result of a
careful investigation, that the more nearly the structure of an
amine approaches to that of adrenin, the more intense and the
more specific is its sympathomimetic action. All the chemical
products which possess this specific action are primary and
secondary amines. The quaternary amines corresponding to
the aromatic members of the series have an action closely
similar to that of nicotine. There are two optimum conditions
of chemical structure in which the action is most pronounced.
The first is a benzene ring with a side-chain of two carbon
atoms, the terminal one bearing the amino group. The second
is the presence of two phenolic hydroxyls in the 3 : 4 position
relative to the side-chain ; when these are present an alcoholic
hydroxyl still further intensifies the activity. A phenolic
hydroxyl in the 1 position does not increase the activity.

As a practical result of these investigations 3 : 4 dihydroxy-
phenylethylmethylamine, one of the most active of the sympa-

THE ADRENAL BODIES 199

thomimetic amines, has been put upon the market and is
advertised under the name of " epinine " ("the synthetic
haemostatic "). It is claimed that this product " possesses the
characteristic physiological action of the extract of the supra-
renal gland, but is superior in that its purity is chemically
controlled, its stability is greater, and the rise of blood-pressure
it produces is more prolonged." According to Burridge,
epinine is capable of altering the reaction of the heart to
calcium salts in a solution perfusing that organ. When the
substance is acting the heart can remain active on a solution
of much lower calcium content than before. If the heart be
perfused with a solution of such low calcium content that the
beats cannot be recorded, the addition of traces of epinine to
the perfusing fluid causes long-continued good contractions.
Epinine can restart beating in hearts inhibited by potassium
salts. Larger doses render the heart less susceptible to certain
actions of calcium.

There are now on the market several other substitutes for
adrenin.

As bearing on the general question of the functions of
adrenin throughout the animal kingdom, attention must be
called to the discovery by Abel and Macht of adrenin in the
poison glands of a tropical toad (Bufo agua). The adrenin-
producing acini are limited to the glandular masses behind the
eye and surrounding the tympanum, known as the " parotoid "
glands, the chromaphil reaction being negative in all other
cutaneous glands. But in these glands there is no true chroma-
phil tissue. The cells themselves do not react to potassium
bichromate, nor does the poison-sac contain chromaphil
material until long after the disappearance of all epithelial
elements. The adrenin is probably the result of a change
produced in a mother substance which is very likely an amino-
acid. Wiechowski could not find adrenin in the glands of the
Bohemian toad, though he describes the secretion as chroma-
phil, that is to say, it is stained brown by salts of chromic
acid. Examples of tissues which give the chromaphil re-
action and yet do not contain adrenin are gradually accu-
mulating.

In Bufo agua we have an example of the external secretion of
adrenin. It is not clear what effect the adrenin has upon the
poisonous activity of the other important ingredient

200 THE DUCTLESS GLANDS

(" Bufagiii ") in the venoin. The crude poison of the toad
contains nearly 7 per cent, of adrenin.

N. The Origin of Adrenin in the Body

Nothing is definitely known of the nature of the parent
substance from which adrenin is derived. It has been sup-
posed that the waste products of muscular metabolism are
converted into adrenin. This view appears to be based upon
results obtained by Boruttau and Langlois upon frogs whose
adrenal bodies had been removed, and which were benefited
by injection of adrenal extracts. The theory would imply the
formation of adrenin from some such substance as creatin.
This is the least probable of the three suggestions.

Abelous, Soulie, and Toujan are of the opinion that adrenin
is manufactured in the cortex from tryptophane.

Halle has suggested that one of the substances from which
adrenin is formed in the organism may be tyrosin, and has
brought forward some evidence for this view. He points out
that adrenin might be produced from tyrosin by (1) introduc-
tion of a hydroxyl group into the benzene ring ; (2) elimination
of C02 from an amino-acid to form an amine ; (3) the methyla-
tion of nitrogen ; (4) the introduction of a hydroxyl group into
an aliphatic chain. He states that when two portions of
emulsion of fresh ox or pig adrenal were taken, to one of them
tyrosin being added, both being kept under aseptic conditions
for six days in an incubator, the sample containing the tyrosin
was found to have from 14 to 33 per cent, more adrenin than
the control.

Gessard imagines a relationship between tyrosin and adrenin,
because both substances become pigmented in a similar manner
by the action of tyrosinase.

The theoretical speculations of Halle would appear to be
open to criticism, as pointed out by Ewins and Laidlaw.
Moreover, the last-named observers were unable to confirm
Halle's experimental results. The matter is by no means
settled, and, although the hypothesis that adrenin may be
derived from tyrosin is not supported by the evidence before
us, yet it would be rash to dismiss this substance from con-
sideration as one of the possible precursors of adrenin in the
animal economy.

THE ADRENAL BODIES 201

0. The Mode of Disposal of Adrenin in the Body

It was found by Oliver and Schafer that adrenal extracts
not only produce a contraction or increase of tone in cardiac
and vascular muscle, but that frogs which had received a
subcutaneous injection show an increased power of contraction
of the skeletal muscles on stimulation of their nerves. This
also applies to mammals, and the effect lasts for some time
after the effects upon the vascular system have disappeared.
It was therefore concluded that the active substance is
probably taken up by, and remains for a time stored within,
muscle, and that this may in a measure account for its
disappearance from the blood. It is not excreted by the
urine, nor is it at once reabsorbed by the capsules. Its
ultimate disappearance is probably due to a process of
oxidation in the tissues. Oxidation of the active principle
does not occur in the blood.

Langlois found that the rate of destruction is proportional
to the activity of the tissues generally. Thus, in hibernating
or cooled animals, the process of destruction is slow. Accord-
ing to the author, destruction of the active principle occurs
throughout the whole body, though chiefly in the liver. The
injection into the mesenteric vein of a dose sufficient to raise
the blood-pressure considerably, if injected into the general
circulation, produces no effect. Athanasiu and Langlois also
found that Frankel's " sphygmogenin," when injected, is
destroyed in the liver. It was also stated that adrenal extracts
are rendered inactive by ozone or other oxidizing agents.

The experiments of Embden and v. Furth show that digestion
of adrenin for two hours with normal blood, laky blood, or
blood-serum, causes a considerable destruction of the active
principle. On the other hand, addition of muscle, liver, or
lung extract to the blood (as also perfusion experiments) causes
a less destruction or none at all. Comparative experiments
with weak alkaline solutions teach that the destruction in the
blood is essentially due to the alkali, and the hindrance to
destruction in the organs to the formation of acid. Neverthe-
less, these authors are not of opinion that the rapid cessation of
action on the vessels is to be attributed to a rapid oxidation ;
they consider, rather, that the contraction of the muscles of

202 THE DUCTLESS GLANDS

the bloodvessels ceases so soon as the concentration of the
adrenal solution by diffusion or dilution with the blood and
tissue fluids sinks to a certain level.

The disappearance of the effect of a dose of adrenin has been
attributed to the alkalinity of the blood. Thus, Kretschmer
finds that if this is diminished by the administration of acids,
the effect of the drug upon the blood-pressure is prolonged.
It is even affirmed that the active substance does not disappear
from the blood, and that the blood of a rabbit which has
received a dose of adrenin will cause the typical rise of blood-
pressure if injected into another rabbit, although the effects
upon the first animal may have disappeared.

The subject of the inactivation of adrenalin and one of the
sympathomimetic amines in vitro and in vivo has recently been
investigated by Cramer, who reports that a solution of adrena-
lin can be completely inactivated by allowing it to stand with a
dilute solution of formaldehyde for a few minutes. " Epinine "
(see p. 199), under similar circumstances, also becomes in-
activated. Pituitrin and the other hormones are not so
inactivated by formaldehyde. It is suggested that the in-
activation of adrenin in the organism is brought about not by
a process of oxidation, but by a combination with a product of
metabolism produced by the cells on which adrenalin has
acted, and that it is a process similar to the reaction in vitro
previously described.1

P. The Proteins, Lipoids, etc., of the Adrenal Bodies

There is nothing very special or characteristic in the proteins
which can be extracted from the adrenal bodies. They consist
of the albumins, globulins, and nucleo-proteins which are found
in animal tissues generally.

The extractives and salts, moreover, do not call for any
special mention.

The subject of the occurrence of choline in animal tissues has
already been sufficiently dealt with (p. 25 et seq.). It is
probable that we are justified in considering that whatever

1 It has been stated that in cases of sudden death the adrenals contain
more adrenin than in cases of gradual death. This observation, if it can be
confirmed, may be of considerable medico-legal importance.

THE ADRENAL BODIES 203

choline may be present in the adrenal bodies is of no special
functional significance.

The lipoid substances contained in the cortex of the adrenal
body are possibly of considerable importance, and their
chemical nature may yet reveal the secretory function of the
cells of this part of the adrenal gland. Their presence in the
cells has been known to histologists and morphologists for a
long time, but attempts to deal systematically with their
chemistry are of recent date. So far as they are involved in
a treatment of the microscopic structure of the adrenal cortex,
they will be discussed in a later section of this work (p. 239).
At this stage it will be desirable to state what is known of these
substances from a more purely chemical standpoint.

According to Frankel, the different organs of the body
contain different lipoids, which are characteristic for each
particular organ. The difference between the lipoids of
various organs on the one hand and the lipoids of the same
organ in different groups of animals vary both qualitatively
and quantitatively.

Biedl has devoted special attention to the lipoids of the
adrenal bodies of the pig. He finds that the glands contain
74-61 per cent, water and 25-39 per cent, of dry substance.
Of this dry substance, 61-12 per cent, consists of protein, and
38-88 per cent, lipoids and extractives. It is pointed out that
since the extracts were made from the whole gland, the cortex
must contain a much greater proportion of lipoids. In order
to prove this point definitely it is proposed to investigate
the inter-renal body (which consists of cortex only) in the
Elasmobranch fishes.

Thus we see that the adrenals must be placed among the
organs richest in lipoids, since a third of the total dry substance
is made up of these materials. Among the definite chemical
compounds recognized by Biedl in the adrenal extracts are
cholesterinpalmitate [C^H^O (C16H310)], the cholesterin
ester of carnaubic acid [C27H45O (C24H470)], and kephalin.

According to Biedl, it appears probable that the cholesterin
esters are specific for each particular organ and perhaps for
each particular species, but not that they are to be regarded
as a definite secretory product of the gland.

204 THE DUCTLESS GLANDS

Q. The Medical and Surgical Employment of Adrenal

Preparations

After the observation of Oliver, that an artery in the frog's
mesentery is contracted by adrenal extract to such an extent
that blood ceases to be driven through it, he began to use
the extract as a styptic in his experimental operations ; its
application for this and similar purposes is now general.

Surgical Employment of Adrenin alone or combined with other
Drugs. — A subcutaneous injection of adrenalin solution (1 in
10,000) produces a bloodless condition of the tissues quite as
readily as the method of bandaging or freezing. If adrenalin
is combined with cocaine for subcutaneous injection, it is found
that the effect of the cocaine is increased and lasts for a longer
time. A combination of adrenalin with eucaine is also found
to be very beneficial. It is stated that the toxic effects of
cocaine are to a certain extent neutralized by the simultaneous
employment of adrenalin.1

Braun has made extensive use of this method, employing
the following solution : 100 c.c. of a 0-05 per cent, solution of
cocaine hydrochloride, using 6 per cent, sodium chloride solu-
tion as a solvent, to which 3 to 5 drops of adrenalin hydro-
chloride (1 in 1,000) are added ; the dose is 50 c.c. to 100 c.c.
The operation may be performed ten minutes after the injec-
tion. The lower part of the rectum may thus be rendered
insensitive, and operations for fistulae or haemorrhoids, or
dilatation of the sphincter, may be performed in a painless
manner. The method may also be used for excision of a piece
of rib, for operations on the scalp, for removal of sebaceous
cysts, for amputation of a finger, etc.

Major operations under spinal anaesthesia produced by 1 in
2,000 adrenalin solution in conjunction with 0-0075 to 0-015
gramme cocaine, have also been performed without ill
effects.

Honigmann uses /?-eucaine instead of cocaine for local
anaesthesia. The use of cocaine and adrenalin combined is
also recommended by several other authors.

1 Novocaine is now frequently employed.

THE ADRENAL BODIES 205

Barker recommends the following formula :

Distilled water . . . . . . . . . . 100 c.c.

0-eucaine . . 0-2 gramme.

Sodium chloride . . . . . . . . . . 0-8 gramme.

1 pro mille adrenalin chloride solution . . . . fl^x.

The actual strength of adrenalin in this solution is one in
two hundred thousand (1 : 200,000). On production of local
and regional anaesthesia by means of this fluid, Barker has
performed the following operations with the most satisfactory
results : (1) Amputation through the knee-joint for gangrene
of the foot due to diseased arteries and diabetes ; (2) abdominal
section and opening of the stomach and jejunum in search of
a source of severe bleeding (not found) ; (3) removal of a cyst
of the thyroid ; (4) Bassini's radical cure of inguinal hernia ;
(5) removal of a silver wire from round the patella.

Equally favourable results are recorded by other surgeons.

Local anaesthesia produced by the combined use of adrenalin
and cocaine, or /?-eucaine, has also been employed in gynaeco-
logical operations besides those involving abdominal section.
The method has been found useful in operations for prolapsus
uteri and plastic operations on the vagina ; owing to the
anaemia produced by these solutions, they were serviceable
also in amputation of the cervix.

Application of Adrenal Preparations to the Conjunctiva and
other Mucous Surfaces. — Oliver found that a congested and
inflamed conjunctiva is at once rendered pallid under the
influence of adrenal extract. The use of adrenal derivatives
in ophthalmological operations and examinations has been
attended with great advances in this department. In various
operations on the eye the field of operation may be kept free
from blood by the use of adrenalin solution, 1 to 50 drops of a
solution of the strength of 1 in 5,000, or 1 in 10,000. Darier
recommends the following solution for the purposes of removal
of a foreign body from the eye, cauterization, etc. : 10 drops
of a solution of adrenalin hydrochloride (1 in 1,000) ; cocaine
hydrochloride, 0-1 gramme ; distilled sterilized water, 10
grammes. Adrenal extracts whiten the conjunctiva in
trachoma, conjunctivitis, keratitis, iritis, and other conditions.
An eye with a foreign body on the cornea is whitened. During
operations on the ocular muscles, tenotomy, and advancement,
the extract whitens the eyeball ; the astringent effect is

206

THE DUCTLESS GLANDS

temporary, and there is no subsequent congestion. The local
action of adrenin is very evanescent, and the application has
to be repeated every four or five minutes.

In diseases of the nose and throat adrenal preparations have
found a useful application.

Adrenal preparations are also employed for rhinological
purposes. The marked ischaemia produced is most useful in
revealing causes of obstruction. It has been used as a haemo-
static with good results, also in hay fever, epistaxis, and,
paroxysmal sneezing and rhinorrhcea.

A solution of cocaine and adrenalin is very generally em-
ployed for the painless extraction of teeth.

In bronchial asthma adrenalin applied to the nasal mem-
brane has been used for some years. Kaplan has more recently
employed subcutaneous or intravenous injection (5 to 15
minims of the 1 in 1,000 solution). Miller reports favourably
on the drug administered in one of these ways for bronchial
asthma ; the relief was considerable, but in no cases could he
observe any curative effect. On the other hand, there were no
untoward results. It is not known how the beneficial effect is
produced in these cases — perhaps it is due to inhibition of the
bronchial musculature. But Miller is inclined to think that
the results point to the pathology of bronchial asthma being
due to a hyperaemia of the bronchial membrane.

Use of Adrenal Preparations in Diseases of the Bladder. —
Braun recommends a mixture of adrenalin and cocaine for
injection into the bladder preparatory to a cystoscopic examina-
tion. Adrenalin has been found useful in catheterization
for urethra! stricture. Adrenin has also been successfully
employed to relieve bleeding in the urinary tract and in atony
of the bladder.

The Use of Adrenal Preparations and of Adrenin in Hcemor-
rhages. — Clinical experience has shown that when haemorrhage
occurs from a surface to which adrenin may be applied, relief
is prompt, and in the large majority of cases, lasting. The
drug then finds ready application in epistaxis, bleeding from
granulating wounds, and in cases of tears of the cervix uteri,
and in many other similar cases.

Schafer believes that when adrenin is given by the mouth
there is " very distinct evidence of vascular constriction, for
bleeding from internal parts, such as the stomach, intestine,

THE ADRENAL BODIES 207

bladder, and uterus, and even the bleeding of post-partum
haemorrhages, may thereby be effectually controlled." The
explanation offered is that injured vessels are more sus-
ceptible to the extract and react to a slight excess of it in
the blood more readily than do normal vessels. But Miller
considers that as regards vessels not accessible to local applica-
tions the constrictor action of adrenin is more than counter-
balanced by the sudden increase of general blood-pressure.
He states that in rabbits he has observed that in a wound the
vessels that have stopped oozing often start bleeding after an
intravenous in j ection of adrenalin . In pulmonary haemorrhage ,
he thinks, there is the additional danger of possible absence of
vasoconstriction, and therefore the bleeding might increase by
having a condition of dilated vessels with increased pressure.
Schafer replies to this that administration by the mouth does
not perceptibly raise the systemic blood-pressure, and that,
nevertheless, there is considerable clinical evidence that inter-
nal haemorrhages, when not too profuse nor coming from large
vessels, may be brought under control by oral administration,
especially if, as he suggests, the extract has a greater effect
upon injured vessels.

The question just discussed, naturally, is of great import in
relation to the treatment of haemoptysis. Batty Shaw inclines
to the view that hypodermic or oral administration of adrenin
can have little effect upon bleeding occurring from destructive
tuberculous disease of the lungs, and he attaches comparatively
little importance to the clinical reports which so far have been
published, and in which it is impossible to say that the good
results were not due to other factors.

Quite recently Wiggers has investigated the value of adrena-
lin in inaccessible internal haemorrhages. He concludes that
large doses of the drug (0-05 to 0-1 milligramme) cause a short
preliminary increase of haemorrhage followed quickly by a
decrease or cessation of bleeding. On account of the great
preliminary loss of blood, they are always contra-indicated.
Small doses (0-01 to 0-025 milligramme) cause little or no
preliminary increase, but shorten the course of haemorrhage.
As they save the red blood cells in every way, they are thera-
peutically desirable. Continuous intravenous injection of
weak solutions maintains a slight elevation of pressure, and
haemorrhage is simultaneously checked. This can also be

208 THE DUCTLESS GLANDS

accomplished by intramuscular injections. Adrenalin is not
indicated in all intestinal haemorrhages. The condition of the
blood-pressure is the criterion for its use. In haemorrhages of
short duration, when the pressure has not fallen to any extent,
a judicious dose of nitrites proves of more benefit than adrena-
lin. When the bleeding has been profuse, however, and a low
pressure already exists, it becomes vital that haemorrhage
should be checked without further reduction of pressure.
Adrenalin finds its use in this field. The use of adrenalin should
always be closely followed by blood-pressure observation. A
dose sure to be below the safety limit should first be tried and
the pressure carefully estimated. If no rise occurs, gradually
increasing doses may be injected until a slight elevation of
pressure is present, in which case we may be certain that
enough has been introduced to affect haemorrhage, and at least-
no significant preliminary increase has resulted.

Adrenin in Cardio-Vascular Conditions. — In cardio-vascular
conditions adrenin is most distinctly indicated when there is
marked vasodilation and the heart muscle is in good condition.
These indications are present in chloral-poisoning, shock, and
asphyxia. Gottlieb pointed out that when a rabbit has re-
ceived increasing doses of chloral until the heart comes to a
standstill, adrenal extract will start the heart beating and
maintain it for from twenty to thirty minutes. He considers
that adrenalin is superior to digitalis for this purpose. Crile
strongly advocates the use of adrenalin in " surgical shock,"
and although good results have been stated to accrue from its
employment in ether-poisoning, yet, according to Schafer and
Scharlieb, it is of little avail to restore a heart paralyzed by
chloroform.

In the cardiac insufficiency of diphtheria — in which disease,
as Elliott and Tuckett have shown, there is a deficiency of
chromogen in the adrenal medulla — Gottlieb has reported that
adrenin administered intravenously is of temporary benefit.
The same applies to phosphorus-poisoning. Schafer suggests
that administration by the mouth or subcutaneously, having
a slower effect, might be beneficial in such cases. Rolleston
has recently discussed the value of adrenalin in such cases as
the cardiac failure of diphtheria, and lays stress, as others ha\ <
'Inne, upon the possibility that the increase of the peripheral
resistance may give the failing ventricle more work to do.

THE ADRENAL BODIES 209

He states, however, that he has for some time been in the habit
of giving adrenalin by the mouth in cases of pneumonia in
adults, and in broncho -pneumonia in children. In these cases
it appears to prevent cardiac failure, and has not given rise to
any bad symptoms such as oedema of the lungs. He mentions,
however, the possibility that such administration of adrenalin
may give rise to arterial degeneration.

Adrenal extract is stated to be useful in functional disorders
of the heart associated with lowered arterial tension. In
certain cases, therefore, it may be indicated in migraine and
neurasthenia, where these disorders are associated with a low
blood-pressure.

Kauert has quite recently recommended the use of synthetic
suprarenin in medicine. He reports that it is useful in cases
of vasomotor paralysis, and may be used both therapeutically
and prophylactically. The dose is from 1 to 6 milligrammes
subcutaneously, J to 1 milligramme intravenously. The drug
is contra-indicated in organic heart disease, nephritis, and
arterio-sclerosis with high blood-pressure.

Adrenal Preparations in Addisoris Disease. — The clinical
evidence as to the value of adrenal extracts and preparations
in the treatment of Addison's disease is very conflicting. A
cure can, indeed, scarcely be expected by treatment directed
towards remedying adrenal inadequacy, for the reason that
this inadequacy is only one result of a tubercular or malignant
disease, or a definite atrophy of the gland. Shaw points out
that there are several other reasons why such treatment should
fail. Among these he mentions our ignorance of the functions
of the cortex of the gland and the difficulty of securing the
absorption of an adequate amount of adrenin.

The beneficial results which have been alleged are to be
found chiefly in diminishing the weakness and sense of lassitude.
Numerous cases have been treated with varying degrees of
success.

Rolleston refers to cases of chronic adrenal inadequacy, or
" Addisonism." Boinet recommends adrenalin in these cases.
Various diseased conditions, such as cyclical albuminuria,
neurasthenia, with low blood-pressure, purpura, status lym-
phaticus, and haemophilia, have been attributed to adrenal
inadequacy, and hence adrenalin has been recommended.
But in these cases, as in those of Addison's disease, it seems

14

210 THE DUCTLESS GLANDS

very unwise to administer simply the pressor substance ex-
tracted from the medulla. In the present state of our know-
ledge it would be far more desirable to give either the fresh
whole gland or extracts prepared from the whole gland, both
cortex and medulla. The pigmentation in Addison's disease
has probably never been experimentally induced, and certainly
has never been satisfactorily explained, and we are in the dark
as to whether this, one of the most striking symptoms of the
disease, is due to a lesion of cortex or of medulla, or is due to
damage to both.

We have seen that the results of treatment of Addison's
disease by means of adrenal gland substance are — as compared
with the effects of thyroid treatment in myxoedema — distinctly
disappointing, though it may be that in some instances good
results have been obtained. Dr. Byrom Bramwell, who regards
the symptoms of Addison's disease as partly due to glandular
inadequacy, and partly the result of irritation of the sympa-
thetic in the neighbourhood of the adrenal bodies, explains the
failure of the extract in some cases by supposing that in these
instances there are adhesions to the sympathetic plexus and
irritation of it ; while the cases which react satisfactorily to
the extract are those in which there is only glandular inactivity
or inadequacy.

Rolleston says : "It should be remembered that the medulla
alone contains the active physiological principle, the cortex
appearing to be inert, and that the extract is at present largely
made from the whole gland, and not, as would be physiologically
more correct, from the medulla alone. This must lead to a
certain amount of uncertainty as to the amount of active
principle contained in any pill or tabloid." It will be gathered
from what has been said above (p. 152) that it appears to the
present writer that it is far from certain that it would be
* ' physiologically more correct ' ' to give extracts made from
medulla only, or to give, as would probably be suggested at
the present time, pure adrenin. It seems safer, in view of our
ignorance of the precise pathology of the disease, to give an
extract made from the whole gland, or, better still, if adminis-
tration by the mouth be considered advisable, the fresh minced
gland. Because the medulla is the only part which yields a
powerful active substance to extracts, we must not assume that
n is the only part concerned in Addison's disease,

THE ADRENAL BODIES 211

Various Applications of Adrenal Preparations and of Adrenin.
— Barr found that after withdrawal of fluid from the pleural
cavity of a patient suffering from carcinoma of the lung, the
fluid did not accumulate again after the introduction of
adrenalin. The same applies to tuberculous pleurisy, tuber-
culous and malignant peritonitis, and to ascites due to cirrhosis.
The method was, after removal of the fluid, to inject 40 to 60
minims of adrenalin chloride, 1 in 1,000. In ascites the success
was not so great as in the other cases.

Plant and Steele report good results in cirrhosis of the liver
and pleural effusion, and state their belief that the injection of
adrenalin chloride is strongly indicated in all cases of serous
effusion when simple tapping does not effect a cure. The
empirical results obtained by Barr and others are explained by
the experiments of Exner and Meltzer and Auer. Exner found
after experimental injection of adrenalin that absorption of
strychnine and physostigmine is delayed, and so the life of the
animal may be saved. This was confirmed by Meltzer and
Auer, who also showed that fluorescin transfused from the
blood into the peritoneum much more slowly in animals that
had previously received adrenalin intravenously. It has also
been demonstrated that intraperitoneal injection of adrenalin
will lessen the tendency of transudation into the peritoneal
cavity, after excessive transfusion of normal salt solution.

Milian states that certain symptoms due to salvarsan can
be prevented by previous intramuscular injection of adrenin.

Jona recommends adrenin in the emergency treatment of
non-corrosive poisoning by the mouth (cyanide, strychnine,
aconite), on the ground that it diminishes the rate of absorp-
tion.

Mode of Administration of Adrenal Preparations. — It is well
to recall that adrenal extracts were first administered by
subcutaneous injection. But since Oliver and Schafer reported
that the activity of the gland is not impaired in vitro by pepsin
and hydrochloric acid, it has become customary to give it by
the mouth. Raw sheep's adrenal bodies have been given, and
a tincture has also been employed, but most usually a dried
extract is employed in the form of a pill. In addition to these
modes of exhibition all the various forms of the active substance
adrenin have been used from time to time.

Some years ago the present writer failed to observe any

212 THE DUCTLESS GLANDS

physiological effects upon dogs, cats, and rabbits of feeding
with the adrenal bodies of the sheep, and the administration
of large doses of extracts (in some cases made from medulla
only) failed to produce any noticeable rise of blood -pressure
in the human subject. But Ley ton states that adrenal
extract, although when administered by the mouth it ordi-
narily fails to produce elevation of blood-pressure, will bring
about this effect in cases of Addison's disease. However this
may be, the most certain method by which to obtain any
definite pharmacodynamical effects is that of subcutaneous,
intramuscular, or intravenous injection. The intravenous
method should be employed in all cases of extreme emergency,
such as ether-poisoning and heart failure in diphtheria.

Miller urges that adrenin ought to be employed with great
care in all patients with suspected arterial degeneration, and
in elderly people. The danger of causing glycosuria in the
human subject does not appear to be great.

K. Theories as to the Function or Functions of the
Adrenal Bodies

Our scientific knowledge of the adrenal bodies may be said
to date from the year 1 855, when Addison published his famous
work. The known facts about the organs in question are,
very briefly stated, as follows : Disease of the glands gives rise
to a characteristic train of symptoms, among which are pig-
mentation of the skin and extreme muscular weakness. Extir-
pation of both adrenal bodies is a very dangerous operation,
and, according to the majority of investigators, invariably leads
to death. It is the cortex and not the medulla which is essential
to life. Extracts of the medullary portion of the body are
toxic when administered to an animal subcutaneously, in-
tramuscularly, or intravenously, among the symptoms being
glycosuria and degeneration of the arteries. Intravenous
injection produces a powerful effect upon the heart and blood-
vessels, and is chiefly manifested by a very marked rise of
the arterial blood-pressure. The general pharmacodynamical
effects are strikingly similar to those brought about by a
stimulation of the sympathetic nervous system ; these physio-
logical or pharmacological effects are obtained only by admin-
istering extracts of the medulla, the cortex being inactive.

Comparative anatomy and comparative physiology reveal

THE ADRENAL BODIES 213

the fact that the medulla of the adrenal body is not the only
representative of the tissue which forms it (chromaphil tissue) ;
there are numerous scattered bodies of the same nature in close
relation to the sympathetic ganglia and nerves in different
regions of the body. In lower vertebrate animals the medulla
(chromaphil bodies) and cortex (inter-renal bodies) form two
separate and independent systems, having no anatomical (and,
so far as we know, no physiological) relationship to each other.
Indeed, strictly speaking, the medullary substance is not part
of the adrenal body at all, but simply an accumulation of the
chromaphil tissue which has arisen from the sympathetic in a
certain region of the body, and has insinuated itself into the
adrenal proper, or what we call the " cortex."

In discussing the function or functions of the adrenal bodies
these facts of comparative anatomy must not. for a moment be
lost sight of. The ultimate question which we have to solve is,
from the standpoint of comparative physiology, not so much
what is the function of the adrenal body or of its two constituent
portions, but what are the functions respectively of the inter-
renal system (cortical system) and the chromaphil system
(medullary system), which are, as we have seen, separate and
distinct in Elasmobranch fishes (Figs. 44, 45) ? It is difficult
to say whether we ought to expect that these functions should
be of a kindred nature, or in any way related to each other, in
the case of the mammals. There certainly would be no a
priori reason for suspecting the existence of any such relation-
ship in the Elasmobranch fishes, but we cannot overlook the
fact that phylogenetically and ontogenetically portions of the
two systems become attracted, so to speak, to each other, and
finally in the adult mammal form a single compound organ.
One cannot escape from the suspicion that the coming together
may have some significance affecting the functions of the gland
as a whole. We are, however, at present completely in the
dark as to any functional correlation between the two con-
stituents. It is possible, moreover, that cortex and medulla
have separate and distinct functions ; at any rate, most of the
accurate knowledge which we possess and nearly all our most
plausible hypotheses have reference to the medulla of the
organ, and this notwithstanding the fact that the cortex is
larger than the medulla, and more distinctly glandular in type
and appearance.

214

THE DUCTLESS GLANDS

Qvromaph

( paired. Supra- re/io/s

Sympathetic Gang

ympMetic Aferve.

Sympathetic (?ang//a

dortical Bodies

Kidney

FIG 44. — Diagram of the adrenal representatives in Elasmobranch fishes
showing the cortical gland (inter-renal body) and the medullary glands
(chromaphil bodies, " paired suprarenals ") in relation to the sympathetic
and the kidneys.

THE ADRENAL BODIES

215

Groups of Chromaphil Cells
in Sympathetic Ganalia

Medulla of Ad

Kidney

Groups oi
hi-omaphil(el
Abdomen

f*<arotid Body
upenor Cervical Goncjlia

Inferior Cervical Ganglia
fellate Ganqlia

ympathetic Nerve

^Acxessory Comical Bodies

-Corf ex of Adrenal Body
tfedulla of Adrenal

Ki

'dney

Abdominal Chromaphil Boc/y

ccessory Cortical Body
Tesficle

FIG. 45. — Diagram of the adrenal constituents and outstanding " cortical "
and " medullary " (chromaphil) bodies in the mammal, showing the
adrenal bodies, the chromaphil cells of the sympathetic, the abdominal
chromaphil body (" accessory medullary ") and accessory cortical
adrenals in relation to the sympathetic and the kidneys.

216 THE DUCTLESS GLANDS

1. Theories as to the Function of the Medulla

Prior to the discovery of the active principle of the medulla
of the adrenal body, some authors considered that the gland had
an excretory function. Thus, MacMunn found hsemochro-
mogen in the gland, and especially in the medulla, and drew
the conclusion that in the adrenals a downward metamorphosis
of worn-out pigments — haemoglobins and histohsematins — is
taking place, and that the function of these organs is to pick
out of the circulation these worn-out or effete colouring matters
with their accompanying proteins. Others considered that the
waste products of muscular metabolism are eliminated by the
glands. Still others attributed a blood-destroying function
to the gland. But since the discovery of the pressor principle
the excretory theory has almost entirely been replaced by that
of secretion — internal secretion.

It is now generally admitted that most, if not all, of the
recognized effects produced by the administration of adrenal
extracts are to be ascribed to the adrenin which is contained
in them. Three questions immediately arise : Is adrenin to be
looked upon as the product of the secretory activity of the
medulla of the glands ? Is it actually poured out into the
blood-stream ? Supposing these questions to be answered in
the affirmative, then what is the use of this internal secretion
—this hormone — in the animal economy ?

Kohn, from morphological considerations, is opposed to the
view that the chromaphil tissues have an internal secretion.
He is certainly justified in insisting that we have no right,
simply because adrenin has certain pharmacodynamical effects,
therefore to assume, without further definite evidence, that it
is one of the functions of chromaphil tissues to pour out this
substance into the blood-stream in order that it may produce
such effects upon certain tissues of the body. He considers
that the cells forming the medulla of the adrenal body and the
chromaphil tissues elsewhere are not " epithelial," and there-
fore cannot secrete.

But the active substance of the adrenal medulla is of a very
exceptional and extraordinary character, and is not to be
classed with the less active bodies found in extracts of organs
and tissues generally, and the medulla of the adrenal body is
not a mass of chromaphil cells of irregular shape and indefinite

THE ADRENAL BODIES 217

arrangement, but an organ arranged in the form of definite
columns of cells, with intervening blood-spaces — in fact, a
" gland." It is therefore a priori probable that the adrenal
medulla may secrete into the blood-stream an active material
which is of benefit to the economy. Again, a careful compara-
tive study of the chromaphil tissues in general, and the adrenal
medulla in particular, has led to the conclusion that the latter
is probably to be regarded as a specialized development of the
former (see p. 116).

Considerable evidence has, however, been accumulated that
adrenin under certain conditions is secreted through the adrenal
veins into the general blood-stream. It has been stated by
several authors that the blood of the adrenal vein contains a
sufficient amount of the active principle of adrenal extract to
produce marked rise of blood-pressure when intravenously
injected. This, however, has not been confirmed.

Ehrmann, basing his investigations upon the discovery of
Lewandowsky, and relying upon the observations of Meltzer
and Auer that frogs, after adrenin injection, show a^ maximum
dilatation of the pupil, worked out a method for the estimation
of adrenin. He used the enucleated frog's eye, as recommended
by Meltzer and Auer, and measured the amount and rapidity of
widening of the pupil on placing the eye in adrenin solution.
By this method it could be shown that the blood coming from
the adrenal bodies contains the active substance, adrenin, and
Ehrmann concludes that it passes into the blood as a physio-
logical secretion. Pilocarpine and atropine lead to no marked
increase or diminution. In diphtheria intoxication it is some-
what increased. Raising or lowering the blood-pressure has no
effect on its amount, which varies considerably in different
animals. According to Ehrmann, the rabbit pours into its
adrenal veins adrenin in a concentration of between 1 : 1,000,000
and 1 : 10,000,000. There is a parallelism between the amount
secreted and the sensibility of the animal to the actipn of the
substance.

Waterman and Boddaert, however, have shown that the
mydriatic action on the enucleated frog's eye is not absolutely
specific for adrenin. Gautier says that the solutions employed
must befaintly acid, since dilute alkaliin sodium chloride solution
gives by itself a positive result. Schultz says that the time taken
for a certain degree of widening is of more value than the extent

218 THE DUCTLESS GLANDS

of total dilation. The method is now considered by Meltzer to be
untrustworthy, as the amount of adrenin necessary to produce
an action upon the frog's eye varies not only in different frogs,
but even in the two eyes of the same frog. Trendelenberg now
uses the method of perfusion through the vessels of the hind-
limb of the frog. Ritchie and Bruce, using the bichromate
coloration and the blood-pressure testing, have recently
reported (contrarily to Ehrmann) that in diphtheritic toxaemia
in guinea-pigs there is complete exhaustion of all adrenin from
the medulla of the adrenal bodies.

Another test for adrenin in the blood consists in injecting
hypertonic solutions into the auricular vein, and noting the
occurrence of glycosuria. It was found that this, like the
diabetic puncture, also renders the serum mydriatic. It is
considered that these experiments show that adrenin stimulates
the sympathetic. It is believed also the sympathetic may be
stimulated by means of thyroid material, and, on the other
hand, stimulation of the sympathetic leads to increased secre-
tion of the thyroid.

An elaborate series of metabolism experiments by Eppinger,
Falta, and Rudinger have been regarded as pointing to a
definite internal secretion on the part of the adrenal medulla,
or rather of the whole chromaphil system, and a functional
relationship between adrenal body, thyroid, and pancreas
through the medium of the sympathetic nervous system. A
relationship between pancreas and adrenal body in regard to
hyperglycaemia is indicated by the experiments of Zuelzer and
others. Ritzmann claims that the degree of glycosuria depends
on the quantity of adrenin present in the blood at any given
moment. But the quantitative result of this observer cannot
be regarded as correct, since it has been proved by Underhill
that the glycosuria obtained by Ritzmann with small doses of
adrenin, intravenously administered, was dependent on the use
of urethane as the anaesthetic. Adrenin introduced in very
dilute solutions (1:500,000 to 1:125,000) fails to induce
glycosuria in the normal rabbit. On the other hand, when the
animal is under the influence of urethane narcosis, these dilute
adrenin solutions are a sufficient stimulus for the production of
glycosuria. It seems, then, that urethane renders a rabbit
unusually sensitive to the glycosuria-inducing action of
adrenin. The subcutaneous administration of adrenin in a

THE ADRENAL BODIES 219

dilution of 1 : 1,000 to normal rabbits is far more efficacious in
causing glycosuria than the same quantity of adrenin intro-
duced intravenously in much greater dilution. The same
quantity of adrenin injected subcutaneously at different
periods into the same animal under constant conditions
causes the appearance in the urine of variable quantities of
sugar.

Underbill and Fine have discovered that subcutaneous
administration of hydrazine is capable of preventing the
appearance of sugar in the urine of dogs from which the
pancreas has been removed. They suggest that hydrazine has
an action upon sugar metabolism entirely similar to that exerted
by the internal secretion of the pancreas. According to this
idea, injections of hydrazine cause hypoglycsemia by increasing
the efficiency of the pancreatic secretion or by augmenting its
output. They find definitely that the secretion of adrenin is
not notably inhibited by hydrazine.

As a working hypothesis, the authors make use of the scheme
of interaction between the pancreas and the adrenal bodies
given on page 220.

Ringer has brought forward some results which indicate that
adrenalin, by its constricting effect on the bloodvessels, produces
anaemia of the tissues, resulting in imperfect oxidation, and this
anaemia is followed by the conversion of glycogen into dextrose,
by hyperglycaemia, and consequently by glycosuria.

In 1891 Jacobi described nerves branching from the splanch-
nics, and supplying the adrenal bodies. The same observer,
in his experiments on the nervous functions of the adrenals,
without, of course, having any knowledge of the pressor effects
of extracts, reports that in two experiments stimulation of the
gland itself produced a rise of blood-pressure. But Apolant,
in a series of more than thirty experiments upon rabbits, could
obtain no such result. Biedl found that stimulation of the
splanchnics or the ramus suprarenalis gives rise to vasodilation,
and suggested that this is accompanied by increased secretion
from the gland. We must consider, however, the result open
to question, as no test of the active principle was made, but
only a study of changes in certain granules in the blood of the
adrenal vein (vide infra).

More definite results were obtained by Dreyer, who records
that the physiological action of the blood from the adrenal vein

220

THE DUCTLESS GLANDS

(Sugar Content)
* Blood.

Pancreas Secretion

Adrenal Secretion.

Liver.
(Glycogen Store)

(Sugar Content)
Blood.

(Sugar Content)
Blood.

> ' /

\ Pancreas Secretion/

N <;'

/Adrenal Secretion\

Liver.
(Glycogen Store)

Adrenal Removal
( indicated by broken lines)

leads to
Hypoglycaemia

I
Anuria

No Glycosuria.

Liver.
(Glycogen Store)

Pancreas Removal
(indicated by broken lines)

leads to
Hyperglycaemia

I

Diuresis

I
Glycosuria.

Diagram indicating influence of the 'organs on the metabolism of carbo-
hydrate (Underhill and Fine).

THE ADRENAL BODIES 221

during splanchnic stimulation is greater than that of the same
blood under normal conditions. He looks upon the splanchnic
as a true secretory nerve for the adrenal body.

After the very important discovery that adrenal extracts
raise the blood-pressure, there was a growing tendency to
assume that the function of the adrenal (or, at least, of its
medullary portion) is to help to maintain the normal blood-
pressure and to keep up the tone of sympathetically innervated
structures in general. The present writer was one of the first
to grow suspicious on this point. If the constant secretion of
adrenin into the blood-stream and its action upon the sym-
pathetically innervated vascular muscle is an important factor
in the maintenance of the normal blood-pressure, then it ought
to be possible by tying or clamping the veins issuing from the
glands, to keep down the blood-pressure at a low level during
the period of clamping or tying, and to allow it to reach its
normal level on releasing the clamp or the ligature. Some
writers have claimed that they have obtained this result. Such
has been definitely recorded by Strehl and Weiss, who extir-
pated the adrenal body on one side, and found that when a
clamp was put upon the adrenal vein of the other side the
blood -pressure immediately fell, and rose again when the clamp
was released. Their experiments were performed upon rabbits.
They gave a tracing which shows a very marked depression
during the period of the clamping of the vein.

Kretschmer finds that if adrenalin solution is injected intra-
venously into rabbits each new dose produces a rise of pressure,
and between the doses the pressure falls to normal owing to the
rapid destruction of adrenalin in the body. For this reason
repeated injections cannot keep up the blood-pressure, but
continuous injection can do so. The action on the blood-
pressure lasts just so long as there is any adrenalin in the blood.
According to Kretschmer, the continuous internal secretion of
adrenalin from the adrenal bodies is probably of significance
for the maintenance of the normal vascular tone. If, as in
vitro, the destruction of adrenalin in the body is dependent on
the amount of alkali present, then should intravenous injection
of alkali cause a lowering of blood-pressure due to a breaking
down of the continuous supply of adrenalin. A lengthening of
the action of adrenalin is in fact produced experimentally by a
simultaneous injection of nitric acid.

•2-2-2 THE DUCTLESS GLANDS

At the suggestion of the present writer, the experiment of
Strehl and Weiss has been repeated by Young and Lehmann.
In their experiments an attempt was made upon dogs to dam
back any secretion which the glands may pour into the blood-
stream, and after an interval to remove the obstruction and
allow the accumulated adrenin to flow into the general circula-
tion. A cannula was inserted into the carotid artery, the
adrenal glands were exposed through an abdominal incision,
and a double ligature passed beneath the organ on each side ;
the ligatures were tied on each side of the gland above the vein,
so as to form two pedicles. The ligatures were left in place for
from ten to thirty minutes, and then released, and the tracing
continued. Out of eight experiments, there was no effect on
the blood-pressure in three ; in two there was a slight rise after
releasing the ligatures ; in the remaining three there was a
decided rise of pressure (similar to that which follows the
injection of the extract), lasting about three minutes. In one
case the effect was repeated by tightening the ligatures a
second time, and again releasing them.

It is important to note that in these experiments after
tightening the ligature there was very little, if any, fall of blood-
pressure. In fact the experiments merely show that adrenin
is poured out into the adrenal veins.

Dr. Young repeated these experiments and found that even
after the lapse of several hours with the blood from the adrenal
bodies absolutely excluded from the circulation, there was no
appreciable fall of blood-pressure. Austmann and Halliday
have also at my suggestion performed a series of experiments
in which the adrenals were removed or whose vessels were tied
off while the blood-pressure was continuously recorded for many
hours. It was found that when the experiment was continued
until the animal died the blood-pressure curve was not appre-
ciably different from that obtained from an animal simply kept
under ether as long as possible. These experiments appear to
show conclusively that the secretion of adrenin into the cir-
culation is not to be regarded as a factor in the maintenance of
the normal blood-pressure.

But there is another argument which militates powerfully
against the theory just mentioned. It was shown by Moore
and Purinton that very small doses of adrenin will lower the
blood -pressure, not raise it, so that the amount of adrenin

THE ADRENAL BODIES

223

which is normally poured out by the adrenal veins would tend
to keep the blood-pressure down rather than up.

Stewart and Rogoff have given another proof that the
discharge of adrenin from the adrenal bodies is not indispens-
able for life and health. When one gland is removed from a
cat and the secretory nerves to the other are cut the animal
appears to suffer no ill- effects. Now in this case adrenin could
scarcely have been present in the blood in a concentration of
more than one part in four millions, which, as Stewart observes,
" the most enthusiastic
upholder of the physio-
logical importance of
adrenin will probably
consider below the
threshold of any
definite physiological
reaction. Yet the
animal was in good
health."

Hoskins is of the
opinion that there is
no reliable evidence
that under normal con-
d i t i o n s circulating
blood contains any
adrenin at all. He

points OUt that as the FlG- 46.— This tracing shows the rise of

i £ . ,. blood -pressure due to release of pressure

technique Ol mvestlga- on adrenal vein. The vein has been

tion has improved the compressed for some time, and was re-

T ,., . . leased at the point signalled (Gardner

reported dilution of and Gunn).

the adrenin in arterial

blood has constantly approached infinity.

The subject of adrenal secretion has been investigated by
Asher and Tscheboksaroff. Asher performed his experiments
upon rabbits. All the arteries coming off from the abdominal
aorta and supplying the viscera, with the exception of those
running to the adrenal bodies, were ligatured, and then all
the abdominal organs, excepting the liver and the adrenal
bodies, were extirpated. The blood was squeezed out of the
veins, and the portal vein tied off. Electrodes were then
placed under the two splanchnic nerves., the spinal cord was

224 THE DUCTLESS GLANDS

cut across high up, and artificial respiration carried out. The
blood-pressure was recorded from the carotid or the femoral
artery. Stimulation of the splanchnic nerves gave rise to a
marked rise of blood-pressure, and continuous stimulation
produced a long -continued elevation of pressure. The rise did
not occur if the adrenal veins were tied.

Tscheboksaroff has reached the same conclusions as Dreyer
did — viz., that the great splanchnic nerve in dogs is the true
secretory nerve of the adrenal body, and that its stimulation
leads to an increase of the adrenin which is found in the venous
blood. Section or ligature of this nerve diminishes the amount
of adrenin in the blood.

The theory that the chromaphil tissues (and especially the
medulla of the adrenal bodies) maintain, or help to maintain,
the normal tone of the bloodvessels and other sympathetically
innervated structures, has been already discussed. Evidence
has also been given that the medulla of the adrenal body is
not essential to life, and that the reduction of the adrenin
content of the blood to a minute fraction of the normal amount
does not affect the health of an animal.

These statements, however, do not exclude the possibility
that the chromaphil tissues play a part in certain reactions
which are initiated elsewhere, as, for example, in those which
result from stimulations of nerves in laboratory experiments.

We have referred above to certain experiments involving
stimulation of the splanchnic nerve, and its effect on the blood-
pressure. This question must now be treated in greater detail.

It has been known for a long time that the rise of blood -
pressure brought about by stimulation of the peripheral end
of the splanchnic nerve is not simple. The curve obtained sug-
gests at once that there is more than one factor concerned in
its production.

Johansson found that in the dog the curve presents two
summits, and it has since been found that the same is generally
true in other animals also.

Lehndorff also worked with dogs and came to the conclusion
that the first rise is due to vasoconstriction in the splanchnic
area, the " step " to a temporary dilation of the heart, and the
second rise to increased force and frequency of the heart-beat
accompanied by vasoconstriction in the somatic area.

Elliott, who investigated the subject in cats, stated that in

THE ADRENAL BODIES 225

animals recently admitted and still in a frightened condition,
the typical splanchnic curve cannot be obtained. But he
regarded the typical curve as something different from that
obtained by previous workers in the case of dogs. According
to this author a well marked characteristic of the pressure curve
seen when the splanchnics are stimulated under good condi-
tions in the cat, is that it rises rapidly for nine or ten seconds ;
then, without any check in the heart's rhythm, the curve is
sharply cut down nearly to the level from which it came, whence
it rises slowly again so long as the stimulus is continued. The
drop, according to Elliott, is due to the liberation of adrenin
into the blood, and he gives what seems to be very convincing
evidence in favour of this view.

Anrep, who used dogs for his experiments, reports that
stimulation of the splanchnic nerve causes a rise of blood-
pressure which occurs in two phases. The second phase is
accompanied by constriction of peripheral bloodvessels (even
after denervation) and by acceleration and increased tone and
augmentation of the heart (also after denervation). The
secondary rise and all the concomitant phenomena are due
to the discharge of adrenin into the circulation, and are absent
after extirpation of both adrenal bodies. Every rise of blood-
pressure, brought about by the agency of the nervous system,
involves the co-operation of the chemical mechanism repre-
sented by the adrenal bodies. The constriction of bloodvessels
in denervated limbs under splanchnic stimulation, which was
regarded by Bayliss as a local reaction to increased pressure,
is interpreted by Anrep as due to the action of adrenin.
The rise of blood-pressure in asphyxia is also looked upon by
this author as being partly due to constriction of somatic
vessels as a result of the action of adrenin upon them.

Gley and Quinquaud have recently thrown doubt upon the
validity of these experiments. They think that ligature of
the vessels of the adrenal bodies or extirpation of the organs
in the dog involves damage to some of the splanchnic vaso-
constrictor fibres and that this accounts for the alteration in
the splanchnic blood-pressure curve. In the cat and the
rabbit, according to these authors, such alteration does not
occur. In these animals the nerves are not so intimately
connected with the adrenal bodies.

These criticisms on the part of Gley and Quinquaud

15

226 THE DUCTLESS GLANDS

prompted Pearlman and myself to a re-investigation of the
subject. We have performed a very large number of
experiments upon dogs, cats and rabbits.

At the outset it was found that the conditions under which
the experiment is performed makes a very considerable differ-
ence in the character of the curve obtained by splanchnic
stimulation. There may also be differences characteristic of
the different species and of different conditions of the animal.
Anrep seems never to have obtained in his dogs under normal
conditions a form of curve which we now look upon as the

FIG. 47. — Dog, 12 K. Ether, vagi cut. Left splanchnic stimulated in thorax.
Time tracing in seconds.

typical or normal, namely, a sharp rise (having a " hump "
about half-way up) followed by a marked " dip " nearly down
to the original level, and succeeded by a rise which lasts as
long as stimulation is continued (see Fig. 47).

This occurs in dogs under ether with both vagi cut. Anrep
used A.C.E. mixture and morphine. Chloroform, curare, and
morphine sometimes modify the curve in such a way as to
abolish the " dip," leaving only the "hump" on the rise
(see Fig. 48).

In many of our tracings the " hump " and the subsequent
"dip" are quite distinct (see Figs. 47, 48, 49) and the

THE ADRENAL BODIES 227

augmentation of the heart is very manifest (47, 48, 49, and
others).

The curve just described is, we believe, to be regarded as
the normal effect of stimulation of the peripheral end of the
splanchnic nerve in the dog, as well as in the cat and the rabbit,
when these animals are under the influence of ether alone, or
under morphine and curare in addition, although under the
influence of the latter drugs the " dip " is much less pronounced
and sometimes altogether abolished.

Anrep, in discussing Elliott's results, says " Eliott investi-
gated the question in the cat, in which animal the ' step '
becomes a distinct fall." As we have already stated, in our
experiments there was no essential difference in this respect

FIG. 48. — Dog, 10 K. Ether, vagi cut, both splanchnics cut in thorax, (a)
Stimulation of left splanchnic five minutes after injection of 2 cc. of 1 %
morphine sulphate. (6) Stimulation fifteen minutes later. (c) Stimu-
lation fifteen minutes still later. The effect of the morphine wears off and
the normal curve tends to appear again.

between dogs and cats. The "step" referred to by Anrep
is therefore not what we have called the " hump," but some-
thing which occurs later and which we call the " dip . " We have
not been able to convince ourselves that the nature of the
normal curve is dependent on nervous or emotional conditions
either in dogs or in cats.

According to Elliott the " dip " of the splanchnic curve
in cats does not occur if the adrenal bodies are excised or tied
off. Anrep reports that the " step " in dogs is in a similar
manner abolished by suppression of the adrenal bodies. Gley
and Quinquaud, on the contrary, believe that there is an impor-
tant difference in the results between dogs and cats . They state
that interference with the adrenal bodies does not affect the

228

THE DUCTLESS GLANDS

result in cats, and that it does so in dogs only because of a
different anatomical arrangement. In their opinion, extirpa-
tion or ligature of the glands in dogs necessitates damage to
nerve fibres, while in cats it may not.
According to our experiments there is no such difference

FIG. 49. — Dog, 10 K. Ether, vagi cut, both splanchnics cut in thorax,
(a) Stimulation of left splanchnic. (6) Do. after clamping adrenal
veins, (c) Do. after clamps have been released.

in the results obtained in dogs and cats, respectively. Our
results, indeed, entirely confirm those of Elliott and apply
equally to dogs, cats, and rabbits. We have usually obtained
quite satisfactory positive results by simply clamping and
unclamping the adrenal veins. Moreover, all necessary dissec-

FIG. 50. — Bitch, 10 K. Ether, morphia, vagi cut, both splanchnics cut in
thorax, (a) Left splanchnic stimulated. (6) Left splanchnic stimulated
after left adrenal has been tied off. (c) Right splanchnic stimulated with
right gland intact.

tion in the neighbourhood of the gland was carried out before
the control experiment was performed (see Figs. 49, 50).

Fig. 51 shows that the results in the cat were similar to those
obtained with the dog.

THE ADRENAL BODIES

FIG. 51. — Cat, 2 K. Ether, vagi cut, both splanchnics cut in thorax.
1. Right splanchnic stimulated. 2. Right splanchnic stimulated after
the adrenal veins had been clamped on the right side.

During the period of the first rise of blood-pressure under
splanchnic stimulation there is marked passive dilation of the
denervated limb. This is followed by pronounced constriction.
In experiments on this subject we have always employed ether,
morphine, and curare. When the adrenal veins are clamped or
tied this constriction does not occur. Thus, our results are in
accord with those of Anrep (see Figs. 52 and 53).

Anrep believes that the constriction of a denervated limb
during the pressor response to stimulation of the central
end of the sciatic nerve is due to the action of adrenin. He

FIG. 52. — Dog, 16 K. Ether, morphine, curare, vagi cut. Upper curve, volume
of denervated hind limb ; lower curve, carotid blood-pressure. Time
tracing in seconds. The right splanchnic was cut in the thorax and
the peripheral end stimulated.

230

THE DUCTLESS GLANDS

was led to this conclusion by the observation that after removal
of the adrenal bodies from the circulation, the limb does not
constrict, but follows passively the blood-pressure. Our own
results enable us to confirm this observation (see Figs. 54
and 56),

Although suppression of adrenal function does not appear
to affect the alteration in blood-pressure brought about by vaso-
motor reflexes, yet it seems exceedingly probable from the above

FIG. 53. — Same dog as in Fig. 52. In this tracing we see the effect of stimu-
lating the right splanchnic after the adrenal veins had been clamped on
both sides.

experimental results that, even when the limb is intact, the
adrenals must play a considerable part in determining the dis-
tribution of blood in the body, when a stimulus is applied to an
afferent nerve. It can scarcely be imagined that the presence
of a nerve-supply can totally mask the action of the chemical
agent. But it is difficult to be certain that the adrenal bodies
play a part in vasomotor reactions in the normal state of the
animal.

THE ADRENAL BODIES

231

What follows after adrenal suppression when a weak
stimulation causes a depressor response we have not ascer-
tained.

If we investigate the difference between the intact and the
denervated limb in regard to their respective responses to
injection of small doses of adrenin (0'2c.c.tolc.c.ofal : 100, 000
solution) we must bear in mind the results obtained by Hoskins,

FIG. 54. — Dog, 10 K. Ether, morphine, curare, vagi cut. Upper curve, volume
of denervated left hind limb. Lower curve, carotid blood-pressure.
The abdominal cavity was open and the adrenal bodies had been cleaned
in readiness for tying off. Stimulation of central end of right sciatic.

Gunning, and Berry. It was found that with nerves intact
adrenin causes active dilatation of the muscles and vaso-
constriction in the cutaneous vessels, so that while the entire
limb usually constricts, a skinned limb will invariably dilate.
This result we have been able to confirm. As further pointed
out by Gruber, the results just described are obtained only when
the nerves to the limb are intact. In the denervated limb, at

232

THE DUCTLESS GLANDS

any rate within a certain period after the denervation, adrenin
does not cause active vasodilatation in the muscles. These
results agree well with what we find, namely, that when the
splanchnic nerve is stimulated peripherally and the sciatic
centrally in such a way as to give pressor responses, the intact
limb follows passively the blood-pressure, while the denervated

Fio. 55. — Same dog as in Fig. 54. The tracing is taken five minutes later
than in Fig. 54, after the adrenals on both sides had been tied off. Stimu-
lation of central end of right sciatic.

limb constricts. It is only reasonable to suppose that this is
a natural consequence of the fact that in the denervated limb
the muscles do not actively dilate, and therefore fail to produce
the masking effect upon the skin constriction. We have been
able to satisfy ourselves on these points by injection of adrenin
as well as by stimulation of the nerves just referred to. This is,
in our opinion, to be regarded as a provisional answer to the

THE ADRENAL BODIES 233

query above, as to why the presence of intact nerves should
interfere with the response to the chemical agent.

In regard to the effects of asphyxia, our results differ from
those of Anrep. We have been unable to obtain tracings
showing any significant difference in the behaviour of a dener-
vated limb during asphyxia in an animal with adrenals sup-
pressed as compared with one in a normal animal.

It seems impossible to avoid the conclusion that when power-
ful impulses are transmitted along certain afferent or efferent
paths, the adrenal bodies (or, more correctly, the masses of
chromaphil tissue contained within these bodies) play a part
in the total response. Whether, under normal condition of the
animal, the impulses which are so transmitted are sufficiently
powerful to give rise to results similar to those of the laboratory
experiments, or whether they are of such a character as to be
adequate for such results, we cannot pretend to say. It is
tempting to assume that the impulses may become adequate
in physiological emergencies, as was suggested by Cannon and
de la Paz.

It appears from our own tracings and from those of Elliott
that, although the character of the splanchnic curve is seriously
modified by elimination of the adrenals, the total rise of blood-
pressure may not be affected, or may even be greater than
before. It follows that in these cases the effect of the adrenin
actually poured out into the circulation is a fall of blood-
pressure and not a rise. This corresponds with the fact that
small doses of adrenin produce a fall and not a rise. In other
cases, however, the total rise is greater in the intact animal.

The question arises as to the nature of the process by which
the adrenin is poured out into the circulation in sufficient
quantity to produce, in laboratory experiments, the effects
detailed above. It is generally assumed that the process is a
true secretion, and that the splanchnic nerve is the channel
along which the secretory fibres run. This is supposed to apply
equally to experiments in which the splanchnic itself is stimu-
lated and in those in which changes in the circulation are
brought about reflexly by stimulation of different afferent
nerves.

Some observers have alleged that the discharge of adrenin
is the result of vaso- dilation of the adrenal body as a result of
direct or reflex stimulation of its vaso-motor nerves. It would

234 THE DUCTLESS GLANDS

appear very extraordinary if stimulation of the splanchnic
caused vaso-dilation in the adrenal bodies, while it caused vaso-
constriction in all the other abdominal viscera to which it sends
fibres. Moreover, the experimental evidence on this point is
not satisfactory. We might even go as far as to assume for the
present that stimulation of the splanchnic constricts the vessels
of the adrenal body. If this is the case, the constriction of the
vessels of the gland might actually be the cause of the discharge
of adrenin. For a certain amount of this substance contained
in the veins and capillaries of the organ would be almost
instantly driven out into the general circulation. This effect
could, of course, be only of the briefest duration, though it might
easily be sufficiently prolonged to produce the temporary effects
above referred to. These effects, as we have seen, consist prac-
tically in a fall of the carotid blood -pressure and a constriction of
vessels in certain somatic areas. This theory would account for
the fact, observed by Elliott, that it is not possible to exhaust
completely the gland by continued splanchnic stimulation.
It would also explain the fact that the effects above detailed
cannot be repeated until a certain time has elapsed since the
first stimulation. If this were found to be the true explanation
of what happens, we should then not have to deal with a true
secretory activity of the glands, but only a mechanical expul-
sion of adrenin as a result of vaso-constriction.

In all such discussions it is important to bear in mind that
the medulla of the adrenal body constitutes only a portion of
the total chromaphil tissue in the body. In fact, it seems more
than likely that there is more chromaphil tissue outside the
adrenal bodies than within them. We can scarcely avoid this
conclusion when we remember that the tissue in question is
distributed widely in the sympathetic ganglia and in masses
of various sizes throughout the abdomen.

This being so, it is remarkable that elimination of the adrenal
medulla alone produces such marked and definite results as
we have described. In the case of the effects of stimulation
of the splanchnic nerve, it may be that the stimulation produces
greater or more direct effects on the adrenal medulla than on
such structures as the " abdominal chromaphil body," though
the innervation of the latter would also be from the splanchnic.
There is another possibility. Assuming that the glandular
theory of adrenal activity is the true one, it might be urged

THE ADRENAL BODIES 235

that the adrenal medulla is a chromaphil gland of a more
highly developed type than that of the scattered masses of
chromaphil cells in other regions.

Cramer has recently come to the conclusion that an increased
activity of the thyroid gland leads to an increased liberation
of adrenin from the adrenal bodies. He has formulated the
conception that the thyroid and adrenal bodies form part of a
mechanism for the chemical heat regulation of the body. He
uses osmic acid vapour as a fixing agent to show the adrenin
granules under varying conditions. The method has been
applied to the adrenal bodies of mice and rats subjected to
the conditions which were expected to produce alteration in
the functional activity of the glands ; these were thyroid feed-
ing, thyroidectomy, injection of ^-tetrahydronaphthylamine
and other procedures. In all cases, he says, the method gave
evidence of distinct changes in the medullary cells. There was
evidence of the passage of adrenin granules into the blood-
vessels of the medulla after injection of ^-tetrahydronaphthyla-
mine. The granules disappear if the glands are exhausted, and,
in the various conditions demanding increased activity of the
glands, fine black granules, similar to the granules of the
medulla, appear in the cortex, especially in the layers of cells
nearest the medulla. Cramer suggests that this is evidence
that the cortex takes part in the functional activity of the
medulla and that these two parts of the gland are not two
physiologically independent organs.

These observations, if confirmed, have a very important
bearing on the question of the relationship between cortex and
medulla of the adrenal bodies. Up to the present time there
has been no satisfactory evidence that the two portions of the
gland have any relation to each other, either embryological or
physiological.

Even if it could be shown conclusively that under certain
conditions adrenin granules are found in the part of the cortex
next to the medulla, this would by no means prove that the
cortex normally takes a part in the production of adrenin. It
might be supposed that under pathological conditions adrenin
might not be able to escape by the usual channels, and so would
overflow into the neighbouring cortex.

The histological evidence as to a secretory function of the
adrenal medulla seems to us to be far from satisfactory.

236

THE DUCTLESS GLANDS

A very interesting contribution to the subject of the internal
secretion of the adrenal bodies has been made by Cannon and
de la Paz. They point out that, according to the researches of
Dreyer, Asher, and Tscheboksaroff, the adrenal secretion is
under control of the thoracicolumbar autonomic (sympathetic)
system. They further call attention to the fact that the
phenomena of a major emotional exhibition in an animal
indicate the dominance of sympathetic impulses. When, for ex-
ample, a cat becomes frightened, the 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 sympathetic paths. The authors put to the test the sug-
gestion that the adrenal glands share in the widespread subjuga-
tion of the viscera by sympathetic control.

The inhibition of contraction in strips of longitudinal
intestinal muscle was used as a physiological test.1 Blood
was obtained from a cat when quiet, and again after the animal
was excited by the presence of a barking dog. After an initial
shortening the strip contracted rhythmically in blood from a
quiet animal. In no instance did such blood produce inhibition.
On the other hand, blood taken from animals after the emo-
tional disturbance showed more or less promptly the typical
relaxing effect. The effect was obtained in blood from the
inferior vena cava near the liver. The authors believe that
the effect was due to secretion on the part of the adrenal glands,
and they offer a further suggestion that the persistence of the
emotional state after the exciting object has disappeared may be
in part due to an autogenous continuance of adrenal secretion.

A number of histological observations have been recorded,
which have been interpreted as pointing to an active secretion
on the part of the adrenal medulla. Manasse described brown
masses in the bloodvessels of the adrenal body, and small
highly refractive, colourless granules in the adrenal vein of the

1 The authors discuss the various methods of testing for adrenin. The
frog-eye method of Meltzer and Ehrmann did not give sufficiently striking
results. Strips of ox artery, employed by Meyer, though highly sensitive,
did not seem serviceable because of Schlayer's discovery that the method
is less efficient when used with foreign blood. The uterus method requires
several hours. So they finally decided upon the longitudinal intestinal
muscle. One of the chief advantages of this preparation is that it responds
by relaxing. This is very important, for other substances in blood than
adrenin — e.g., CO8 — will cause smooth muscle to contract, whereas known
substances evoking relaxation of smooth muscle are few and unusual in blood.

THE ADRENAL BODIES 237

dog, and others have found in blood taken from the adrenal
vein a considerable number of highly refractive granules.

Carlier investigated the adrenal of a hedgehog, and described
in the medullary cells deeply staining granules of varying size.
These he found also in the lumina of the venous sinuses either
singly or in clumps, and states that they could be observed
in different stages of elimination from the cells. Stilling records
that in " hunger " frogs the medullary cells are vacuolated,
and take on the bichromate reaction in an irregular fashion.
In summer frogs there is a distinct reduction in the amount
of the medullary substance.

Hultgren and Anderson give a description of characteristic
granules in the medullary cells and in the blood of the adrenal
vein. They believe that they observed the passage of these
through the endothelium of the bloodvessels. Some writers
have described sharply defined spaces between the medullary
cells, which are regarded as intercellular canals. These com-
municate with blood spaces, and sometimes it may be observed
that not only the medullary vessels, but also the lacunae and
the intercellular spaces are filled with fine, darkly staining
particles.

Ciaccio describes pericellular canaliculi, which he considers
are intimately related to the processes of secretion, and specific
granules in the medullary cells, which are of two kinds : the
one having a special affinity for the salts of chromic acid — the
chromaphil granules ; the other having a special affinity for
perchloride of iron.

Recently Stoerk and v. Haberer have stated that the char-
acteristic granules of the protoplasm of the adrenal medulla
are not cast out into the lumina of the vessels, but they repre-
sent structural units which are possibly to be regarded as the
seats of chemical action whose products are to be looked upon
as the true secretory materials of the medullary cells, which
materials pass into the blood by some such process as diffusion.
The fluid secretory product is the true bearer of the chroma-
phil reaction of the medullary cells, the granules having the
reaction only in their secretory phase, when they are just
forming the chromaphil substance. The fluid secretion can
be recognized intracellularly (in both the protoplasm and the
nucleus), and extracellular ly (in admixture with the serum of
the capillary -and venous blood). Besides the typical fine gran-

238 THE DUCTLESS GLANDS

ules of the medullary protoplasm there are coarse structures
which occur on the side of the cells turned towards the vessels,
and which reveal a different staining reaction from the gran-
ules. The capillaries are everywhere bounded by endothelium
between the blood and the medullary cells.

Thus it would appear that the evidence physiological and
histological that the adrenal medulla is, in fact, an internally
secreting gland, and that adrenin is the product of its secretion
is not very convincing. We have next to inquire whether
adrenin acts directly upon the sympathetically innervated
tissues, or whether it acts in some other more indirect or round-
about manner. Several writers believe that the function of the
adrenal medulla is to render harmless the poisonous products
of muscular activity, and render them serviceable for the regula-
tion or the nourishment and innervation of the whole motor
apparatus. Some are of the opinion that the waste products of
muscular metabolism are, in fact, converted into adrenin.
Thus the antitoxic theory is combined with that of internal
secretion.

Notwithstanding the paucity of good evidence, clinicians and
pathologists have now very generally adopted the internal
secretion theory of the adrenal medulla, and the chromaphil
or " hypertensive " system generally. Thus, Rolleston dis-
cusses the possible pathological relations of the internal secre-
tion, and divides these into (1) Alteration in quantity — (a)
absence, (b) diminution, and (c) excess ; and (2) alteration in
quality. There is no need to pursue this subject further.

2. Theories as to the Function of the Adrenal Cortex

We cannot at the present time allocate any definite function
to the cortical portion of the adrenal body, though there can
be little doubt that it exercises a very important influence
upon the economy. The cortex is larger than the medulla, and
is composed of epithelial cells, the appearance and micro-
scopical structure of which suggests a high degree of secretory
activity. Moreover, as we have seen (p. 152), there are strong
reasons for thinking that the cortex is of more importance for
the maintenance of life than the medulla.

The presence of fatty or fat -like substances in the cortical
cells has been known for a long time, and has already been

THE ADRENAL BODIES 239

referred to from the chemical standpoint (p. 203). They
appear to have been first described by Ecker. The earlier
observers referred to them definitely as fat droplets and fat
granules. Kolliker calls attention to differences in the amount
of the cortical fat in different classes of animals. The human
being has a moderate amount.

Rabl investigated the micro -chemical reactions of the cor-
tical cells in birds. He showed that the cortical granules are
soluble in alcohol, ether, and chloroform, turn black with osmic
acid, and red with alkanna. While, however, fat after treat-
ment with osmic acid is insoluble in chloroform and oil of ber-
gamot, the cortical granules are soluble in these reagents as
well as in xylol. For this reason Rabl considers them only as
" fat-like " bodies. These observations were found to be true
also of the cortical granules of the horse and the dog. Alex-
ander, however, noted that the cortical granules do not stain
black with osmic acid, but only take on a brownish tinge ;
therefore, they must consist of some substance other than fat.

Kaiserling in 1895 reported that a large part of the granules
in question are doubly refracting. Orgler concluded that the
particles are not fat, but are related to myelin.

The granules are present in embryonic life, and, according
to Plecnik, are not to be regarded as representing a fatty
degeneration. In the medullary cells in the embryo there are
granules which blacken with osmic acid, but these are not
abundant, and at the fifth year granules are not present in all
medullary cells. Now we find more and more cells which
stain black with a clear centre, and after puberty these ring-
shaped granules are alone present. After this time any
solid granules in the cells show that they really belong to
the cortex. Adrenal fat is different from other fat. In the
external part of the cortex there are hollow spaces which are
often lined with a layer of flat cells or ordinary cortical cells ;
these are best seen shortly before birth, and are absent in
adults.

According to Bernard and Bigart, the cortex produces
lecithin and pigment. It contains cells with compact (dark
protoplasm, and cells with less compact (light) protoplasm,
In the formation of the lecithin, fat-like droplets arise in the
cells, and the process appears to progress from the periphery
to the centre of the gland. In the pigment formation vacuoles

240 THE DUCTLESS GLANDS

occur in the cells and become filled with fluid. This first
occurs in the centre of the cells. Then the pigment appears
in the form of granules at the border of the vacuolated part
of the cells.

Labbe concluded that what Bernard and Bigart called
" labile fat " is lecithin or a mixture of lecithins. He
made an estimation, on the one hand, of the total fat by
extraction with ether and alcohol, and, on the other hand
the total quantity of phosphorus contained in the adrenal
bodies, and found that the ratio of phosphorized fat to the
total fat is 45-3 : 100 in the horse, 48-8 : 100 in the sheep,
5? -7 : 100 in the rabbit. The phosphorized fat constitutes
6*77 per cent, of the organs in the horse ; in man the ratio of
the lecithin to the total fat is 13-1 : 100 ; the lecithin amounts
to 2-08 per cent, of the total weight. The lipoids are in-
creased after muscular labour.

Babes believes that the pigment of the zona reticularis
arises from the lipochrome of the fatty layer. When the
organ is very rich in fat, this is deposited in crystalline,
doubly refracting structures resembling protagon in their
reactions.

It is by no means clear that these lipoid (phosphorized fat)
granules represent the actual secretion of the adrenal cortex.
Nor, if such were the case, is it possible at the present time
to suggest any reasonable theory as to their function.1 (See,
however, pp. 235-248.)

1 Ciaccio claims that the lipoids in any tissue may be distinguished from
the neutral fats by the following histological method : (1) Fixation for
twenty-four to forty-eight hours in the following fluid :

Five per cent. pot. bichrom. .. .. .. 100 c.c.

Formalin . . . . . . . . 20 c.c.

Acetic acid . . . . . . . . . . 5 c.c.

(2) Five to eight days in potassium bichromate solution, 3 per cent. (3) Run-
ning water, twenty-four hours. (4) Alcohol, twenty-four hours. (5) Absolute
alcohol, two hours. (6) Xylol. (7) Paraffin.

The sections are stained with a saturated solution of Sudan III. in 80 per
cent, alcohol.

According to Ciaccio, the droplets in the tissues shown by this method
consist of lecithin and other lipoids.

Bell has shown, however, that potassium chromate acts upon droplets
of neutral fat in the tissues as well as upon the lipoids. It is certain that some
lipoids, such as cholesterin, fatty acid mixtures, cerebroside, etc., are much
more readily chromated than neutral fat. But the size of the droplet of
neutral fat is a factor of great importance. A small droplet of triolein is com-

THE ADRENAL BODIES 241

Mulon is of the opinion that in the adrenal cortex a complex
lecithalbumin, elaborated by the activity of mitochondria, is
poured into the blood-stream. This lecithalbumin he regards
as the internal secretion of the adrenal cortex.

There are four views as to the function of the adrenal cortex :

1. That it is related to growth and development, especially
of the sexual organs.

2. That it has an antitoxic function.

3. That it plays some part in the elaboration of the adrenin
which is found in the medulla.

4. That the enormous development of the adrenal cortex in
the human embryo is connected with the highly developed
brain of man.

It is now tolerably certain that there is an intimate connec-
tion between sex characters and the adrenal cortex. Most of
the evidence on this point is of a clinical nature.

Wooley and Bullock and Sequeira reported that tumours
or hypertrophies of the adrenal body are sometimes associated
with precocious development of the reproductive organs.

Glynn has given an excellent account of the tumours and
rests of the adrenal cortex with their relationships to sex
abnormalities. The following is a brief abstract of his classi-
fication :

A. Benign tumours. Cortical. Group 1. Diffuse hyper-
plasia passing into

Group 2. Adenomata, which may be bilateral. The cells
contain a considerable amount of fat, and their arrangement
is like that of the zona fasciculata.

B. Malignant tumours. Cortical. Group 1. Sarcomata :
round-celled often lymphosarcoma, i.e., small cells with an
alveolar arrangement. These are common in children ; espe-
cially males between the ages of two and three.

Group 2. Hypernephroma or mesothelioma, a tumour
having large polyhedral epithelial cells, recalling the structure
of the adrenal cortex.

Hyperplasia of the adrenal gland or of accessory adrenals is
frequently associated with pseudohermaphroditism. The great

pletely chromated in the same time that is required to chromate a large lipoid
droplet. Ciaccio's technique is, however, a valuable method for the study of
the fatty substances in the tissues, though it gives only a rough distinction
between neutral fats and lipoids.

242 THE DUCTLESS GLANDS

majority of these cases occur in female pseudohermaphrodites,
that is to say, in females with internal organs of the male type,
illustrating the tendency of neoplasia or hyperplasia of the gland
to be associated with the appearance of male characters in the
female. In most of the females the hermaphroditism was
advanced, for prostates were present. Glynn quotes thirteen
cases in illustration of this condition.

Adrenal hypernephromata are almost invariably character-
ized in children by precocious growth of the body generally and
of the sexual organs in particular, with overgrowth of hair and
fat. The skin becomes pigmented and the children are below
the average in intellect. According to Guthrie, there are two
types : (1) the obese type, met with in both sexes, but apart
from the development of pubic hair the development of the
sex organs is not exaggerated, though one of the females men-
struated ; (2) the muscular or "infant Hercules" type,
occurring only in males, who may show true sexual precocity.

Hypernephromata of the adrenal body in children are much
commoner in females than in males, and tend to increase the
male primary and secondary sexual characters at the expense
of the female.

Glynn quotes six examples of the tumour referred to in the
last two paragraphs. These examples were found in young
adult females and the growth was associated with changes in
sex characters. It will be interesting to quote one of these :

A girl aged 16f years began to menstruate at 15, and continued
to do so regularly for one year. When menstruation ceased she
grew a beard and moustache, and hair developed also on the
thorax and linea alba. The voice changed to the male type.
She became very obese ; the mammae were well developed. She
died of phlegmon of the hand. The external genitals were of
the feminine type, the uterus measured 8 centimeters exter-
nally and was normal, but the ovaries were small and hard,
showing no trace of ovulation, neither macroscopically nor
microscopically. The right adrenal contained two yellow
nodular tumours the size of a cherry, and the left was con-
verted into a mass as big as a fist. Microscopically the right
tumour consisted of round or polygonal epithelial cells in a
network of capillaries ; those in the left showed similar struc-
ture, but the meshes were wider and more irregular. A few
larger cells, rich in chromatin and often multinucleated, were

THE ADRENAL BODIES 243

also present. The condition is described as typical of " struma
suprarenalis."

Gallais has recently observed and collected a number of
cases in which tumours have given rise to striking abnormali-
ties in the development of the reproductive organs. He groups
them together under the title " genito-adrenal syndroma."
One form of this syndrome is characterized by sexual precocity,
other forms being such as are described above. He regards
the cortex of the adrenal body as essentially a " puberty
gland."

There are other evidences derived from comparative ana-
tomy and physiology of the association between the adrenal
cortex and the sexual functions.

Functional variations. Stilling, in his researches upon the
adrenal body of the rabbit, observed periodic variations in the
weight of these organs. There was enlargement of the glands
in male rabbits during the breeding -season. In the same
communication he reports that the peripheral part of the cortex
in the frog contains, during the summer, certain peculiar
elements, the " summer cells," which atrophy later on during
the pairing season. Patzelt and Kubik have, however, come
to the conclusion that Stilling's summer cells are present the
whole year round and are independent of age, sex, or state of
nutrition. These authors prefer to call the cells in question
acidophile cells from their staining reactions. A curious point
is insisted upon by these writers. They find that the acido-
phile cells are only present in one species, viz., in R. esculenta.
They are entirely wanting in the adrenal bodies of the other
anura which they investigated, as also from the glands of the
urodela and the reptilia. They note also that similar cells are
found in the parathyroids of mammals and in the pituitary
gland throughout vertebrates.

As far back as the year 1806 Meckel noted a relationship
between the adrenal bodies and the reproductive organs.

Nagel in 1836 remarked that animals with large sexual
organs and well -developed reproductive instincts possessed
large adrenal bodies, which in birds and amphibians became
still larger during the breeding season. Glynn remarks that
it is highly probable that a similar change occurs in human
beings, but that there are no recorded observations on this
point. He suggests that such an enlargement, if it does take

244 THE DUCTLESS GLANDS

place, may explain the curious tendency of any hair or "down "
upon the face or body of a woman to increase in amount during
pregnancy.

A hypertrophy of the adrenal bodies during pregnancy was
noted by Guieysse in the guinea-pig, which enlargement chiefly
affected the zona fasciculata.

It has been stated that removal of the ovaries results in
hypertrophy of the adrenal cortex, especially the zona glomer-
ulosa.

It has long been noticed that there is a resemblance between
the cells of the adrenal cortex and the interstitial elements of
the ovary and testis and those of the corpus luteum. Janosik
looked upon all these cells as being very closely related. Pod-
vissotzky insisted specially on the resemblance between the
cells of the adrenal cortex and those of the corpus luteum.
This was further emphasized by Mulon who, from observations
on guinea-pigs, goes so far as to speak of the corpus luteum of
pregnancy as a temporary cortical adrenal body.

It seems hopeless at present to attempt any explanation of
the precise manner or the essential mechanism of the influence
of the adrenal cortex upon the reproductive organs. It is
perhaps most in accordance with current views to admit the
hypothesis that a certain hormone, or certain hormones are
secreted by the adrenal cortex which are passed into the blood-
stream and so reach and exert their action upon the reproduc-
tive organs. It has been suggested that the adrenal body may
act through the mediation of the pituitary, but so far as I am
aware, no changes in the latter organ have been observed in
any of the cases referred to above.

Much has been written and many hypotheses have been put
forward on the subject of the relationships between the various
organs furnishing an internal secretion. Much of this is purely
hypothetical, and a great deal remains to be discovered before
we can formulate any general statements. (See p. 395.)

It is possible that the simpler physiological conception of
underaction or overaction respectively of the various ductless
glands, now used to account for the various pathological states,
may have to be supplemented or superseded by a consider-
ation of modified or deranged function.

Recently an attempt has been made to investigate the
relations between the adrenal bodies and the reproductive

THE ADRENAL BODIES 245

organs by studying the effects of feeding animals with the
adrenal bodies or preparation made from them.

Some years ago the present writer failed to observe any
immediate physiological effect upon dogs, cats, and rabbits,
after feeding with the adrenal bodies of sheep ; just as the
administration of large doses of extracts (in some cases made
from the medulla only) failed to produce any noticeable rise
in the blood-pressure in the human subject. D'Amato has
also shown that very large doses do not increase pressure,
although they may cause arterial degeneration. As we have
seen above, Leyton states that adrenal extract although
it ordinarily fails to produce elevation of blood-pressure when
administered by the mouth, will bring about this effect in cases
of Addison's disease.

But the experiments about to be described are of a different
character. They involve the administration of comparatively
small doses of gland substances over a long period, in order to
test the effect upon the growth of the body as a whole, and the
reproductive organs in particular. R. G. and A. D. Hoskins
have carried out a series of experiments on white rats in which
certain of the young animals were fed with desiccated adrenal
gland * while certain others were kept as controls. Forty -five
rats were fed with adrenal body for varying periods of irom
two to nine weeks. Twenty-six animals from the same litters
were kept as controls. The rate of growth and the weights of
various glands were determined in each series. No differences
between the two series could be detected in the case of the
kidneys, heart, pituitary body, thyroid, thymus or adrenal
bodies. The spleens of the experimental series were somewhat
smaller than those of the controls, but highly variable in size.
The ovaries in the few cases studied were larger in the experi-
mental series. The testes (twenty-six experimental, thirteen
control) showed hypertrophy. These results are in confirma-
tion of the clinical evidence above stated, and indicate that the
adrenal bodies exercise a stimulating effect on the growth of
the testes in young animals.

The authors of the communication just referred to discuss
the question as to what constituent of the gland the testicular
hypertrophy is due to. They conclude that it is in all pro-
bability to be ascribed to the cortical portion. But it is

1 Parke, Davis & Co.

246 THE DUCTLESS GLANDS

obvious that the experiments would be more satisfactory as
regards this point if the cortex only were employed for the
feeding. A further criticism of the experiments above described
seems justified from the fact that desiccated gland was used.
I believe that the material is " degreased " before it is " desic-
cated," and the former process would be likely to remove
many " lipoids," some of which might be among the physio-
logically active substances. In future experiments, therefore,
it would be well to use fresh cortex only, in order to eliminate
these sources of error.

It has been stated that the injection of adrenal cortex in
white rats causes falling out of hair and some changes in the
ductless glands.

Linser has recorded the case of a giant with a huge adrenal
growth, and Scudder has put forward some evidence to show
that malignant growths of the cortex tend to produce meta-
stases in bone.

2. The theory that the cortex has the power of neutralizing
toxic substances has presented itself in two principal forms :
(a) That the gland destroys the poisonous products of body
metabolism, especially those arising from muscular activity.
This is the theory of auto-intoxication, put forward by Abelous
and Langlois, and was originally applied to the whole gland
before the active principle of the medullary chromaphil tissue
was discovered. But a modification of the view is now held
by Boruttau and Langlois to apply to the secretion of adrenin
by the chromaphil cells, (b) That the cortex has the duty of
destroying poisons which come from without the body. That
the cortex may exert antidotal properties is suggested by
Myers' observation that cobra poison, after being mixed with
an emulsion of the adrenal cortex, was no longer toxic, control
experiments with emulsions of the medulla and of other organs
giving negative results. Experimental infections with various
organisms, such as the tubercle bacillus, and with toxins, such
as the diphtheria toxin, give rise to hypertrophy of the cortex,
and in some instances apparently to deficiency of the medulla.
Ritchie and Bruce report in diphtheritic toxaemia in guinea-
pigs exhaustion of all adrenin from the adrenal medulla.

3. It has often been suggested that in the cortical cells the
material which is to furnish the active agent of the medullary
secretion — the adrenin — passes through the initial stages of

THE ADRENAL BODIES 247

formation, and that the process of elaboration is completed in
the medulla. This view has been tentatively proposed by
Schafer and Herring, and more definitely formulated by
Abelous, Soulie, and Toujan. These authors believe that the
active principle can be obtained in small quantities from the
cortex, where it is manufactured from tryptophane. It is then
passed into the medulla and stored there. These views have
not received support, and the experimental evidence in their
favour is not convincing.

Elliott and Tuckett have made an attempt to solve the
problem of a possible functional relationship between cortex
and medulla. Among mammals the guinea-pig is conspicuous
by the huge development of its adrenal bodies, the growth
being chiefly of cortex. They point out also that the lower the
animal is in the scale of vertebrates the larger is its stock of
chromaphil tissue. Gestation accelerates the growth of the
gland.

As signs of secretory activity Elliott and Tuckett recognize
four substances in the glands :

(1) A fatty substance.

(2) A doubly refracting substance.

(3) Brown granules of the cortex.

(4) The chromaphil substance of the medulla.

The first two are nearly related ; the doubly refracting
substance increases with rest, when the fat becomes less
abundant. In phases of " exhaustion " the doubly refracting
substance vanishes and the fat spreads over all the cortex.
But neither are essential factors in a generalized type of cortical
activity, for neither appears in the sheep. The brown granules
occur characteristically and plentifully in the guinea-pig, and
over a restricted area in the ornithorhyncus. They accumulate
with rest, and disappear very early in exhaustion ; the
cytoplasm of the cells in which they have been stored then
develops fat. Exhaustion of the medulla is shown by a
progressive thinning of its yellow stain with potassium
bichromate. In states of extreme exhaustion this stain
finally vanishes.

The only indication found by Elliott and Tuckett of any
functional relationship between cortex and medulla is the
observation that the changes described above, both in cortex

248 THE DUCTLESS GLANDS

and medulla, move in close parallelism with one another in
pathological states of the body. On the other hand, stimu-
lation of the splanchnic nerves seems to affect chiefly the
medulla (see p. 224 et seq.).

4. The enormous development of the adrenal cortex in the
human embryo is possibly connected with the highly developed
brain of man. Alexander has suggested, and Kohn supports
the suggestion, that the connection may depend upon a
lecithin product in the adrenal cortex in accordance with the
lecithin requirements of the growing brain.

It must be confessed that both as to the function of the
cortex and as to a possible relationship between it and the
medulla, we are still almost entirely in the dark.

S. Summary of Views as to the Probable Functions of
the Adrenal Bodies

As we have seen above, it is difficult to adduce any satis-
factory evidence that the secretion of the chromaphil tissue is
of any use whatever in the normal state of the animal.

We have also seen that the suggestion has been made that
the secretion is of great service in certain emergencies. Certain
experiments seem to show that during times of emotional
stress the adrenal bodies pour into the blood sufficient adrenin
to be of some service, possibly in increasing the power of
sustained muscular activity. This view has received very
general approval, but it would be rash to affirm that it has
been firmly established. Stewart and Rogoff conclude that
fright has nothing to do with the results.

The experiments of Hoskins and McClure, taken in con-
junction with others above referred to, furnish sufficient
evidence to warrant us abandoning the tonus theory of adrenal
secretion. But the theory is still put forward by writers on
clinical subjects, and is made to account for the low blood-
pressure in Addison's disease. The fact is that we have not a
single physiological observation (except perhaps the effect of
adrenin on the contraction of skeletal muscles) which throws
any light on the pathology of Addison's disease.

The following is a brief summary of what, in the opinion of
the present writer, represents the state of our knowledge
concerning the adrenal bodies.

THE ADRENAL BODIES 249

1. What we call the adrenal body represents the anatomi-
cal association of two elements, each one of which is derived from
a separate and independent system. The adrenal body proper
or cortex is part of the " cortical " or " inter-renal " system.
The medulla is simply an accumulation of chromaphil cells of
the same nature, histologically, chemically, and pharmaco-
dynamically, as similar but smaller masses along the
sympathetic at other levels.

2. There is no clear evidence that these two systems are
functionally related to one another.

3. The adrenal medulla (as well as the " chromaphil tissue "
generally) is derived from the sympathetic nervous system,
and is alleged to facilitate this system's functions in certain
physiological emergencies.

4. The cortex is derived from the germ epithelium and
there is considerable evidence that it has important functions
in connection with the development of the reproductive
organs.

5. There is a considerable mass of clinical evidence that
tumours of the adrenal cortex are frequently associated with
sex abnormalities.1

6. Additional evidence in the same direction is furnished by
the enlargement of the cortex during breeding and pregnancy.

7. It is possible that a final solution of the problem as to the
relation between the adrenal gland and sex will only be arrived
at when the wider problem of the relationships between the
various ductless glands shall have been solved.

8. Feeding young animals with adrenal gland substance
seems to stimulate the growth of the testis.

9. Inanition produces marked hypertrophy of the adrenal
bodies (McCarrison, Vincent and Hollenberg).

10. The cortex is the part of the gland which is essential to
life. We do not know why its removal causes death, but it is
possible that this is due to some defect in muscular metabolism.

1 The association is frequent, though not constant.

CHAPTER XII

THE CAROTID AND COCCYGEAL BODIES

A. The Carotid Body

Historical

THE carotid body has been known for a very long time.
Neubauer described and depicted the body in the year 1786,
and Haller had mentioned it many years previously. Andersch
was the first to call the body the " gangliolum intercaroticum."
In the nineteenth century, Mayer rediscovered the body and
showed that it is an organ of constant occurrence.

It was Luschka who substituted the name " glandula
carotica " for Andersch's " gangliolum intercaroticum," and
thereby initiated a controversy which has lasted up to the
present time. He was struck with the difference between the
" ganglion intercaroticum " and the other ganglia of the
sympathetic. A careful examination convinced him that the
structure was not a ganglion, but a gland made up of cell
columns and vesicles. He could find only a few nerve cells
in the body.

The glandular tubes and vesicles described by Luschka were
regarded by Arnold as ramifying branches of the artery which
supplies the body, while the epithelial cells are those of the
lining wall of the bloodvessels. This author proposed the
name " glomeruli arteriosi intercarotici."

Eberth places the carotid body side by side with the coccy-
geal ("plexus vasculosus coccygeus ") as the " plexus arteriosus
caroticus," and this view was adopted by anatomists generally.

Katschenko investigated the development of the carotid
body in the pig, and reported that it is not of epithelial origin.
It is formed in the outer coat of the carotid artery, and is
intimately related to the neighbouring nervous ganglia.

Marchand describes the development of the carotid body

250

THE CAROTID AND COCCYGEAL BODIES 251

in the human subject. He suggests the name " nodulus
caroticus," and considers the body in question to be a rudi-
mentary organ.

Stilling made the important discovery that the carotid body
contains some cells which stain brown with potassium bichro-
mate. This observation was confirmed by Kohn, who has
added to the long list of names attached to this tiny body, by
suggesting that it be called the " paraganglion intercaroticum."

Comparative Anatomy and Embryology

In the human subject the carotid glands are small bodies
situated just above the bifurcation of the common carotid
artery on each side, and between its internal and external
branches. According to Luschka, the gland is of an elongated
spherical shape, 5 to 7 millimetres long, 4 to 2J millimetres
broad, and 1J millimetres thick. Sometimes it is divided into
two or more nodules. The body is greyish or brownish-red
in colour. Its consistence is more compact than that of a
nerve ganglion, and its substance cannot be easily teased out
with needles.

In all, or in nearly all mammals so far investigated, the
carotid body has been found in the neighbourhood of the
bifurcation of the common carotid artery, either exactly at the
bifurcation or somewhat higher up in the connective tissue
between the internal and external carotid arteries. Both
these and the common carotid may give twigs to the body.

Many observers have noted the richness of the nerve-supply
to the carotid body ; this supply is mostly from the sympathetic
nervous system. According to Luschka, there is situated
between the internal and the external carotid arteries a rich
nervous plexus beset with tiny ganglia — plexus intercaroticus
—which is a complex of fibres from the superior laryngeal and
the glosso-pharyngeal nerves, and a variable number of twigs
from the superior cervical ganglion. According to Svitzer,
there are twigs to the body from the superior cervical ganglion,
from the nervi molles Halleri, from the trunk and the pharyn-
geal branch of the vagus, from the superior laryngeal branch
of the vagus, from the hypoglossal, and from the sympathetic
above and below the superior cervical ganglion.

According to Maurer, the body is absent in fishes, but present
in Amphibians and all higher vertebrates. In the Anura an

252 THE DUCTLESS GLANDS

epithelial bud occurs in the region of the second gill-cleft,
which at first resembles the parathyroids from clefts 3 and 4,
but soon becomes distinguished by its relation to the branchial
arteries. Zimmerman states that there are no epithelial
elements, but only a proliferation of the vascular wall. Maurer
believes that the carotid body of Rana is homologous with the
carotid body of higher vertebrates. The matter is doubtful
in reptiles and birds, though Maurer believes that in Echidna
the origin of the structure is the same as in the frog. Schaper,
however, believes that in mammals the body is a development
of the wall of the artery. Maurer acknowledged that our
knowledge of the development is still very imperfect, and
suggests that under a single name several different structures
have been described. Kohn believes that the carotid body is
derived from the embryonic ganglion cells of the sympathetic
plexus.

Microscopical Structure

According to Kohn, there are four principal types of the
organ according to the arrangements of the cellular elements.
In the first type the body is compact and circumscribed. The
connective tissue is so finely divided that the cellular character
of the tissue is predominant. The carotid gland of the cat is a
good example of this type. (See Fig. 56.)

In other cases the connective tissue is distributed into the
gland in larger amount, and so two new types arise. In one of
these the organ has a kidney-like form. At the hilus there is a
considerable accumulation of connective tissue with blood-
vessels and nerves. From this region radial septa run into
the interior, which divide up the organ into lobules after the
manner of a secreting gland. The lobular formation is found
typically in the carotid gland of the monkey (Macacus rhesus).
In man the gland is divided by its connective tissue into small
separate islets.

The fourth type is exemplified in the carotid body of the
rabbit, which consists of scattered islets and strands of cellular
tissue. This may be called the diffuse type (Kohn).

The cells are of variable, for the most part of considerable,
size. Their form is manifold ; they may be prismatic or
cylindrical, but they are frequently flat. Kohn does not deny
that there is a certain resemblance to an epithelial structui

THE CAROTID AND COCCYGEAL BODIES 253

though he is opposed to the view that the chromaphil tissues
are of a secretory nature.

The cell body is finely and uniformly granular. The nucleus
is large, granular, and shows a distinct nuclear membrane and
nucleoli. As a rule there is one nucleus, but there may be
two. In some cells the nucleus is so poor in chromatin that
the cell resembles a nerve cell. Many cells, moreover, possess
a cell membrane.

According to Kohn all the true specific cells of the body are
chromaphil cells — that is to say, they become stained of a
yellowish or brownish tinge by solutions containing bichro-
mate of potassium. Kohn states that the degree of coloration
varies within very wide

limits. The cells are '£&fy*^Q^*£-Ji

arranged in groups, and
the body is permeated

by non -medullated >\f~^' ft \L j®)^

nerve fibres and scat- '^>(5^^jfe^^'»?*^65^^^
tered nerve cells. &J£!r)t'^J^J&ffiH^®'\

The organ is richly ^* Oc ••* ^^•Qfcfmfis£^'*-*'~

provided with blood- <l"/ r>V*

vessels. The arteries
break up into a close

.,, , FIG. 56. — Portion of a section through the

Capillary network, carotid body of a cat. (Drawn by Mrs.

which penetrates the Thompson.)

cell groups, and where

the amount of connective tissue is small, come into close

contact with the cells.

Kohn lays great stress upon the intimate relation existing
between the nerve fibres in the body and the specific carotid
cells.

The carotid body is developed from the embryonic ganglion
cells of the intercarotid sympathetic plexus.

From the foregoing account it would seem that we are
justified in including the carotid body in the category of the
chromaphil tissues. The body, then, has no special functions,
other than those of the chromaphil tissues generally, and all
that has been said on the pharmacodynamical effects of
adrenin, the chemistry of adrenin, and the functions of the
adrenal medulla, applies in all probability to the carotid
body.

254 THE DUCTLESS GLANDS

B. The Coccygeal Body

The coccygeal body in the human subject is a small organ, at
most 2-5 millimetres in diameter, sometimes broken up into a
number of smaller bodies, placed immediately in front of the
apex of the coccyx, and receiving branches of the middle sacral
artery.

The body was discovered by Luschka in 1860, and since that
date various opinions have been held in regard to its structural
elements and its essential nature. These opinions have been
classified by Schumacher as follows :

1. The cells of the body are not constituents of the vessel
walls, but thread-like accumulations of specific cells, into which
bloodvessels penetrate.

2. The cells are constituents of the bloodvessel walls :

(a) They are derived from the endothelium.

(b) They are derived from the. adventitia (" perithelium "
cells).

(c) The cells are related to those of the middle coat of the
middle sacral artery and its branches.

Schumacher has given a full description of the " glomus
coccygeum " in the human subject, and the " glomeruli
caudales " of other mammals. According to this author, the
former corresponds in all essential points to the latter, the only
difference being that the " glomeruli caudales " of animals
consist of several detached portions corresponding to the
caudal segments, while the " glomus " of man is represented
by a principal structure at the tip of the coccyx and some
smaller nodules.

It has been shown by Stoerk that the cells of the coccygeal
body do not give the chromic reaction at any period of life,
and that they bear no histogenetic relation to the sympathetic
nervous system.

The "glomeruli caudales" and the "glomus coccygeum"
appear to be arterio-venous anastomoses (Schumacher), and
the epithelioid cells are transformations of the smooth muscle
fibres of the middle coat of the artery.

The structures in question are probably to be regarded as
safety-valves in the course of the peripheral circulation. The
balance of evidence is against their having any kind of internal
secretion*

CHAPTER XIII

THE FUNCTIONS OF THE THYROID AND PARATHYROIDS

A. Introductory : The Organs derived from the
Region of the Pharynx and Gill -Clefts

THE organs in question may be divided into two groups. The
first group is represented by structures which arise simul-
taneously with the gills and gill-clefts — viz., the thyroid, the
thymus, and the post-branchial bodies (the suprapericardial
bodies of v. Bemmelen). The organs of the second group are
developed concomitantly with the degeneration of the gills and
the closing of the clefts, from whose epithelium they arise.
These are the " branchial bodies " of the Anura and the para-
thyroids throughout Amniota.

B. The Comparative Anatomy and Histology of the

Thyroid and Parathyroid Bodies

Cephalochorda and Cyclostomata

1 . In Amphioxus and Ammoccetes the thyroid is a sausage-
shaped glandular body which branches in a fork-like manner
and retains its opening into the pharynx. This indicates a
relationship to the hypobranchial furrow or endostyle of
Tunicates. The epithelium lining this " saccular gland is
ciliated, and secretes mucus.

In Petromyzon the connection with the pharynx is broken,
and the gland consists of a number of closed vesicles lined by
tall columnar epithelium, and containing a colloid substance
in their interior.

The details of the metamorphosis of the endostyle in
Petromyzon have been recently worked out by Marine. The
endostyle persists throughout the larval period in full activity.
Then, at the metamorphosis, it undergoes involution, all but a
remnant disappearing. This remnant assumes the form of the

255

25(3 THE DUCTLESS GLANDS

ductless thyroid, and persists throughout life. The endostyle
in Amphioxus and Ammoccetes appears to be a gland which
secretes a slime of service in the collection and possibly in the
digestion of the food.

2. Simon found the thyroid in all classes of Fishes. In Elas-
mobranchs the thyroid is a moderately large compact organ
situated at the anterior end of the ventral aorta, in front of the
bifurcation of the branchial artery. The gland is yellowish-
white in colour, and the anterior extremity is elongated and
prolonged to a point in some species. In other species the
thyroid is nearer the end of the tongue, situated on the coraco-
hyoid muscles, immediately under the coraco-mandibular, and
may be spheroidal, flat, or irregular in shape. Groups of
follicles are sometimes detached, forming accessory thyroids.

There is a striking uniformity in the general microscopic
appearance of the thyroid gland throughout all vertebrates
above the Cyclostomata, and the thyroid of the Elasmobranch
fishes would be immediately recognized as such by any student
who had once seen under the microscope a preparation made
from the mammalian thyroid. Such differences as are found
throughout vertebrates, in regard to the amount of inter-
vesicular connective tissue, intervesicular epithelial tissue, size
of the vesicles, and so on, are equally to be recognized among
the glands of Elasmobranchs themselves.

Perhaps the most interesting of the species examined is
Scyllium canicula. In this fish the thyroid contains not only
the usual vesicles, but also several bodies composed of two
kinds of cell — lymphoid and epithelial. Since parathyroids
have not been described by the embryologist, these bodies
are probably nodules of thymus.

Throughout Elasmobranchs the shape of the cells lining the
vesicles varies extremely in different species. Thus, in some
it is of a tall columnar, and in others of a low cubical, form.
The colloid contents appear to be of the same character as in
other vertebrates.

3. Among Teleostean fishes McKenzie gave an account of
the anatomy of the thyroid in Amiurus. The gland is placed
beneath the copulae of the branchial arches and surrounds the
anterior end of the branchial artery. It is an unpaired structure
extending in the median line from the origin of the vessels at
the first pair of gill arches to a short distance behind the origii

THE THYROID AND PARATHYROIDS 257

of the single stem for the third and fourth pair of arches.
Although richly supplied with blood, it appears of a whitish
colour contrasted with the bloodvessels among which it lies.
The framework of the organ consists of loose connective tissue
which does not form a lining membrane, but simply passes
over into the like tissue sheathing the adjacent parts and the
vessel which it surrounds. The usual vesicles of the thyroid
are scattered throughout this connective tissue, showing a
tendency to arrange themselves in short rows. The wall of
the vesicle consists of a single layer of columnar epithelium
resting on a basement membrane formed from the surrounding
connective tissue. The epithelium is readily made out in the
young fish, but disappears frequently in the adult.

On re-examining Amiurus it was found that the connective
tissue in which the vesicles lie is very compact and not loose, as
described by McKenzie. Further, in none of the slides was the
epithelium columnar, and the statement that the cells of the
vesicles rest upon a basement membrane could not be verified.
In an embryo specimen the vesicles were filled not with colloid,
but with some material full of nuclei [epithelium or adenoid
tissue (?)].

The thyroid of Teleostean fishes is of special interest owing
to the fact that goitre (active thyroid hyperplasia) is not
uncommon (Marine and Lenhart, Gudernatsch), and is stated
to become carcinomatous. The tendency of the growth to
spread seems to be connected with the fact that the gland is
not circumscribed, has no capsule, and so the gland follicles are
distributed over a wide area, and outstanding groups of cells
may become fresh foci of tumour formation.

No parathyroids have jDeenJiound in fishes, but the post-
branchial body is developed.

4. In the Urodela the thyroid occupies a more superficial
position than in the Anura. The development has been
worked out in Triton, Siredon, and Necturus. The gland
arises from a median rudiment, and subsequently becomes
paired.

In Sperlerpes ruber the vesicles are approximately of the
same size as in the frog. They do not number more than a
dozen. There is less connective tissue than in the frog, and
the vesicles are therefore more closely packed together. The
colloid contents are of the same character as in vertebrates

17

258 THE DUCTLESS GLANDS

generally. The gland is distinctly more vascular than in the
frog.

In Triton there appear to be two, or even three, parathyroids
developed on either side. In Sperlerpes there is sometimes
only one. The general histological features appear somewhat
different from those of the corresponding structure in the frog.
The body is of extremely small dimensions, but contains fairly
large blood capillaries. It is encapsuled, but its constituent
cells do not possess the whorl arrangement so characteristic
of7the parathyroids of the frog.

The post-branchial body occupies a corresponding position
to that in the frog ; it consists of about eight vesicles. These
have a taller epithelium than the thyroid vesicles and contain
colloid.

5. In the Anura (a) the thyroid has been most carefully
studied in the frog. In this animal the gland of each side is
an oval corpuscle placed ventrally to the root of the processus
postero-medialis of the hyoid cartilage, and occupies a deep
concealed position. It is very difficult, as a rule, to find by
ordinary dissection.

Like the thyroid of all animals, that of the frog consists
of a number of closed vesicles, the walls of which are composed
of a single layer of epithelial cells. The cells lining the vesicles
are cubical, but small, corresponding with the small size of the
vesicle and of the whole gland. The intervesicular tissue,
instead of being cellular as in mammals, is formed of fibrous
connective tissue with scattered nuclei and bloodvessels. The
colloid contents of the vesicles call for no special notice.

(b) Accessory thyroids are not uncommon in the frog ;
they have the same structure as the main thyroid.

(c) Parathyroids in the frog are first mentioned by Ecker,
who considered them as representatives of the thymus, and
by Leydig, who considered them, together with the " ventral
branchial body," as representing the thyroid. That they are
very different from the thyroid in their structure Leydig
himself stated. The suggestion that one of the bodies de-
scribed by Leydig was the ventral branchial body and the
other the parathyroid is made by Gaupp, and on referring to
Leydig's monograph and looking at his plates, it seems clear
that this is the case. After the work of Toldt, the bodies were
called for some years " Nebenschilddrusen," a term which

THE THYROID AND PARATHYROIDS 259

has naturally led to much confusion, owing to the fact that
the same term has been sometimes applied to the true acces-
sory thyroids. The matter was finally made clear by Maurer,
who recognized the homology of these organs with the glan-
dulse parathyroidese which were discovered in higher animals
by Sandstrom in 1880, and independently by Baber, Horsley,
and Gley.

The parathyroids of the frog are represented on either
side of the body by two oval or spheroidal corpuscles placed
one behind the other at the side of the jugular vein in the sinus
sternalis. They are sometimes quite close to the ventral
branchial body, and sometimes at some distance from it ;
they are greyish-red or yellowish in colour, and in adult speci-
mens of Bana esculento may reach 1 millimetre in diameter.

The arteries to the corpuscles come from the musculo-
glandular branch of the external carotid. The veins pass
into the external jugular.

There may be more than two glandules on either side.

The parathyroid has a tough, fibrous capsule, and the
interior of the body is compact. There are closely placed
elliptical or spindle-shaped nuclei which stain deeply. The
cells are longish, and so disposed that they describe spiral
turns. The cell outlines of the glandules are distinct even
when viewed under a low power of the microscope. Some
of the nuclei are rounded, while others are distinctly elon-
gated. Some of the cells are vacuolated, probably owing
to the removal of fat droplets in the process of preparation
for microscopical examination. In some sections the disposi-
tion of the more central part of the organ is such as would be
found if the body had been subjected to a process of torsion.
The cells vary very considerably in shape ; they may be oval,
cubical, pentagonal, spheroidal, or elongated.

(d) The post-branchial body is of considerable importance
in any discussion of the development of the thyroid body.
Its relationship to the latter body in higher vertebrates will
be fully discussed later (p. 261). De Meuron was the first
to discover the structure in the frog and in the toad, and
to work out its development. He considered that it is homo-
logous with the suprapericardial body which had been described
by v. Bemmelen in Elasmobranchs. Maurer has supported
this view, and introduced the name " post-branchial body " to

260 THE DUCTLESS GLANDS

express its relation to the gill-clefts. V. Bemmelen looked
upon his suprapericardial bodies as homologous with gill-
clefts, but Maurer considers them to be of a different nature,
because in all vertebrate animals in which they occur they
arise immediately behind the last gill-cleft, whether this be
the fourth, fifth, or sixth.

The post-branchial body has so far been discovered in all
Gnathostomata, but in many forms it appears only on one side.

The post-branchial body of the frog is a tiny structure which
lies at the side of the aditus laryngis under the epithelium of
the floor of the pharynx. It consists of three or four small
vesicles lined with cylindrical epithelium. Maurer states that
these cells sometimes carry cilia. The vesicles contain a
coagulated albuminous substance and debris, but no colloid.

6. In Reptilia the thyroid is unpaired in some families
(Ophidia and Chelonia), while in the Lacertilia the organ is
bilobed in young specimens, paired in older ones. The organ
lies immediately in front of the pericardium. The parathy-
roids and post-branchial bodies are intimately united, paired,
and placed anteriorly to the thyroid. Their precise anatomy
differs in different groups. The thyroid gland presents no
special features so far as microscopical structure is concerned.

In Chrysemys picta and Pseudemys scripta the parathyroid
contains vesicles, and in the latter species some of these
vesicles contain colloid.

In C. picta the post-branchial body also contains colloid,
but the parathyroid and post-branchial body are very con-
siderably confused together in this and some other species.

In Testudo grceca there exists on each side an " inferior
internal" parathyroid, applied to the carotid ("glandule
parathyroidienne "), and a "superior external" parathyroid
included within the substance of the thymus ("glandule
parathymique "). These bodies are about 1 millimetre in
size, round, oval, or triangular, and possess processes which
may be as long as the organ itself. The glandule which is
embedded in the thymus is particularly rich in such processes
(Aime).

7. In Aves the general features of the thyroid are the
same as in reptiles. The adult gland is a paired organ placed
near to the large vessels of the neck. The vesicles are fre-
quently small and irregular in outline. The intervesicular

THE THYROID AND PARATHYROIDS 261

tissue is large in amount, and in certain regions and in certain
specimens forms large areas of solid tissue, which is indistin-
guishable from parathyroid. This condition of affairs in the
avian thyroid has been emphasized by Forsyth, and it has been
pointed out that from the very wide variations in the amount
of the intervesicular tissue found in different specimens of the
same species, and from feeding experiments, we must conclude
that the proportion between vesicular and intervesicular
tissue varies under different physiological conditions.
The parathyroid of birds (see Fig. 57) contains an abundance

fe^Ts

&£>&

FIG. 57. — Pigeon. Portions of post-branchial body (on the left) and para-
thyroid (on the right), separated by a connective-tissue septum. Note
the presence in both of structures identical with Hassan" s corpuscles of
the thymus. These are numerous in the post-branchial body, and few
in the parathyroid. In both, the concentric bodies frequently show a
lumen. (F. D. Thompson.)

c.c., concentric corpuscles ; c.t., connective tissue ; p. thyr., parathyroid.

of fat. It does not contain vesicles like those of the reptilian
glandule.

In close relationship, and in some regions anatomically
continuous, with the tissue of the parathyroid, we find a body
having an extraordinary structure. It is obviously of epithe-
lial nature, and is composed largely of structures which at
first sight resemble small arteries, but whose walls are com-
posed entirely of concentrically disposed spindle-shaped cells,
and projecting into the lumen are irregular cells lining the
tubules (Fig. 57). The rest of the body appears to be made

262 THE DUCTLESS GLANDS

up of structures identical with the various well-known forms
of HassaU's concentric corpuscles of the thymus. There is a
mass of this tissue in the centre of the parathyroid, and small
portions of it in other regions of the glandule. There are also
true thymus nodules in close connection with the body. Thus
the structure which is commonly called the post-branchial
body in birds (a yellowish-white body some little distance
posterior to the thyroid), is composed not only of post-bran-
chial tissue, but also of parathyroid and thymus. Although
a parathyroid is derived from both third and fourth clefts,
yet the one derived from the latter does not become enclosed
in the thyroid tissue as is the case in mammals.

8. Mammalia. — (a) The general position and anatomical
relations of the thyroid in mammals is too well known
to call for a description. It will, however, be useful to
describe in a series of mammals the probable number and
the usual position of the parathyroids in relation to the
thyroid.

The parathyroids of mammals are usually four in number.
They are small, oval, or spherical bodies, in most cases of a
distinctly lighter tint than the thyroid tissue, and occupy
very variable positions not only in different species, but in
different individuals. On either side of the median line of
the body there are typically two of these glandules, which
are referred to at the present time either as " external " and
" internal " or as " parathyroid III " and " parathyroid IV "
respectively, the Roman numeral indicating the number of
the gill-cleft from whose epithelium the gland was originally
formed. The latter mode of signification is by far the most
precise, but the majority of writers prefer to refer to an external
and an internal glandule on either side. The terms " external ' '
and "internal" appear, however, to be used by different
authors in different senses. Kohn's definition of the terms is
given in the following words : " Das eine lag in der Regel der
Aussenflache der Seitenlappen lose an das andere innerhalb
derselben. Ersteres wurde ' ausseres' letzteres ' inner es ' . . .
gennant." By "external" and "internal" here is implied
"on the surface of" and "in the interior of" respectively.
But Schafer interprets the terms differently. Thus, " there
is one parathyroid (' outer epithelial body ') constantly to be
met with in mammals on the lateral surface of each lobe of

THE THYROID AND PARATHYROIDS 263

the thyroid, and another on the mesial surface of each lateral
lobe ('inner epithelial body')."

Despite this confusion in terminology, for most animals,
at any rate, the terms " external " and " internal " are suffi-
ciently suitable for designating the two parathyroids respect-
ively ("III" and "IV"), because it so happens, that the
glandule which lies on the surface of the gland lies also in the
majority of cases on the lateral aspect of the lobe, and the one
which is buried in the thyroid substance is nearer the mesial
surface.

(6) In Man the anatomy of the thyroid is too well
known to need any description. It belongs to the group of

FIG. 58. — Semi-diagrammatic sketch
showing the position of the parathy-
roids, the thyroid, and the trachea
in the human subj ect. Front view.
Parathyroids projected on to the
surface.

FIG. 59. — Semi-diagrammatic sketch
showing the position of the para-
thyroids in the human subject.
Posterior view.

thyroids possessing an isthmus. There are many points of
interest, embryological and surgical, connected with some
common varieties, but there will not be space to treat of these.
The parathyroids, according to most observers, are four in
number — two on each side of the median line of the body.
The average dimensions are about 6 or 7 millimetres in length,
3 or 4 millimetres in breadth, and 1'5 or 2 millimetres in
thickness. The length is very variable, while the thickness
is fairly constant. In shape they are oval or pyriform, and

264 THE DUCTLESS GLANDS

they may be connected by a stalk, in which run the para-
thyroid vessels, to the thyroid gland. The average weight
is 0*035 gramme. There seems to be no relation between
the weight of the parathyroids and that of the thyroids.
The parathyroids are of a lighter colour than the thyroids,
and yellowish owing to the presence of fat. The surface is
smooth and soft.

The two glands on each side are described under the names
of the "posterior superior parathyroid," and an "anterior
inferior " parathyroid, the names indicating their relation to
each other. (See Figs. 58 and 59.) The posterior superior
glandule is more constant in position than the anterior inferior.
It lies usually on the posterior wall of the oesophagus or pharynx
at the level of the lower edge of the cricoid cartilage, imme-
diately internal to the posterior margin of the lateral thyroid
lobe, and in front of the prevertebral division of the cervical
fascia. The parathyroid is usually separated from the thyroid
by a septum of connective tissue.

The anterior inf erior^hyroids are very inconstant in position
and relations. Sometimes their position is more anterior,
sometimes more posterior, and they may, especially in the
former case, be placed very low down, even at the level of the
tenth tracheal ring.

(c) Monkey. — The writer is not acquainted with any descrip-
tion of the parathyroids in the anthropoid apes. In the
different species of monkey usually employed for operations
in the laboratory, the arrangement of the parathyroids is
quite different from that in the human subject. The present
writer, working in conjunction with Professor W. A. Jolly,
found that in the monkey the thyroid lobes are sometimes
united by an isthmus, sometimes unconnected. There is a
well-developed isthmus in Macacus rhesus, and the parathyroids
are four in number, two on each side, and are always, so far
as we have seen, embedded in the substance of the thyroid.

(d) Dog. — The thyroid of the dog usually consists of two
distinct lobes unconnected by any isthmus. Ellenberger and
Baum, however, state that the thyroid consists of two lateral
lobes and an isthmus, which latter structure is wanting in
small dogs and present in large ones, while in dogs of medium
size it is sometimes present. The lateral lobes are elongated,
oval, and taper slightly at oral and aboral ends. They are

FIG. 60.

FIG. 61.

FIG. 62.

FIG. 63.

FIG. 64. FIG. 65.

FIGS. 60-65. — Semi-diagrammatic sketches showing the position of the
parathyroids, the thyroid, and the trachea in the dog. The para-
thyroids in dotted lines are " internal."

265

266

THE DUCTLESS GLANDS

placed at the side of and towards the dorsal aspect of the
trachea, immediately aboral from the larynx.

The parathyroids are usually four in number, but there
may be as many as five, and sometimes it is not possible to
see more than three with the unaided eye. The external
parathyroids are as a rule very easily found. Sometimes they
are at some distance from the thyroid
lobe, while at other times they are more
or less embedded in its substance, though
never so deeply as the internal glandule.
Sometimes their blood supply is such as
/ 1 '•-. 2 7T\ to permit of their being left behind in

/ j * / \ the operation of thyroidectomy. This,
i however, is rare. The internal para-
thyroid, on the contrary, is small, deep
in the thyroid substance, and very vari-
able in position, so that in the living
animal the experimenter has frequently
to abandon the attempt to find it, while
even post mortem it cannot always be
revealed except by serial sections. It is
very rarely found that the internal
parathyroids can be seen on both sides
(see Figs. 60-65).

(e) Cat. — In the cat, as is most usual
throughout mammals, there are four
parathyroids, two internal and two
external. Their arrangement resembles
that in the dog. (Fig. 66.)

(/) Rabbit. — There are usually four parathyroids, but the
external glandules are uniformly placed at a considerable
distance from the thyroid lobe. For this reason, in tlio
earlier extirpation experiments they were always left behind
at the time of the operation. (See Figs. 67-71.)

(g) In the Guinea-pig the distinction between internal and
external parathyroids seems largely to break down. There
are usually four parathyroids, sometimes three, or even only
two. (Figs. 72-76.)

(h) In the Rat the thyroid consists of two lobes united by
an isthmus. There is only one parathyroid in connection
with each thyroid lobe, and this seems to correspond with

FIG. 66. — Shows the
relative positions of
the parathyroids,
thyroid, and trachea
in the cat. This
may be described as
an average condi-
tion of affairs. The
" internal " parathy-
roids are in dotted
outline.

THE THYROID AND PARATHYROIDS

267

the external body of the cat and dog. McCarrison states that
there is sometimes an internal parathyroid in the rat.

(i) In the Wolf and Badger there are four parathyroids
whose precise location does not call for any description.

0

0

FIG. 67.

FIG. 68.

FIG. 69.

FIG. 70.

FIG. 71.

FIGS. 67 to 71 are semi -diagrammatic, and show the relationship of the
thyroid, external parathyroids, and trachea in a series of rabbits. The
" internal " parathyroid is not shown, since it was found only oil micro-
scopical examination.

The general arrangement conforms fairly closely with that
in the dog and cat.

(j) In the Pig the internal parathyroid is stated to be
absent. In this animal and in Ruminants the external para-
thyroid is not close to the thyroid, but is in connection with

268

THE DUCTLESS GLANDS

the thymus. In the ox, in addition to the four typical para-
thyroids, it is stated that there are accessory parathyroids
of macroscopic size in different regions of the neck and medias-
tinum.

(k) In the Horse the relationships of the parathyroids have

FIG. 72.

FIG. 73.

FIG. 74.

FIG. 75.

FIG. 76.

FIGS. 72 to 76. — Parathyroids in the guinea-pig. The extreme variability in
number and position is shown. In none of this series were any true
" internal " parathyroids seen with the unaided eye.

not been fully ascertained. In a recent paper Estes states
that the external glandule of the horse is found in close relation
to the upper end of the thyroid or in the perithyroid areolar
tissue. The internal parathyroid is variously placed beneath
the capsule of the thyroid, usually near its upper pole. The
external gland i< much the larger. The horse then appears

THE THYROID AND PARATHYROIDS 269

to resemble the other Herbivora in the distribution of its para-
thyroids.

(/) In Sheep and Goats there are two parathyroids embedded
more or less in the thymus, and two others in the substance of
the thyroid. The thyroid of the sheep varies extremely in
size in different individuals.

C. Histology of the Thyroid in Man and Mammals

The larger lobes of the thyroid are surrounded by a thin
capsule of connective tissue, and are divided, by processes

k^tf^-d >w" x

\

e. ves.

' interves.

FIG. 77. — Thyroid of normal dog. (X 120.)

c., colloid ; e, ves., epithelium lining vesicles ; e. interves., ephitelial intervesi-
cular tissue ; c. ves., colloid vesicles.

running into the interior of the organ, into smaller and smaller
lobules. The ultimate lobules are of irregular form and size,
but are, for the most part, roughly circular or oval in section,
and have a diameter of about 0-5 to 1-0 millimetres. The
interior is mostly occupied by vesicles of varying size, 45 /^ to
110 //, and varying shape. It was formerly thought that the
gland was made up of a system of branching alveolated canals,
but it has been conclusively shown that the glandular substance
is composed of closed vesicles, which are separated from one
another by fine strands of connective tissue, and a variable
amount of an inter vesicular cellular tissue. Most of these

270 THE DUCTLESS GLANDS

vesicles are of roundish, long, oval, or polyhedral form, but
occasionally one meets with forms somewhat resembling the
tubules of alveolar glands, only that they are closed at both
ends ; these have sometimes side branches, or two or three
large vesicles may freely communicate with each other. In
many lobules one finds in addition to the vesicles solid cords
and nests of epithelium cells. These are more numerous in the
young and developing thyroid.

The ensheathing capsule of the organ and the interlobular
connective tissue consist of bundles of white fibres with
numerous elastic fibres. This connective tissue carries numerous
bloodvessels and lymph vessels into the interior of the lobules,
and finally surrounds the vesicles of the gland substance. 'The
vascular connective tissue comes into immediate contact with
the epithelial lining of the vesicles. It is said that there is no
membrana propria ; the vesicle is enclosed by very fine bundles
of connective-tissue fibres, outside of which is the endothelium
of the lymph spaces.

The epithelium cells lining the vesicles are of a fairly uniform,
cubical, or columnar form, 9 ^ to 13 ju, in height. They tend to
become flatter in old age, but cylindrical cells are not un-
commonly found, even in the adult. When examined in 0-75
per cent, normal saline, the epithelial cells of the human thyroid
show, in most instances, a number of granules of varying size.
These are chiefly aggregated in the part of the cell next to the
cavity of the vesicle ; they are highly refractive, and show a
characteristic greenish tinge. These are apparently of a fatty
nature ; but, in addition to these, there are found in the cells
smaller granules of a different character. The larger granules
appear to be characteristic of human thyroid.

According to Langendorff, the epithelium cells are of two
kinds — " Hauptzellen " and " Colloidzellen." In osmic-acid
preparations stained with the Ehrlich-Biondi mixture, the
former are unstained, while the latter appear red with green
nuclei. According to v. Ebner, these do not represent two
distinct varieties of element, and there is nothing in the vesicular
epithelium corresponding to the two kinds of cell in the glands
of the stomach. The cell protoplasm shows a retiform struc-
ture, with frequent longitudinal striation. The nuclei are
spherical, have a homogeneous appearance, or show a very fine
chromatin network. As in other gland epithelia, mitosis is

THE THYROID AND PARATHYROIDS 271

only to be observed in young individuals. Zimmerman
describes a double centrosome close to the free surface of the
cell.

Occasionally one finds solitary cells in the interior of a vesicle.
These are normal epithelium cells, which have become separated
from the lining layer of the vesicle. Sometimes they are in a
good state of preservation ; mostly, however, they appear to
be in some stage of resorption. The nucleus stains faintly.
According to v. Ebner, leucocytes do not occur either in the
epithelium or in the cavity of the normal vesicle.

As regards the contents of the vesicles, they are filled with
the yellowish sticky fluid which is observed to flow from the
surface when the gland is cut. The abundant presence of cells
and their debris in the interior of the vesicle may be due to post-
mortem changes. Verson states that the free surface of the cell
wall may be seen to project irregularly, and spheroidal, tena-
cious, and hyaline drops, which after some time coalesce in the
centre of the vesicle, gradually develop from the bodies of the
cells.

Peremeschko found that the contents of the vesicles change
with the age of the animal. In young embryos there is a finely
granular mass, enclosing cells and nuclei. In larger embryos
one finds occasionally vesicles filled with transparent masses of
colloid ; in young animals this is the case with the larger
number of the vesicles, and in adults one rarely finds vesicles
without colloid. In adult animals the colloid substance
completely fills the cavity of the vesicles.

Zeiss looks upon the colloid as nothing more than a concen-
trated form of the fluid originally appearing in the vesicles. In
this fluid he often finds a lump of colloidal material, around the
periphery of which new layers of colloid are being continually
laid down, until the entire cavity is filled with a compact mass
of colloid. The drops of secretion described by Peremeschko,
Zeiss considers to be simply appearances due to shrinkage. He
was never able to isolate the clear, transparent, unstainable
drops.

Baber finds in the vesicles, in addition to a small quantity of
a clear substance, a solid mass which has retracted from the
wall of the vesicle. By staining with picrocarmine it shows a
finely granular structure, and is strongly differentiated by its
yellow colour from the red-stained epithelial wall. Hsematpxy-

272 THE DUCTLESS GLANDS

lin gives it an opaque grey or greyish- violet tinge, and shows a
homogeneous or granular structure. The vesicle varies from
time to time both as to the amount of the contents and as to
their staining reactions, depending upon the state of functional
activity of the gland.

According to Biondi, the vesicles contain a homogeneous
substance which becomes dark and granular after fixation with
osmic acid. This substance is a product of the epithelial cells,
as shown by the fact that these frequently contain granules
which have the same staining reaction as the colloid.

Langendorff was the first to give a clear account of the micro-
chemical reactions of the colloid substance. There is no doubt
that the contents of the gland vesicles completely fill their
interior. If these contents become hard as the result of
chemical treatment, they may either preserve their original
volume or may undergo change in this respect ; if the harden-
ing is the result of dehydration or heat, considerable shrinkage
occurs. The best fixing agents are those which coagulate
proteins without change of form, such as osmic-acid mixtures.
If such be employed, one sees that the masses of colloid lie in
close contact with the follicular epithelium, and have a per-
fectly homogeneous aspect. Langendorff's micro-chemical
tests were carried out upon the gland of the calf and the rabbit,
which were hardened in alcohol. Acetic acid caused enormous
swelling of the vesicular contents, which were rendered trans-
parent. By washing with 0-6 per cent. NaCl one could restore
their former appearance. A 0-2 per cent, solution of HC1 also
caused this swelling ; 33 per cent. KOH or stronger NaOH
has the same effect, only to a much less extent. If, now, water
be added, rapid breaking up occurs, and only the connective-
tissue framework of the glands remains. A 10 per cent,
solution of KOH makes the colloid masses indistinct and
deliquescent. Strong HN03 causes the masses to shrink some-
what ; after some minutes a yellow coloration occurs, even in
the cold. This reaction (xanthoproteic) comes on almost
instantaneously on heating. Addition of ammonia changes
the light yellow tinge into an orange. With pepsin, in presence
of 0-2 per cent. HC1, the colloid masses are soon dissolved.
Copper sulphate and KOH at 40° C. give a strong violet tinge
to the colloid (Biuret reaction). After many hours in the
reagent the colloid masses also give Millon's test. If a section

THE THYKOID AND PARATHYROIDS 273

be treated with acetic acid until considerable swelling occurs,
and then, after washing, be treated with sulphuric acid, a violet
coloration is perceived (Adamkiewicz's reaction).

The colloid masses are not dissolved in boiling water, but
are coagulated. The colloid is also coagulated by the other
ordinarily used fixing and hardening reagents. These are
alcohol, inorganic acids, solutions of metallic salts, and picric
acid.

Langendorff considers that the colloid masses are composed
either of protein or a substance containing a large proportion of
protein. Mucin is not present, as the reaction to acetic acid
shows. The protein can hardly be alkali-albuminate, since it
coagulates on heating. It may possibly be an alkali albumin
modified by containing abundance of sodium chloride. The
reactions do not allow of the supposition that any appreciable
amount of globulin is present.

The staining power of the colloid is considerable. With
picrocarmine the colloid appears bright yellow. If one stains
with ammoniacal carmine the colloid takes on the carmine
tint very slightly. Eosin and the rest of the aniline dyes
stain the colloid powerfully. After treatment with osmic
acid or mixtures containing it, the colloid masses are stained
dark ; the reduction is particularly marked if one stains
for a short time with Ehrlich's hsematoxylin. After long
treatment with logwood the colloid becomes bluish-grey or
violet.

The consensus of opinion at the present time is that the
colloid material arises as a secretion from the epithelial cells
lining the vesicle. The epithelium consists of cells having all
the characters of true glandular cells, and as in these, the
secretion is formed as specific granules in the reticular proto-
plasm.

In the foetus the structure of the thyroid resembles that of
the adult, while in the new-born it is stated to be quite different.
It is said that after birth and for some weeks or months, the
vesicles shrivel up and the colloid disappears, and the gland
consists of elongated or rounded heaps of epithelial cells, closely
pressed together. It is possible that this change after birth is
pathological.

274 THE DUCTLESS GLANDS

D. The Intervesicular Cellular Tissue of the Thyroid

It has been stated above that " in many lobules one finds in
addition to the vesicles solid cords and nests of epithelium cells,
and that these are more numerous in the young and developing
thyroid." It will be desirable to call particular attention to
this intervesicular material. This tissue very closely resembles
that forming the parathyroids.

The amount of the intervesicular cellular material varies
within very wide limits in the thyroid of different species of
animals, in different individuals of the same species, and, to
some extent also, in different regions of the same gland. It is
not rare to find a pair of vesicles in close juxtaposition to each
other, so that the colloid of one is separated from the colloid of
the other by nothing more than two rows of vesicular cells.
In other cases there is a certain amount of connective tissue
separating the vesicles ; but, speaking for mammals generally,
it is more usual to find, separating the colloid vesicles from one
another, a variable mass composed of cells which are almost
identical in size, nature of cytoplasm, size and form of nucleus,
with those lining the colloid vesicles. This intervesicular
cellular tissue is proportionately much greater where the
vesicles are small. This is notably the case in the rabbit, and
is also strikingly true in young animals generally (see above,
p. 271). In the monkey the amount of intervesicular tissue is
proportionately great, and it is not possible to determine any
fundamental differences between its cells and those of the
vesicles. In the human thyroid there is often as much inter-
vesicular as vesicular material.

This intervesicular cellular substance is shown in Fig.
77.

E. Structure of the Parathyroids

The parathyroids in man are built up of closely packed
polygonal cells, which are divided up by connective-tissue
septa into masses and cords of varying sizes and shapes. The
glandules are usually surrounded by their own capsule ; but
in the case of those placed on the surface of the thyroid, the
connective-tissue sheath is seen to be derived from, and
continuous with, that of the thyroid lobe, The capsule

THE THYROID AND PARATHYROIDS 275

sends septa into the interior of the organ, which septa convey
bloodvessels and nerves destined for the supply of the gland
substance.

The protoplasm of the cells often appears to be homogeneous ;
it does not stain well with eosin, and is vacuolated. The
nuclei are spherical and about 4 /m in diameter, and frequently
show a chromatic network. Permeating the whole glandule,
and even separating the individual cells in many places, is a
delicate network of fine fibres, which appear to be of a distinct
nature from ordinary connective tissue. It is stained by
eosin and faintly also by orcein. Near the periphery of the
organ the cells are smaller and lack this special sheath.

bid. v.

FIG. 78. — Normal parathyroid of dog. (X 120).
.9.c.c., solid columns of cells ; bid. v., bloodvessel.

In man and different mammals, Kohn distinguishes three
different arrangements of the epithelium cells which may be
met with : (1) A compact cell mass ; (2) a retiform tissue ;
and (3) a lobular conformation. These different arrangements
are not characteristic of any species or any age, but may be
found side by side in the same glandule.

In the cat the internal parathyroid has a peripheral layer
of cylindrical cells, and there appear to be other differences
in structure between this body and the external parathyroid.
Thus the cells 'are not so closely packed in the internal as in
the external gland, and their outlines are more easily distin-
guished. Further, the cell nuclei of the internal parathyroid
(Jo not stain so deeply as those of the external body. This

276 THE DUCTLESS GLANDS

last difference, however, can only be detected in adult animals.
In some species, as the rabbit, the internal parathyroid is
intimately connected with a " central canal " (post-branchial
body) and with the thyroid itself.

FIG. 79. — Human. A drawing, as seen under a simple
lens of a portion of the thyroid and a parathyroid

p. thyr. -\ which is considerably hypertrophied and otherwise

modified. The specimen is pathological, but there
is no record of the patient. The object of this
figure is to show that the structure in question

thyr.- is in reality morphologically and topographically

a parathyroid.

p. thyr., parathyroid ; thyr., thryoid.

In close contact with each of the parathyroids we may
find a thymus nodule, and occasionally the central portion
of this last is seen to be directly continuous with the tissue

FIG. 80. — A portion of the thyroid and neighbouring parathyroid, with a
fairly thick connective-tissue partition ; low power. On the left \\ <•
see the colloid vesicles of the thyroid ; on the right the parathyroid, which
is of(a typical parathyroid structure near the- connective-tissue septum ;
but which shows several undoubted colloid vesicles in the left-hand
portion of the drawing.

THE THYROID AND PARATHYROIDS 277

of the parathyroid. Again, parathyroids may be found either
in the cortex or in the medulla of the thymus gland. When
we bear in mind the development of these various organs (see
below, pp. 277 and 279), such intimate anatomical connections
and occasionally even apparent confusions are not astonishing.
In some cases the parathyroids are found to contain colloid
vesicles. Figs. 80 and 81 illustrate this very clearly. The
drawings represent what topographically is, or, to be more
correct, was, parathyroid ; but many parts of the substance
are studded with colloid vesicles.

F. Development of the Thyroid

The thyroid is the chief of the organs arising from, or in
close topographical relation to, the gill-clefts. Other organs
in the same group are the thymus, the parathyroids, the
post-branchial bodies,

and the branchial >- end.

bodies of the Anura. %•-*" "v" ^

The origin of the ^«2^ffi^«

thyroid is practically ** «^te- '

the same throughout ', -/' *^5?fe^

vertebrates. It arises
from the ventral wall of
the pharynx in its an-
terior region, as an, ^s^

unpaired Outward pro- FIG. 81.— A small portion of the parathy-

iection of epithelium. roid shown in the Jfs* two figures.

. . Section is from a part of the parathyroid.

AS Stated above, in , The drawing was made with a camera

AmpMoxuS and Ammo- lucida ; high power. It is seen that the

. -vesicles, although small, are typically

C03tes, the Opening into thyroidal in character.

the buccal alimentary end., endothelium ; c. ves., colloid vesicle.

tube remains patent,

and the thyroid appears to be an organ of very ancient
origin, which shows relationship to the hypobranchial furrow
of Tunicates. In Petromyzon the organ detaches itself com-
pletely from its place of origin, the opening becomes closed,
and a number of closed vesicles are formed, lined, with
cylindrical epithelium, and containing colloid.

In all vertebrates above the Cyclostomata the unpaired
rudiment of the thyroid arises as an evagination of the floor

278 THE DUCTLESS GLANDS

of the pharynx between the bases of the first and second
branchial arches. The structure then separates itself com-
pletely from its original point of growth, and appears as a
closed vesicle. In fishes the organ remains unpaired, but
in Amphibia it divides into two portions whoseTposition differs
in different species.

In the Sauropsida the origin of the thyroid is very similar.

The original vesicle becomes a compact organ, and in
Lacerta becomes developed into a bilobed organ with a median
isthmus. In the interior one can for a long time trace a
lumen which is the remains of the aperture of the original
vesicle. This is lined with cylindrical epithelium. The
colloid-containing vesicles do not, however, communicate
with a canal.

In birds the two lobes become quite separate.

The origin of the thyroid in mammals has been, and still
is, a matter of considerable controversy. There can be no
doubt about the median rudiment, which arises in the same
way as in other vertebrates — i.e., as an evagination of the
floor of the pharynx between the first and second branchial
arches. In the human embryo the evagination is a small
pouch beginning to expand laterally in an embryo of 5 milli-
metres in length ; in an embryo of 10 millimetres the lateral
expansion has much increased, and there is a median duct,
the opening of which upon the surface of the tongue corresponds
to the foramen caecum ; the duct itself is known as the ductus
ihyreo-glossus. The whole structure now consists of a bilateral
epithelial vesicle connected by a slender hollow pedicle with
the surface of the tongue. The duct persists up to the eighth
week, gradually elongating as the thyroid and the tongue
separate. The duct usually begins to be obliterated during
the fifth week, but sometimes persists. After the fifth week
the vesicular portion expands rapidly.

The development in other mammals does not call for a
separate description.

Many authors describe a lateral rudiment in addition to
the median, and this is accepted as the true account by the
authors of some textbooks, but this lateral rudiment appears
to be that of the post-branchial body (vide infra, p. 279).

In most mammals the thyroid remains a single organ,
consisting, as in man, of two lobes, with a connecting isthmus.

THE THYROID AND PARATHYROIDS 279

In some, however, the right and left lobes are completely
separate. The colloid does not begin to be formed in mammals
till towards the end of foatal life, and sometimes even not till
after birth.

But before going further it will be necessary to give some
account of the post-branchial bodies, which are present in all
Gnathostomata except Heptanchus and Teleosts.

In Selachii the organ was first observed by v. Bemmelen,
who called it the " suprapericardial body." He describes
it as an evagination of the ventral wall of the pharynx behind
the last gill-clejt. This becomes separate from the wall of
the pharynx, and now consists of a vesicle lined with epithelium
cells. It bears some resemblance to the original rudiment
of the median thyroid, and soon consists of a mass of separate
vesicles. Whether these contain colloid is not known.

In Amphibia, Reptilia, and Aves, the post-branchial body
is formed as an evagination behind the last gill-cleft, some-
times, however, only unilaterally. In these classes of animal
the vesicles never contain colloid.

Of peculiar interest are the researches of Maurer upon
Echidna. In this animal, as in all vertebrates, the post-
branchial body arises behind the fourth gill-cleft, and soon
develops into a gland having a structure like that of the thyroid,
the important point being that colloid is contained in the
vesicles. In Echidna these post-branchial bodies (colloid
glands) never unite with the thyroid proper, which is a large
gland, with two lobes and a connecting isthmus.

In other mammals the post-branchial bodies may assume
a structure identical with that of the median thyroid. How
much, if any, of the fully developed thyroid is derived from
the post-branchial bodies still remains an open question.

G. Development of the Parathyroids and some other
Branchial Cleft Organs

The development of the thymus will be treated hereafter
(p. 225), but it will be convenient in this place to .deal with
the development of the parathyroids and the thymus nodules
found in connection with the thyroid.

The particular gill-clefts with which we are at present
specially concerned are the third and fourth.

280 THE DUCTLESS GLANDS

From the epithelium on the ventral aspect of the third
cleft arises the main portion of the thynius. This may be
called "thymus III." (see Fig. 82, p. 281). The ventral
proliferation of the epithelium of the fourth cleft also gives
rise to thymus tissue, but this is usually simply a small nodule
in the substance of the thyroid, and is called " thymus IV."

The dorsal aspects of the third and fourth clefts show
thickenings of the epithelium which, however, do not develop
into thymus tissue, but retain a typical " epithelial " struc-
ture. These are the parathyroids named respectively " para-
thyroid III." and "parathyroid IV." In connection with
the last is found a cavity lined with epithelium. This is the
post-branchial body.

The thymus nodule sometimes found in close relation to
the external parathyroid ("parathyroid III.") is simply an
isolated portion of the main thymus ("thymus III.").

The accompanying diagrams (from Kohn) will help to make
the matter clear (Figs. 82, A and B).

EXPLANATION OF FIG. 82.
(Diagrams A and B.)

A. illustrates the development of the branchial organs of mammals, B. shows
their actual relations in the adult.

The different related rudiments of the same branchiomere are represented
by a similar direction of shading lines ; so also the corresponding organs. Thus
the rudiments from the third cleft are represented in A. by horizontal lines,
as also the organs thus arising in B. The rudiments and organs from the
fourth cleft are characterized by vertical lines. The post-branchial body is
shown in thick outline, the thyroid by crossed lines.

The different kinds of tissue arising from one and the same branchiomere
are indicated by differences in the shading. The parathyroid tissue is shown
by lines, the thymus tissue by alternate continuous and interrupted lines.
The post-branchial body is represented in the developed condition as a hollow
space with several glandular nodules (shown in dark circles).

A. shows the four internal gill slits (I. to IV.), the epithelial origins of the
parathyroids (p. thyr. III., p. thyr. TV.), the origin of the thymus (thym. III.,
thym. IV.), the rudiment of the thyroid (thyr.), and that of the post- bran oliial
body (p. b. b.).

B. represents a schematic transverse section through the fully developed
thyroid (at about the level of the junction of the upper and middle third of the
thyroid lobe of a cat). The lettering corresponds to that in Diagram A. The
structures which arise from the third cleft become the " external " para-
thyroid and thymus nodule (separated fragment of thymus III. ) ; those which
arise from the fourth cleft become the " internal " parathyroid and the thymus
nodule (p. thyr. IV., and thym. IV.). The post-branchial body is surrounded
by thyroid tissue.

(A. is after Groschuff in ruminants ; B. from Kohn in the cat.)

THE THYROID AND PARATHYROIDS 281

p. thyr. Ill

thy m. Ill

thym.IV

p. thyr. HI

thym.III

thyr.

p.b.b,

282 THE DUCTLESS GLANDS

H. Diseases of the Thyroid

Thyroiditis acuta, carcinoma, sarcoma, syphilis, tuber-
culosis, and echinococcus are all known, but apparently none
of these lesions give rise to any of those symptoms usually
associated with absence of thyroid function — viz., myxoedema,
cretinism, etc. This seems to be the case even when gangrene
occurs.

The diseases which will be referred to are — (1) Goitre, (2)
endemic cretinism, (3) myxcedema, (4) cachexia strumipriva,
and (5) Graves's disease.

1. Goitre

The aetiology of endemic goitre is a long-standing puzzle,
and there are many aspects of the question which still remain
in obscurity. The distribution of the disease is so extra-
ordinary and so well known that it need not be described here.
It is now generally recognized that it is an infection due to a
living germ confined to certain geological formations, and
transmitted to man by means of drinking-water.

McCarrison, from observations carried out in Gilgit, Kashmir,
concludes that goitre can be experimentally produced in man
by the administration of the matter in suspension separated
by filtration from waters that are known to be goitre-producing.
Goitre cannot be produced when the suspended matter is boiled.
The disease is due, therefore, not to mineral, but to the living
component of the suspended matter — in other words, to a
living organism of disease. The incubation period of experi-
mentally produced goitre is usually about ten to fifteen days.
Goitre can be cured by the administration of intestinal anti-
septics. Thus the lactic -acid ferments exercise a curative
action when applied to the treatment of incipient goitres. It
is probable, therefore, that the organism which is the cause of
the disease is parasitic in the human intestine. The faeces of
most cases of goitre in Gilgit show a plentiful amoebic infection,
but whether the disease is due to this infection has not been
determined. The disease cannot be communicated to dogs
by means of extracts from the faeces of goitrous individuals.
Bircher finds that filtering does not destroy the contagion,
while boiling does. This theory of McCarrison has not been
universally accepted.

THE THYROID AND PARATHYROIDS 283

Professor Cameron and myself have recently described an
enlarged thyroid in an Elasmobranch fish — Squalus Mecklii.
The structure showed active hyperplasia and in certain parts
all the appearances of true carcinoma. We are not aware of
any previous observations on thyroid growths inElasmobranchs.
Teleostean thyroid enlargements have been described by
Marine and others. One of the chief points of interest about
the Teleostean growths is that the gland is unencapsuled and
consists of scattered vesicles and groups of vesicles. The
Elasmobranch thyroid, on the other hand, is definitely encap-
suled, and forms a compact organ. Again the change we
have described occurred in a wild fish, and one for which a
constant supply of iodine is readily accessible. Marine finds
that in fresh- water fishes iodine is a valuable curative agent.

It is usual to classify goitres as parenchymatous, vascular,
and cystic. But Marine has emphasized the importance of
a physiological cycle as explaining the innumerable forms of
goitre.

In interpreting the thyroid changes in goitre, according to
Marine, one must bear in mind the simple thyroid cycle which,
beginning with the normal cell, consists of progressive changes
through all degrees of hypertrophy and hyperplasia and regres-
sive changes either (1) throughout all degrees of atrophy, or
(2) throughout all degrees of involution to the resting or colloid
or nearest normal state that such thyroids can again assume
which have once undergone hyperplasia.

The cycle may be represented schematically as follows : —

/'atrophy

Normal thyroid— hypertrophy— hyperplasia •< involution ;to

\colloid state

/atrophy
Colloid state— hypertrophy— hyperplasia j involutiqn to

Vcolloid state
_ I

Colloid ....

This conception has made it possible to interpret the many
gradations of thyroid reactions found in diffuse overgrowths
of the thyroid (goitre), and now one looks upon any given

284

THE DUCTLESS GLANDS

specimen of thyroid reaction as a phase of this cycle and not as
an entity either anatomically or physiologically.

Iodine is usually recommended for goitre, especially in its
early stages.

2. Endemic Cretinism

The precise relationship between goitre and cretinism has

been the subject of
much discussion and
speculation.

The subject has re-
cently been reinvesti-
gated by McCarrison in
the Chitral and Gilgit
Valleys. He concludes
that the degree to
v which cretinism is

associated with goitre
is determined by the
age of the endemic,
and varies directly with
the extent to which the
latter disease prevails
among the adult popu-
lation. Cretinism is
rarely, if ever, due to
the development of a
goitre in the individual.
The thyroid enlarge-
ment is, or may be, an
effect ; it is not the
cause of the disease.
Defective thyroid func-
tion in the mother is
the essential factor in the production of cretinism.

Cretinism is due to the action of toxic agents, notably that
of endemic goitre, on the developing thyroid of the unborn
child. The thyroid defect is congenital, but it may remain
latent pending its manifestation through the impulse of some
accidental circumstance.

The symptoms of cretinism have been so often and so fully

FIG. 83. — Cretin before treatment. Age 28
(June, 1895). Height 34£ in. (From Murray.)

THE THYROID AND PARATHYROIDS

285

described that it is unnecessary to make more than a brief
reference to some of them. The changes in the skin are stated
by many observers to be identical with those found in myxce-
dema.

McCarrison states that in the Chitral and Gilgit Valleys there
are two distinct
types of the
disease — (1) the
myxoedema t o u s
type, and (2) the
nervous type.
Cases commonly
present the clini-
cal features of a
combination o f
these. Deaf-
mutism is an
almost constant
accompani m e n t
of both types of
the disease. The
myxoedema t o u s
type corresponds
with the form
met with in
Europe.

The nervous
cretins are help-
less, and usually
deaf and dumb.
There is a
"knock -kneed"
spasticity of the
lower limbs, in-
creased knee-

jerk, and there may be marked flexion of the toes on
the sole. The upper limbs assume a position of right-angled
flexion ; the thumb may be drawn into the palm and the fingers,
closed over it, whilst the wrist is flexed. Among other nervous
symptoms are movements of the head, grimaces, convulsions,
nystagmus, and internal strabismus, and idiocy, It is impor-

FIG. 84. — Cretin after treatment. February, 1899.
Height 38£ in. (From Murray.)

286 THE DUCTLESS GLANDS

tant to note that these nervous cases are considerably benefited
by treatment with sheep's thyroid. Cretinism is often classified
as a form of infantilism (q.v., p. 380).

3. Myxoedema

(a) Symptomology . — In 1874 Sir William Gull communicated
to the Clinical Society of London a paper bearing the title,
" On a Cretinoid State supervening in Adult Life in Women."
This account was based upon five cases. In 1877 Ord proposed
the name " myxoedema," which has ever since been employed.
This writer describes changes in the thyroid. Curling and
Fagge had previously described atrophy of the gland in cretin-
ism. The early history of the subject may be completed by
referring to the work of Charcot, who called the disease
" cachexie pachydermique " ; Savill, who first described a case
in a male subject ; and Hadden, who first definitely ascer-
tained that atrophy of the thyroid is commonly associated with
myxcedema.

The aetiology of myxoedema is obscure. Heredity, traumat-
ism, tubercular family history, alcohol, syphilis, and many
other factors have been alleged. The disease is chronic, and
the onset is very gradual.

In most cases myxoedema shows itself in a gradual swelling
of the skin. This may be accompanied by nervous disorders,
neuralgia, convulsions, " tetany," mental disturbances, and
skin diseases. The swelling of the skin is at first most notice-
able on the face. The chin, eyelids, nose, lips, and cheeks swell
up, and the palpebral cleft is narrowed. A slowly increasing
languor is often felt in early stages, and a sensitiveness to cold
is frequently noticed. Headache is an early symptom in
some cases.

The skin may become yellowish , and shows in fully developed
cases what is called " solid oedema." The swelling resembles
oedema or fat, but on palpation feels softer and more elastic
than fat, and unlike ordinary oedema, it does not pit on pres-
sure, nor does any fluid exude if the skin is pricked. The weight
of the patient is increased very considerably. The skin is
wrinkled in some regions, pendulous in others. The swelling
is fairly uniform over the trunk and limbs, but is most noticeable
in the hands and feet. The skin becomes dry and rough and

THE THYROID AND PARATHYROIDS

287

B

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8£

f!

10 3

oo n3

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288 THE DUCTLESS GLANDS

cold. In later stages of the disease perspiration may be entirely
absent. Warts and moles may occur.

The hair becomes thin and scanty. In some cases the head
is almost completely bald, and the skin of the scalp becomes
dry, brown, and scaly. The teeth often become brittle and
carious. The mucous membranes may be swollen, and there
is dryness in the mouth and nose. In fully developed cases
the temperature is almost continuously one, two, or three
degrees below normal. Mental dulness, drowsiness, and slow-
ness of reaction are characteristic of most marked cases. There
may be hallucinations going on to definite insanity. Sight,
hearing, taste, and smell are often more or less impaired, and
sexual feeling may be diminished.

We shall see later on (p. 289) how far these symptoms corre-
spond with those observed in human beings after operations
upon the thyroid, and in animals after experimental thyroidec-
tomy (p. 300).

(6) Morbid Anatomy. — The most interesting changes are
found in the thyroid lobes. The Myxcedema Committee in
1858 found that out of fifteen cases in which the thyroid was
examined post mortem, there were six of atrophy of the glands,
and all were diminished in size, of a pale yellowish-white colour,
hard, and fibrous. There was a connective-tissue overgrowth
which led to a destruction of the parenchyma. At the same
time there was a new formation of lymphatic tissue.

Similar conditions have been reported by other observers.
The cells of the vesicles are reduced in number, and their nuclei
in staining capacity. The intervesicular tissue is cedematous
and poor in nuclei and in fibrils.

The pathological process consists of a very slowly progressive
atrophy. In most cases this seems not to be the result of
ordinary inflammatory processes, though Ponfick records
diminution in size of the thyroid as a result of a violent inter-
stitial inflammation. Even when the thyroid is increased
in dimensions, as occasionally happens, the vesicular substance
has for the most part disappeared, and its place has been taken
by interstitial growth.

In the skin the connective tissue of the corium has its ele-
ments torn asunder. The fibres are hyperplastic. The cell
nuclei and the fibrils of the gelatinous substance between
the fat lobules are multiplied. The whole 1is>u< lias a trans-

THE THYROID AND PARATHYROIDS 289

parent appearance. It is as if the skin were saturated with a
semi-fluid substance. Peculiar, glistening, highly refractive
bodies, whose nature is not known, have been found. A
similar condition is reported in other organs and tissues.

The chemical nature of the infiltration is not certainly known.
It is very doubtful whether it is mucin, and there are many
reasons for thinking that it has not the composition of ordinary
oedema. Cases in which a chemical examination of the skin
may be carried out are so rare that it will probably be many-
years before the matter can be satisfactorily settled. Ewald
thinks that there is a trophic change in the direction of degenera-
tion of fatty tissue or a persistence of the embryonic mucous
tissue.

(c) Paihogeny. — In the view of perhaps the majority of
physicians and pathologists who have studied the subject,
the pathogeny of myxcedema is very simple. Thus, Murray-
says : ' ' These facts clearly show that myxcedema in man is
entirely and solely due to disease or removal of the thyroid
gland and the consequent failure of the supply of its in-
ternal secretion." We have seen (p. 140) that in the case
of Addison's disease it is difficult or impossible to produce
artificially the symptoms of this disease by extirpation of the
adrenals in animals. The most striking of all the symptoms—
namely, pigmentation of the skin — does not occur in the oper-
ated animals. Similarly we shall see (p. 303) that in animals
deprived of their thyroids swelling of the skin and subcutaneous
tissues is, at any rate, not a common symptom, and according
to some observers cannot be induced at all. It must be remem-
bered, however, that it is scarcely possible to imitate artificially
the exceedingly gradual fibrosis and destruction of glandular
tissue which occurs in myxcedema.

The parathyroids are intact according to the majority of
observations, but there is some evidence that the pituitary
body may be concerned.

4. Cachexia Strumipriva

In 1882 Reverdin described the results of goitre extirpation.
In the following year Kocher published his classical report
on eighteen cases. Later in the same year J. and A. Reverdin
noted the resemblance of the symptoms to those described by
Gull, and hence called the condition " operative myxcedema."

19

290 THE DUCTLESS GLANDS

Kocher's term was " cachexia strumipriva." " Cachexia
thyreopriva " is a more correct term, but is less usually
employed.

It is important to note carefully the symptoms recorded
when the thyroid is totally removed from the human subject.
The cachexia comes on at a very variable period after the opera-
tion— from six to eight days up to months or years. Patients
advanced in years suffer less than young people under twenty.
The patients first complain of fatigue, weakness, and heaviness
in the limbs, sometimes associated with pains, tremblings, and
sensations of cold. There is a diminution of mental activity,
loss of memory, slowness of thought, speech, and movements.
Then one notices fugitive swellings of the face, hands, and feet,
which gradually become stationary and lead to a coarseness
and puffiness of the whole body. The skin loses its suppleness,
and becomes infiltrated, dry, and scaly. The hairs of the head
fall out.

There are also nervous symptoms, such as are observed in
myxoedema. The symptoms, in fact, as they were described by
Kocher and Reverdin, are very much like those of myxoedema,
except, perhaps, that not so much stress is laid on the "solid
oedema."

The majority of writers since the year 1896 have assumed
that the precise nature of the symptoms depends on the amount
of injury inflicted upon the parathyroid bodies — in other words,
that myxoedema properly so called is due to the absence of
thyroid functions, while the nervous symptoms (tetany) are
due to injury to the parathyroids. This matter will be referred
to again when extirpation experiments on animals are dealt
with.

5. Graves9 s Disease (Exophthalmic Goitre, Basedow's Disease)

The three cardinal symptoms of this disease are tachycardia,
exophthalmos, and increase in size of the thyroid gland. Some
authors consider that certain nervous symptoms are equal in
importance with those here mentioned.

In addition to protrusion of the eyeballs the more impor-
tant eye signs are (1) a widening of the palpebral clefts or
Dalrymple's sign ; (2) dissociation of the movements of the
eyeball and the upper lid (v. Graefe's sign) ; (3) inability
to maintain convergence of the eyes (Moebius' sign).

THE THYROID AND PARATHYROIDS 291

Tachycardia is the most important cardio- vascular symptom.
A rapid pulse with the patient at rest in the absence of some
other obvious cause should always arouse suspicion of Graves's
Disease. In the later stages of the disease auricular fibrillation
may occur.

Of the cutaneous symptoms, profuse sweating, especially of
the palms of the hands and soles of the feet, is the most impor-
tant.

Diarrhoea, nausea, and vomiting also occur. Accelerated
respiration and shallow breathing are suggestive symptoms!

Among the nervous symptoms a marked fine tremor, and
restlessness are the most noticeable. Goetsch's test consists in
an injection subcutaneously of a small quantity of adrenin.
The effect on the pulse rate, the tremor, the blood-pressure,
and the subjective nervous symptoms, is closely watched.
Acceleration of metabolism is an important feature of Graves's
Disease. Though the patients eat large quantities of food they
continue to grow emaciated. It is now customary to estimate
these changes in metabolism by a study of the basal metabolic
rate, by which is meant the minimum heat production when
at rest. This is estimated by an analysis of the end products
of metabolism, more especially the amount of oxygen used, and
of Co2 given off.

In Graves's Disease there may be a rise in basal metabolism
of 50 or 60 per cent.

There may be distinct lymphocytosis as a result of implica-
tion of the thymus.

With regard to the pathology of Graves's Disease, it has been
discussed whether the primary lesion is in the nervous system
or in the thyroid gland. There are certainly changes in the
thyroid, though it is not yet absolutely certain that these are
constant. It has been shown by Halsted and Edmunds that
if a portion of the thyroid be removed from an animal, the
remainder shows certain peculiar changes, described as com-
pensatory hypertrophy. The vesicles become irregular or
stellate in shape, the lining membrane is folded, the epithelium
is proliferated, and the micro -chemical reactions of the secre-
tion are altered so that it stains badly. Now, these changes
are practically identical with those found in Graves's Disease.
According to Marine, an enormous proportion of stray dogs
in Cleveland, Ohio, are thus affected, though they do not show

292

THE DUCTLESS GLANDS

the symptoms of exophthalmic goitre. Dr. Marine has, how-
ever, observed that if these dogs be treated with iodides, tlu*
alveoli again become rounded and filled with colloid, and
according to Kocher, the administration of iodine will prevent
the development of the folded condition after the operative
extirpation of part of the thyroid. Changes in the thymus

and lymph glands
seem to be common.
The most generally
accepted theory as to
the pathogeny of ex-
ophthalmic goitre is
that the disease is due
to over-activity on
the part of the thy-
roid, that an excess
of thyroid secretion is
poured into the circu-
lation. But Oswald
believes that we have,
in fact, a condition of
thyroid insufficiency,
since the gland is
often empty of col-
loid, and contains
relatively little iodine-
holding secretion.
MacCallum, on the
other hand, states
that the removal of
part of the thyroid
improves the condi-
tion of the patients,
FIG. 87.— Grave's Disease (from Adami). and the administra-

tion of thyroid

extract makes them worse. The benefit of surgical treatment
is urged by several surgeons. Marine and Lenhart do not
believe that the thyroid changes in exophthalmic goitre are
either primary or specific, or that the thyroids in these cases
produce an increased amount of a physiologically active secre-
tion. On the other hand, they think that the thyroid changes

THE THYROID AND PARATHYROIDS 293

are always secondary to some more fundamental cause, and
that there is a hypersecretion quantitatively, but a hyposecre-
tion qualitatively (physiologically) ; and, lastly, that the usual
final stage of all cases, unless terminated by death or relative
recovery, is myxoedema.

Reid Hunt has recently found that when small amounts of
thyroid are administered to mice for a few days the animals
acquire markedly increased resistance to poisoning by acetoni-
trile. This is believed to be an exceedingly delicate test for
thyroid substance. It was found, moreover, that it required
nearly twice as much acetonitrile to kill mice which had been
fed upon blood from a case of exophthalmic goitre as it did to
kill those which had received normal blood. This experiment,
Hunt believes, shows that the blood of patients suffering from
exophthalmic goitre contains an excessive amount of thyroid
secretion .

Apart from surgical proceedings, the treatment consists
in absolute rest with the assistance of sedatives if necessary.
Serum therapy in the form of Rogers' and Beebe's serum,
Rodagen (from the milk of thyroidectomised goats), Anti-
thyroidin and Thyroidectin, may be tried. Local application
of iodine preparations may do some good.

If surgical means be employed, we are not yet in a position
to state how much of the thyroid gland should be removed
in any given case. But in some instances it may be advisable
to remove more than one lobe, and it is recommended that
a small part of each should be left behind in order to preserve
with sufficient certainty the parathyroid glandules.

6. Other Conditions due to Thyroid Disorder.
Leopold-Levy and H. de Rothschild believe that in addition
to " la grande insuffisance thyroidienne " there exists a " petite
insuffisance thyroidienne." Under this category they describe
a great variety of constitutional and local changes which they
ascribe to inadequate action of the thyroid. The -symptoms
are of the same general character as in myxcedema, only
less pronounced. They may, moreover, be complicated by
those of hyperthyroidism, or of perverted action of other
glands. They describe changes in general appearance, lowering
of temperature, loss of appetite, swelling of the salivary glands,
delayed development of teeth, dyspepsia, constipation,

294 THE DUCTLESS GLANDS

diarrhoea, haemorrhoids, enteritis, affections of the heart
and arteries, tendency to catch "colds," affections of the
liver, of the urogenital tract and numerous other derangements.

And the final test in all cases as to whether the thyroid gland
was really the origin of the trouble is the success of thyroid
medication. Since many of the symptoms described are
frequently of a temporary or even a trivial character, it is
easily to be imagined that they will frequently disappear
under thyroid treatment.

Notwithstanding the hypothetical nature of much of this
work, yet it may be possible when a large number of critical
observations have been made to diagnose and treat minor
degrees of thyroid insufficiency.

Slight degrees of hyperthyroidism are probably very common,
and may be regarded as almost physiological.

Mongolism is often supposed to be due to thyroid deficiency.
The condition is characterized by interference with growth
associated with anomalies of the skeleton, falling in of the
bridge of the nose, a patent condition of the fontanelles, and
defective intellect. At first there is apathy and sleepiness and
later dementia. The symptoms are fully developed at birth.
It is doubtful whether the primary defect is in the thyroid,
though thyroid treatment is sometimes beneficial. The
patients are restless and idiotic. The complexion is fair,
the eyes are oriental with marked epicanthic folds.

The condition has been supposed to be due to malnutrition
of the foetus in utero occurring when a child is born at the end
of a long family. Reproductive exhaustion of the mother
after prolonged rest from child-bearing has been suggested as
a cause. It is said that in these " mongols " the little finger
and thumb are always short. The disease was described by
Langdon Brown in 1866 as an ethnic degeneration occurring
in European children. The condition is fairly common in
asylums, where it is often attributed to maternal alcoholism.

Progeria is a name given by Hastings Gilford to a condition
in which there is arrest of growth and premature senility. (See
p. 380.)

Fcetal and Maternal Athyrosis. — Ennis Smith describes
thyroid disturbance prevalent among new-born animals in
North America. It affects pigs, sheep, cattle, horses, goats, and
dogs. The condition is endemic and appears to correspond to

THE THYROID AND PARATHYROIDS 295

the distribution of goitre. The most striking feature in typical
cases is the absence of hair. The hoofs are thin-walled,
short, brittle, and clearly undeveloped. There is hyperplasia
of the thyroid, with low iodine content. The pathogenesis
is possibly dependent on lack of available iodine, and it is
stated that the malady can be overcome by providing abun-
dance of this element in the diet.

I. Diseases of the Parathyroid Glandules

Tetany.1 — This condition has been known since 1815, but
it was not until 1890, after the appearance of Gley's physiolo-
gical work (vide infra, p. 319), that it has been associated with
disease of the parathyroids. Many authors have assumed
that all forms of tetany are due to hypo-parathyroidism.
But it seems more likely that some forms are due to other
causes.

Tetany is described as manifest or latent. In the former
there are spontaneous attacks of tonic spasm, limited to groups
of muscles or involving the whole body. In the latter there is
simply an increased excitability of the nervous system, and
the tonic spasms may be brought on by external stimuli.
The spontaneous spasms involve the muscles supplied by
certain nerves and give rise to such characteristic results as the
" obstetrical hand." Or there may be laryngospasm and
trismus. The increased excitability of the motor nerves is
shown by an exaggerated response to the galvanic current
(Erb's phenomenon). The large indifferent electrode is placed
upon the abdomen and the small electrode is placed upon the
point to be stimulated. If a cathodal opening contraction
(KOC) occurs with a current below five milliamperes in strength,
we can be sure that there is increased galvanic excitability of
the motor nerves. If cathodal opening contraction does not
occur, a small degree of hyperexcitability can be assumed if
an anodal opening contraction (AOC) appears with currents
feebler than five milliamperes.

There is also some hyperexcitability of the sensory nerves.

The "Trousseau phenomenon" is easily elicited in most
cases. If the cuff of an ordinary blood-pressure apparatus be
applied at the middle of the upper arm and the pressure be

1 This account is largely taken from Barker.

296 THE DUCTLESS GLANDS

raised till the arterial flow is interrupted, in cases of tetany
the " obstetrical hand " attitude will be assumed.

Much reliance is placed upon V Chvostek's sign " in tetany.
The region of the pes anserinus of the facial nerve is tapped
and one notes contraction of the muscles of the face. In
marked hyperexcitability there may be a contraction of all
the muscles of the side of the face stimulated (Chvostek I).
When the excitability is somewhat less great, there may be
only a movement of the nostrils and a drawing of the angle
of the mouth to the side (Chvostek II), while, when there is
only slight increase of excitability, there may be only a slight
twitch at the angle of the mouth (Chvostek III).

The so-called arm and leg phenomena (Poole) are stated to be
useful in diagnosis. In tetany there is a constant response of
contracture of the muscles of the upper extremity upon
forcible abduction of the arm, and of contracture of the muscles
of the lower extremity extended at the knee.

In chronic tetany certain trophic disturbances may occur.
Children who have suffered from tetany often show transverse
furrows and other defects of the teeth due to faulty develop-
ment of the enamel. As will be seen below, similar defects are
found after parathyroidectomy in animals. In the eye peri-
nuclear cataract has been described.

Many different forms of tetany have been described. Among
these may be mentioned the idiopathic tetany of workmen,
maternity tetany, gastric tetany, tetany in infection and
intoxications, post-operative tetany, and tetany after pro-
longed forced respiration. It is not to be assumed that all
these forms are due to disease of the parathyroids.

Parathyroid treatment does not appear to be of much
use, but calcium often does good. Transplantation is almost
always impracticable.

It seems reasonable to suppose that a great many different
conditions may give rise to the phenomena of ' ' tetany." It has
recently been shown that administration of thyroid substance to
animals will frequently produce this condition.

Parathyroid insufficiency has also been suspected to be the
essential pathological condition in paralysis agitans. But
hyperfunction has also been alleged to occur in this disease,
and the majority of observers fail to find any connection
between the parathyroid glandules and the disease in question.

THE THYROID AND PARATHYROIDS 297

Endemic Tetany. — Endemic tetany, as it occurs in Europe,
seems to be a disease of large cities, usually appearing in the
spring ; it has a tendency to assume epidemic proportions, and
it is very local in its distribution.

In India there is an endemic tetany in rural districts.
Attention has been specially called to this affection by
McCarrison.

The distribution of tetany in India is peculiarly local, and
appears to correspond more or less with the distribution of
goitre. Sufferers from tetany appear to be able to rid them-
selves of it by going to a locality where it does not prevail.

In India tetany is a disease of child-bearing women, and there
is a marked family tendency to the disease. The children
of women who suffer from tetany are frequently cretinous.

Menstruation appears to increase the frequency and the
severity of the attacks of tetany, especially so when this
function is in any way disordered.

The seasonal prevalence of tetany — its practical limitation
to the spring months — is very striking. " Chill," fright, and
mental distress often provide the stimulus which produces the
spasms. The patients are nearly all goitrous, and incomplete
myxcedema may be present.

McCarrison finds thymol very useful in treatment, and this
affords proof of the now generally accepted opinion that the
spasms of tetany are due to the action of toxic substances
absorbed from the alimentary canal. Goitre is an important
cause of tetany, because it reduces the efficiency of the thyroid
gland.

In various forms of tetany lesions of the parathyroids have
been found, but in many cases no such changes are discoverable.

There is no definite syndrome which can be clearly associ-
ated with increased function of the parathyroids.

J. Early Views as to the Functions of the Thyroid

According to Handfield- Jones, Galen does not give any very
distinct account of the thyroid, but seems to allude to it in his
work " On the Use of the Parts of the Human Body." In
speaking of the glands of the larynx, he says these " are always
found more loose and spongy than others, and which, by the
common consent of anatomists, have been created for the

208 THE DUCTLESS GLANDS

purpose of moistening and bathing all the parts of the larynx
and the passage of the throat." Morgagni also quotes the
following, which shows that Galen was informed of the absence
of a duct : " Now, the neck has two glands in which a mois-
ture is generated. But from the two glands which are in the
neck there come forth no vessels by which the moisture may
flow out, as those do from the glands of the tongue."

Wharton, in 1656, gives a good account of the anatomy of
the thyroid and notes that "it is much more full of blood
than any other gland, also more viscid and solid, and more
resembling muscular flesh. This is the only difference, that
it is not of a fibrous structure but rather of a glutinous nature."
He allots four functions to the gland: "(1) The first and
principal use of these glands appears to be to take up certain
superfluous moistures from the recurrent nerve, and to bring
them back again into the vascular system by their own lymph
channels. (2) To cherish the cartilages to which they are
fixed, which are rather of a chilly nature, by their own heat ;
for they are copiously supplied with arteries, and abound with
blood, from whence they may conveniently impart heat to the
neighbouring parts. (3) To conduce by their exhalations
to the lubrication of the larynx and so to render the voice
smoother, more melodious, and sweeter. (4) To contribute
much to the rounded contour and beauty of the neck ; for
they fill up the empty spaces about the larynx, and make its
protuberant parts almost to subside and become smooth,
especially in the female sex, to whom on this account a larger
gland has been assigned, which renders their necks more even
and beautiful."

The third function, it will be noted, is only Galen's view
more definitely formulated. This theory, in one form or
another, long remained in vogue.

Verheyen, in 1720, says : " This gland, beyond doubt,
serves also to moisten the neighbouring parts ; but, because
it is very large, there is an apparent reason why it should
have rather large excretory ducts, or one at least very con-
spicuous, which yet hitherto has not been discovered."

Morgagni is undecided whether or no the gland has a duct.
He describes vesicular cavities in enlarged thyroids, and these
he correctly supposed to be the normal vesicles (" natural
cavities ") distended by the accumulation of their secretion.

THE THYROID AND PARATHYROIDS 299

He is inclined to think that there must be a duct opening
into the pharynx or the trachea.

Santorini fails to find a duct, but still thinks that the thyroid
gland may be forced to expel its secretion by the contraction
of the overlying muscles and other causes.

Haller, in his textbook, written in 1776, after discussing the
anatomy of the gland and detailing the fruitless attempts to
discover an efferent duct, says : " Alii Cl. viri, cum penitus de
inveniendo ductu desperassent, ad aliam omriino utilitatem
se converterunt. Liquorem peculiarem in ea glandula parari,
qui receptus venulis sanguini reddatur, quse lienis et thymi
fit utilitas, ipse Ruyschius autumavit."

Thus, in the year 177\6, we have the thyroid, the thymus,
and the spleen classed together as glands without ducts, which
manufacture a special fluid, which is received into the veins,
and so returned to the general circulation. This, so far as it
goes, and, so far, at any rate, as it refers to the thyroid, is not
far different from the modern conception.

Although from this time on the glandular nature of the
thyroid was universally conceded, and there wTas much specula-
tion as to the precise mode of secretion and the elimination of
the product from the vesicles into the circulation, yet the
active function of the secretion itself was for a long period not
the subject of any serious inquiry, and, indeed, the possibility
of its being of any great importance in the economy was
scarcely suspected. Thus, Cruveilhier, in 1834, states that the
use of the secretion of the thyroid is unknown, and about this
time Sir A. Carlisle supposed that the gland forms a protection
to the delicate organs of the voice, against the variations of the
external air.

In 1844 Simon put forward a very interesting theory in
regard to the function of the thyroid, all the more interesting
as it has quite recently been revived. Simon considered that
the thyroid exercises a regulatory function on the blood-
supply to the brain, exerting also its secretory function in an
alternating manner with the substance of the brain. " What
diversion is to the stream of blood viewed quantitatively,
alternative secretion would be to the composition of the blood
viewed qualitatively ; and I should conceive that the use of
the thyroid gland, in its highest development, may depend on
the joint exercise of these two analogous functions. I should

300 THE DUCTLESS GLANDS

suspect not only that the thyroid receives, under certain
circumstances, a large share of the blood which would otherwise
have supplied the brain, but also that the secretion of the
former organ bears some essential relation (which chemistry
may hereafter elucidate) to the specific nutrition of the latter ;
that the gland — whether or not it appropriates its elements in
the same proximate combination as the brain does — may,
at all events, affect in a precisely similar degree the chemical
constitution of the blood traversing it, so that the respective
contents of the thyroid and cerebral veins would present
exactly similar alterations from the characters of aortic blood.
Finally, I should suppose that these actions occur only or
chiefly during the quiescence of the brain, and that when this
organ resumes its activity, the thyroid may probably render
up again from its vesicles to the blood, in a still applicable
form, those materials which it had previously diverted from
their destination."

Writing a few years later (1849-1852), Handfield-Jones still
thought it necessary to criticize adversely the various ancient
theories which supposed the thyroid to bear some functional
relationship to the larynx. He says that there seems no doubt
that the relative position of the thyroid to the larynx is quite
unimportant, so far as the function of the organs is concerned.
This is borne out by the variations of its site, which occur in
birds, and by the results of morbid action, since prodigious
goitre does not induce disease of the larynx, except in a me-
chanical way — i.e., by injurious pressure.

Referring to Simon's theory, Handfield-Jones remarks,
" It is the only one yet promulgated which can be said to
be even probable." He does not, however, declare himself
an adherent to the theory, of which, in fact, he offers several
criticisms.

K. Extirpation Experiments upon Mammals

The earliest extirpation experiments upon animals appear
to have been performed by Raynard. This observer reports
that the treatment of goitre in dogs can be carried out just
as in man. Complete removal of the thyroid was successfully
carried out in dogs of medium age and in old dogs, but in young
animals death occurred within a few days. The post-mortem
examination did not reveal the cause of death.

THE THYROID AND PARATHYROIDS 301

Astley Cooper gave some account of the structure of the
thyroid and extirpated the gland from two pups ten weeks old.
The animals recovered after suffering from stupidity and
malaise. The animals were killed very soon after the opera-
tion.

Moritz Schiff, during the years 1856, 1857 and 1858, carried
out a series of thyroidectomies upon various animals. Some
rabbits, some rats, some fowls, and some dogs survived the
operation, but several dogs, a cat, and a rat died after some
days.

The earlier results of Schiff were apparently read before the
Royal Academy of Science in Copenhagen and then buried in a
work on the formation of sugar in the liver. It is not surprising
that they remained unnoticed for many years. Cretinism
had long been recognized, and in 1874 Gull described the condi-
tion which Ord, in 1878, called " myxcedema." In 1882 the
Swiss surgeons noted the symptoms of " cachexia strumi-
priva," or " operative myxcedema," after operations for goitre
in the human subject.

After an interval of a quarter of a century Schiff was led by
the observations of Kocher and Reverdin in Switzerland to
take up the problem again. In 1884 he recalled his earlier
experiments of 1856-1858, and published the results of a new
series of investigations. In the rat and the rabbit, thyroid-
ectomy was not followed by any serious result. In the
dog and cat, however, complete removal was fatal. He
gives an admirable account of the nervous symptoms after
removal of the thyroid in the dog, and states that these may be
avoided by a previous graft of the thyroid of one dog into the
abdominal cavity of another. Other symptoms noted by
Schiff were general malaise, arrest of growth, and in two cases
oedema.

It must be noted that some of these symptoms, particularly
those of a nervous nature, are at the present time attributed
to loss of parathyroid tissue which must have occurred when
the thyroid was extirpated in dogs and cats.

Wagner and others confirmed Schiff's observations, and it
has been stated that the first-named author found an increased
response in the nerves to galvanic currents after removal of the
thyroid (and parathyroids) in cats.

Horsley was the first to operate on monkeys. He states

302

THE DUCTLESS GLANDS

that a week after the operation fibrillary twitchings of the
muscles were noted, and that these ceased on voluntary move-
ment. The animal then became " cretinoid." There was a
" myxcedematous " condition of the subcutaneous tissues.
The tremors were relieved by keeping the animal warm.
According to Horsley, there were swellings of the skin of the
face and abdomen, due to the infiltration of the tissues by
mucin. The salivary glands became enormously hypertro-
phied and the parotid gland produced large quantities of
mucin.

We are not concerned in this place with the nervous symp-
toms described by Horsley, but it may be observed in passing
that so far as I am aware no subsequent observer has been
able to obtain these " myxoedematous " symptoms in monkeys
or in other animals. Horsley gives no detailed protocols of
his experiments.

Removal of the thyroid from different animals was carried
out by a number of observers during several succeeding years.
The majority of these confirmed the general views of Schiff as
to the effects of total extirpation of the thyroid. It must be
remembered that at this period the possibility of a separate
functional importance of the parathyroids was not suspected,
so that while in dogs, cats and monkeys thyroids and parathy-
roids were always removed together, in the herbivora the two
external parathyroids were left behind in what was called
" total thyroidectomy." For, although the external para-
thyroids were discovered by Sandstrom in 1880 and by Baber
in 1882, it was not until Gley rediscovered them and demon-
strated their functional importance in rabbits that experi-
menters gave them due consideration. This was in 1891.

Following Horsley's work came a series of papers by numer-
ous authors. These all supported the view of Schiff as to the
effects of total extirpations of the thyroid. But some were
inclined to deny the supreme importance of the thyroid in the
animal economy and attributed the untoward symptoms
recorded by other workers to injury to nerves, reflex action,
and similar causes. Munk's observations are specially inter-
esting in view of the results obtained by some more recent
observers (vide infra). He came to the conclusion that the
chronic disturbance of nutrition in thyroidless animals is
nothing more than " gefangenschaftkachexia " which may

THE THYROID AND PARATHYROIDS 303

often be observed in unoperated animals. He states that
out of four monkeys operated on in England one was
sent to him as " myxoedematous." The animal had nothing
more than an ill-defined facial swelling, probably due to
a carious tooth, and an intermittent paresis of a fore
limb. The animal was, according to Munk, otherwise in good
health and lived for ten months after the operation. Munk
insisted that although removal of the thyroid is a dangerous
operation, it does not follow that the thyroid is absolutely
essential to life. And this statement must be admitted as
justifiable, even if the survivals are due to thyroid or parathy-
roid tissue which is so placed that it cannot be removed. It
will be necessary to return to this point.

The further account of Gley's work, as well as that of Vassale
and Generali and Kohn, will be found in the section on the
physiology of the parathyroids.

The experiments of Vincent and Jolly may be briefly recalled
so far as they relate to the general question of extirpation of
thyroids and parathyroids, and more particularly in regard to
the effects alleged to be due to elimination of the function of
the thyroid. On these points the general conclusions were :
" Neither thyroid nor parathyroids can be considered as organs
absolutely essential for life. Rats and guinea-pigs do not seem
to suffer at all as the result of extirpation. Monkeys show
only transient nervous symptoms. Dogs, cats, foxes and
prairie wolves frequently suffer severely and die. On the other
hand, badgers do not appear to be affected by the operation.

" In no animals, not even in monkeys, have we been able to
induce any swellings of the subcutaneous tissue, which is the
most striking feature of myxcedema in the human subject. We
think, therefore, that the pathology of myxoedema must be
more complex than simple thyroid insufficiency." l

Several previous observers from Schiff onwards had noted
the fact that thyroidectomy in dogs and cats is by no means
always fatal. At the same time there has been a tendency to
disregard the exceptions, and, when any explanations have
been offered it has been suggested that they are due to parathy-
roids having been overlooked at the operation, or to the exist-
ence of accessory thyroids. Munk (vide supra) indeed is among

1 On other points discussed in these papers the present writer has changed
his opinion. This applies to the change of parathyroid into thyroid.

304 THE DUCTLESS GLANDS

the few observers who have laid due stress upon the cases of
survival. This observer, as we have seen, admits that removal
of the thyroid is dangerous, but not that the gland is an organ
essential to life. We cannot assail the logic of the position
that an organ which may frequently be removed with impunity
is not " essential to life " and the results obtained by Vincent
and Jolly forced them to extend the observation so as to
include not only the thyroid but also the parathyroids.

According to Noel Paton, a * * contention that the removal of
the parathyroids does not produce the train of symptoms
terminating fatally, must in the light of the work of other
investigators be explained as due to a failure to remove all the
parathyroid tissue." Now, in the case of rabbits, Paton quotes
Pepere to the effect that accessory parathyroids are nearly
always found in the thymus in rabbits. So that in rabbits
parathyroidectomy is only fatal in the few animals which
happen not to have any parathyroid tissue in the thymus.

In the monkeys employed by Vincent and Jolly no symptoms
of myxoedema were observed when thyroids and parathyroids
were completely removed. These results differ from those
obtained by Horsley (loc. cit.), Murray and Edmunds, who state
that it is possible to induce myxoedema by operation. This m ay
be compared with the results obtained by Munk (vide supra) and
Kishi. The last named only recorded one death out of six. Our
animals were subject to catarrh, and one died of some laryngeal
affection, and it seems probable that as in the case of other
animals, removal of the thyroid gland leaves monkeys in a
condition in which they are less capable of resisting disease.
There is no reason to attribute death, when it occurred, to
loss of thyroid or parathyroid. The animals were in good
health, were active, and but for loss of weight showed no ill
effects.

Carlson and Woelf el report that myxoedema does not develop
in thyroidectomized rabbits, at least in seven months, nor in
the monkey in several months.

In some groups of animals age seems to make a great differ-
ence to the results both of thyroidectomy and of ' ' complete ' '
thyro- parathyroidectomy. Sutherland Simpson found that
removal of the thyroid with the contained internal parathyroids
in thirteen adult sheep and sixteen lambs from seven to eight
months old, led to practically no ill effects (see Fig. 88). As a

THE THYROID AND PARATHYROIDS 305

FIG. 88. — Photograph of group of thyroidectomized sheep taken five months
after operation (after Simpson — Quart. J. Exp. PhysioL).

result of a similar operation, three lambs about two months old
became "typical cretins."

The complete operation (thyro-parathyroidectomy) in four
young lambs (five to seven weeks old) resulted early in acute
and fatal tetany. Removal of the two external parathyroids

FIG. 89. — Photograph of cretin lamb about one year old, and of normal
lamb of eleven months (after Simpson — Quart. J. Exp. PhysioL).

20

306 THE DUCTLESS GLANDS

from the three cretins when about one year old was followed
by only slight symptoms. According to Simpson, age is an
important factor with regard to the effects of both thyroid-
ectomy and parathyroidectomy. The " typical cretins " of
Simpson are described as " small and stunted, with broad
faces and rickety limbs. The wool was coarse, but did not
tend to fall out." In some of the young animals (cats and dogs)
operated on by Vincent and Jolly interference with growth
was very striking, but the other " cretinoid " symptoms were
absent.

Basinger in 1916 carried out an extensive research on
thyroidectomy in rabbits. Out of 140 animals operated upon
"typical cretinism" was produced in 86. The experiments
were carefully controlled as to feeding, and selection of subjects
and normals from the same litters. The thyroidectomy was
performed at the age of 2 to 3 weeks when the body weight
was about 175 gms. Great care was taken to remove all
thyroid tissue, leaving the external parathyroids intact, but it
was subsequently found that in a considerable proportion of
cases minute bits of the gland had been left behind and pre-
vented the onset of cretinism. In different litters the propor-
tion of successful results varied from 25 to 90 per cent.

About two weeks after the operation the onset of cretinism
was detectable. The hair became dryer than normal, did not
lie smoothly and could easily be pulled out. Retardation of
growth was noticeable as early as the third week ; it was
greatest from the eighth to the twelfth weeks. By the end
of the tenth week the average weight of the cretins was 750
gms., while that of the controls was 1400 gms. The posture
of the cretins was typical. The bones were short and the
muscles of the limbs too weak to support the body weight.
The bones showed a pseudo -rickety condition (Hofmeister's
" chondrodystrophia thyreopriva "). The skin became in-
creasingly dry and scaly and finally eczematous. The typical
"pot belly " seen in human cretins developed. No evidence
of the typical myxcedema such as is seen in human cases was
observed. Neither did chronic, progressive cachexia appear
in any of the cretins, although they were kept for a year.

Trail-fusion of normal blood serum into the cretins had no
apparent effect on their condition. Some improvement, how-
ever, resulted from transfusion of serum from thyroid-fed

THE THYROID AND PARATHYROIDS 307

rabbits. Administration of desiccated thyroid gland substance
markedly relieved the symptoms but failed to bring about a
complete cure. The cretins proved more susceptible than
normal rabbits to the toxic action of thyroid feeding.

It seems clear from the experiments of Sutherland Simpson
and others that in young animals removal of the thyroid (one
or more parathyroids being left behind) will bring about a
condition resembling cretinism in the human subject. In older
animals symptoms may not be observed, but thickening and
dryness of the integument with a tendency to loss of hair
and wasting followed by adiposity have been described. It is
stated that there is loss of muscular tone, and that regeneration
of tissues is slower than normal. There may be anaemia. The
body temperature is low ; the power of heat regulation is
diminished and the animal becomes poikilothermic ; the
sexual functions are interfered with. It has been stated that
the limit of assimilation of carbohydrates is raised. " The
nervous system is markedly affected, dulness and apathy
being prominent symptoms. Many nerve-cells, especially those
of the cerebral cortex, exhibit a shrunken appearance, and
present a strong contrast with those of the normal animal
(Schafer). A myxoedematous condition of the skin has been
described by some authors, but the present writer has never
seen this (vide supra).

Thyroidectomy in the amphibia interferes with the normal
metamorphosis, and retards or completely stops growth and
ossification of bone. The operation does not appear to hinder
the development of the gonads.

Several observers have reported a diminution in the alexins
and opsonins in the serum after removal of the thyroid.

L. The Mechanism of the Thyroid Secretion

It used to be asserted that the secretion of the thyroid gland
passes, not directly into the blood-stream, but indirectly by
means of the lymphatics. But more recent investigations have
rendered this theory very doubtful.

Asher and Flack utilized the observation of Cyon that the
excitability of the depressor nerve is increased by the action of
thyroid substance. They believe that the thyroid furnishes
an internal secretion which increases the excitability of the

308 THE DUCTLESS GLANDS

depressor nerve, and augments the effect of adrenin upon the
blood-pressure. According to these authors the secretory
nerves to the gland are the laryngeal nerves.

More recent investigation seems to point to the sympathetic
as the origin of the secretory fibres to the thyroid. Rahe,
Rogers, Fawcett, and Beebe find that stimulation of vessels with
the accompanying nerve filaments causes a diminution in the
amount of iodin contained in the gland. These authors con-
clude that the thyroid is at least in part under nervous control,
and that its physiologically active substance is discharged into
the circulation in response to a nerve stimulus.

The view that the sympathetic fibres are true secretory nerves
to the thyroid is supported by the observations of Cannon
and Cattell upon the electrical response of the gland during
activity. (See p. 33.) Control by the sympathetic suggests that
adrenin may stimulate the thyroid to increased activity, and
this was proved to be the case by intravenous injection of
adrenin, and by stimulation of the adrenals through the
sympathetic nerves. By continuous stimulation (fusion with
the phrenic) of the cervical sympathetic a condition resembling
exophthalmic goitre was produced. It seems possible that the
thyroid (like the adrenal) has an emergency function, which
would increase the rate of metabolism and augment the
efficiency of the adrenin secreted simultaneously.

Rogoff tried to detect in the blood coming from the thyroids
of three dogs a physiologically active secretion, tested by
feeding tadpoles with the dried blood. The number of
experiments recorded is not sufficient to warrant us in
drawing any very definite conclusion.

M. The Chemistry of the Thyroid

The most striking feature of the thyroid gland from a
chemical standpoint is the constant presence in it, under
normal conditions, of measurable amounts of iodine.

The following elements have been stated to be present in
the thyroid : carbon, hydrogen, oxygen, nitrogen, sulphur,
phosphorus, sodium, potassium, calcium, magnesium, silicon,
arsenic, fluorine, chlorine, bromine, and iodine. It was in
1854 that Macadam found iodine in food plants, but it was
not until 1895 that Baumann discovered the presence of this

THE THYROID AND PARATHYROIDS 309

element in the thyroid. It is now generally recognized that
the vertebrate thyroid invariably contains iodine. The per-
centage varies from O'Ol to 1*16 for dried glands. Other
mammalian tissues do not contain more than about O'OOl
per cent.

There are now three reliable methods for the detection and
estimation of iodine : those of Bourcet, Hunter, and Kendall.
The two latter with 0*5 gramme of material will detect the
presence of O'OOl per cent, of iodine with accuracy. Utilizing
these methods, Cameron finds that iodine is an invariable
constituent of all marine Algae (O'OOl to 0*7 per cent, of dried
tissue). Land plants contain much less. All marine animals
contain iodine. In vertebrates this is found practically
entirely in the thyroid. Small amounts of the other halogens
are also found.

The relative amount of thyroid tissue seems to increase as we
ascend the scale of evolution. But the iodine content does
not increase in a corresponding degree. It would appear that
in cattle both thyroid tissue and iodine content are greater in
the female than in the male. In regard to age, the maximum
iodine content in the human subject is found between 40 and
60 years. The lowest figures are obtained from subjects
under 15. According to Seidell and Fenger there is a seasonal
variation in the iodine content of sheep, pig, and ox thyroids.
Thus, the percentage between June and November is usually
from two to three times as great as that between December and
May. Diet appears to be insufficient to explain the seasonal
variations. They are probably due to metabolic changes due
to temperature.

But the most important factor in the causation of variations
in the iodine content of the thyroid is undoubtedly diet.
The administration of iodine as iodides rapidly raises the
iodine content of the thyroid. From the time of Baumann
numerous observations have shown that the amount of iodine
in the thyroid depends on the amount of this element in the
normal diet. Thus the thyroids of the herbivora have more
iodine than those of the carnivora. Sheep fed largely on
seaweed show a large amount of iodine in the thyroid. In an
ordinary human diet the thyroid iodine is obtained from fish,
molluscs, milk, eggs, wine, etc.

It is probable that the iodine of the thyroid is chiefly con-

310 THE DUCTLESS GLANDS

tained in the colloid substance, though there is some evidence
that the cells of the vesicles also contain a certain amount.

In algae most of the iodine is in soluble organic (non-protein)
combination, a trace only being present as iodide. Drechsel
found an iodo-amino-acid in the skeleton of a coral, which was
later identified as di-iodo-ty rosin. Dibrom-ty rosin is also
found in corals and sponges. It is said that p.-iodophenyl-
alanine is present in sponges.

None of these can be isolated from the thyroid. In the
gland most if not all the iodine is in organic combination.
Some observers state that there is a small amount of iodide
present. Baumann boiled thyroid glands with sulphuric acid.
The residue was extracted with alcohol and evaporated to
dryness. The product was called thyroiodin or iodothyrin.
It contained 10 per cent, of iodine, and amounted to about
4 per cent, of the total weight of the dried thyroid. It has
been found that Baumann's product was not of a constant
chemical constitution, and it has been suggested that the
iodine compound present was iodotryptophane. Various
other thyroid preparations have been made and have been put
forward as the " active principle " of the thyroid gland,
lodothyroglobulin (Oswald) is possibly a definite compound
and exists as such in the thyroid gland.

In 1919 Kendall announced the isolation of a definite
crystalline iodine compound which he calls " thyroxin." His
method of isolation is given as follows : " The fresh thyroid
glands are hydrolyzed in 5 per cent, sodium hydroxide in a
nickel kettle, the fats are removed by rendering the sodium
soap insoluble, and the clear alkaline filtrate is cooled and
acidified. The acid insoluble constituents containing practi-
cally 100 per cent, of the thyroxin present are filtered off. This
material is redissolved in sodium hydroxide and reprecipitatrd.
using hydrochloric acid. The precipitate is now air-dried and
is dissolved in 95 per cent, alcohol. The excess hydrochloric
acid which remains in the air-dried precipitate is neutralized
with sodium hydroxide until it is almost neutral to moistened
blue litmus paper. A heavy, black, tarry precipitate forms,
which may be removed by filtration. The alcoholic filtrate
is treated with barium hydroxide by adding a hot, very con-
centrated aqueous solution of the hydroxide to the alcohol,
and refluxing. The treatment with barium removes some

THE THYROID AND PARATHYROIDS 311

heavy dark impurities. A small amount of sodium hydroxide is
added to the nitrate and carbon dioxide is passed through the
solution. The barium and sodium carbonate are removed by
filtration, and the alcohol is distilled. The last traces of
alcohol are removed by heating in an evaporating dish. The
aqueous residue is now acidified with hydrochloric acid. The
precipitate is dissolved in alkaline alcohol, carbon dioxide is
passed through the solution, the precipitated sodium carbonate
is removed, and the alcohol is evaporated. The last traces
of alcohol are removed by heating on a water bath and the
solution is allowed to stand. The monosodium salt of thyroxin
will separate at this point. The yield is not quantitative, and
it must be further purified by dissolving in alkaline alcohol,
passing in carbon dioxide, distilling the alcohol, and allowing
the monosodium salt to crystallize a second time. This may
then be precipitated from an alkaline alcoholic solution by the
addition of acetic acid. Re- solution in alkaline alcohol and
precipitation with acetic acid for five or six times removes
the impurities and will yield thyroxin containing the theoretical
percentage of iodine."

Kendall states that he has obtained 33 grammes of
thyroxin from 6,550 pounds of fresh thyroid.

Thyroxin is said to be 4,5.6, tri-hydro, — 4,5,6, tri-iodo — •
2 oxybetaindolepropionic acid. It exists in three forms : (1)
the keto form with the carbonyl group adjacent to the imino,
(2) A tautomeric enol form, and (3) A form with an open ring
structure (cp. creatine and creatinine). It can be regarded as
a derivative of tryptophane. According to Kendall the third
form is that in which iodine occurs in the body.

I H

H
I

\

C = 0

N

(1) Keto form

312

THE DUCTLESS GLANDS

I H

V
c

s

C = C— *CH2 — CH2 — COOH

C — O — H

C N

i

I H

\/

C

(2) Enol form

C C = C — CH2 — CH2 — COOH

COOH
NH2

(3) Open -ring form

H

H — C C — C — CH2 — CHNH,

I II II I

COOH

H — C C C — H

C

J. A

Tryptophane

.

\
I/

C C = C — CH2 — CH2 — COOH

C — OH

I
H

C N

/\

O H

H

(4) Amino-lo'drate form

THE THYROID AND PARATHYROIDS 313

The change to the open ring form is effected easily in presence
of certain products of hydrolyzed protein which contain
the indole nucleus.

(1) The keto form (formula 1) crystallizes in needles and is
tasteless and odourless. It is found in the keto form in acid
solution. It is insoluble in organic solvents unless they are acid
or basic. It is soluble in alcohol in the presence of mineral
acid or an alkali. It is not destroyed by heating. The melting
point is 250° C. Mol. Wt. = 585, and empirical formula
CuH10O3NI;l (cf. tryptophane CnH1202N2). It is amphoteric,
It can yield a sulphate, a hydrochloride, a ureide and an
acetyl derivative. It gives also mono- and di-basic salts,
but these are so easily decomposed that they cannot be
obtained in a pure form.

(2) The enol form (formula 2) exists in alkaline solution.
It may be prepared by hydrolysis in the cold of the ammonium
salt, solution in pyridine and addition of water, when it
separates out in needles (melting point 204° C). It is easily
soluble in anhydrous or aqueous pyridine and quinoline and
in formic acid. It is easily changed into the keto form.

(3) The open-ring form (formula 3) is obtained by adding
sulphuric acid to an alkaline watery solution of thyroxin. The
precipitate which is formed is suspended in water and boiled.
Thyroxin is then thrown down in long crystals (melting -point
225° C.). It is soluble in alcohol, changing in solution to the
keto form.

A fourth (amino -hydrate) form (formula 4) may be obtained
from an alkaline solution of thyroxin by heating and adding
10 per cent, ammonium chloride. Fine crystals with a melting-
point of 216° C. separate out. If these are suspended in water
acidified with formic acid and boiled, the crystals are changed
into the open-ring form.

If nitrous acid be added to an alcoholic solution of thyroxin or
to a suspension in water in presence of hydrochloric acid a
yellowish colour is developed which, on addition of ammonia,
changes to deep red. This reaction serves as a test for thryoxin.

Thyroxin is more susceptible to reduction than to oxidation.
Zinc and other metals in acid or alkaline solution split off iodine
and break up the nucleus. Mild oxidizing agents have no
effect, stronger ones break down the molecule. Thyroxin is
unstable in sunlight ; iodine is split off as hypoiodous acid and

314 THE DUCTLESS GLANDS

subsequently as free iodine. The iodine content is 65 per cent.
It is said that a small quantity has already been synthesized.
Thus it appears that two definite compounds containing
iodine have been separated from thyroid tissue, a globulin
(iodo-thyro-globulin) which exists as such in the gland, and
a derivative of tryptophane (thyroxin) obtained as a cleavage
product and containing 65 per cent, of iodine. The evidence
before us points to thyroxin as one of the active compounds
of the internal secretion of the thyroid gland. But it is too
early to affirm that it is the only active compound.

N. Physiological Actions of the Thyroid Secretion

Kendall claims that thyroxin produces all the effects of
thyroid both physiologically and therapeutically. Thus it is
found as useful in myxcedema as other thyroid preparations.

Thyroxin shows a curious delay in its action. Successive
daily administration may bring about death, but a single
injection even of enormous size produces no effect. 1 mg. of
thyroxin in an adult weighing 150 pounds will increase the
metabolic rate 2 per cent.

Kendall suggests that in the normal animal organism
thyroxin is not fundamentally essential to life. This agrees
with the results of extirpation experiments described above,
and further is in accordance with the emergency theory of
Cannon (vide supra). It is suggested that thyroxin is a
catalyst, and that its function is to increase the rate of the
fundamental chemical reactions of the body.

Intravenous injection of thyroid extracts or of thyroid
preparations produces a temporary fall of blood-pressure.
This effect is in all probability not a specific one. It is probably
the same kind of fall as is produced by the injection of extracts
of most organs and tissues in the body. The fall is due to
a dilatation of peripheral vessels throughout the body. We
have no reason to believe that this effect on blood-pressure
has any bearing on the question of the internal secretion of the
organ. The probable nature of the substance has been dis-
cussed above (p. 25).

Gudernatsch and others have observed that feeding tad-
poles with thyroid substance will cause precocious differenti-
ation, while growth is suppressed. The tadpoles begin to

THE THYROID AND PARATHYROIDS 315

undergo metamorphosis a few days after the application of
the thyroid and long before the control animals do so. The
reaction was supposed to be a delicate test for the presence of
physiologically active thyroid substance.

The reaction however does not appear to be a specific reaction
of thyroid substance since it has been found to occur after
administration of iodides and iodized blood-serum. Kendall
states that the action on metamorphosis (which occurs with
small doses of his ' ' thyroxin " ) is not due to the organic
nucleus, but is due to the iodine in the molecule, which breaks
off as hypoiodous acid (HI 0).

Carrel states that tissues grown in vitro increase several
times as rapidly in the presence of thyroid substance as in its
absence.

The administration of thyroid substance and of iodide to
animals has yielded some interesting results. In determining
the effect on gross weight most of the earlier observations were
made on adult animals. In regard to the effect on growth
in young animals, some observers have noted an increase in
the rate of growth, others a decrease, while still others have
recorded that no distinct effect was produced. Cameron was
the first to use a dose based rigidly on and bearing a constant
ratio to the body weight of the animal at the time of adminis-
tration. He has found, as the result of a series of very careful
experiments, that continued small doses of desiccated thyroid
gland administered to young white rats produce (a) a definite
and invariable decrease in rate of growth ; (b.) hypertrophy of
the organs concerned with increased metabolism — heart, liver,
kidneys, adrenals, etc. (confirmatory of Hoskins and Herring) ;
(c) disappearance of fat (confirmatory of Hoskins and Herring).
The decrease in rate of growth is proportional to (a ) the amount
of thyroid administered and (b) the iodine content of the gland
given. The hypertrophy varies with the dose and length of
time during which it is administered, and appears also to be
proportional to the iodine content of the dose. Sodium iodide
given in quantities varying from amounts equal in iodine
content to the thyroid doses to amounts a hundred times as
great produces no effect on growth rate and no hypertrophy.
The effects produced are not due to protein feeding, autolytic
products, or any similar .cause, but specifically to thyroid
tissue, or some constituent of it. Both thyroid and iodide

316 THE DUCTLESS GLANDS

feeding increase the colloid in the thyroid. Thyroid feeding
inhibits the growth rate of the thyroid while iodide does not.
Similar effects were obtained in experiments upon rabbits.
Since among all the. organs and tissues of the body thyroid
alone produces a definite effect and since iodide does not pro-
duce this effect, it is suggested that decreased rate of growth,
hypertrophy of liver, heart, kidneys, and adrenals, and rela-
tively decreased thyroid may be used as tests for preparations
alleged to be the essential thyroid secretion. According to
more recent observations of Cameron, Kendall's thyroxin
produces effects similar to those of thyroid when given by the
mouth. But quantitatively, compared on a basis of iodine
content, the effects of thyroxin are distinctly less than those
of desiccated thyroid. This is probably due to bacterial
decomposition ; thyroid acts as a shield. The hypertrophy of
heart and lymphatic tissue resembles that observed in cases
of hyperthyroidism.

Many attempts have been made to induce symptoms of
exophthalmic goitre by means of the administration of thyroid
substance to animals. It is doubtful whether a condition
strongly resembling Graves's disease has ever been brought
about by such methods. But there can be little doubt that
definite toxic effects can be produced by thyroid feeding.
These are loss of body weight, gastro-enteritis, and diarrhoea,
rather than tachycardia, nervousness, and exophthalmos.
Kendall believes that in order to get " hyperthyroidism " we
must have thyroid and adrenal cortex acting together. It
has not yet been determined how far the toxic symptoms just
described are due to iodine qua iodine.

O. The Effects of Thyroid Gland, and Preparations
made from it, upon Metabolism

Many years ago it was observed that myxcedematous sub-
jects, when treated with thyroid, suffered loss of weight due
to reduction of fat and water. Since then various thyroid
preparations have been employed to reduce obesity.

When systematic metabolism experiments were carried out
it was usually found that thyroid causes an increase of nitrogen
in the urine, showing increased ^protein metabolism. The
same or similar results were obtained with "iodothyrin " and

THE THYROID AND PARATHYROIDS 317

" thyreoglobulin," in the case of the latter the effect varying
with the amount of iodine present.

According to Cramer the administration of thyroid prac-
tically abolishes the store of glycogen in the liver. The
increased katabolism of protein and fat is secondary to increased
mobilization of the glycogen in the liver. According to Fron-
tali and Hunter there is a very great elimination of creatine in
sheep and dogs after removal of both thyroids and parathy-
roids. Kendall's thyroxin produces a notable effect on meta-
bolism. The statement has been made that certain amines
derived from proteins have an effect on metabolism of the
same character as that brought about by thyroid substance.

P. Transplantation of the Thyroid Gland

A large number of transplantation experiments have been
performed, with very variable results. Many different methods
and many kinds of animals have been used. In some cases
rapid degeneration and loss of the grafted organ has occurred.
In others apparently the tissue has remained alive and active
for months.

When the gland from one animal is grafted into another of
different species (heteroplastic transplantation) the operation
is always unsuccessful. When the thyroid from one animal
is grafted into another of the same species (homoioplastic
transplantation) the proceeding is perhaps sometimes success-
ful. When a piece of thyroid is grafted on to various parts of
the same animal (autoplastic transplantation) the operation
is quite likely to be successful. The grafts frequently " take "
and are said to remain in functional activity for long periods.
When transplantation takes place into nearly related indivi-
duals of the same species (syngenesioplastic transplantation,
Loeb ) the results obtained are intermediate in point of success
between those obtained by auto- and homoioplastic trans-
plantation. The transplanted gland lives for a certain time,
but subsequently becomes absorbed by lymphocytal infiltration.

By the vessel suture method of Carrel and Guthrie the
thyroid may be removed from its proper position and replaced
in the neck. It would appear that by this method the auto-
plastic form of transplantation is the only one which has been
successful. One case of homoioplastic grafting has been
recorded as successful in the human subject.

318 THE DUCTLESS GLANDS

Q. The Relationships between the Thyroid Gland and
the Reproductive Functions

In the case of women some kind of relationship between
the thyroid gland and the functions of reproduction has been
recognized for a very long time. Thus it has been known
that the gland is relatively larger in women than in men, and
the conspicuousness and relatively large size are more marked
after puberty and during the periods of menstruation and
pregnancy. We know from observations on cretins and upon
thyroidless animals that the proper growth and development
of the sexual organs depends on the functional integrity of
the thyroid gland. It is stated that sexual intercourse both
in men and in women entails increased activity of the gland
and gives rise to an increase in volume. McCarrison believes
that married men and women under forty years of age owe
their superior physique to the maintenance of thyroid activity
which marriage assures.

The ovaries are believed to exert an inhibitory action on
the thyroid gland, so that the latter becomes over active after
castration. This hyperactivity is revealed by an increase in
the amount of colloid matter. This is also put forward in
explanation of the large number of cases of exophthalmic
goitre which occur after the menopause. Bearing in mind the
important though ill-understood relation between, the adrenal
cortex and the reproductive organs it seems probable that the
relations of the thyroid to the sexual functions will only be
fully understood when the functions of the adrenal are better
known.

R. The Functions of the Thyroid Gland

The evidence before us points to the conclusion that the
thyroid gland provides a substance or substances which aid
in the growth, morphological differentiation, and metabolic
processes of the body. One of these substances seems to be
an iodized amine — thyroxin. Most of the activities attribut-
able to the active principle or principles are in the direction of
katabolism, though, according to some authorities, there are
indications of the existence of an anabolic principle. It is m.t.
known whether there are two separate active substances — one
anabolic, the other katabolic. The secretion of the active

THE THYROID AND PARATHYROIDS 319

principle or principles is probably under the control of the
sympathetic. Whether the influence of the active material
is direct on the tissues themselves, or indirect through the
nervous system, is still doubtful. The thyroid is not equally
important in all groups of animals. Adult herbivora can live
in good health without a thyroid while the carnivora under
such conditions will frequently suffer severely and die.

Kendall regards the action of the thyroid substance as
that of a catalytic agent. The substance does not alter the
character of the fundamental reactions but increases their rate.

The antitoxic action of the thyroid gland depends in all
probability on its metabolic function. The slowed changes
of material in the body after removal of the thyroid will
diminish the amount of alexins and opsonins and so render
the animals more liable to infection. Regarding the perplexing
problem of the iodine, it seems wise to assume provisionally
that this element, in certain organic combinations, is of service
as a catalytic agent in aiding or accelerating the fundamental
metabolic processes of the body. We may also assume that
the thyroid has for its function the utilization of the iodine in
the diet to build up the particular compound or compounds
which are necessary. Kendall believes that the essential
part of the active substance is the NH2COOH group, and that
the iodine modifies the action, but is not essential. But he
has riot yet succeeded in preparing the active nucleus without
iodine.

S. Extirpation Experiments upon the Parathyroid
Glandules

The external parathyroids were discovered by Sandstrom in
1880. But it was not until their rediscovery by Gley in 1891,
and the description of the internal parathyroids by Kohn in
1895, that extirpation experiments could be carried out with
due regard to anatomical considerations.

Vassale and Generali removed all four parathyroids from
nineteen animals — ten cats and nine dogs — leaving the thyroids
intact. Of the ten cats, nine succumbed within ten days,
most of them at about the fifth day after the operation, after
presenting a typical train of symptoms. There were fibrillary
twitchings, muscular spasms, psychical depression, stiff and

320 THE DUCTLESS GLANDS

tottering gait, loss of appetite, tachycardia, rapid emaciation,
and lowering of body temperature. One of the cats, operated
upon on January 5, 1896, was still alive in March of the same
year, but was much emaciated and in a state of chronic
cachexia. The nine dogs all died within eight days, mostly on
the third or fourth day after the operation. They were as a
rule in good health the day after the operation, but began to
show symptoms on the second or third day, and then rapidly
died, after manifesting a variety of morbid symptoms. These
were psychical depression, muscular tremors, paresis of the
muscles of mastication, trismus, rigidity of the hind-limbs,
uncertain gait, general muscular feebleness, and convulsions.
There were also anorexia and vomiting, palpitation and
dyspnoea. The urine was scanty and sometimes contained
traces of albumin.

The symptoms after removal of the four parathyroids were,
as Vassale and Generali pointed out, analogous to those
observed after removal of thyroid and parathyroids, an
operation which had been so often unwittingly performed
since the time of Schiff. The Italian observers did not note
very marked convulsions ; these only occurred near the fatal
termination. The predominating features were, in fact, ex-
pressive of diminution of the excitability of the nerve centres ;
there was, in fact, a rapidly fatal paralysis. The autopsy
usually revealed nothing abnormal in the lung ; spleen and
kidneys were congested. The nervous system was normal with
the exception (in some cases) of a certain degree of anaemia.

The authors were satisfied that the fatal issue was not due
to complications arising from the operation itself, or to lesions
of the thyroid or the surrounding nervous structures. In
most cases the wound was in process of healing by first inten-
tion ; in the cats there was very often complete cicatrization.
Vassale and Generali state that the thyroid suffered little or
not at all in the operation. In some cases the thyroid left
behind possessed no colloid in its lymphatic spaces. They
were surprised to find that death supervened in a shorter time
than after removal of both thyroids and parathyroids.

In their second communication Vassale and Generali re-
corded a series of variations upon their original experiments.
Thus they extirpated the two parathyroids of one side, with
practically no effects. Removal of the four glands in two

THE THYROID AND PARATHYROIDS 321

operations (first those of one side, then those of the opposite
side) showed that the first operation produced little or no
result ; the second operation proved rapidly fatal. Dogs could
be kept in good health with only one parathyroid remaining,
but the authors suspected that chronic symptoms might arise
at a later period.

In a still later communication the Italian authors state that
the tetany induced by thyroidectomy is less marked in old dogs
than in young ones. The tetany is particularly well-marked
in dogs, if, after removal of the thyroids, they are fed abun-
dantly on a meat diet. If the animals are allowed to get into a
condition of hunger, the tetany becomes much less noticeable.

Results similar to those of Vassale and Generali have been
obtained by several observers.

The present writer, working in conjunction with Professor
W. A. Jolly, encountered difficulties where, from previous study
of the literature, they had not been led to expect them, and
could by no means always induce death in animals by total
parathy roidect omy .

From the writings of most authors it would appear to be a
simple matter to remove, in some cases, the parathyroids
leaving the thyroid intact, and in others the thyroid leaving
the parathyroids in situ. Variations of these experiments
would appear to be equally simple. Welsh, indeed, who
worked with the cat, in which parathyroidectomy presents,
perhaps, least difficulty, admits some difficulties in performing
complete parathyroidectomy. According to Vincent and Jolly,
Welsh has understated these. The obstacles in the way of
success in this operation are mainly anatomical. The para-
thyroids are extremely variable in position. The external pair
may, as a rule, be easily seen and removed, but the internal are,
in the majority of cases, embedded deeply in the substance of
the thyroid. When it is remembered how vascular thyroid
tissue is, how slightly the parathyroid differs from it in appear-
ance to the naked eye, and how this difference, slightr as it is,
entirely disappears when there is any bleeding, it will be seen
that the operation of digging out the internal parathyroid is
one of extreme delicacy. A further difficulty presents itself in
the fact that there is a nodule of thymus also embedded in the
thyroid lobe, frequently in close proximity to the internal
parathyroid, resembling it on naked-eye examination, and

21

*2-2 THE DUCTLESS GLANDS

therefore easily mistaken for it in the course of the operation.
Bearing all these difficulties in mind, the present writer and
Professor Jolly did not hesitate to declare that, except in very
favourable cases, where the internal parathyroid chances to lie
near the surface of the thyroid lobe, the operation is an impos-
sible one. The injury caused to the thyroid in endeavouring
to excavate an almost invisible body from its substance, com-
bined with the accompanying profuse haemorrhage, may account
for some of the deaths which other experimenters have attri-
buted to parathyroid insufficiency. It will be obvious that the
other operation — viz., to remove all the thyroid tissue, while
leaving the parathyroids with their blood-supply uninjured—
is still more difficult, and it was not attempted, though it was
found possible in some cases to leave one or two external
parathyroids.

The animals upon which the experiments were performed
were cats, dogs, foxes, monkeys, rats, guinea-pigs, and rabbits.

Ten out of fifteen cats on which the total operation was
performed, either at one or more times, died soon after, the
respective periods of survival varying from three to thirty-four
days. Five survived the operation. Of the animals which
survived, three showed grave nervous symptoms as the result
of the operation. The fourth, which was a young cat, ceased
for a time to grow, while remaining otherwise perfectly normal.
The fifth showed no symptoms. On what theory are we to
account for the exceptions to the rule that death rapidly
follows the complete operation ? These exceptions are fairly
numerous, and they have also formed a conspicuous feature of
previous investigations. The presence of accessory thyroid or
parathyroid tissue suggests itself as a probable explanation,
but it must be borne in mind that a careful post-mortem
dissection of neck, thorax, and even abdomen, failed to disclose
such bodies.

The symptoms usually following the complete operation
in the cat are as follows : The cat is perfectly well on the day
following the operation ; on the second day, there is usually
a curious " paw-shaking " and some malaise. This is followed
in rapid succession by tremors, stiffness of gait, and convul-
sions. Even in a quiescent state, the fore-legs tend to be flexed,
while the hind-legs are extended, a position exaggerated during
convulsions. Hallucinations are fairly common. Of symp-

THE THYROID AND PARATHYROIDS 323

toms not directly referable to the nervous system, conjunc-
tivitis and respiratory catarrh were observed.

In the dog the following symptoms have been described :
restlessness, anxiety, fibrillary twitchings, stiffness, and
staggering gait, convulsions and fits of rapid breathing. This
may reach 250 a minute. The rectal temperature is raised
as a result of the muscular activity. Exhaustion may super-
vene and in extreme cases death. Emaciation is common
and increased excitability of the peripheral nervous system is
now regarded as pathognomonic of parathyroid tetany. The
symptoms are extremely variable, so that it is difficult to
judge of the effect of any curative agents.

The nervous symptoms required more careful consideration.
The convulsive disturbances probably proceed from the
central nervous system, since division of the motor fibres to
any of the muscles will abolish them. The effect seems due
to the condition of the spinal cord and does not depend upon
any higher centres. As already stated the electrical excitability
of the peripheral nerves is increased. It has been known for
a long time that the phrenic nerve may be excited by the
action currents of the heart, so that we get " cardiac respira-
tion," in which the diaphragm contracts with each heart
beat, a phenomenon very familiar to all who have carried out
extirpation experiments on dogs. Hoskins and Wheeler have
shown that there is also a marked increase in the irritability
of the sympathetic nervous system.

Many theories have been brought forward to explain why
removal of the parathyroids should give rise to the above
symptoms. The two principal views are (1) calcium deficiency,
(2) some toxic agent. Sabbatani and others had shown that
soluble calcium salts diminish the excitability of nervous
tissues. Utilizing this f act MacCallum has suggested that the
pathology of tetany may consist in a deficiency of calcium in
the body. An injection of soluble calcium salts into the
circulation of an animal in tetany promptly checks the symp-
toms. The hyperexcitability of the nerves which is char-
acteristic of tetany is due to some change in the blood. It
has been shown by cross-circulation experiments, that if the
leg of a normal animal is supplied with tetanic blood, this
condition of hyperexcitability soon manifests itself in the
nerves of the normal leg. The most powerful objection to the

324 THE DUCTLESS GLANDS

calcium theory is that simply bleeding the animal and then
replacing the blood shed by an equal amount of calcium free
isotonic solution of sodium chloride (thus still further diminish-
ing the calcium content of the tissues) also brings about prompt
relief.

Various toxic agents have been suggested as being responsible
for the phenomena of tetany. Among these are ammonia,
xanthin, histamine, thymus secretion, inosinic acid, guanidine,
and methyl guanidine. The only substance in this list which
need be seriously considered is guanidine. In 1912, W. F.
Koch made the very important discovery that methyl-guanidine
is constantly present in considerable amount in the urine of
parathyroidectomized dogs. In 1913 he definitely attempted
to correlate this observation with the function of the parathy-
roid glands. He suggests that the parathyroid secretion is
concerned with anabolic processes closely related with the
building up of nucleins. This hypothesis has been developed
more fully by Paton and his co-workers. They claim that
guanidine injected into an animal will produce all the symptoms
of tetany. They attribute this condition as found experi-
mentally or clinically to an abnormal accumulation of guanidine
in the body, which accumulation it is the duty of the parathy-
roid to prevent.

It has been supposed that the thymus produces a toxin
tending to give rise to tetany, and that it is the duty of the
parathyroid to reduce or destroy this.

The parathyroids do not contain any measurable amount of
iodine. Other than this there is nothing to be said on the
subject of the chemistry of the glandules. Attempts have been
made to isolate the " active principle," but so far no very
definite results have been obtained.

CHAPTER XIV

THE FUNCTION OF THE THYMUS

A. Comparative Anatomy and Development of the

Thymus

1. NOTHING is certainly known of the thymus in the Cyclo-
stomata.

In Elasmobranchs the thymus arises on each side as epi-
thelial outgrowths of the dorsal gill-pockets. The number of
clefts which give rise to thymus elements varies in different
species, but it is probable that thymus buds originally arose
from all the clefts.

A similar origin may be assigned to the thymus in Dipnoi,
Ganoids, and Teleosts : but in these groups modifications
occur in the directions of resorption and fusion of originally
separate portions. In Teleosts the separate rudiments unite
into a single mass which, in contrast with the course of events
in Elasmobranchs, remain in connection with the gill epithe-
lium. Growth is generally in a backward direction dorsal to
the branchial arches, but the position varies in different species.

2. In Urodela the thymus arises in the form of compact
outgrowths from the epithelium of the dorsal gill-pockets
from 1 to 5.

In the Anura the organ arises exclusively from the second
cleft.

In adult Amphibians the thymus lies behind and above
the mandibular articulation. In the frog the gland is found
behind the annulus tympanicus, covered by the depressor
mandibube muscle. It is a small, longish, oval body, which
may be 2 to 3 millimetres in length.

3. The thymus of reptiles has been specially investigated
by de Meuron, Van Bemmelen, and Maurer. The organ

325

326

THE t)UCTLESS GLANDS

p. thyr. in

thy m. Ill

p.b.b.

p. thyr. IV

thym.IV

A.

p. thyr. HI

p.b.b.

THE THYMUS 327

arises, as in the lower groups of vertebrates, from the dorsal
gill-pockets, in the lizard from II. and III., in snakes from
IV. and V.

4. In birds, thymus buds have been described from third,
fourth, and fifth clefts.

5. The thymus of mammals apparently differs very materi-
ally in many respects from that of all lower animals, inasmuch
as it is much more complex, and it is not the dorsal, but the
ventral, pockets of the gill-clefts which furnish its rudiment.
In most cases the third cleft is the most important, but some-
times the fourth, and occasionally, also, the second, plays
a part. This portion of the origin of the gland is entodermal
(see Fig. 90).

Recent work has confirmed the observations of Kastschenko
as to the occurrence of an ectodermal component, derived
from the " ductus prsecervicalis," in the thymus of certain
mammals. This conception must have a far-reaching effect
upon our views as to the origin and nature of the mammalian

EXPLANATION OF FIG. 90.

(Diagrams A. and B.).

A. illustrates the development of the branchial organs of mammals, B. shows
their actual relations in the adult.

The different related rudiments of the same branchiomere are represented
by a similar direction of shading lines ; so also the corresponding organs. Thus
the rudiments from the third cleft are represented in A. by horizontal lines,
as also the organs thus arising in B. The rudiments and organs from the
fourth cleft are characterized by vertical lines. The post -branchial body is
shown in thick outline, the thyroid by crossed lines.

The different kinds of tissue arising from one and the same branchiomere
are indicated by differences in the shading. The parathyroid tissue is shown
by lines, the thymus tissue by alternate continuous and interrupted lines.
The post- branchial body is represented in the developed condition as a hollow
space with several glandular nodules (shown in dark circles).

A. shows the four internal gill slits (I. to IV.), the epithelial origins of the
parathyroids (p. thyr. III., p. thyr. IV.), the origin of the thymus (thym. III.,
t]\ym. IV.), the rudiment of the thyroid (thyr.), and that of the post-branchial
body (p.b.b.).

B. represents a schematic transverse section through the fully developed
thyroid (at about the level of the junction of the upper and middle third of
the thyroid lobe of a cat). The lettering corresponds to that in Diagram A.
The structures which arise from the third cleft become the " external " para-
thryoid and thymus nodule (separated fragment of thymus III.) ; these which
arise from the fourth cleft become the "internal " parathyroid and the thymus
nodule (p. thyr. IV., and thym. IV.). The post-branchial body is surrounded
by thyroid tissue.

(A. is after Groschuff in ruminants ; B. from Kohn in the cat.)

328 THE DUCTLESS GLANDS

thymus. From a phylogenetic standpoint the ectodermal
and the entodermal thymus representatives must be regarded
as two distinct organs, which, through a parallelism in develop-
ment, have acquired a similar structure.

There are three types of thymus in mammals :

1. A purely entodermal thymus. This is found in the
human subject and in the rabbit.

2. A purely ectodermal thymus. This is found in the
mole.

3. A mixed entodermal and ectodermal thymus. This
condition is found in the pig and the guinea-pig.

While in crocodiles and birds the thymus is situated in the
neck, in mammals it is for the most part situated in the thorax.
But in some mammals there is a cervical portion as well
as a thoracic portion, while, again, in some species, such as
the guinea-pig, the structure is entirely cervical. How far
the distinction between an entodermal and an ectodermal
thymus corresponds to the cervical and thoracic representatives
of the gland is not known. But it is stated that the cervical
thymus of the guinea-pig is entirely entodermal, being derived
from the third cleft, and corresponds to the human gland,
which, however, is thoracic.

This acceptance of a dual origin of the mammalian thymus
will necessitate a reinvestigation of the development of the
organ throughout vertebrates. But it must be borne in
mind that a definite statement as to whether a derivative
of a gill-cleft is ectodermal or entodermal in origin is often
a matter of extreme difficulty.

The human thymus is derived from the third visceral pouch,
but it is not yet decided as to whether there is an accessory
rudiment from the fourth pouch. The thymus is thus in
its- first origin bilateral. A pocket develops from the third
cleft on each side, and extends itself as a thick-walled tubular
prolongation along the carotid artery. The pocket persists
as the ' c thymus vesicle ' ' in the proximal section of each
rudiment. From the lower end of the tube solid epithelial
buds are given off, and from these lateral buds again come
off, so that this part of the gland acquires a ramified lobular
appearance like an acinous gland. The acini, however, are
solid. The two rudiments are brought into close contact
with one another in front of the trachea, and unite to form

THE THYMUS 329

a single-lobed body, which comes to lie in the anterior media-
stinum in close relationship with the pericardium.

B. Structure of the Thymus

The thymus is made up of several lobules, which vary in
size, and are separated from one another by connective-
tissue septa, bearing bloodvessels and lymphatics.

Each lobule may be divided into a cortical and a medullary
portion. The cortex is incompletely separated into " nodules "
by connective-tissue trabeculse, the arrangement bearing a
strong resemblance to that of a lymphatic gland. The cortex
is very vascular, and is similar in appearance to a lymphatic
gland. Its structure also agrees with that of lymph glands
and tonsils in exhibiting numerous signs of mitosis, but without
definite germ centres. In addition to the lymph cells, there
are also a number of peculiar granular cells.

The medulla, like that of a lymphatic gland, is more open
in its texture than the cortex, and its reticulum is made up
of large, transparent, branched cells, which are sometimes
arranged in an epithelioid manner. The medulla does not
contain so many leucocytes as the cortex, but is characterized
by the presence of the peculiar concentrically striated bodies —
the concentric corpuscles of Hassall (see Fig. 91). These vary
very considerably in general appearance, and their precise
origin and significance are still matters for discussion.

The above account is largely derived from that given by
Schafer. It seems possible that there are many points in
connection with the thymus upon which current views may
have to be changed. It has long been taught that the human
thymus reaches its greatest development at about the second
year, and then begins to degenerate. But it was shown in
the year 1890 by Waldeyer that even in advanced age a con-
siderable amount of thymus tissue persists, and probably
maintains its function. Zoja had previously shown that the
thymus frequently persists till the age of puberty. Recently
Hammar has insisted that the organ continues to grow up to
the period of puberty, and reaches its greatest development
between the fourteenth and sixteenth years. From that time
onwards it gradually loses in weight, but microscopical investi-
gation shows that it still functions. A true atrophy of the

THE DUCTLESS GLANDS

parenchyma, with elimination of function, comes on at about
fifty to sixty years of age.

It seems, then, that we must regard the thymus as an organ
regularly present, and probably in an active functional con-
dition up to the age of puberty. The explanation offered
by Hammar of the opposite conclusion reached by former
anatomists is this : Wharton in the seventeenth century
observed that a reduction in size of the thymus frequently
occurred in exhausting or wasting diseases. This has been

H.c..

;

•

H.c.

FIG. 91. — Portion of the thymus gland of a monkey, as seen under a low
power of the microscope. (Drawn by Mrs. Thompson.)

c., cortex ; H.c., Hassall's concentric corpuscles ; m., medulla.

frequently noted, and so it has been customary to look upon
the thymus as a kind of ' ' barometer ' ' to indicate the state
of nutrition. But more often the mistake has been made
of confusing this * ' accidental involution ' ' with the age involu-
tion.

It seems somewhat doubtful whether we are to look upon
the thymus in its fully developed condition as a lymphoid
organ. According to Wiedersheim, " Jedenfalls stellt die
thymus zu^keiner zeit ein ' lymphoides Organ ' dar." Ham-
mar has brought forward evidence that, not only in its origin,

THE THYMUS 331

but throughout life, the thymus has the characters of an
epithelial organ. But there are undoubtedly leucocytes
present, and Hammar believes, as did the older observers,
that these are of mesodermal origin, invading the gland
secondarily, and there undergoing further proliferation.

Stohr believes in the epithelial origin and nature of the
small thymic cells. These arise in situ from the repeated
multiplication of the reticular epithelium, and though morpho-
logically they come to assume a structure indistinguishable
from that of the true lymphocytes, they remain throughout
true epithelial elements.

We have, then, four prevailing theories as to the nature of
the thymus element : (l)That the original epithelial elements
are entirely replaced by a leucocytal invasion from the meso-
derm, and that the thymus in its fully developed condition
is a lymphoid organ ; (2) that the original epithelial elements
give rise to lymphoid cells in situ, and that the thymus becomes
a lymphoid organ ; (3) that the thymus remains an epithelial
organ, but that there are lymphoid elements which have
invaded it ; (4) that there are no true lymphoid elements,
but that the small thymic cells, which appear to be of a
lymphoid nature, are, in reality, epithelial. This last is the
view of Pappenheimer.

If this last view be correct, we should expect to find some
differences between these cells and lymphoid elements. The
present writer has given some little attention to the structure
of the thymus (apart from embryological considerations),
and it would seem that many of the thymus cells are indis-
tinguishable from the lymphoid cells. But the matter is
still in a very doubtful state, and needs further investigation.
The question is not only of morphological, but also of con-
siderable physiological, importance. If the thymus cells are
in truth epithelial throughout the life of the organ, we may
with reason look for an internal secretion in the sense in
which we defined it in an earlier chapter. On the other
hand, if the cells be finally included among lymphoid ele-
ments, then we shall expect to find that the functions of the
thymus are allied to, if not identical with, those of lymphatic
glands.

Hammar's most recent view is that the thymus is an epithe-
lial organ with a leucocytal infiltration. Hassall's corpuscles

332

THE DUCTLESS GLANDS

represent a functional differentiation of the epithelium. Under
the influence of certain common disturbances, the thymus
may undergo an "accidental involution" of a more or less
transitory nature. Puberty normally brings on an " age
involution," which is brought about by diminution of the
leucocytal part of the organ, then by increased degenerative
processes, by which the function of the organ and gradual
destruction of the parenchyma are brought about.1

Pigache and Worms report an " accidental involution "
after thyroidectomy in dogs and rabbits ; while Utterstrom
finds that feeding rabbits with thyroid substance has two
distinct and opposing actions on the thymus, the one a depressor
action due to the condition of reduced nutrition, the other a

direct thymus excitation.
This last action explains the
enlargement of the thymus
found in cases of exopthal-
mic goitre. Hoskins notes
that this hypertrophy of the
thymus after thyroid feeding
affects only the cortex.

It has been proved that
leucocytes are already pre-
sent in the body before
the lymphoid transforma-
tion of the gland, so that
the thymus cannot be the
original source of the leuco-
cytes, as suggested by Beard.

In regard to the Hassall concentric corpuscles modern
investigation appears to show that these structures are not
to be looked upon simply as remains of the original epithelium
which have not become transformed into lymphocytes. Ham-
mar has shown that the concentric corpuscles are derived
from hypertrophic reticular cells. The formation of these
structures begins early in foetal life, and continues long into
the period of post-natal evolution of the organ. Wallisch
has pointed out that the total volume of the Hassall bodies

1 The bursa fabricii of birds is an organ which in some respects may be
regarded as analogous to the thymus. Thus it undergoes leucocytal invasion
and a degeneration at about the age of puberty.

FIG. 92. — HassalTs concentric cor-
puscle from the thymus of a cat.
This body shows a typical con-
centric arrangement. (Drawn by
Mrs. Thompson.)

THE THYMUS 333

in young children exceeds that of the whole thymus in a three
months' embryo.

It will not be possible to give a full account of the various
thymus elements,. One other thymic structure must, never-
theless, be briefly referred to. In 1888 Sigmund Mayer
described certain peculiar elements in the frog's thymus.
These he regarded as rudimentary voluntary muscle fibres.
Similar structures were observed in Teleosts by Schaffer, who
described them as sarcolytes in various stages of disintegra-
tion. Similar structures which have been discovered in birds
and reptiles are considered to be of a muscular origin and nature.
Hammar, however, regards them as specially differentiated
hypertrophic reticular cells, and therefore as closely related to
the concentric corpuscles. Pappenheimer has recently found
these myoid cells in the human embryonic thymus, and holds
the same view as Hammar as to their nature and origin.

,C. Extirpation of the Thymus

Abelous and Billard reported that the removal of both
thymus glands in the

frog always resulted , f^^^^l£'®*e® o

fatally within three to ^9 J&* oj*&«?8%-

£ T7 "^ ^§^&®

fourteen days. Ver ,QP©

Eecke, however,
pointed out that death
did not occur if pre-
cautions against inf ec - ' < •.*•'/'
tion were taken by a£| o.e^
regularly renewing the J*
water in the frog-
tanks. The latter in-
vestigator was of
opinion that removal

of the thymus lowers FIG. 93. — Hassall's concentric corpuscle from

the resistance of the the human thymus gland. The concentric

. arrangement is not so regular or so marked as

frog to Septic mrLu- in the cat. (Drawn by Mrs. Thompson.)

ences, and that this

accounts for the fatality in the experiments of Abelous and

Billard.

The present writer came to the conclusion that in the case

334 THE DUCTLESS GLANDS

of frogs extirpation of both thymus glands does not necessarily
end fatally. Some of the animals experimented upon survived
as long as thirty-six days, and have either been killed at the
end of this time or have died of some cause independent of
the operation.

The earliest experiments upon mammals appear to be
those of Friedleben. This observer operated upon twenty
dogs and three goats ; none of his animals died as the result
of the thymus extirpation.

Tarulli and Lo Monaco found that in dogs the thymus
is not an indispensable organ. Only in very young animals
had extirpation any results ; there were in these cases disturb-
ances of nutrition, diminution of muscular power, diminution
in the number of the red blood-corpuscles, and of haemoglobin,
etc. These disturbances were only of short duration, and
disappeared when the dogs grew older.

The present writer could not ascertain that the removal
of the thymus in guinea-pigs affects the animal in any way
whatever. Litters of guinea-pigs of ages varying from ten
days to a month were procured, and while some of the litter
were submitted to operation, others were kept as controls.
The young guinea-pigs appeared perfectly well an hour after
the operation, and no symptoms of any kind supervened.
They grew at the same rate as the controls, and no signs of
changes in the blood were detected.

Within the last few years the thymus has received a great
deal of attention, and a large amount of anatomical and
physiological work has been carried out. The conception
of the thymus as being not altogether a lymphoid organ
seems to be gaining ground. A nutritive role has been sug-
gested for the gland on account of the richness of the tissue
in purin bodies. On the whole, the verdict seems to be that
the organ is not essential to life, even in quite young animals.

In young dogs it is stated that changes can be detected
some months after extirpation of the thymus. The nutritive
processes became defective, and none of the animals lived
more than a year. On post-mortem examination, enormous
dilatation of the heart was usually discovered. It is suggested
that the thymus has an action antagonistic to that of the
adrenal, so that, when the former is removed, there is a pre-
dominance of adrenal activity, and consequently hypertonus

THE THYMUS 335

of bloodvessels and dilatation of the heart. Grafting additional
thymus glands into young dogs caused serious disturbances
to health (Hart and Nordmann).

Klose, and Klose and Vogt, performed a series of extirpation
experiments upon dogs between ten days and four weeks old.
These authors divide the post-operative period into three
stages : (1) A latent period, lasting from two to four weeks ;

(2) an adipose stage, which lasts two or three months ; and

(3) a cachectic stage, or the stage of " cachexia thymopriva "
and "idiotia thymopriva." This period extends to three
to fourteen months. Death occurs with "coma thymicum,"
which often lasts a long time. The skeleton remains hypo-
plastic and dwarf -like, and the bones become atrophic.
There is a deficiency of undissolved calcium. Bodily move-
ments are feeble, and there are disturbances in the nervous
system.

Interference with the growth, especially of the skeleton,
is also described by several observers.

Changes in the pituitary and in the spleen after thymec-
tomy have been recorded. Perrier states that in the pituitary
there is an increase of the chromophilic cells. In the spleen
there is an increase of the reticulum and a hypertrophy of the
lymphoid tissue.

The thymus does not appear to have anything to do with
the formation of red blood-corpuscles, nor with the growth of
epithelial organs.

Soli states that extirpation of the thymus in adult hens
causes them to lay eggs without shells. This is the only evidence
which has been put forward up to the present time that the
thymus has any function after the period of involution of the
organ.

D. A Probable Relation between the Thymus and the
Reproductive Organs

Calzolari in 1898 suggested a relationship between the
thymus and the reproductive organs, and performed a series
of experiments upon rabbits, with the object of putting the
matter to the test. He found that in castrated male rabbits
the volume and the absolute weight of the thymus were
greater than in normal animals. He concludes that the

336 THE DUCTLESS GLANDS

thymus atrophies move slowly in animals from whom the
testes have been removed.

Henderson obtained similar results in rabbits, guinea -pigs,
and cattle. He states, further, that in bulls and unspayed
heifers the normal atrophy of the thymus which begins after
the period of puberty is greatly accelerated when the bulls
have been used for breeding, and when the heifers have been
pregnant for several months. The retarded atrophy is due,
according to Goodall, to a persistent growth of the lymphoid
tissue, a delay of the fatty invasion, and a delay in the process
of disintegration of the epithelium composing the Hassan's
corpuscles.

According to Marrassini and Gellin, castration gives rise
to an enlargement of the thymus. Squadrini believes that
castration interferes with the normal involution of the gland.
From these observations it would appear that the normal
involution of the thymus is due to the development of the
reproductive organs, though this cannot be the only cause.
The experiments, further, tempt one to the hypothesis that
the thymus furnishes an internal secretion of some kind which
ministers to the needs of the economy before the reproductive
organs are fully developed. Normally this internal secretion
is provided by the testes (or ovary) after puberty, but if
castration is performed, the thymus maintains its original
structure and functions. This internal secretion must, of
course, be of a different nature from that which determines
the development of the secondary sexual characters, as these
do not become manifest in castrated animals.

It must be added that recent careful experiments by Parke
cast considerable doubt upon the intimate relation between
testis and thymus.

E. Physiological Effects of Extracts of Thymus

Svehla found that the thymus of the ox during embryonic
life yields to extracts a substance which lowers the blood-
pressure. This he considers as a manifestation of an internal
secretion. From what has been said in an earlier chapter,
it is clear that this depressor substance is simply that unknown
material which is common to all animal tissues and organs.
It is not specific for the thymus.

THE THYMUS 337

F. Pathology of the Thymus

Perhaps the chief medical interest attaching to the thymus
arises from certain remarkable cases of thymic death (" mors
thy mica "). In cases of thymic enlargement the essential
symptom is a respiratory disturbance resulting from the
diminution of space in the superior thoracic strait. This
disturbance may vary from a mild stridor to a fatal dyspnoea.
Sometimes the dyspnoea is of an asthmatic character (" thymic
asthma ").

" Mors thymica " is a term applied to those cases in which
death occurs suddenly, without a definite history of previous
respiratory difficulty. This may happen even when there
are no other symptoms of the status lymphaticus, but very
frequently this condition is present, and the thymus enlarge-
ment is associated with adenoids, and with enlarged tonsils
and lymphatic glands.

The cause of death in these cases has been the subject of
much discussion. It is probable that in the majority of
instances the case is one of suffocation from tracheal stenosis
and secondary laryngeal spasm. It seems certain that many
cases of so-called " mors thymica " are not of thymic origin.
At any rate, a detailed discussion of this subject is not likely
to shed light on the function of the organ.

Some cases of Addison's disease appear to be combined
with the status lymphaticus.

22

CHAPTER XV

THE FUNCTION OF THE PITUITARY BODY

A. Comparative Anatomy of the Pituitary Body

1. The Mammalian Pituitary Body

RATHKE was the first to point out the double origin of the
pituitary body, from the brain and from an invagination of
the mucous membrane of the alimentary tract. Other observers
of this period looked upon the body as part of the brain.
Luschka called the body a "nerve gland," consisting of two
parts, separated by pia mater ; while Ecker includes the
structure of both portions under the name " Blutgefassdrusen."

Burdach regarded the nervous portion as the " filum ter-
minale anterius " of the cerebro- spinal canal; and Virchow
and others noticed in the anterior portion colloid vesicles
like those of the thyroid.

The anterior lobe is admittedly glandular in its nature,
but the structure of the posterior lobe has been variously
described. Earlier writers looked upon it as a mass of con-
nective-tissue cells and fibres, which, during the course of
development, have destroyed all trace of the original nerve
tissue. Berkley described nerve cells and glia cells in the
posterior lobe. Kolliker speaks very doubtfully about the
matter, even about the results of investigation by the silver
chromate matter.

Osborne and Swale Vincent could detect only very few
undoubtedly nerve cells in the infundibular portion. These
observers also confirmed and utilized experimentally the fact
that the posterior lobe has an epithelial investment.

The pituitary body consists of three portions : (1) The
anterior lobe ; (2) the intermediate portion ; and (3) the
posterior lobe, or nervous portion.

338

THE PITUITARY 339

There are three types of mammalian pituitary body. In
the first, of which the organ of the cat furnishes an example,
the posterior lobe is hollow, and its cavity is in free com-
munication with the third ventricle of the brain, and the
epithelium of the anterior lobe almost completely surrounds
the posterior lobe. In the second type (as, for example,
in the dog) the body of the posterior lobe is solid, but the
neck is hollow, and communicates with the third ventricle,
and the posterior lobe is almost completely surrounded with
epithelium, as in the first type. In the third type — e.g.,
man, monkey, ox, pig, and rabbit — the body and neck of
the posterior lobe are solid, although traces of a cavity are
occasionally found in the neck. In this last type the epithe-
lium of the anterior lobe does not spread so far round the
posterior lobe, but is gathered around the neck and spreads
over and into the adjacent surface of the brain (Herring).
(Fig. 94.)

The epithelial portion is again divided into two parts :
(1) An anterior lobe proper, consisting of solid columns of
cells, between which run wide bloodvessels ; and (2) an inter-
mediate portion, which lies between the anterior lobe and
the nervous portion, forming a close investment to the latter.
(Figs. 94 and 95.)

The anterior lobe presents all the appearances of a true
internally secreting gland. Its structure is clearly that of
a gland — an "epithelial body," in Kohn's phraseology. It
is made up of a branching, compact network of epithelial
threads and columns. In the spaces of the epithelial network
run wide, thin -walled bloodvessels, so that in many cases
the epithelial cells are placed directly on the delicate vessel
wall. This arrangement is most admirably adapted for the
purposes of internal secretion. The general scheme of structure
is the same as in the adrenal cortex, the islets of Langerhans,
of the pancreas, the thyroid, and the thymus (in its epithelial
stage). (See Fig. 95.)

The general nature of the cells found in the glandular
pituitary may be thus stated :

((a) Acidophile.
. Chromoph,le F

2. Chromophobe. (See Fig. 95.)

340 THE DUCTLESS GLANDS

Besides the colloid, it is probable that there are other
secretory products.

In no other endocrine gland are the granular products of
secretion so well seen as in the anterior lobe of the pituitary
body. Secretory granules are also seen in the vessels belonging
to the gland.

Leyton, as a result of, the examination of a large number
of human pituitaries, came to the conclusion that colloid
material may be found in the bloodvessels, both in the an-
terior lobe and also in the so-called pars intermedia. Colloid
material was not seen in the pars nervosa.

In children and in the foetus the distinction between the
different varieties of cells in the anterior lobe is not marked,
and colloid material is small in amount.

Stalk of pituitary
Infundibular cavity

Cleft in pars
intermedia

FIG. 94. — Diagram showing relations of principal parts of pituitary body.

The size and weight of the gland and the amount of colloid
material are subject to very great variation.

Gushing and Goetsch find colloid masses in the posterior
lobe of the pituitary, and agree with Herring that the colloid
masses in this lobe are secretory products of the epithelial
covering of the pars intermedia. They find in the cerebro-
spinal fluid a substance which gives the same reactions as
the pars nervosa itself.

The intermediate portion consists of finely granular cells

THE PITUITARY

341

arranged in layers of varying thickness closely applied to
the body and neck of the posterior lobe and to the under-
surface of adjacent parts of the brain. The part of it which
is separated from the anterior lobe by the cleft is almost

p.l.

p.n.

FIG. 95. — Section through a portion of the pituitary body of the dog, showing
the glandular and nervous portions and the pars intermedia. (Drawn by
Mrs. Thompson.)

c., cleft in glandular portion (between glandular portion proper and the inter-
mediate portion) ; p.g., glandular portion ; p.i., intermediate portion ;
p.n., nervous portion.

In the glandular portion are seen three kinds of cells.

devoid of bloodvessels. Colloid material occurs between the
cells of the pars intermedia. (Fig. 95.)

The nervous portion is made up of neuroglia cells and
fibres, and is invaded by the epithelial cells of the pars inter-
media. A substance resembling the colloid of the thyroid
gland occurs in the nervous portion. The glia cells are longish

342 THE DUCTLESS GLANDS

or cylindrical, with one, two, or more nuclei, and a granular,
at times pigmented, cell protoplasm. From the protoplasm
stretches a long, thin homogeneous fibre, which is sharply
contoured, like an elastic fibre. These cells are young forms
of ependyma cells — the ' ' radial cells ' ' of Retzius. In addition,
there are " protoplasmic cells " which are multipolar, and
send out fine glia fibres. There are also " spindle cells,"
" giant glia cells," " keratin cells," etc. All these build up a
primitive neuroglia.

One of the most interesting features of the posterior lobe
is the pigment, which has been known for a long time. Accord-
ing to Kohn, the pigment is contained within the threads of
the neuroglia, and distends them here and there. When
unstained, the substance is of a greenish-yellow tinge, and
consists of closely packed, irregular clumps. The amount
of the pigment is found to become notably increased in age
and disease. For this reason it is supposed to represent some
kind of breakdown product. It has been suggested that the
pigment bears some relation to the functions of the organ,
and especially to the secretion of the anterior lobe.

Clunet and Jonnesco have also given an account of the
pigment in the neurohypophysis. According to these authors,
the substance does not give the iron reaction. It is insoluble
in alcohol, xylol, benzol, cedar oil, chloroform, and ether.
It is stained red with osmic acid, red also with Sudan and
Scharlach red, while it is blackened with iron hsematoxylin.

Haberfeld finds in the human subject at all ages a " pharyn-
geal pituitary"— a solid string of cells about 5 millimetres
long, which runs from below upwards and backwards imme-
diately behind the vomer. It contains cells like those in the
pituitary itself, but here the chromophobe elements pre-
dominate, and the basophiles may be absent. Histologically
it resembles the pars intermedia. It is the origin of most of
the pituitary tumours. This structure is probably the remains
of the original pituitary duct.

Haberfeld describes a cystic structure in intrauterine life,
which is made up of glia cells and fibres, and possessing lumina,
surrounded by ependyma cells. This body is frequently,
he alleges, the starting-point of gliosarcomata.

Staderini gives an account of the " eminentia saccularis "
(an elevation on the base of the brain immediately behind the

THE PITUITARY 343

stalk of the pituitary). He considers that the structure is
not homologous with the " succus vasculosus " of fishes, as
Retzius thought.

A very rare abnormality which has been described in con-
nection with the sphenoid bone is a persistent, perforating
foramen in the basisphenoid — the canalis craniopharyngeus.
This is regarded as the place of exit of the original duct of
the anterior lobe of the pituitary body.

Haberfeld finds the canal wanting in all acromegalic skulls
in the Vienna Pathological Institute. He reports that it is
very variable in individuals of the same species of animals.
He calls attention to the fact that the pharyngeal pituitary
is constant in man, while it is frequently absent in the lower
animals. This is not what would be expected if the structure
really represents the remains of the original duct of the
pituitary.

2. The Pituitary Body of Birds and Lower Vertebrates

In birds the epithelial cleft appears to be absent. The
cells of the anterior lobe are for the most part small and finely
granular.

The posterior lobe is small and hollow, and much con-
voluted. Colloid bodies are sometimes present. The cells
of the pars intermedia come into -close contact with the nervous
portion of the posterior lobe, but are gathered together for
the most part in the neighbourhood of its neck and on the
thin lamina of nervous tissue forming the floor of the third
ventricle.

In Teleostean fishes the posterior lobe has a complex vascular
structure of a glandular nature, which was called the ' ' saccus
vasculosus " by Gottsche.

The Teleostean pituitary is composed of three kinds of
tissue, two of which are epithelial and the third nervous,
the latter being comparatively small in amount. The anterior
lobe of mammals is represented by a wedge-shaped mass of
large and deeply staining cells. These cells vary in situation
and extent in different species. The pars intermedia consists
of small, round, feebly staining cells, which surround and
invade the nervous tissue. The pars intermedia in the cod
is divided into two main portions, which are continuous

344

THE DUCTLESS GLANDS

with, and separated from one another by, the true anterior
lobe (Herring).

The nervous part of the cod's pituitary is small, and appears
to be composed of neuroglia and ependyma cells, without
any true nerve cells. It is continuous with the brain in
front by the lamina post-optica, or anterior lamina, and at
the sides by lateral laminse. The nervous substance is more
freely invaded by cells of the pars intermedia than is the
nervous substance of the mammalian body.

In Elasmobranchs (Raja batis) the pituitary is a long,
club-shaped body which lies for the most part behind the
small lobi inferiores. Its structure is very different from
that of mammals, birds, and Teleosts. There are no cells
having the deeply staining characteristic of those of the
anterior lobe of other vertebrates, and there are no cells
exactly like those of the pars intermedia. There is no differ-
entiation into anterior and posterior lobes, and the only trace
of a posterior lobe is a thin lamina of nervous tissue which
bounds the infundibular cavity. The saccus vasculosus is
well developed. The Elasmobranch pituitary appears to be
quite different from that of other vertebrates.

B. Development of the Pituitary Body

The earlier observers believed that the whole of the pituitary
body is derived from the brain. Rathke, however, described
the invagination of mucous membrane, since called " Bathke's
pouch," and put forward the view that from this pouch is
derived the epithelial portion of the pituitary (which he further
stated has been derived from the entoderm of the fore -gut).

Dursy described the origin of the epithelial part from the
fore-gut, and of the vascular stroma from the notochord.
W. Muller showed that the anterior lobe arises from Rathke's
pouch, but believed this to be entodermal. It is now usually
considered that the pouch is of ectodermic origin.

The posterior lobe was originally conceived as the anterior
extremity of the brain, but more recent researches have shown
that it is an outgrowth of the thalamencephalon.

Mihalkovics has given a complete account of the early de-
velopment of the pituitary body in the rabbit and the chick.
According to this author, the anterior lobe is developed from

THE PITUITARY 345

Rathke's pouch, and is ectodermal. The beginning of the
pouch is in front of the oral plate. When this ruptures, its
upper stump, containing in its upper part the head of the
notochord, bends forward and narrows the mouth of the
epithelial pouch, leading to the formation of a definite sac —
the hypophysial sac. The wall of the sac presses upon the
base of the anterior brain vesicle, giving rise at its upper ex-
tremity to a fold in the wall of the brain, which becomes the
primitive infundibulum. The primitive infundibular process
comprises the surrounding tissue of the tuber cinereum as
well as the origin of the infundibulum, and the true infundi-
bulum is formed at a later stage by its own growth from a
portion of the primitive infundibular process. The head of
the notochord, beyond presenting a barrier to the backward
growth of the sac, takes no part in the formation of the pituitary
body.

Mihalkovics' work has been confirmed in the main by
numerous authors. Kupffer described an additional origin of
part of the anterior lobe of the pituitary from the entoderm
of the fore-gut, and this view has received support. Herring,
however, believes that the epithelial portion of the pituitary
is entirely ectodermic. The account of the last-named author
is briefly as follows : —

Development of the pituitary body begins very early in
embryonic life. In mammals the epithelial portion is derived
entirely from the ectodermic wall of " Rathke's pouch." Its
origin is single and mesial. The epithelium is early distinguish-
able into two parts. One of these — the intermediate part — is
closely adherent to the wall of the cerebral vesicle ; the cells
are clear, and tend to form colloid. The other portion of the
buccal epithelium gives rise to the anterior lobe proper. Its
cells are granular, and form solid columns separated by blood-
channels.

The infundibulum is an invagination of part of the wall of
the thalamencephalon, which is adherent to the anterior and
upper wall of Rathke's pouch. It therefore possesses an epi-
thelial covering derived from the latter. The infundibular
process grows backwards, and, in the cat, retains its central
cavity. It is lined by ependyma cells, which, during develop-
ment, become elongated, so that ependyma fibres run obliquely
in its neck. The posterior lobe of the pituitary is, from the

346 THE DUCTLESS GLANDS

first, a composite structure of epithelium of the pars intermedia
and of neuroglia and ependyma, and the relations between the
two tissues become more and more intimate.

The early stages of development of the Elasmobranch
pituitary resemble those in the mammal, except that there is
no invagination of the wall of the cerebral vesicle in Elasmo-
branchs to form an infundibular lobe. The body is derived
entirely from the buccal epithelium of Rathke's pouch.

The relation of the pituitary to the brain ventricles is similar
to that in higher vertebrates, but this is accounted for by the
development of a paired saccus vasculosus, each of which
pours its secretion into a common infundibular canal. The
wall of this is lined with epithelium similar to that lining the
saccus vasculosus. Its nervous structure is lost, being replaced
by connective tissue and numerous thin- walled bloodvessels.
There is no invasion of the wall of the canal by epithelial cells,
and no hyaline bodies are formed.

The pituitary body of the Elasmobranch is a gland, the
secretion of which is poured directly into the bloodvessels.
There is no evidence of any direct secretion by the pituitary
into the brain ventricles.

C. Older Views as to the Functions of the Pituitary

Body

The oldest theory concerning the pituitary body is trans-
mitted by, and survives in, the name the organ bea'rs. The
secretion of the mucous membrane of the nose (pituita) was

^supposed to be derived from the " glandula pituitaria." This
was the view of Galen, held also by Vesalius. At the period of

/ Vieussens and Sylvius, the body was supposed to have to do
with the formation of the cerebro-spinal fluid.1

Gushing calls attention to a remarkable paper by Lower

/ (Dissertatio de Origine Catarrhi, 1672), who was the first experi-
mentally to disprove the Galenic doctrine. " For whatever
serum is separated into the ventricles of the brain and tissues

1 It is interesting, as pointed out by Gushing, to note that a substance
from the gland may under certain conditions enter the nose, ami that.
according to modern conceptions, the pituitary body does add something to
the cerebro-spinal fluid.

THE PITUITARY 347

out of them through the Infundibulum to the Glandula pitui-
taria distils not upon the palate but is poured again into the
blood and mixed with it."

Majendie regarded the pituitary as a kind of lymphatic
gland, which collects the cerebral lymph and passes it into the
circulation. "Its pars anterior does discharge its elaborated
products into the circulation, and the pars nervosa apparently
contains certain inter-neurogliar spaces resembling lymph
channels."

For a long period, the pituitary body was looked upon as a
" vestigial relic," and of no importance in the animal economy.

The association of Addison's disease with adrenal lesions was
the starting point of adrenal physiology, and the connection
between myx oedema and thyroid mischief was the beginning of
our knowledge of the functions of the thyroid. In the same
way, the appearance of Marie's publications (1888-1889) on
acromegaly and pituitary tumours, was the chief impetus
towards all the modern investigation into the structure and
functions of the hypophysis cerebri.

Of supreme importance in the history of our knowledge of
the pituitary, as indeed of all the ductless glands, was the
discovery by Oliver and Schafer (1894) of the physiological
activity of adrenal extracts. This led directly to the observa-
tion by the same authors of the power in raising blood-pressure
of extracts made from the pituitary body, and has instigated
a vast amount of work depending on the investigation of the
action of various tissue extracts upon the body generally and
on the different systems.

D. Physiological Action of Extracts of the Pituitary

Body

1. Effects on the Heart and Bloodvessels
Oliver and Schafer discovered that aqueous or saline extracts
of the pituitary body produce, when injected into the blood-
vessels, a rise of blood-pressure, which is comparable to that
produced by extracts of the adrenals. The rise is produced
by an action on the peripheral arterioles, as is that brought
about by adrenal extracts. The action of pituitary extracts,
however, is more prolonged than that of adrenal extracts.

348 THE DUCTLESS GLANDS

There was no marked effect upon the rate of the heart-beat.
(See Figs. 96, 97.)

Howell made a considerable step in advance. He divided
the gland into its two chief portions — the anterior and posterior
lobes — and determined that, while an extract of the former
is devoid of physiological activity when injected into a vein,
that of the latter produces the effects upon the blood-pressure.
Howell further found the rise of blood-pressure to be accom-
panied by a slowing of the action of the heart, and that both
the raised blood-pressure and slow cardiac rhythm might be
maintained for a considerable time ; and that if a second dose
be administered intravenously within a certain time — which
varies from half an hour to an hour or more — after the first
dose, these effects are not repeated — in other words, a certain
immunity is established, which only slowly passes off.

Cyon has noticed, as did Howell, that the rise of blood-pres-
sure is accompanied by slowing of the pulse. Both these effects
he attributes to stimulation of the pituitary body by the extract
which has been injected. He states that stimulation of the
hypophysis in the body, either electrically or mechanically,
will produce similar results through the vagi, and that after
extirpation of the organ the effects can no longer be produced
by injections.

There is slowing of the isolated mammalian heart, if extract
of the "posterior lobe " be perfused through it.

Schafer and Vincent, working with cats, found that pituitary
extract, on administration of a second or third dose, always
produces a fall, and not a rise, of pressure (see Fig. 97).
The depressor substance was subsequently shown, by the
present writer and collaborators, to be common to extracts of
all organs and tissues.

Osborne and Vincent, working with dogs, found, with Howell,
a preliminary fall before the rise, but, in most cases, a rise as
well as a fall on a subsequent injection. This is what I have
observed in a recent series of experiments.1

The main facts have been found to hold good as well for
extracts made from the human pituitary.

According to Schafer and Vincent, the cardiac slowing is

1 In one experiment, even the first administration of pituitary extract
produced no Cise, and this result seems to have been due to the previous
administration of adrenin.

THE PITUITARY

349

not constant, and, when present, it is not abolished by section
of the vagi or the action of atropine. It is, therefore, of
peripheral origin, and is not due to the same cause as the
inhibition which often accompanies the action of adrenin, and
is brought about by an action on the car dio -inhibitory mechan-
ism in the bulb.
This action of pituitary extracts upon the heart and blood-

FIG. 96. — Effect upon the arterial pressure and intestinal volume of intra-
venous injection of decoction of infundibular body. Cat under morphine
and curare. The time of marking indicates five seconds.

vessels is a special case of their action upon most of the involun-
t.ary muscles. The rise of blood-pressure already referred to
is due to constriction of many of the bloodvessels of the body,
combined with augmentation of the heart-beat.1

With large doses, the depressor effect may be so marked as
to mask the usual subsequent rise.

1 Paton and Watson state that in the duck there is dilation of vessels and
not constriction.

350 THE DUCTLESS GLANDS

According to Ho well, the responses become less and less
pronounced with each repeated injection. There is great
variation in the effects produced not only between different
species of animal, but even between different individuals of
the same species.

It has been doubted whether the depressor action, seen with
injections subsequent to the first, is wholly due to a different
principle, though the evidence before us seems to the present

FIG. 97. — Effect upon the arterial pressure of intravenous injection of decoc-
tion of infundibular body. Cat. Morphine and curare.

writer to be strongly in favour of such a view. Hoskins and
McPeek discuss the question, whether the pressor effect of
pituitary extract is due to adrenal stimulation, and come to a
negative conclusion. Experiments upon the isolated heart
of the frog and of mammals show that the slowing of the
heart-beat is due to a direct action upon the musculature of
the heart. Einis finds that the first effect of pituitary extract
upon the heart is a diminution of the frequency, this is followed
by an increase.

2. Effects on the Vasomotor Reflexes
The facts that adrenin diminishes the. excitability of the

THE PITUITARY 351

vagus,1 and that fluid from the thyroid appears to increase the
excitability both of the vagus and the depressor, led to an
investigation of the action of these and other tissue extracts
upon the vasomotor reflexes.

The extract of the pituitary body, sold under different names
by different firms, appears to convert a depressor reflex into a
pressor, or very considerably to exaggerate the pressor effect.
The latter effect is, in some cases, much more marked after
previous administration of adrenin. This action of pituitary
extract occurs only on a first injection.

Brisk kneading of the intestines evokes normally a very
distinct vasomotor response, which is frequently accompanied
by a slowing of the heart-beat. The effect upon the heart is
very noticeable after the administration of pituitary extract,
and the beat is frequently of a grouped character.

3. Effects on the Respiration

Mummery and Legge have noted a diminution of the ampli-
tude of respiration, as a result of pituitary injection. Pantow
states that breathing stops for some time after the injection,
then begins again, then once more stops ; the primary stoppage
appears to be due to peripheral vagus stimulation.

4. Effects on involuntary Muscles other than those of the
Vascular System

(a) The Uterus. — It was first recorded by Dale that in-
fundibular extract excites uterine contractions. The obser-
vation was confirmed by several investigators. The uterus
is extremely sensitive to the action of the extract, whether
in the body or treated as an isolated organ. Kehrer first
used the uterus in the latter way, and noted the action of
pituitary extract upon it. Engeland and Kutscher affirm
that they have succeeded in separating, by a method of
fractional precipitation, from an extract of the whole pituitary
body a basic fraction possessing the characteristic action on
the uterus, but not that on the blood-pressure. According to
Dale and Laidlaw, the isolated horn of the uterus of the non-
pregnant cat gives fairly good results, responding with but

1 This is not always the case ; the precise conditions under which this,
occurs require careful investigation.

352 THE DUCTLESS GLANDS

little diminished contraction to a second dose, after the first
has been carefully washed away. It is subject, however, to
inconvenient spontaneous slow variations of its average tonus,
and is apt to acquire a disconcerting rhythm. The uterine
horn of the young virgin guinea-pig is greatly superior in these
respects, its natural tendency, when left undisturbed in the
Ringer's solution, being to acquire a condition of complete
relaxation, broken only by a small rhythm. It is very sensitive
to the extract, which can therefore be given in very small
doses, and the tissue normally relaxes with promptitude to its
original level of minimal tonus on washing out and changing
the solution. This method is found to detect differences of
activity which escape recognition by the blood-pressure test,
and is employed by Dale and Laidlaw for standardizing pituitary
extracts.

(6) The Bladder. — The action of pituitary extract on the
bladder was first noted by Bell and Hick. In dogs and cats,
pituitrin stimulates to a considerable extent the musculature
of the bladder, and increases the excitability of the pelvic
nerve.

(c) The Intestine. — Bell observed the power of pituitary
extract to restore peristalsis to the paralytically distended
bowel, a capability which, according to Dale and Laidlaw,
is not represented by any definite action on the bowel of the
normal animal. But Beyer and Peter, working with the
surviving small intestine of rabbits, find that, after a preliminary
diminution in rhythm and tone, both these are very strikingly
increased. The rhythmical movements are often increased
tenfold. The first phase is considered by the authors to be
due to stimulation of the sympathetic fibres which inhibit
the muscle. The second phase, on the other hand, is due to
stimulation of Auerbach's plexus and the post-ganglionic
fibres. With very powerful doses, this second effect is very
slightly manifested or may be absent altogether, so that an
immediate and lasting inhibition may be the only result.

It is usually supposed that the most distinctive difference
between the action of adrenin and that of pituitrin is that
the former relaxes the unstriped intestinal muscle, while the
latter uniformly contracts these fibres. But it has been shown
by Shamoff that certain posterior lobe preparations are capable
of producing relaxation of the isolated intestinal loop and of

THE PITUITARY 353

inhibiting its rhythmical contractions, resembling in this respect
the extracts of the chromaphil tissues.

Just as Schafer and Vincent found two separate substances
acting on the blood-pressure — a pressor and a depressor — so
Beyer and Peter distinguish two separate substances having
respectively the two actions on the intestine just described,
the sympathetic inhibitory substance being insoluble in alcohol,
the autonomic augmentor substance soluble.

These effects on the intestine can be repeated at frequent
intervals, while the effect on the bladder rapidly becomes less
in successive trials.

It is doubtful how far these effects are truly specific for
extracts of pituitary.

(d) The Stomach. — The effects of pituitary extract on the
stomach appear to resemble very closely those upon the
intestine just described. There is at first some inhibition,
which is followed by a powerful and persistent augmentation.
The rhythmical movements are very markedly exaggerated.
These actions were first noted by Houssay in the frog, and
then in other animals and man.

Clinical observations have been made in the same direction.

(e) The Pupil. — It was discovered by Cramer that pituitary
extract dilates the pupil of the enucleated frog ' s eye . Franchini
noted also that the serum of animals which have received
intravenous injections possesses slight mydriatic properties.

There is thus a close resemblance between the reactions,
due to administration of pituitary (posterior lobe, infundibular)
extracts and those so familiarly called forth by means of
adrenin. The chief differences consist in the preliminary
fall (in some animals) and prolonged rise due to pituitary,
and the fact that this drug causes slowing of the pulse after
atropine or section of the vagi, in the constriction of the
coronary and dilatation of the renal vessels, adrenin .having
an opposite effect.

5. Effects on the Secretion of Certain Glands

(a) The Mammary Gland. — Ott and Scott discovered that
injection of pituitary extract into goats causes a marked increase
in the flow of milk, Schafer and Mackenzie found that ex-

23

354 THE DUCTLESS GLANDS

tracts of pituitary body, corpus luteum, pineal body, involut-
ing uterus, and lactating mammary gland all manifest a
galactagogue action, but the pituitary body produces the most
marked results.

Gavin found that the daily yield of milk in cows is not
increased by the administration of corpus luteum and pituitary
extract. Schafer also reports that injection of pituitary extract
into a muscle of a lactating woman caused only a temporary
increase in the flow of milk.

It has been suggested that the hypertrophy of the mammary
glands is brought about by some secretion produced during
pregnancy, which neutralizes the tendency of the cells to
discharge under the influence of secretion from the pituitary
and other organs. When this inhibitor is removed, the
hormones causing the discharge of the gland come into action,
and so cause the secretion.

This seems likely from the experiments of Mackenzie, who
states that by injecting extracts of foetus or placenta together
with pituitary extract into a lactating animal, the action of
the pituitary is inhibited.

In regard to the corpus luteum, there is a theoretical dis-
crepancy between the views of those who regard the body as
one of the building-up factors, and the results of Schafer and
others who find that corpus luteum extract produces an imme-
diate secretion.

Hammond finds, as did previous observers, that the galac-
tagogue effect of pituitary extract is only temporary. The
effect is not muscular. The daily yield is only slightly increased,
and is not dependent on increased blood-pressure. The pitui-
tary gland seems not to be the origin of the ordinary changes
in Ihe mammary gland. Histological evidence points to a
direct action of the extract on the glandular epithelium. The
milk obtained after injection has a higher percentage of fat
than normal ; in the subsequent milkings, however, there is
a drop in the percentage of fat, although that of the other
ingredients remains normal.

While the proteins, lactose, and ash are secreted in close
connection with the water of the milk, the amount of fat is
not so connected with the amount of water. The ratio of
"nitrogen to lactose" is relatively conMant throughout.

Hill and Sutherland Simpson state that pituitary extract

THE PITUITARY 356

increases the immediate secretion of milk, but causes after-
wards a decrease below normal.

(b) The Kidney. — The diuretic action of pituitary extracts
was discovered by Magnus and Schafer. The increase of
secretion is accompanied by dilatation of the renal arteries,
so that the organ swells. The action is, therefore, different
upon the renal vessels from that on the arteries in general,
which are strongly contracted by it. The rise in blood-pressure
produced by this general contraction is not the sole cause of
the increased secretion of urine, for a second dose administered
a short time after the first will again accelerate secretion,
although the second dose may not cause any rise of general
blood-pressure, but rather a fall. There is, therefore, a specific
diuretic effect upon the renal epithelium, just as there is upon
the epithelium of the mammary gland. The tolerance pro-
duced by a first injection is then less marked than in the case
of the blood-pressure response, but with large doses it is well
marked.

It is reported that, under certain circumstances, there
is a secondary diminution of the flow of urine, following
upon vasoconstriction of the kidney.

Hoskins and Means believe that the pituitrin diuresis is
due primarily to direct stimulation of the renal cells — usu-
ally aided, perhaps, by a concomitant vasodilatation in the
kidneys.

(c) The Stomach. — It was shown by Edkins that extracts
made from the pyloric mucous membrane in boiling water or
0'4 per cent, hydrochloric acid contain an active substance
which, on injection into the bloodvessels of an animal, leads
to a secretion of gastric juice.

Frouin found a similar action on the injection of gastric
juice. Eirenhardt confirmed the results of Edkins, but Ems-
mann obtained some definite effects upon the flow of gastric
juice as a result of injection of extracts of other organs, such
as the intestine.

Houssay has recently reported a very decided action of
pituitary extracts upon the flow of gastric juice, and has pub-
lished some very convincing tracings. This appears to be a
direct action on the secreting cells, as in the case of the mam-
mary gland and the kidney. At any rate, the effect can be
observed upon the isolated stomach.

356 THE DUCTLESS GLANDS

6. General Physiological Effects (Subcutaneous and Intravenous

Injections)

In 1899, Schafer and Vincent reported that they had made
a few experiments upon the effects which can be produced by
the subcutaneous injection of decoctions of the infundibular
part of the pituitary body. These were performed upon mice
and young rats, and, although the dose required was much
greater, showed that the pituitary extracts can produce results
resembling in a general way those of adrenal extracts. They
cause quickened respiration, increased heart's action, and
ultimately paralysis, beginning in the hind-limbs.

Similar experiments have since been carried out by many
observers. Diuresis, hsematuria, and albuminuria have been
recorded. Etienne and Parisot further record a permanent
hypertension as the result of repeated injection of pituitary
extracts.

It is stated that the effects of subcutaneous injection are
modified by previous injection of thyroid extract, or extract
made from the anterior lobe of the pituitary body or the
pharyngeal pituitary.

The toxic effects of pituitary extracts are not nearly so
pronounced as those of the adrenals. The symptoms observed,
in addition to those mentioned above, are apathy and somno-
lence, excitation followed by muscular weakness, sudden
cessation of heart-beat, and loss of weight after repeated injec-
tions, cardiac hypertrophy, ulceration, and haemorrhages in the
intestine, and hypersemia and haemorrhages in the kidney.

Urechia found that a reinjection after an interval of ten days
gave rise to symptoms of an anaphylactic nature.

E. The Question as to which Elements of the Pituitary
Body furnish the Active Substance or Substances
—Functions of the Different Parts of the Pituitary
Body

As we have already seen, Howell discovered that it is from
the posterior lobe only that active extracts can be obtained.
This was confirmed by Schafer and Vincent. The observation
was contrary to what might have been expected, since, from the
Distinctly glandular na.ture of the anterior lobe, it would apj

THE PITUITARY 357

a priori that it would be more likely to furnish active physio-
logical substances.

But we must remember that there are epithelial elements
in, and in close relation to, the nervous portion (Figs. 94 and
95), and it was a natural assumption that these, and not the
nervous portion proper, would be found to yield the pressor
substance. But some years ago, Professor Osborne and myself
tested the matter, and found that an extract made from the
central part of the infundibular portion — devoid of epithelial
elements — is much more active than one from the peripheral
epithelial part. We expressed the opinion that probably the
external layer would be found to be inactive if it could be
obtained quite free from admixture with the central portion.

Schafer and Herring found this to be the case too with the
substance which acts as a diuretic. Improbable, then, as it
would appear at first sight, the conclusion is inevitable that it
is the nervous portion proper which contains the substance
or substances having such pronounced pharmaco-dynamical
properties, different from those possessed by other kinds of
nervous tissue.

I have never had an opportunity of repeating the experi-
ments carried out in conjunction with Professor Osborne, but,
since they have been amply confirmed, I am strongly inclined
to adopt the view of Houssay that the substance or substances
are secreted by the cells of the pars intermedia, and then collected
and concentrated, or changed into more active forms in the nervous
portion proper.1

No physiologically active substances can be extracted from
the anterior lobe (except a depressor substance, which is
common to all organs and tissues). This part of the pituitary
is related to the general growth of the body, and especially of
the skeleton. (See Section F.)

F. Feeding and Metabolism Experiments

The first metabolism experiments were performed by Schiff.

1 Herring has recently confirmed the results of Osborne and Vincent.
" The pars nervosa is from two to five times more powerful than the pars
intermedia in its action." He thinks that the substance acting upon the
uterus is formed at an early stage in the pars intermedia, but the substance
acting upon the blood-pressure and kidney is a later product, resulting from
the breaking down of the hyaline bodies or disintegrating pars intermedia
cells in the pars nervosa.

358 THE DUCTLESS GLANDS

He found that there was no influence on the nitrogen in any
case, but that the phosphorous output was sometimes increased,
due to katabolism of bony tissue. But the increase may have
partly been due to nuclein.

Moraczewski found in a case of acromegaly that the nitrogen
output was increased, also that of phosphorus, while Oswald
found no effect on nitrogen or phosphorus.

Malcolm noted that the anterior lobe, administered dry,
tends to cause a retention of nitrogen ; the dried nervous
portion has a similar effect. The fresh entire gland, in large
doses, increases the output of nitrogen. The anterior lobe
causes a retention of phosphorus, while the posterior lobe
causes a loss followed by retention. On the whole, Malcolm's
results pointed to a greater activity on the part of the nervous
portion.

Caselli observed no effect on growth from long-continued
injections of extracts made from the whole gland, but in some
cases feeding with the gland retarded growth. Sandri fed
young mice and guinea-pigs with pituitary emulsion, and states
that this caused an arrest of growth. Cerletti injected pituitary
emulsion intraperitoneally into young animals, and found that
the animals receiving the injection fell uniformly below the
controls in weight, and that the bones of the animals receiving
the emulsion were, as compared with the controls, somewhat
shorter as regards the diaphyses, but longer as regards the
epiphyses.

Schafer has carried out a series of feeding experiments on
white rats, the general conclusion from which is that the addi-
tion of small amounts of pituitary tissue to the diet of rats has
little or no effect upon growth.

Franchini, working with rabbits and guinea-pigs, reports
that the calcium and magnesium metabolism is much reduced.
Elfer reports that subcutaneous injection of pituitary extract
does not affect the protein metabolism, but induces a tem-
porary retention of phosphorus, calcium, and magnesium.

Quite recently Rosalind Wulzen has investigated the effects
of administration of anterior lobe of pituitary body to young
growing birds. A very distinct effect is shown in the direction
of retardation of growth, which is manifested both in the body
and in the length of the long bones. Involution of the thymus
accompanies this retardation, and the suggestion is made that

I

THE PITUITARY 359

the former may bear a causal relation to the latter. The
effects are more marked in males than in females.

In very few of these investigations (the last -mentioned series
forming a notable exception) has sufficient attention been paid
to the difference between the anterior and posterior lobes of
the pituitary. It must be pointed out that, even when ordinary
care is taken to separate the anterior from the posterior lobe,
the former will include a strip, which varies in thickness in
different animals, of the pars intermedia. The reflection of
this part over the nervous portion is now well known, and
account has been taken of its presence in the consideration of
the effects of posterior lobe extracts (see Section D ), but the fact
which I have just pointed out, viz., that there is a reflection of
the pars intermedia over the anterior lobe, is not so generally re-
cognized (Fig. 94) . If the pars intermedia be traced round from
the nervous on to the glandular portion, it will be noticed that
the cells forming it gradually fuse with the cells of the glandular
portion in the depth of the latter structure, but are continued
as a layer, retaining at any rate some of the characters of the
pars intermedia, along the edge of the cleft. Although the
amount of pars intermedia adhering to the anterior lobe is not
very considerable, it is possible that it might make a difference
to the physiological extract.

Houssay is the only author, so far as I am aware, who has
definitely drawn this as a continuation of the pars intermedia ;
though Herring states that the anterior lobe in the cat is
separated from the cleft by cells, " which are larger than endo-
thelial cells," and are continuous at the anterior and posterior
ends of the cleft with the cells of the epithelial reflection. He
admits too that the cells of the intermediate portion occasionally
spread down a little over the front of the anterior lobe. The
general arrangements are shown in Fig. 94, and the microscopi-
cal structure in Fig. 95.

Pituitary feeding is stated to have very similar effects to
those produced by thyroid in bringing about precocious meta-
morphosis in amphibia. It is also said that the rate of fission
of planarian worms is increased by a diet of pituitary substance.

G. Grafting Experiments

The effects due to increased functional activity of the pit-
uitary body cannot be induced by glandular transplantation.

360

THE DUCTLESS GLANDS

dishing adopts the theory of W. 8. Halsted that an existing
" physiological deficit " is one of the essentials for a successful
organo -transplantation. In support of this, Crowe, Gushing
and Homans observed that the life of animals, after a total
pituitary extirpation, could be prolonged by the immediate
reimplantation into the cerebral cortex of the excised gland,
which lived for a month.

In the absence of such a previously established deficit, the
transplanted gland becomes absorbed in a short time. In
Schafer's experiments the only distinct effect noticed was with
the posterior lobe, which caused a temporary increase in the
flow of urine. As the implanted gland soon became absorbed,
this result is probably to be looked upon simply as the effect of
the administration of an equivalent amount of pituitary extract.
It is possible, however, that the transplanted gland may have
functioned for a short time.

In Exner's experiments on rats, transplantations were made
of glands taken from young animals, and there was a temporary
increase in growth and weight. But it is possible, in this case
as well, to assume that the effect was comparable to a long-
continued administration of an equivalent amount of extract.1
It is pointed out by Gushing that the results of these various
transplantation experiments suggest some therapeutic possi-
bilities for this method, as the slow absorption of the secretion
may be an effective means of administering the active principle.
Gushing appears to have obtained some clinical evidence that,
when a patient is actually suffering from a physiological
deficiency, fragments of a transplanted pituitary body may
survive and remain permanently active.

H. Stimulation of the Pituitary Body in situ.

Cyon has studied the functions of the gland by the method
of direct excitation. He exposed the hypophysis by trephining
the base of the skull beneath the sella turcica. Then he
exerted light pressure upon the gland by means of a small pad
of cotton. He observed immediately a considerable variation

1 It must, however, be noted that the effects produced, viz., increase in
growth and weight, are in a contrary sense to those observed by the majority of
recent experimenters, administering the gland by the mouth. But the effect
of giving whole gland would possibly be different from that of giving anterior
lobe only.

THE PITUITARY 361

in the blood-pressure and in the number and intensity of the
heart-beats. These variations occurred to some extent as the
result of the trephining, but were much exaggerated by a very
slight electrical stimulation. Cyon worked with rabbits, and
noted a considerable slowing of the heart- beat, with increase of
amplitude.

Different results have been obtained by the majority of
subsequent workers ; but Masay obtains results similar to those
of Cyon, though his interpretation is different. The effect of
direct stimulation of the gland he attributes to an increased
discharge of the internal secretion into the blood-stream,
where it produces the usual result due to the action of the
extract upon the heart.

Schafer reports that, in dogs, partial injury to the pituitary
by means of a thermo -cautery or mechanical agents induces
marked diuresis. This result is specially interesting in relation
to the polyuria, which occurs in injuries and tumours affecting
the base of the brain. This polyuria is more likely to occur
when the pars intermedia is involved.

I. Extirpation Experiments

The first to perform experimental extirpation of the pituitary
was Horsley, in 1886. Subsequent observers obtained con-
tradictory results ; but it was established by Paulesco, in 1906, "
that the organ is essential for life, and that the onset of the acute
symptoms depends on the loss of the anterior rather than on
that of the posterior lobe. Paulesco's results have been con-
firmed in the main by Gushing and his co-workers. These find
that puppies survive total extirpation longer than do adults ;
that life can be prolonged (see Section G) by transplantation
of the removed gland ; that, in all cases which recovered, a
fragment of the anterior lobe was invariably found to have
survived ; that animals with a fragment of anterior lobe,
temporarily insufficient to support life, could be tided over a
period of threatened cachexia hypophyseopriva by subcuta-
neous injections, or by feeding with anterior lobe ; and that
removal of the posterior lobe leads to no very definite
symptoms.

The acute symptoms observed were tremors, fibrillary
twitching, arching of the back, insensitiveness, slow pulse and

362 THE DUCTLESS GLANDS

respiration, a terminal abrupt fall in body temperature, and
apathy passing into coma and death.

Gushing and his collaborators describe in animals, which
recover after partial extirpation, certain constitutional disturb-
ances, some of which (e.g., carbohydrate tolerance) they now
admit to be due in part to posterior lobe deficiency. These
constitutional disturbances are adiposity, changes in the skin,
disturbances of carbohydrate metabolism, of temperature, of
growth, and of secretion by the kidney. Sexual inactivity and
changes in most of the ductless glands are also described.

In some cases, the adiposity was so extreme that the weight
of the animals became doubled, the deposition of fat is widely
distributed, and in some regions oedema is recorded.

The skin becomes dense, dry, and less movable than usual.
The hair becomes bristly and tends to fall out in patches —
changes, as pointed out by Gushing, not unlike those found
after thyroid extirpation.

When much pituitary substance has been removed, a sub-
normal temperature is the rule, and it may fall nearly to room
temperature. The normal temperature may be restored by
applying heat, but this hastens the end. In some cases,
Gushing found, when the temperature was not very low, that it
could be raised by ingestion, or subcutaneous injection, of pitui-
tary extract. He states that a thermic reaction occurs, upon
the injection of pars anterior preparations, only in cases of
anterior lobe deficiency, and can be used as a clinical test when
anterior lobe deficiency is suspected.

Pulse rate and respiration may be slow, and the blood-
pressure low.

In young animals, partial pituitary extirpation results in
disturbances of growth, especially in skeletal undergrowth.

Gushing also reports mental dulness, irritability, and a
tendency towards epileptic fits.

After extirpation, a temporary glycosuria usually ensues,
followed by a short period during which the assimilation limit
is below normal. Subsequently, the animals acquire such a
tolerance for sugar, that it is often difficult to produce alimen-
tary glycosuria with the amounts of sugar that can be retained.
According to Cushing's observations, these facts are connected
with removal of, or damage to, the posterior lobe, and the inter-
pretation given by this writer is as follows : " Normal posterior

THE PITUITARY 363

lobe activity is essential to effective carbohydrate metabolism ;
an intravenous injection of posterior lobe extract produces
glycogenolysis, and its continued administration in excessive
amounts leads to emaciation. A diminution of posterior lobe
secretion occurring in certain conditions of hypo-pituitarism
(whether experimentally produced or the result of disease)
leads to an acquired high tolerance for sugars, with the resultant
accumulation of fat."

It is reported that, contrary to what might have been
expected, removal of the posterior lobe increases the flow of
urine rather than diminishes it. There is often a true diabetes
insipidus, lasting for some time.

Experiments upon puppies disclose a persistence of sexual
infantilism. There are as well changes in the testes, ovaries,
thyroid, thymus and adrenal cortex and medulla. Moreover,
changes occur in the reverse direction, for example in the
pituitary after castration or thyroidectomy, and Gushing reports
changes in the posterior lobe after extirpation of the pancreas.
So far as can be gathered from Cushing's account, this author
attributes most of the disturbances above described to deficiency
of the anterior lobe; indeed the only changes, which he
definitely attributes to damage to the posterior lobe, are the
effects upon carbohydrate tolerance and upon the secretion by
the kidney. He does not state definitely whether these changes
are due to loss of the nervous portion proper, or to that reflec-
tion of the pars intermedia which passes over the nervous
portion.

Hanselmann and Horsley have failed to confirm the results
of Gushing and his colleagues. In their experiments there was
a very high death-rate from shock, haemorrhage, and infection ;
but in the animals which survived, there were no characteristic
symptoms like those described by Gushing. Hanselmann and
Horsley further state that they observed a parallel death-rate
in animals, in whom incomplete extirpation had been carried
out. It is clear that the results of this series of experiments are
quite different from those obtained by Paulesco and Gushing.

Aschner has opposed the view that the pituitary body is -
essential to life. He operates through the roof of the mouth.
In adult animals, according to Aschner, there are no serious
symptoms after the complete operation, although there are
slight metabolic changes. In young animals, on the contrary,

364 THE DUCTLESS GLANDS

profound effects are produced. In these cases, the symptoms
described are analogous to those given by Gushing, and which
are detailed above. His operative proceedings are criticized by
Biedl and by Gushing.

Quite recently, Aschner has emphasized the relationships
between the pituitary body and the genital organs, and points
out the bearing of these upon pathological conditions in the
human subject.

Staderini believes that extirpation experiments have given
contradictory results in the hands of different observers,
because operators have not always taken account of the " lobi
laterales " and the " lobus premamillaris," described by him in
the cat and in the ox. Perna has given a full description, with
illustrations, of a " post-glandular prolongation " in the human
subject. Other " accessory pituitaries," which may be men-
tioned here, are the " pharyngeal pituitary bodies " described
by Haberfeld and others.

Complete extirpation can never be said to have been per-
formed, unless these accessory bodies have been removed along
with the main pituitary. Moreover, according to Biedl, total
extirpation can only be described as such when, in addition to
the removal of both lobes, the hypophyseal peduncle is severed
as well. This latter operation is in itself, according to Biedl, as
/ fatal as complete extirpation of the pituitary body. This was
found to be the case also by Paulesco, and Aschner has only
recorded the survival of animals in pituitary operations when
not too much of the infundibulum was removed. Morawski,
however, found that cutting through the peduncle has no
serious effect on the monkey, while cats will not survive the
procedure. This difference is explained by him by the fact that,
in the monkey, cutting through the peduncle does not make an
opening into the third ventricle, which must happen in cats and
dogs. Biedl thinks that the real explanation lies in the anato-
mical relationships of the pars intermedia in the different
animals, and is of the opinion that the opening of a communica-
tion with the third ventricle is a matter of no consequence.

Summing up, so far as is possible, these somewhat contra-
dictory experimental results, we may conclude with some degree
of probability that : —

1. Total extirpation of the pituitary body is a fatal opera-
tion, though the duration of life in the operated animal varies

THE PITUITARY 365

very considerably according to its age. Adult dogs and cats
will not survive more than two or three days ; young animals
may live as many weeks.

2. Partial extirpation of the pituitary body (if a small part of
the anterior lobe be left behind) gives rise to disturbances in
growth and metabolism already described, and these may be
induced in young animals by deficiency of anterior lobe only.

3. The effects upon the genital organs may be due to de-
ficiency of the pars intermedia, and the preponderance of
evidence is that the polyuria and disturbance of carbohydrate
metabolism (tolerance) are due to deficiency of this part as well.

4. It seems possible that removal of the nervous portion
proper would be without any serious effects. This operation
can, however, scarcely be carried out without damage to the
pars intermedia, and this damage brings with it the metabolic
disturbances just referred to.

It is interesting to note that, just as in the case of the adrenal
body, so we have in the pituitary two main portions, one of
them glandular, the other nervous. In the case of both organs,
the physiologically active substances are found in the nervous
portion (neurohypophysis, adrenal chromaphil tissue), while
the glandular portion seems to be that w^hich is essential to life.

The above summary represents the views of the majority of
those who have devoted themselves to the subject of pituitary
extirpation. But it is somewhat disconcerting to find careful
observers who express themselves in such a sceptical vein as do
Camus and Roussy. These authors believe that the polyuria
which occurs on extirpation of the pituitary is not due to the
removal of this organ, but to a lesion of the opto -peduncular
region at the base of the brain. This region lies at the level of
the grey substance of the tuber cinereum in the vicinity of the
infundibulum. This zone seems to play some part in the
mechanism of water retention in the organism. Atrophy of
the genital organs and the " adiposo-genital syndrome " are
likewise due less to any hypophyseal lesion than to trouble at
some point in the base of the brain. The same applies to the
changes in tolerance to carbohydrates and the appearance of
alimentary glycosuria. These experiments, if the results are
confirmed, will necessitate a reconsideration of our whole attitude
in relation to the pituitary body.

366 THE DUCTLESS GLANDS

J. The Question as to a Functional Relationship between
the Pituitary and the Thyroid Bodies

From the time when the ductless glands first began to be
known, there has been a decided tendency to regard them as
physiologically more or less related to one another. In the
earliest days, there can be little doubt that the grouping
together of these organs was very largely to be ascribed to our
uniform ignorance of their functions. But during recent years
a certain amount of information has been accumulated, which
renders it probable that there are true interrelationships
between certain of the glands endowed with the power of
internal secretion. The whole question constitutes a very
fascinating, albeit a very abstruse, chapter in the physiology
of internal secretion. We are, however, in this place concerned
only with a possible functional relationship between the thyroid
and pituitary bodies.

Many of the suggestions which have been made were of an
a priori character. Cyon has put forward a theory of an
elaborate kind about the mutual function of the thyroid and
pituitary bodies, and he regards the latter as a centre from
which the vascular supply of the brain is influenced through the
former.

Rogowitsch, in 1888, observed in rabbits, killed at periods of
from two to ten weeks after thyroidectomy, a marked hyper-
trophy of the pituitary body. This result was confirmed by
many observers.

Quite recently Lydia M. Degener has found that the increase
in weight of the pituitary, after the thyroid glands have been
" completely removed " l from rabbits, runs parallel with the
time which intervenes between thyroidectomy and the death
of the animal. After an interval of 179 days, the pituitary body
had increased to about three times the normal size.

In these hypertrophied pituitaries there is increased activity
of the cells of the pars intermedia, and in the proper nervous
part of the posterior lobe. In these situations, granular,

1 Thin meaiiK, presumably, ihat the thyroid and internal parathyroid on
both sides were removed, leaving behind both external parathyroids.

THE PITUITARY 367

hyaline, or colloid bodies become very numerous ; they appear
to be partly of a cellular nature and to find their way between
the ependyma cells into the infundibular recess and ventricles
of the brain. The colloid appears to arise from the epithelial
cells of the pars intermedia.

The precise nature of the relationship existing between the
thyroid apparatus and the pituitary body is by no means clear.
Simpson and Hunter report that complete removal of the
thyroid gland in lambs does not lead to the appearance of
iodine in the pituitary. On the assumption that the iodine
containing substance of the thyroid represents its active
secretion, this does not support the Rogowitsch theory that, in
thyroid insufficiency, the pituitary vicariously takes on its
function. In the experiments of Simpson and Hunter, there
was, however, some compensatory hypertrophy of the pituitary
body.

It only remains to make reference to some experiments of
Masay in opotherapy, with the object of ascertaining whether
pituitary extract can replace the internal secretion of the
thyroid ; the results were entirely negative.

K. Pituitary Insufficiency and a Pituitary Antiserum

or Cytotoxin

Masay has attempted to produce pituitary insufficiency by
the method employed by Demoor and Van Lint in order to
obtain an " anti-thyroid serum." Guinea-pigs were injected
intraperitoneally with an emulsion of dog's pituitary at intervals
of two days. After three, four, or five injections the blood of
the guinea-pig was collected and centrifugalized, and the serum
(about 10 c.c.) was injected under the skin of a dog. Masay
gives his results in considerable detail, and the effects upon the
animal are shown in a series of illustrations. After a certain
number, usually two or three, of such injections the dogs show
symptoms, such as loss of flesh, muscular weakness, especially
in the hind limbs, changes in the skeleton and in the structure
of the pituitary, the symptoms constituting, according to
Masay, a veritable cachexia hypophyseopriva.

Ossokin reports that the " hypophyseolytic serum," prepared
from the blood of dogs immunized with posterior lobe of

368 THE DUCTLESS GLANDS

pituitary, produces a marked fall of blood -pressure. The
precise significance of this is difficult to understand.

It is yet too early for us to be able to determine the value of
these antiserum experiments.

L. Chemistry of the Pituitary Body

Schafer and Vincent, who described a pressor and a depressor
substance, found that the latter could be separated from the
former, on account of the fact that it is soluble in alcohol, in
ether, and in normal saline solution. This is of course the
depressor substance common to all animal tissues.

Schafer and Herring contend that two active principles exist
in pituitary extracts, one acting on the circulatory system, the
other specifically on the kidney. Dale does not consider the
evidence on this point to be satisfactory.

Within recent years three observers have claimed to have
obtained, apparently independently, the active substance in a
pure form. Houssay, in 1911, prepared the active substance as
follows : — " The fresh hind lobes were boiled in water ; the
filtrate was then precipitated with lead acetate and sulphuric
acid, filtered, and the filtrate dried in vacua. The residue is
washed with chloroform, ether, and alcohol, and finally crys-
tallized in vacuo. The product is insoluble in alcohol, ether,
or chloroform, but very soluble in water, and is dialy sable. It
is precipitated by picric acid, platinum chloride, etc. If burnt
on platinum foil, it gives off the smell of burnt feathers."

Solutions of this product in normal saline produce the effects
of pituitary extracts upon the heart and vessels.

Fiihner claims as well to have isolated a pure crystalline
basic substance, which has been put upon the market in the
form of its sulphate, and is called hypophysin. Fiihner 's
product is said to possess all the activities of pituitary extracts
on respiration, blood-pressure, and the uterus.

Herzberg has tested Fiihner's substance clinically, and reports
that its action upon the uterus is powerful and prompt.
" Hypophysin " is stated to consist of four separate substances.

In still later papers, Fiihner and Schickele declare that the
substance acting upon the uterus is independent of that acting
upon the blood-pressure, and can be obtained from extracts of
the anterior as well as of the posterior lobe.

THE PITUITARY 369

Robertson states that he has succeeded in isolating from
the anterior lobe a substance called tethelin which quickens
growth in young animals and is thought to have a possible
value in hastening the healing process in wounds.

M. The Comparative Physiology of the Pituitary Body

Professor Osborne, working in conjunction with the present
writer, showed that extracts of the pituitary body of the cod
produce effects upon the heart and bloodvessels similar to
those of extracts of the mammalian posterior lobe.

Schafer and Herring demonstrated that extracts made from
the cod's pituitary produce kidney dilatation and diuresis
when injected, just as do extracts from the mammalian posterior
lobe.

The subject has been recently more thoroughly investigated
by Herring. This observer finds that the posterior lobe of the
pituitary body of the fowl produces an effect on blood-pressure,
kidney volume, and urine secretion, which is very similar to
that produced by extracts of the posterior lobe of the mam-
malian pituitary. It was found to be impossible to determine
whether the active principles in the posterior lobe of the bird's
pituitary are products of the epithelial cells of the pars inter-
media, or are formed solely in the nervous substance. No
distinct effects were produced by extracts of the avian anterior
lobe.

In regard to Teleostean fishes, extracts of the anterior lobe
proper — chromophil portion of Sterzi and Gentes — have little
physiological effect. The general effect of extracts of the
posterior lobe is similar to that brought about by extracts of
the mammalian and avian posterior lobes. In Teleosts the
cells of the pars intermedia predominate in the posterior lobe,
and are inseparable from the pars nervosa, so that one cannot
determine which produces the active material. According to
Herring, both are probably concerned, for wherever cells of
pars intermedia — chromophobe cells of Sterzi — are bound up
with pars nervosa, extracts of the resulting tissue produce the
effects on blood-pressure, kidney volume, and urine secretion
which have been associated with extracts of the posterior lobe
of the mammalian pituitary. Extracts of the saccus vasculosus
are practically inactive, and Herring supports the supposition

24

370 THE DUCTLESS GLANDS

of Gentes that this structure has a function similar to that of
a choroid plexus.

The Elasmobranch pituitary, as we have already seen, is
quite different in structure from the pituitary bodies of mam-
mals, birds, and Teleosts. There is no differentiation into
anterior and posterior lobes. According to Herring, there are
no cells precisely corresponding to those of either the anterior
portion or the pars intermedia of the mammalian body. The
presence of the true nervous portion seems also doubtful.
Extracts of the Elasmobranch pituitary give rise to no
characteristic physiological effects.

N. Diseases of the Pituitary Body

1. Introductory

According to Gushing, a pronounced constitutional dys-
pituitarism is not incompatible with a tolerable state of health
and comfort. In regard to symptoms due to each of the two
lobes, there may be an overaction or underaction of one lobe
only, or an overaction of one lobe associated with insufficiency
of the other. In the minds of many authorities the subject is
rendered still more complex by a tendency to regard every
disorder of the ductless glands as a poly glandular disease.
This is said to be sometimes so pronounced as to make it
doubtful which of the organs is primarily at fault. It is
generally believed that derangement of any one of these corre-
lated glands leads to disturbances in others, but a primary
disorder of any one will produce its own special symptoms.

A functional hyperplasia of the pars anterior promotes
tissue growth, chiefly shown in the skeleton, skin, and sub-
cutaneous tissues, and at the same time there is an excitatory
effect on the reproductive organs, as seen in the secondary
sexual characters. On the other hand,, insufficiency of the
anterior lobe inhibits skeletal growth and sexual development.

Little is known about functional hyperplasia of the posterior
lobe. This part seems to be concerned with tissue metabolism.
Insufficiency gives rise to slowed metabolic processes. There
is a high tolerance for carbohydrates, which are stored as fat,
there is drowsiness, slow pulse and respiration, subnormal tem-
perature, low blood-pressure, etc. This complex of symptoms
just described strikingly resembles the phenomenon of hiberna-

THE PITUITARY 371

tion, in which there is markedly slowed metabolism and in which
histological changes in the pituitary body have been described.

There is a tendency for pituitary diseases to lapse into a
condition where glandular insufficiency is the most noticeable
feature, and this is especially the case with disorders of the
anterior lobe.

Gushing divides symptoms of pituitary disorder into three
main groups : —

1. Endosecretory symptoms on the side of hyperpituitarism.

2. Endosecretory symptoms on the side of hypopituitarism.

3. Endosecretory symptoms of a polyglandular character.
As one might expect, many and very complicated systems

of classification have been attempted.

2. Acromegaly

(1) Introductory

The disease, which is characterized by enlargement of certain
bones of the body, especially of the hands and feet, was first
described by Marie, of Paris, in 1886. It was observed by
Marie that the disease is associated with tumours of the
pituitary body. It had, however, been described previously
under other names, as " hyperostosis of the entire skeleton "
by Friedreich, as "general hypertrophy " or " makrosomie "
by Lombroso, as " giant growth " by Fritsche and Klebs.

(2) Symptoms

There is usually a history of definite symptoms before the
characteristic deformities occur. Headache, pains in other parts,
irritable temper, moroseness, loss of memory, disturbances of
vision, increased appetite, thirst, and polyuria are enumerated
among the early symptoms. In women amenorrhcea is fre-
quently noted, while in men there may be loss of sexual power.

The head increases in size, the brows become arched and
prominent, the forehead retreating. The nose is large. The
zygoma and malar prominences are exaggerated. The upper
jaw is not much altered, but the lower is distinctly enlarged
(Fig. 98). The lower teeth may project beyond the upper.
The chin is thick and the face may be oval or square. The
tongue becomes enlarged and may force the mouth open and
plays a part in the deformity of the alveolar processes. It is
usually indented at the sides and the papillae are enlarged.

372

THE DUCTLESS GLANDS

The thorax is en-
larged, especially from
back to front. There
are various degrees of
kyphosis, scoliosis and
lordosis.

The hands are in-
creased in size, the
fingers are thick and
sometimes sausage-
shaped. Though the
bones of the hand are
sometimes increased in
length, most of the en-
largement is in the sub-
cutaneous tissue, with
increase of the points
of attachment of the
tendons. (See Fig. 99.)
The ankles and feet
are decidedly enlarged.
The skin is usually
dry, but perspiration

is easily induced. Flushing tingling and other vasomotor
changes are frequent. In the
later stages the muscles become
small and weak, a change which
accounts for the peculiar posi-
tion of the head, the kyphosis,
and other deformities.

Affections of sight are common,
blurring of vision, concentric nar-
rowing of the visual field, bitem-
poral hemianopia, optic atrophy
are often met with. The pupils
may be dilated. The sixth and
third nerves may also be affected.
Painful noises in the ears are fre-
quent and deafness may super-
vene. Loss of memory, mental

slowness, depression Or delusions creases. (From Gushing.)

FIG.

J. — Typical acromegalic profile.
(From Gushing.)

THE PITUITARY 373

are frequent. Somnolence is often marked, and may pass
into stupor. The urine is normal or there may be glyco-
suria (Dock).

(3) Etiology and Onset

Acromegaly has been sometimes ascribed to syphilis, or some
other specific infection. Heredity has also been claimed as
having some part in the causation. There is, however, no
sufficient evidence that any of these bear any essential relation
to the disease.

The disease occurs, perhaps, most frequently in early adult
life, between the age of puberty and the thirtieth year. It is
more common in women than in men. The onset is gradual.

(4) Metabolism in Acromegaly

If acromegaly be, in fact, due to a hyper secretion of the
pituitary body, we should naturally expect that in this disease
the metabolism would be modified in the same direction as in
animals fed upon pituitary substance. The few experiments
which have been performed upon acromegalic patients have
given contrary results. Retention of phosphates in the bones
and muscles and increase of urinary calcium have been alleged.

(5) Morbid Anatomy

The bones appear to undergo a true hypertrophy in the
majority of cases, though it is stated that the superior maxillary
appears to be larger on account of a simple dilatation of the
antrum. In the long bones the enlargement affects the ends
as well as the shaft.

The view which has the greatest number of adherents at the
present time is that the characteristic lesion in acromegaly is
adenoma of the pituitary. This belief was first definitely put
forward by Benda. Previously the tumour had been known
by various names, perhaps most frequently as a "round-
celled sarcoma." Hanau had previously suggested that the
typical growth is an adenoma ; and Lowenstein has given
a lucid account of the development of this adenomatous
tumour.

Other tumours of the pituitary do not appear to give rise
to acromegaly. Thus, Pende states that tumours of the
" pharyngeal pituitary " (remains of the pituitary duct) never

374 THE DUCTLESS GLANDS

give rise to acromegaly. Several authors report cases of
pituitary sarcoma without any signs of acromegaly. The
same applies to carcinoma and endothelioma.

Microscopical examination shows that the tumour in acro-
megaly has all the characters of the anterior lobe of the pituitary
body. The various kinds of cells found in the latter structure
are also regularly found in the tumour.

Thus, it would appear that an adenoma of the anterior
lobe of the pituitary is the essential lesion characteristic of
acromegaly.

(6) Pathogeny

Various theories have been sustained as to the origin and
essential cause of the symptoms of typical acromegaly. It
was suggested by Freund that acromegaly is simply an anomaly
of development. Some writers have imagined that the essen-
tial lesions in acromegaly are in the thyroid or in the thymus.
It has also been suggested that defects in the reproductive
organs may be responsible for the conditions (vide infra, p. 375).
The nervous system has from time to time been called in
question. But of late years most of the theories advanced
have assumed that the pituitary is in some way affected in all
undoubted cases of acromegaly.

Of the pituitary theories, the first was that of the original
describer of the disease — Marie. His view was that acro-
megaly is due to destruction of the pituitary, and therefore to
complete abolition of its function. Those who still uphold this
view look upon the gland as supplying a hormone which
regulates the growth of the skeleton, which growth, in the
absence of such regulation, proceeds abnormally. Bleibtreu
has published a record of a case of acromegaly, in which
he states that there was total destruction of the pituitary
gland.

The opposite view, that the symptoms of acromegaly are
due to a hypertrophic condition of the pituitary, more particu-
larly of its anterior lobe, is held by Tamburini and Woods-
Hutchinson. The most important argument in favour of this
view is the frequency with which a true adenoma has been
reported as occurring in typical cases of acromegaly. It may
be supposed that, according to this theory, the anterior lol

THE PITUITARY 375

of the pituitary body furnishes an abnormal, an excessive,
quantity of some hormone which stimulates bone growth,
and that, in consequence, the growth of bone itself becomes
excessive.

The cases referred to above in which after death the sub-
stance of the pituitary has been completely destroyed and
replaced by a malignant growth, would seem to present a
certain difficulty in the way of acceptance of the hypersecretion
theory. They would seem, in fact, to furnish important
evidence that the symptoms of acromegaly have been brought
about as the result of the suppression of an internal secre-
tion. But, of course, it is possible to assume that the
tumour at its beginning was non-malignant, and that the
malignant character has become developed shortly before
death, and that death has resulted from entire suppression of
the function of the gland, owing to destruction of the normal
glandular cells by those of a malignant nature ; for it appears
possible that complete destruction of the gland is incompatible
with continuance of life.

Since, after destructive disease of the reproductive organs,
the pituitary is found to be enlarged, it has been suggested
that the actual commencement of the mischief in acromegaly
may be in the ovary or the testis.

The pathogeny of acromegaly thus appears to be analogous
to that of exophthalmic goitre, the first being due to a hyper-
function of the pituitary, the second to a hyperfunction of the
thyroid gland.

Yamada has recently reported a case in which there were
clear symptoms of acromegaly with a normal pituitary, but the
thyroid was enlarged, the thymus was persistent, the testes
atrophic, the pineal contained masses of colloid, and there was
hypertrophy of adrenal medulla. The case was therefore
characterized as " poly glandular." We must bear in mind the
recent experiments of Camus and Roussy (see above, p. 365).

(7) Course and Event of the Disease — Diagnosis, Prognosis,
and Treatment

The disease runs a slow and prolonged course, and goes on
to a fatal issue.

The diagnosis is usually a matter of no great difficulty.

376 THE DUCTLESS GLANDS

From osteitis deformans and from arthritis deformans it may be
distinguished because the enlargement is general, instead of
affecting only the shaft, as in osteitis deformans, or the cuds,
as in arthritis deformans. In osteitis deformans, too. as
pointed out by Marie, the face is triangular, with the base
upward, while in acromegaly it is ovoid, with the large end
downward. In congenital progressive hypertrophy, or " giant
growth," only one limb becomes affected, and the shaft of the
bone is involved.

But the differential diagnosis from certain diseases of the
nervous system, and in particular from syringomyelia, is stated
to be sometimes very difficult, or even impossible.

In affections of the spinal cord enlargements of the extremi-
ties are liable to occur, and especially is this true in syringo-
myelia. Fischer gives several examples from Schlesinger and
others. It is stated that syringomyelia may give rise to the
typical clinical and anatomical features of acromegaly. If
this is true, then it will be absolutely impossible in certain
cases to make a correct diagnosis during life, and it must
have frequently happened that cases of syringomyelia have
been described as " acromegaly without tumour of the pitui-
tary." The suggestion has been tentatively put forward
that the hypersecretion of the pituitary may, after all, pro-
duce the condition of acromegaly by action upon the nervous
system.

The prognosis is bad, and all treatment hitherto attempted
seems to be without avail. Naturally, treatment with pituitary
preparations has been tried. This, of course, has been done
on the hypothesis that acromegaly is due to diminished action
on the part of the gland. The results are unsatisfactory, and
even definitely unfavourable results were sometimes obtained.
No reduction can be effected in the size of the extremities by
internal administration of the gland. Magnus-Levy records a
case of acromegaly treated with pituitary substance. Symp-
toms arose which recalled features of Graves's disease — marked
perspiration, polyuria, and alimentary glycosuria.

It seems, from all that has gone before, that the only rational
treatment for acromegaly is a partial extirpation of the pitui-
tary body. This was first definitely suggested by Victor
Horsley, and has been extensively carried out by Gushing and
others.

FIG. 100. — Hyperpituitarism with giant overgrowth. Note the narrow chest, large
joints, hypotrichosis ; also large size of hands compared with Dr. Crowe,
whose height is 5 ft. 8 in. (From Gushing).

377

378

THE DUCTLESS GLANDS

(8) Other Conditions involving Pituitary Hyper function

There are reasons for thinking that many forms of gigantism
are due to hyperfunction of the pituitary, and probably to
hyperf unction of the anterior lobe. In these cases there is
rarely, if ever, a definite adenoma of the gland. But it is

FIGS. 101 & 102.— Marked adiposity. 124 Ib. increase in 14 months. (From

dishing.)

possible that the structure might manufacture certain sub-
stances in excess of the normal, without overgrowth of the
gland as a whole, but simply by multiplication of certain cells.

3. Conditions involving Hyposecretion of the Pituitary
Frohlich was the first to point out that in cases of pituitary

THE PITUITARY

tumour without acromegaly there may be manifested a peculiar
syndroma, characterized by the accumulation of fat and dis-
turbance of the genital functions — degeneratio adiposo-genitalis.
Erdheim, however, is of the opinion that not only pituitary
tumours, but other growths in this region
of the base of the brain, may give rise to
a similar train of symptoms. Cf . Camus
and Roussy, p. 365. It is thought by
Fischer that the effects are due to damage
to, or destruction of, the posterior lobe of
the pituitary body. The experiments of
Gushing, however, would seem to teach
that it is deficiency of function of the
anterior lobe which leads to degeneratio
adiposo-genitalis.

Dystrophia adiposo-genitalis (Degene-
ratio adiposo-genitalis). — This condition,
sometimes known as Frohlich's syn-
drome, is very generally supposed to be
due to pituitary insufficiency. The
patient becomes obese and the fat has a
peculiar distribution. It is most abund-
ant on the abdomen, buttocks and the
proximal portions of the extremities.
(Figs. 101 and 102.) Dwarfism is a com-
mon condition, due to deficient skeletal
development. The genital organs remain
in the infantile state and the secondary
sexual characters do not develop. The
skin is in most cases thin, smooth, and soft.

Infantilism. — This term was first used
by Lasegne and the types generally
recognized are those of Lorain, Bris-
saud, and Variot and Pironneau. Lor-
ain's type is an infantilism in which the
proportions are like those in the adult
and there is a hypoplasia of heart and arteries. (Fig. 103.)
Brissaud's type was that due to thyroid deficiency and called the
myxcedematous type. Variot and Pironneau propose adding
another type—progeria. Gilford proposes the following
classification : —

FIG. 103. — Typical case
of Infantilism of
Lorain type with an
enlarged 2 cm. sella.
Patient aged 20 years
6 months. Height 4
ft. 4 in. j(after Cush-
ing.)

380

THE DUCTLESS GLANDS

1. Evolutionary or phylogenetic
infantilism

2. Developmental or ontogenetio
infantilism

A . InfantiK:;m of celVi

B. „ „ organs

C. „ „ the individual as

whole

>

Class I. Symptomatic General Infantilism
Infantilism as a fluctuation

A. Toxic

B. Correlative C. Deprivational
of mixed causation

(a) Endocrinous (6)
Simple
correlative

Class II

Essential Infantilism
Infantilism as a mutation

\

Progeria
Infantilism
" Senilism "
Premature old age
(Cushing thinks these two are possibly pituitary diseases.)

Ateleiosis
continuous youth "

Mr. Hastings Gilford believes that only one form of in-
fantilism has been absolutely proved to be due to a deficiency
of internal secretion, and this is thyroid infantilism. This is
frequently referred to as myxinfantilism (Brissaud's type).
This author sees no objection to the use of the term " pituitary
or Frohlich's infantilism," but thinks that we are not yet
justified in affirming finally that it is the result of a deficiency
of pituitary hormones.

Gushing includes the Lorain type as of pituitary origin.

THE PITUITARY 381

Gilford thinks that many forms of infantilism are due to
quite other causes than deficiency of internal secretion. Thus
ateleiosis (delay of development, sexual organs being most
delayed) is a mutation, and as such is liable to be associated
with other anomalies of development — such as those of the
thyroid or pituitary. These are, however, secondary, and not
the cause of the condition.

Ackondroplasia (chondrodystrophia foetalis). — Achondro-
plasic dwarfs resemble cretins, but shortness of the limbs is
more noticeable in the former. According to some authors,
the condition of achondroplasia is distinguished from chondro-
dystrophia, the former being due to hypof unction of the repro-
ductive organs arising in utero, the latter being the result of
hypofunction of the anterior lobe of the pituitary arising in
foetal life. The latter is sometimes a cause of brow presenta-
tion and dystocia. According to some writers, there is a
diminution in size of the sella turcica, and pituitary extract
should be tried. The patients are not benefited by thyroid
treatment.

The condition has to be diagnosed from cretinism and
rickets.

The disease is, in brief, a foetal disorder which causes a
defective growth of certain of the bones in utero and leads to
congenital dwarfing of the extremities and other deformities
which persist throughout life. It is said that there is an
abnormal arrangement of the cartilage cells along the line of
ossification.

The obscurity involving the condition is shown by the very
numerous names which have been employed to describe it.
In addition to the above-mentioned names, the disease is
referred to as Rachitis fcetalis, Pseudorachitism, Pseudorachitis
foetalis micromelica , Cretinoid dysplasia, Chondritis fcetalis,
Micromelia.

There is no certain proof that the typical cases of Achondro-
p^sia arise from any disorder of any of the glands of internal
secretion.

Carbohydrate Tolerance in Pituitary Disorder. — An increased
tolerance for carbohydrate has been recognized for some years
as a test for pituitary insufficiency. One of the recognized
methods of conducting this test is as follows : Twenty-five,
fifty, or a hundred grammes of glucose dissolved in 150 c.c. of

382

THE DUCTLESS GLANDS

water are administered to the patient on an empty stomach.
The blood-sugar is estimated after half an hour and then at
intervals of one hour. The blood-sugar increases in amount
up to a certain degree and then falls again. The curve obtained
must then be compared with an average normal curve.

2 3

Hours.

The chart illustrates the effect of 25 gms. of carbohydrate on a moderately
severe case of diabetes. The interrupted lines represent a normal blood-
sugar curve ; the upper continuous curve was obtained when the patient was
receiving a diet slightly in excess of his tolerance level for carbohydrate, the
blood-sugar before the test being high in consequence. The lower curve
was obtained after two days' starvation which had reduced his blood-sugar
to a low level. In both the initial level was not regained till after 5 hours.
(From Maclean.)

Diabetes insipidus. — The symptoms of this disease are too
well known to require a description. The point of immediate
interest to us is the connection between the polyuria and
a disturbed function of the pituitary body. A considerable
number of cases have been described in which a lesion of the
posterior lobe was found post mortem. Such lesions are.

THE PITUITARY 383

however, not invariably accompanied by diabetes insipidus.
The experimental and pathological evidence is not conclusive.

Treatment of patients by means of subcutaneous injection of
pituitary extracts seems to have given some very striking
results. According to Kennaway there is very frequently an
immediate restoration of a normal state of the urine when pitui-
tary extract is given in diabetes insipidus. This writer also
urges that the fact provides strong evidence for the normal
activity of the gland in regulating the secretion of urine.

In pituitary disease conditions of primary over-activity
become blended later on with symptoms characteristic of
known stages of functional insufficiency. So that in certain
conditions it may be difficult to tell which predominate (Gush-
ing). It will be remembered that Tamburini in 1894 described
a " two-stage " process in acromegaly ; a glandular hyper-
trophy with hyperactivity characterizing the first stage, while
in the second or terminal there occur degenerative changes
with diminished activity and resultant cachexia.

O. The Use of Pituitary Extracts in Medicine, Surgery,
and Gynaecology

Reference has already been made to the use of pituitary
extracts in acromegaly. We have seen that they have not
been found to be beneficial in this disease. Nor should we
expect them to be of service if acromegaly be, in fact, due to a
hyper secretion of the gland.

But there are many other conditions in which pituitary
preparations have been recommended and employed.

In conditions of shock, pituitary preparations are believed
to be of more value than adrenin. This is due partly to the
fact that pituitary preparations (" pituitrin," " infundibulin,"
etc.) keep the blood-pressure raised for some considerable time,
while the effect of adrenin is very fleeting. Saline infusions
should, however, be used ; reliance should not be placed on
the pituitary extract alone.

Owing to its powerful action on the uterus (see p. 351),
pituitary substance is now employed in many obstetric con-
ditions. The action on the uterus was first noticed by Dale,
and has since been studied by several observers. Foges and
Hofstatter have obtained results similar to those of Dale and.

384 THE DUCTLESS GLANDS

Bell, and recommend pituitrin in post-partum haemorrhage.
Other observers now recommend the use of the drug in labour.

Bell strongly recommends " infundibulin '" in cases of
sluggish intestinal peristalsis and paralytic distension of the
intestines.

It is probable, also, that the diuretic effect of pituitary
extracts may be of clinical value. The value of subcutaneous
injections of pituitary extracts in diabetes insipidus has
already been noted.

CHAPTER XVI

THE FUNCTION OF THE PINEAL BODY

MUCH attention has been devoted to the pineal body from the
standpoint of comparative anatomy. Its relationship to the
pineal eye of lower vertebrates seems to have led to the con-
clusion, which may, after all, turn out to be premature, that
the pineal body of mammals is a purely vestigial organ, and no
longer of any functional importance. Notwithstanding the
numerous investigations which have been carried out upon
the comparative anatomy and development of the organ,
there appear to be few careful and detailed descriptions of the
microscopical structure in Mammalia. Moreover, the number
of -essays in the direction of a physiological study of the struc-
ture are not very numerous. The general appearance of the
body on microscopical examination certainly suggests the
possibility of a secretory function, and, as we shall see, there is
some evidence that the pineal body controls in some way or
other (possibly by means of an internal secretion) the early
growth of the individual.

Anatomy and Development of the Pineal Body

The pineal body, or pineal gland (conarium),1 is a small
pinkish structure situated underneath the posterior region of
the corpus callosum, and resting upon the anterior -elevation
of the corpora quadrigemina.

A section through the diencephalon of an early human
embryo shows the " roof -plate " and the "floor-plate." At
the posterior end of the former is an elevation, which forms a
hollow evagination of the brain-roof — the pineal process. The
distal extremity of this pineal process becomes enlarged to a

1 The epiphysis of the mammal was known to the ancient Greek anatomists,
Galenus described it as the " Sw/ta /ca^oeftSes, KuvdpLov." Descartes, in 1649,
as is well known, considered it to be the seat of the soul.

385 25

386 THE DUCTLESS GLANDS

sac-like structure, which subsequently becomes lobed and
solid. This is the pineal body. The proximal part of the
evagination remains hollow, and forms the pineal stalk, and the
whole structure, body and stalk, is usually called the epipliysis
(McMurrich).

In the Reptilia and other lower groups of animals the out-
growth from the roof of the diencephalon is double, a secondary
outgrowth arising from the base or from the anterior wall of
the primary one. This secondary outgrowth — the anterior
evagination — becomes elongated until it reaches the epidermis
of the head, and here it develops into the pineal eye. In
mammals this anterior process is not developed.

In addition to the epiphysial evagination another evagination
arises from the roof -plate of the first cerebral vesicle. This is
placed farther forward in the region which subsequently
becomes the median portion of the telencephalon. This
structure is called the par&phyeig, and is found in the lower
vertebrates and in the marsupials (Selenka), but up to the
present time has not been found in other groups of the Mam-
malia. It is supposed to be comparable to a choroid plexus
which is evaginated from the brain surface instead of being
invaginated, as is usually the case. There is no evidence
that a paraphysis is developed in the human brain (McMurrich).

Histological Structure of the Pineal Body

The pineal body is covered on its upper surface by the pia
mater, which provides the connective-tissue skeleton of the
organ, and carries the bloodvessels into the interior. This
sheath of connective tissue sends in septa, which break up
into a fine network in the parenchyma of the gland, and divide
up the whole structure into "acini," or "follicles." (Figs. 104
and 105.)

Some writers state that there are no true septa, but irregular
trabeculse. It seems that in regard to the distribution of the
connective-tissue frame-work of the pineal body there is
considerable difference between different species and between
different animals of the same species, but of different ages. In
the connective-tissue cells a yellowish or brownish pigment is
frequently found.

A number of cross -striated muscle fibres may be found in

PINEAL BODY 387

connection with the connective-tissue elements. The con-
nective-tissue septa and bands carry in numerous bloodvessels
and nerves, of which some are doubly contoured.

The cylindrical epithelium of the ependyma not only covers
the part of the pineal body which is nearest to the brain
ventricle, but lines certain hollow spaces found within the body
of the gland itself. The majority of these hollow cavities
become obliterated by the proliferation of their lining cells.

There appear to be no true nerve cells in the adult mammalian
body. It is stated that there are nerve fibres derived from the
brain substance as well as sympa-
thetic fibres, which enter, along with
the bloodvessels, in the interior of the
pineal body.

The parenchyma of the gland is
made up of follicles, which, however, Ji •;.'
are only sharply marked out at the ^
periphery of the organ (Fig. 104). The
cells of these follicles have sometimes
been described as resembling those of
adenoid tissue.

An exact description of the con-
stituent cells of the follicles cannot be v ' '
compiled from the accounts of the
various writers upon the subject. It

seems clear, however, that the cells FIQ w^eci^n ^ the
are of two chief kinds — neuroglia and pineal gland of the sheep,
secretory cells. The latter are slightly ^J™ byMrs- ThomP-
stainable with a large oval granular

nucleus. The cell body contains granules, either distributed
throughout its substance, or arranged round the periphery.
Galeotti described secretory processes in these cells.

The "brain-sand" ("acervulus cerebri") which occurs in
certain follicles, has been known from the earliest times. It
has not been shown to be of any physiological importance.
It is found also in the choroid plexus and in the pia mater of
the lobus olfactorius.

Cysts are also found in the pineal body.

Cutore has recently described a structure in the pineal body
of the ox which is of doubtful significance. It is a rounded
body of variable size in the roof of the diencephalon. It may

388 THE DUCTLESS GLANDS

exist side by side with the diaphysis described by Favaro, and
it is connected with a very distinct bundle of nerve fibres.

This structure, which the author
calls " corpus praepineale," ap-
pears to reach its maximum
development in the later foetal
stages and the earlier period of
extra-uterine life. After this it
becomes reduced, and seems to
be absent in the adult.

Costantini calls special atten-
tion to the granular nature of

FIG. 105. — A small portion of -in j i j „

the pineal gland of the cat, as the pineal cells, and concludes
seen under a high power of that the pineal body is an in-
MlThrpTn.) <DraWn ^ ternally secreting gland. Similar

conclusions have been reached

by Galasescu and Urechia, who called special attention to the

oxyphile cells of the gland.

Physiological Experiments upon the Pineal Body

1 . Injection of Extracts of the Pineal Body

The first experiments in this direction were made by Howell
in 1898. This author reports that glycerine extracts of the
body produce sometimes a slight, sometimes a marked fall of
blood-pressure. This observation has, of course, little or no
bearing on the function of the organ. (See discussion in
Chapter III.)

Cyon in 1903 made extracts from the pineal bodies of the ox
and sheep, and tested their effects upon the heart and blood-
vessels on intravenous injection. There was no effect upon the
blood-pressure, probably because the dose was not large
enough. The number of heart-beats was, however, increased,
while the excursion was diminished. This is an effect similar
to that obtained by stimulation of the true accelerator nerves.
Such are the effects of small doses. With larger doses the
heart-beats become stronger and less frequent, and also
irregular. The pulsus bigeminus and the pulsus trigeminus
are frequently observed ; there is a disturbance of the harmoni-
ous co-operation of the inhibitory and the accelerator cardiac
nerves. With still larger doses there may be a fall of blood-

PINEAL BODY 389

pressure. Cyon concludes that these effects are due to the
calcium phosphate and other salts from the concretions of the
gland.

Dixon and Halliburton find, as might have been expected,
that extracts of the pineal body, when intravenously injected,
give a fall of blood-pressure (see Chapter III.). Extracts
of the choroid plexus also bring about a lowering of the blood
pressure. They find also that while extracts made from the
choroid plexus of the ox, sheep, and man, injected into the
sub-cerebellar cisterna, or the lumbar region, cause a flow of
cerebro -spinal fluid, extracts of pineal body have no such
effect.

Ott and Scott report, in addition to some changes in the
blood-pressure, that pineal intravenous injection has a galacta-
gogue action similar to, though less than, that of pituitary
extract (see p. 353).

Jordan and Eyster in 1911 found on pineal injection a
vasodilation in the intestines, a more forcible beat of the
isolated cat's heart, diuresis and glycosuria. There was also
increased depth of breathing for some time after the injection.
The effects are comparatively slight.

Schafer andMacKenzie (see Chapter XV.) could not confirm
the observation of Ott and Scott as to the galactagogue action
of pineal extracts. But MacKenzie in 1911 obtained a slight
effect which he thought might be due to contamination with
pituitary material by absorption from the cerebro -spinal fluid.

2. Direct Stimulation of the Pineal Body
Cyon appears to be the only observer who has used this
method. He employed electrical stimulation applied to the
pineal body of the rabbit and states that he could observe
slight changes in the form and position of the gland. There
was no alteration in colour, so that the effects could not be due
to vasoconstriction. They were due, he thinks, to con-
traction of muscle, though, it must be observed, the existence
of muscle fibres in the body is exceedingly doubtful. According
to Cyon, these experiments point to a mechanical function on
the part of the pineal body : it is suggested that it controls
the inflow and outflow of cerebro -spinal fluid of the third
ventricle. The part played by the pineal body in this regard
is likened to that of the thyroid and the pituitary, and aU three

390 THE DUCTLESS GLANDS

are supposed to be concerned in regulating the intracranial
pressure.

3. Attempts to destroy the Pineal Body by means of the Cautery

Sarteschi in 1910 had obtained negative results in a series
of experiments upon rabbits.

Exner and Boese destroyed, by means of the thermo-cautery,
the pineal body in ninety-five rabbits. Seventy-five per cent,
of the animals died within the first twelve hours from bleeding
into the ventricle. Twenty-two animals were kept under obser-
vation for some time. In six the authors thought the operation
was complete, and the animals lived to sexual maturity.
There was no sexual precocity. The authors concluded that
in rabbits extirpation of the pineal body produces no noticeable
effects. But, as we shall presently see, it is, in all probability,
impossible to destroy completely the pineal body of the rabbit
by this method.

4. Extirpation of the Pineal Body

Sarteschi attempted extirpation by ordinary surgical means
in some of his rabbits ; but, although he thought that this was
complete in one case, and that in this there was some retarda-
tion of development, yet the conclusion is not satisfactory.

Exner and Boese also made an attempt to remove completely
the pineal body from rabbits by surgical means other than the
cautery. They could not be certain that the operation pro-
duced any specific results.

Foa came to the conclusion that the rabbit is not a suitable
animal for pineal extirpation. He turned his attention,
therefore, to the chicken, and arrived at the following con-
clusions :—

1. Complete extirpation in the earlier months of life gives
rise to a retardation of development during the first two or
three months after the operation ; afterwards development of
the body becomes normal.

2. In cockerels there is an earlier development of both
primary and secondary sexual characters in the operated than
in the control animals.

3. In cocks examined eight to eleven months after th<
operation there is marked hypertrophy of the comb and of th(
testcs.

PINEAL BODY 391

4. There are no corresponding changes in pullets.

These interesting results with cockerels received an important
confirmation by Sarteschi, who had previously failed to extirp-
ate the pineal body. Following the technique employed by Foa
for chickens and first recommended by Lo Monaco (that is to
say, by ligaturing the longitudinal sinus), Sarteschi succeeded
in extirpating the pineal body in very young rabbits and dogs.
In the males which survived the operation there was a notable
hypertrophy of the testes, bodily overgrowth and sexual
precocity — results quite comparable with those obtained by
Foa in cockerels.

More recently Foa reports that pineal extirpation has no
effect on female chickens or female rats. But upon male rats
there is an effect comparable with that produced in cockerels,
viz., a rapid increase in body weight and in size of the testes.
He notes also an advanced development both of the sper-
matozoa and of the interstitial tissue of the testis, both in rats
and cockerels. The premature increase of interstitial tissue, it
is suggested, corresponds to the precocity of the secondary
sexual characters — growth of comb in the cock and increase
of body weight in the rat.

These observations are of the greatest interest and impor-
tance, and point very strongly to the view that the pineal gland
exercises an inhibitory function upon sexual development before
puberty. At this period an involution of the gland occurs.

5. Effects of Castration upon the Pineal Body

Although Sarteschi in 1910 had failed to find changes in the
pineal body of animals castrated in early life, yet Biach and
Hulles report that castration causes atrophy of the pineal.
Castration is stated to have the contrary effect upon the
pituitary body.

6. Feeding Experiments

Pineal feeding was suggested by Kidd in 1913, and the first
actual experiments in this direction so far as I am aware, were
carried out by Dana and Berkeley in the same year. These
authors state that feeding guinea-pigs and young rabbits with
pineal gland causes an increase in body weight, but the opposite
effect is obtained in children.

392 THE DUCTLESS GLANDS

McCord has studied the effects of pineal feeding upon
chicks, dogs, and especially upon guinea-pigs. He finds that
the effects usually attributed to pineal deficiency (hypo-
pinealism) are obtained by supplying an increased amount of
pineal substance by feeding or injecting pineal preparations.
Such administration of pineal substances leads to a more rapid
growth of body than normal, and determines an early sexual
maturity. The excess in rate of growth was most pronounced
in young animals fed with pineal tissue obtained from young
animals. After maximum size was attained, pineal admin-
istration appeared to be ineffective. Both males and females
respond, in rate of growth, to the influence of pineal substances,
but the response has been more definitely manifested in males.

These observations, so far as the effects upon male guinea-
pigs are concerned, have recently been confirmed by Horrax,
and McCord and Allen find that pineal substance causes con-
traction of the melanophores in tadpoles.

Pathological Anatomy and Clinical Pathology

Cysts of the pineal have been known for a long time. Some
of these are without characteristic effects ; others give rise to
serious symptoms.

Teratoma,ta are very common. They were first fully described
by Weigert, and have since received a considerable amount of
attention.

Various other tumours of the pineal body have been described,
such as glioma, sarcoma, carcinoma, and mixed growths.

There is now a general agreement among clinical pathologists
that diseases of the pineal body are accompanied by a char-
acteristic train of symptoms. It is curious that there is some
degree of resemblance between these symptoms and those due
to lesions of the pituitary body.

Our information upon the clinical symptoms in pineal
disease is largely derived from the work of Marburg.

Hempel records a case of carcinoma of the pineal gland in
which there was at the commencement obesity, but later very
marked atrophy of the fatty tissues. In complete destruction
of the body, which occurred in six cases of malignant tumour,
there was a severe disturbance of the trophic functions (Biedl).

Marburg found a very striking obesity in a nine-year-old

PINEAL BODY 393

girl who had the symptoms of a brain tumour. At the post-
mortem examination a compound tumour of the pineal body
was found. It is not certain whether the obesity is due to a
hyper- or to a hypo-function of the gland. Marburg is inclined
to the former view, but the preponderance of evidence is,
perhaps, in favour of the latter (Biedl).

But there are other interesting conditions besides obesity
found in patients with pineal tumours. These are found in
young subjects. It has been found that in boys under
seven years of age symptoms of brain tumour and disease
of the corpora quadrigemina are associated with abnormal
tallness, unwonted growth of hair, premature sexual and
genital development, and early maturity. In these cases
there is frequently found on post-mortem examination a
teratoma of the pineal body. The symptoms just enumerated
are generally supposed to be due to a hypof unction of the pineal
gland. Frankl-Hochwart urges the importance of the symp-
toms mentioned as diagnostic of pineal tumours.

Pellizi has described the pineal syndroma as " macro-
genitosomia prsecox." There is a premature development of
the genitals, which, particularly in regard to the volume of
the penis, gives the appearance of an adult. The degree of
development of the body and of the skeleton corresponds to
that of an age five, ten, or twelve years more advanced. There
is a premature ossification of the bones. The intelligence
almost always corresponds to the age. In these cases one
observes very frequently that there are symptoms of cerebral
tumour and destruction of the corpora quadrigemina. The
condition always becomes developed before the eighth year,
and very frequently before the third, and is commoner in boys
than in girls. The hereditary factor has no special influence
on the causation. The pathogenesis seems to depend in most
cases on a destructive lesion or growth of the pineal body.

In considering the results of clinical observation, it must be
remembered that less than a hundred cases of tumours of the
pineal gland have been recorded. In these cases two groups
of symptoms have been described— the nervous and the
metabolic. In adults only the nervous symptoms occur. In
children, however, we get the metabolic disturbances, pre-
sumably due to an alteration in the secretory activity of the
gland, and these are most marked in young males. They

394 THE DUCTLE8S GLANDS

consist, as we have seen, in precocious sexual and mental
development. This precocity has usually been attributed to
a hypopinealism, and this view was supported by the extirpa-
tion experiments. But, as we have seen, a similar precocity
of development accrues from feeding with pineal substance.
This fact introduces a complication which renders it impossible
to reconcile the results of clinical observation and experiment a!
work upon animals.

CHAPTER XVII

THE INTERRELATIONS OF THE ORGANS OF INTERNAL
SECRETION

ALTHOUGH the allusions to a relationship between the organs
furnishing internal secretions are so numerous, and although
assumptions in regard to such relationships are very common
in medical and surgical literature, yet it may be affirmed that
the theories and suggestions which have been put forward are
out of all proportion to the established facts and any certain
knowledge of the subject.

In this chapter an attempt will be made to examine critically
some of the current views in connection with this part of our
subject, and, if possible, to separate out a portion at any rate
of the grain from the heap of chaff.

The view is now so prevalent as to be almost universal
among clinical workers that derangement of any one of the
ductless glands leads to more or less evident disturbance in
other members of the series. The phrase " polyglandular
syndrome " has become a commonplace of medical literature.
And investigators in the fields of experimental physiology and
pathology have been so impressed by cases where the internal
secretion of one organ appears to stimulate another to activity,
that they have for the most part joined with the clinicians in
regarding the organs of internal secretion as forming a system
whose several functions are very intimately related to each other.

The arguments in favour of such a relationship between the
ductless glands and other organs which yield internal secretions
are derived from very many different sources, experimental
and clinical. Although many of these relationships are re-
ferred to frequently in the literature, yet it is only within recent
years that an attempt has been made to collect the evidence
and state it in compact form. In the compilation of this

395

396 THE DUCTLESS GLANDS

chapter I am indebted to an account of the subject written by
Hoskins in 1911.

It is not always easy to determine from the phraseology
employed precisely what kind of a system is alleged to be
constituted by the association together of the various internally
secreting glands. A recent writer says that the animal body
is controlled by an " interlocking directorate " made up of the
glands of internal secretion, while in modern expositions of the
relations of the endocrinous organs we frequently find that the
" system " is made to include not only the adrenal bodies, the
thyroid glands, and the pituitary, along with the thymus,
parathyroid, and pineal, but also the reproductive organs, the
pancreas, liver, spleen, duodenum, small intestines generally,
the stomach, the uterus, and the mammary gland. When we
remember that certain authors refer to a "kinetic system"
(which includes the brain, the thyroid, the adrenals, the liver,
the pancreas, and the muscles), and that the whole of the
sympathetic nervous system is supposed to be under the con-
trol of the chromaphil tissues, and that the carbohydrate
metabolism of the body is alleged to be under the conjoint
control of the central nervous system, the liver, the pancreas,
the intestine, the chromaphil tissues, the thyroids and para-
thyroids, and the pituitary, it will be conceded that any
attempt to express all the asserted possible relationships
in diagrammatic form must result in failure.

A summary of the connections postulated in the last para-
graph would amount to nothing less than a statement that the
various organs and tissues of the body are functionally related
to each other, and when the view is put forward that the
secretion of one of the ductless glands produces an effect upon
the nervous system as a whole or upon an important section
of it, this amounts to the allegation that the gland in question
exerts its influence upon practically the whole body. It may
be possible in the future, when our knowledge of the ductless
glands and indeed of physiology generally shall be consider-
ably greater than at present and if current views as to the
supreme directing influence of the internal secretions be
confirmed and substantiated, to formulate some satisfactory
theory according to which the organs of internal secretion
dominate the whole of the bodily activities, normal and
pathological.

INTERRELATIONS 397

In the present chapter no attempt will be made to cover the
field just indicated ; it will be necessary to confine our atten-
tion to the known or reasonably suspected instances of influ-
ences exerted by one internally secreting gland upon others
of the series, these influences being not always necessarily
direct — as, for example, when the nervous system is called
into play.

If there has been in many instances undue haste in formu-
lating theories of the functions of individual glands, much more
has this been the case in regard to theories of interrelationships .
It is not certain that the clinicians have been greater offenders
than the laboratory workers, though it must be confessed that
many of the descriptions of syndromata which have been
supposed to accrue from correlated disturbances of the endo-
crinous organs are based upon an inadequate conception of the
actual physiological facts and therefore form a very unsatis-
factory indication for treatment.

A priori and regarding the question chiefly from the morpho-
logical standpoint, it is doubtful if one would expect the
various ductless glands to be related to each other. From a
broadly comparative standpoint, it is very difficult to arrange
these glands in a coherent series. There are reasons, fully
explained elsewhere (p. 227 et seq), for regarding the thyroid,
parathyroids and thymus (along with certain less important
branchial cleft organs), as morphologically related. Some
authors regard the thymus as closely related to the thyroids
and parathyroids from a physiological as well as a morpho-
logical standpoint. The glandular portions of the pituitary
body may possibly be included in this morphological group,
but it must be pointed out that the origin of these different
organs is not quite identical. The only common feature is
that they arise from some part of the primitive alimentary
canal or its vascular outgrowths, the gill clefts. The pituitary
body arises from the ectoderm, while the branchial cleft organs
are of entodermal origin.

The cortex of the adrenal body is a representative of a kind
of tissue which is widely distributed in the region of the repro-
ductive organs (see p. 116), and possibly it might be expected
that the corpus luteum and the interstitial cells (as well as the
rest of the elements) of the ovary and the testis might rank in
the same group.

398 THE DUCTLESS GLANDS

According to modern views, the chromaphil tissues form a
series which may be regarded as sympathetic glandular organs
and which are widely distributed along the course of the
vegetative fibres.

The majority of writers still deal with the adrenal bodies as
if they represented functional entities. But as far as is defi-
nitely known, the chromaphil tissues physiologically have
nothing whatever to do with the adrenal system (or adrenal
cortex and " accessory cortical bodies ").

The pancreas, along with its islets of Langerhans, is an out-
growth from the alimentary canal, and so might be regarded
as belonging to the same system as the branchial cleft organs.

We have not sufficient information to guide us to a decision
as to whether we ought to regard morphological and embryo -
logical connections as an indication of a probable physio-
logical relation.

Elliott quotes Gaskell as classifying together, on morpho-
logical grounds, the pituitary body, the thyroid and the adrenal
cortex, being all modified from the coxal glands, that is, the
segmental excretory apparatus of some primitive arthropod
type. But Gaskell's theory, so far as the ductless glands are
concerned, is open to grave criticism, and the theory as a whole
is, I believe, not generally accepted by morphologists.

It must be remembered that a normal gland may either
excite or moderate the activity of another. If an exciting
organ be suppressed, there will be insufficiency of the second,
and so we get a diminution of two functions. If a moderating
organ be reduced in activity, the disturbance occurring in the
second gland will be overaction. And further, one gland may
exercise an exciting influence upon a second and a suppressing
action on a third. In these actions both the sympathetic and
the autonomic systems may take part.

The evidences in regard to endocrinous interrelationships are
derived from pathological anatomy, from clinical observation,
and from experimental investigations.

A. Interrelationships involving the Thyroid Gland

Action of the Thyroid upon the Adrenal Bodies

Sub-thyroidism has not been shown to have any effect upon
the adrenal bodies, although attempts have been made to show

INTERRELATIONS 399

that thyroidectomy depresses the function of the chromaphil
tissues.

The Viennese school has elaborated a very complicated
theory. The thyroid and parathyroids are antagonistic to
each other. While the former stimulates the sympathetic,
the latter inhibits this system. The parathyroid is the ally of
the pancreas in checking or inhibiting metabolism, while the
adrenals and the thyroid increase it. So that when the thyroid
is put hors de combat four things happen : (1) Loss of thyroid
secretion, inducing slowed or diminished metabolism ; (2)
Absence of stimulation of the adrenals (that is to say, the
chromaphil tissues) ; (3) Relaxation of the inhibition of the
pancreas ; (4) Diminished excitability of the nerves to the
thyroid, that is, branches of the vagus.1

In regard to superthyroidism, there is some evidence that
the amount of adrenin in the blood is increased in this con-
dition. This evidence, though not very positive or great in
amount, supports the theory that the secretion of the thyroid
acts as a direct stimulant to the chromaphil tissues, causing
them to yield adrenin to the blood in larger quantities.

There are grounds for extreme scepticism regarding all this
work.

Cramer has put forward the view that the thyroid and the
adrenal are part of an apparatus which controls the tempera-
ture of the body. He regards the adrenal as a gland in itself
and not as consisting of two independent constituents. One
of its functions is to act with the thyroid as a humoral
mechanism regulating body temperature, and supplementing
the action of the nervous system. The thyroid hormone
mobilizes liver glycogen by increasing the production of
adrenin and sensitizing the sympathetic nerve-endings. At
the same time adrenin constricts the arterioles of the skin,
thereby diminishing the loss of heat from the body. Cramer
has adduced a number of experimental and pathological
observations in support of this theory.

Relations between the Thyroid and Pituitary Bodies
Clinical evidence as to pituitary hypertrophy as a result of
thyroid deficiency is unsatisfactory, but the experimental

1It'is more usually admitted that the specific nerves to the thyroid are
derived from the sympathetic (see p. 308).

400 THE DUCTLESS GLANDS

evidence is convincing. As we have already seen (p. 366), a
very striking effect is caused by removal of the thyroid upon
the pituitary body, which not only undergoes general enlarge-
ment, but exhibits well-marked indications of increased
secretion.

There is, however, no increase in the amount of iodine in the
hypertrophied pituitar'es in these cases, so that a true vicari-
ous functioning seems out of the question.

How far the parathyroids may be concerned in this question
we do not know. According to Halpenny and Thompson,
some of the alterations which have been described in the
pituitary occur when the parathyroids only are extirpated.
But other observers have failed to find any changes in the
pituitary after parathyroidectomy.

When the pituitary hypertrophies as a result of sub-
thyroidism, there are no symptoms of superpituitarism. So
that the pituitary as a whole does not become more active.

Relations between the Thyroid and the Reproductive Organs

Many of the changes found in various organs of the body as
a result of thyroidectomy are not to be attributed directly to
a loss of the thyroid secretion, but to the effects of intoxication
and troubles of metabolism which supervene in these cases.

In the female the thyroid is known to become enlarged at
puberty, at the menstrual periods, and during pregnancy. In
animals from whom the thyroids have been removed at an
early age, the reproductive organs are late in developing or
develop in an imperfect manner, so that we have a condition
of sexual infantilism. Some changes in the reproductive organs
have also been recorded in cases where thyroidectomy was
carried out in the adult.

In exophthalmic goitre the sex functions are often affected
(menstrual disturbances) ; and there is sometimes atrophy of
the genital organs. In myxcedema there may be complete
impotence. The theory that the thyroids have a stimulating
effect on the reproductive organs has therefore some evidence
to support it.

Some authors claim to be able to diagnose thyroid deficiency
in cases of incomplete sexual development and to remedy the
defect by thyroid medication.

INTERRELATIONS 401

Action of the Thyroid on the Thymus

For the anatomical and embryological relationship between
thyroid and thymus see p. 277 et seq. The thyroid secretion
affects the growth of the thymus gland, which has been found
to undergo an increase in size in fcetal animals after thyroid
feeding of the pregnant mother (guinea-pigs). In exoph-
thalmic goitre the thymus is often hypertrophied and has been
supposed to take a part in producing the symptoms of the
disease. But not only in Graves's disease does thymus hyper-
trophy occur ; it may also be associated with simple congenital
goitre. It is not clear whether thyroidectomy causes thymus
atrophy.

Action of the Thyroid on the Pancreas

It is well known that the thyroid has some influence on
carbohydrate metabolism, and this is often explained as indi-
cating a relation between the thyroid and the pancreas. But
Krause and Cramer find that when small amounts of fresh
thyroid gland are administered for two or three days to rats
or cats fed on a carbohydrate-rich diet, the liver will be found
to contain only traces of glycogen. This effect is due to an
inhibition of the glycogenic function of the liver, not to an
increased utilization of carbohydrates. It is not accompanied
by glycosuria, and (in dogs) the tolerance for glucose is only
slightly diminished by thyroid feeding.

If the parathyroids are removed also, the assimilation limit
for sugar is distinctly lowered and the injection of adrenin then
produces more pronounced glycosuria than in the normal
animal. This is usually quoted as one of the instances of an
antagonistic action between thyroids and parathyroids. The
experiments involving removal of thyroids without the para-
thyroids are notoriously difficult, and much further evidence
is required on the subject.

Some observers have reported an increase in the islets of
Langerhans after thyroidectomy.

Notwithstanding the meagre character of the evidence, the
majority of modern writers seem fully to accept the view that
the thyroid has a direct inhibitory influence upon the pancreas,
and affects carbohydrate metabolism through the internal
secretion of this organ.

26

402 THE DUCTLESS GLANDS

Summarizing the effects of the thyroid upon the other
endocrinous organs, we may state that there is some evidence
that it stimulates the chromaphil tissue to increased activity.
There is clear evidence that subthyroidism causes hypertrophy
of the pituitary and this is supposed to indicate some kind of
vicarious function. It seems clear that while the thyroid has
a marked influence upon general metabolism in the young
animal, it has a very special influence upon the development
and growth of the reproductive organs. The direct effects of
thyroid upon thymus are doubtful. The alleged action of
thyroid upon the pancreas can only be proved or disproved
when our knowledge of carbohydrate metabolism has con-
siderably increased. At present there seems no reason to
believe that the effects of thyroid upon such metabolism are
wholly or in part due to a direct effect upon the internal
secretion of the pancreas.

B. Interrelationships involving the Pituitary Body

Action of the Pituitary Body upon the Thyroid

Some recent writers express their belief that a decided anti-
thyroid influence is exerted by the substance ("tethelin"
Robertson) secreted by the anterior lobe of the pituitary.

Superpituitarism (by feeding or injection with pituitary
substance) is said to cause thyroid hypertrophy, but this is
doubtful.

Apituitarism or subpituitarism is alleged by Gushing to cause
hypertrophy of the thyroid. Exner has confirmed this so far
as surgical experience in the human subject is concerned. We
have seen that extirpation of the thyroid causes hypertrophy
of the pituitary. A possible vicarious activity of the two
glands has already been discussed.

Action of the Pituitary Body upon the Reproductive Organs

It seems clear that certain cases of infantilism are associated
with lesions of the pituitary body. Although there has been
some discussion as to whether these defects are due to super-
or sub-pituitarism it seems from a consideration of the most
recent investigations that they are the result of the latter
condition. The usually accepted view is that the pituitary

INTERRELATIONS 403

normally supplies a secretion which stimulates the sex glands
to activity.

As bearing upon the relationship between the pituitary and
the sexual functions, the work of Erdheim and Stumme is of
great interest. These authors describe three types of cell in
the glandular part of the pituitary :

1. Eosinophile granular cells (chromophile 1 ; acidophile).

2. Basophile granular cells (chromophile 2 ; basophile).

3. " Hauptzellen " (chief cells ; chromophobe cells) (see

p. 339).

The chief cells have very badly defined and poorly staining
protoplasm. In pregnancy the pituitary may become hyper-
trophied to two or three times its normal size. The increase
consists entirely in the glandular portion. There are no longer
to be seen either chromophile or chromophobe cells, but there
are peculiar large, finely granular cells (the " pregnancy cells ").
These are derived from the chief cells, which grow from the
centre of the alveolus, and occupy a large part of the secretory
structure. These slowly retreat again during the period of
involution.

The pituitary during pregnancy resembles an epithelial
tumour. The increase in the amount of secretion is seen by
the fact that one can squeeze a milky juice out of the gland.
The hypertrophy persists to a certain degree, even after preg-
nancy, so that the weight of the gland in a multipara may be
three times as great as that of a normal gland.

Erdheim and Stumme thought that the hypersecretion of the
pituitary in pregnancy is manifested by an enlargement of the
hands and lips which is sometimes observed. Occasionally,
also, there may be more striking symptoms, due to the effects
of the pituitary tumour. Among these may be mentioned
hemianopia.

Mayer is of opinion that the pituitary changes are due to
functional changes in the ovary — in other words, that the
pituitary may function vicariously for the ovary. A relation
between pituitary and ovary is shown by the fact, already
mentioned, that in castrated women and animals there is
frequently enlargement of the pituitary. Further, after
destructive diseases of the reproductive glands the pituitary
reacts by hypertrophying. Mayer is even inclined to believe

404 THE DUCTLESS GLANDS

that the actual commencement of the mischief in acromegaly
may be situated in the reproductive organs.

Action of the Pituitary Body upon the Adrenal Bodies

Certain French observers have described hyperplasia of the
adrenal cortex after feeding with pituitary substance. Gottlieb
has shown that extracts of the posterior lobe of the pituitary
and of the chromaphil tissues mutually assist the action of one
another upon the bloodvessels. Thus an injection of a email
dose of adrenin will increase the subsequent effect of a dose of
pituitrin, and vice versa. It is also stated that an excess of
adrenin is poured out into the blood-stream as the result of an
injection of extract of the posterior lobe of the pituitary. The
evidence for a direct action of pituitary upon either the chroma-
phil tissue or the adrenal crotex is not, however, very con-
vincing.

Action of the Pituitary Body upon the Pancreas

How far the facts before us point to a direct action of the
pituitary upon the pancreas is doubtful. We know that sub-
pituitarism leads to an increased sugar tolerance. According
to Gushing, this depends upon the function of the posterior
lobe. Animals from whom this lobe has been removed will
not develop glycosuria when the pancreas is extirpated. But
the production of glycosuria by removal of the pancreas is due
to an action on the liver.

Glycosuria occurs in acromegaly, and this has been sup-
posed to be due to changes in the pancreas. The evidence on
this point is unsatisfactory.

Many authors believe that there is some kind of functional
correlation between pituitary, chromaphil tissue, pancreas,
liver, and thyroid, so that any interference with the function
of any one of them may affect the carbohydrate metabolism
through its influence upon the others.

To sum up the influence of the pituitary upon the other
ductless glands it may be definitely affirmed that the organ
has some influence upon the growth of the reproductive organs,
but the evidence for a direct effect upon the thyroid, adrenals
and pancreas is much less convincing.

INTERRELATIONS 40 5

C. Interrelationships involving the Adrenal Bodies
(Ghromaphil Tissues and Adrenal Cortex)

Action of the Adrenal Bodies upon the Gonads

An important connection between the adrenals and the
reproductive organs has long been recognized. The main facts
are given in another chapter (see Chap. XI). In this place
we need only remind the reader of the frequent association
between sex anomalies and tumours of the adrenal cortex. It
is stated also that vigour of reproduction is reduced by partial
adrenal extirpation. The theory is that the cortex -of the
adrenal body stimulates the growth of the reproductive organs,
especially in the male.

So far as I am aware, there are no observations which point
to any direct connection between the adrenal medulla or other
chromaphil tissues and the sex organs.

Action of the Adrenal Bodies upon the Thymus

Hypertrophy of the thymus has been recorded in cases of
Addison's disease, and the association of adrenal hypoplasia
and thymus hypertrophy is said to be common in status lym-
phaticus. There is also some experimental evidence that
adrenal deficiency is frequently associated with hypertrophy
of the pancreas.

Action of the Adrenal Bodies upon the Pituitary
At present there is little evidence of any relationship of the
adrenals to the pituitary.

Action of the Adrenal Bodies upon the Thyroid
Hypertrophy of the thyroids has been reported in some cases
after extirpation of the adrenals, but we have not sufficient
data to justify any statement as to a direct action of the former
organ upon the latter.

Action of the Adrenal Bodies upon the Pancreas
This matter has already been discussed in the chapter

devoted to the adrenal bodies (see Chap. XL).

Here it is only necessary to point out that the whole of the

effect of the adrenal bodies upon carbohydrate metabolism is

406 THE DUCTLESS GLANDS

not exerted through the pancreas, but part must be directly on
the liver. As we have previously seen (p. 162), adrenin has
a direct effect on the glycogen storage of the liver.

We have then considerable evidence that the adrenal cortex
stimulates the growth of the gonads, and some little evidence
that adrenal hyperplasia induces overgrowth of the thymus.
The most usual theory as to the relation of the adrenal body to
the pancreas is that the former inhibits the latter. According
to some observers, this effect is not direct, but related to an
action on the vasoconstrictor nerves.

D. Interrelationships involving the Organs of
Reproduction

Action of the Reproductive Organs on the Pituitary Body

Several authors report that pregnancy causes increased
activity of the pituitary gland. But it has been pointed out
that this may be simply a reaction to the changed metabolic
conditions obtaining during pregnancy. Castration in both
sexes is followed by hypertrophy of the anterior lobe of the
pituitary body. There seems to be a special overgrowth of the
eosinophile elements.

Recent investigations lends support to the view that it is the
loss of the internally secreting elements of the testes (tlir
interstitial cells of Ley dig) which leads to hypertrophy of the
pituitary body.

These observations indicate that the pituitary body is
normally held in check by the secretions of the reproductive
organs. When the inhibition is removed the pituitary shows
increased activity leading to overgrowth of different parts of
the body, as in acromegaly and after castration (Hoskins).

Action of the Reproductive Organs on the Thymus

The thymus normally persists till puberty, when the repro-
ductive organs grow. A priori, castration would tend to
prolong the period of persistence of the thymus. This has
been found experimentally to be the case. The work of
Calzolari, Henderson, and Goodall in this direction is referred
to in Chap. XIV. The sex glands then tend to exert a
depressant effect on the thymus.

INTERRELATIONS 407

Action of the Reproductive Organs on the Adrenal Bodies
During pregnancy there is a distinct enlargement of the
adrenal bodies. This chiefly affects the cortex, but there is
some growth of the medulla also (Elliott and Tuckett). What
is the mechanism or what the significance of this overgrowth
is not known.

Action of the Reproductive Organs on the Thyroid

A direct influence of ovary and testes upon the thyroid body
is not known to exist.

It appears probable, then, that deficiency of the sex organs
leads to hypertrophy of the pituitary body possibly by remov-
ing a normal check upon it. Activity of the sex glands seems
to lead to depression of the thymus. The influence of the
gonads on the adrenal and thyroid bodies is of a doubtful
nature.

E. Interrelationships involving the Thymus

Activities of the thymus upon the gonads and upon the
thyroids have been alleged, but the experimental evidence is
not conclusive.

F. Other Interrelationships

In regard to the influences exerted upon the other endo-
crinous organs by the pancreas, the parathyroids and the
pineal body, there is little that need be said here. There is
little direct evidence that the pancreas does actually depress
the thyroid, though this supposition is an important part of
the theory of the Vienna school. The relation of the para-
thyroids to the thyroid is sufficiently discussed in Chapter
XIII. and the relations of the pineal to the organs of repro-
duction in Chapter XVI.

The " Pluriglandular Syndrome"

Within recent years a great deal has been written about
what is called the " pluriglandular syndrome." The general
conception which has been evolved is by no means definite.
But in general terms it may be stated as follows. In

408 THE DUCTLESS GLANDS

diseases affecting the glands of internal secretion it is very
common (perhaps even the rule) that more than one of these
glands are from time to time or simultaneously involved. The
nature of the clinical picture produced depends upon the
preponderance of symptoms arising from disorder of one or
more of the glands in question whose dysfunction results in
recognizable changes.

Lereboullet classifies pluriglandular disorders as follows :
(1) A primary change in one gland with secondary disorders
in one or more, e.g. Graves's disease, with ovarian insufficiency
and amenorrhoea ; (2) Association of two uniglandular syn-
dromes, e.g. myxoedema and acromegaly ; (3) Association of
several uniglandular syndromes without predominance of any
one. The last condition may be due to syphilis or tubercle
and affects commonly thyroid, testis, and adrenal.

Timme has recently described a condition depending upon
disease of thymus, adrenal, and pituitary in combination. He
says that this condition is frequently met with and that its
various stages are easy of recognition. The chief symptoms
are extreme liability to fatigue, a low blood-pressure, head-
ache, and inordinate growth of the whole body. A restoration
to a normal condition, or to something which approaches this,
may be brought about spontaneously by compensatory over-
growth and over activity of the pituitary. Feeding with
pituitary extracts is the treatment which is found to be most
beneficial.

Pubertas prcecox apparently may arise from affection of the
whole ductless gland system, but primarily from the repro-
ductive organs, pineal and adrenal cortex. The majority of
cases are probably due to some affection of the gonads ; next
in frequency are cases apparently due to tumours of the pineal
and finally we have those due to growths in the adrenal cortex.
It is stated that pineal types occur mostly in the male, the
adrenal and gonadal in the female.

Dercum's Disease, or Adiposis dolorosa, has been included by
some writers in this group. It is characterized by irregular,
sometimes symmetrical, deposits of fatty masses in various
portions of the body, preceded by and attended with pain. It
occurs mostly in middle-aged women. There may be a history
of alcohol, syphilis, rheumatism, or bodily injury. The fatty
masses are of variable size and distributed on the trunk and

INTERRELATIONS 409

extremities. The pain is sometimes spontaneous, sometimes
induced by manipulation. The new fatty tissue has a soft
feel, or there may be harder tumours. Haemorrhages from
mucous surfaces may be observed. The disease is chronic and
progressive.

The morbid anatomy consists in an increase of fatty and
connective tissue and degenerative changes in nerves. The
thyroid has been found hard and calcareous. Dercum's
disease differs from other forms of obesity in its irregular dis-
tribution, in the presence of pain, and sometimes of impaired
sensibility. It differs from myxoedema in that face, hands, and
feet are not affected and in the absence of mental symptoms.

Thyroid treatment is said to do good in some cases (Allbutt).

Arachnodaciyly.

Some seven or eight cases have foeen described under this
name, notably by Morvan and Poynton. The patients are
children with overgrowth of the long bones, phalanges, meta-
carpals and metatarsals. The growth of bone is out of pro-
portion to that of muscles and tendons ; so that contractures
are produced.

It is possible that the condition may be due to some defect
in the organs of internal secretion.

INDEX

ABDOMINAL chromaphil body,

117-122
physiological effects of

extracts of, 121
Accessory adrenals, 114-122, 147

cortical bodies, 116
Acervulus cerebri, 387
Achondroplasia, 381
Acromegaly, 371-377. See Table of

Contents
Adamkiewicz reaction (of thyroid

colloid), 273
Addison's disease, 127-138. Ste

Table of Contents
adrenal preparations in,

209-210

blood changes in, 130
ergographic test in, 130
origin of pigment in, 136
Adiposity after removal of pituitary,

362

effect of castration upon, 73-74
in pituitary tumours, 378
pineal tumours and, 392-393
Adiposis dolorosa, 408
Adrenal bodies, 14, 93-249. See

Table of Contents
accessory, 114-122

relation to adrenal ex-
tirpation, 147-149
chemistry of, 185-200, 202-

203, 240
defective development of,

138

extirpation of, 140-153
extractives from, 202
heat -regulating mechanism

of, 235

hyperplasia of, in arterio-
sclerosis, 139
hypertrophy of, in inanition,

249

in pregnancy, 243
(Marchand's), 116
of birds, 112, 114
of fishes, 98-109
secretory function of, 216-

248
signs of secretory activity

in, 237, 247
tumours of, 139, 241

Adrenal cortex, 93, 112, 115, 127,
238-248. See Table of
Contents
antitoxic function of, 241,

462
brain of man, influence on,

241, 248
functional relationship to

medulla, 235, 247
mechanism of influence on

reproductive organs, 244
relation to sexual organs,

241-245

Adrenal extracts. See also Chroma-
phil tissues, pharmaco-
dynamics of
effects of, 158-165
special physiological effects

of, 165-185
Addison's disease, 210
mode of administration,

211-212

therapeutic uses of, 204
Adrenal medulla, 112, 127

theories as to functions of,

216-238, 249
pharmaco-dynamics of. See

Chromaphil tissues
total deficiency of, 138
tumours of, 139-140
Adrenalin (see also Adrenin), 192 ;

formula of, 194
Adrenalon, 194-195
Adrenal secretion, excessive pro-
duction of, 138

Adrenal vein blood, effect on blood-
pressure of injection of, 217
Adrenal white line (Sergent), 131
Adrenin :

Origin and chemistry of, 185-6,
192-20& See also Adrenal
medulla

estimation of, 197, 217-18
effects of, general, 158-165,

166-185, 187-191, 229-233
intestinal relaxation test for, 236
medical and surgical applications

of, 204-12

not essential to life, 223
pharmaco-dynamics of. See
Chromaphil tissues

411

412

INDEX

Adrenin :

secretion of, mechanism of, 233-4
synthesis of, 196
glycosuria, 218-220
Alimentary canal, actions of adrenin

on, 187
Alveoli, 4

Amines, physiological activity of, 31
sympathomimetic action of,

197-9
Amiurus, anatomy of thyroid in,

256-7

Ammoccetes, thyroid in, 255
Ammonia, hepatic conversion of, 15
Amniota, adrenal bodies in, 95,

112-114

Amphibians, adrenal bodies in, 109-
112

thymus gland in, 325
Amphioxus, thyroid in, 255
Anaesthesia, local adrenin combina-
tion with, 204-5
Anamnia, adrenal bodies of, 95-98-

112

Anaphylaxis, 7

Animal extracts, effect on blood-
pressure, 25, et seq.
organs, use of, 6
Ancestrum, 75-76
Antitoxic action of adrenal cortex,

241, 246

function of ductless glands, 15
Aiiura, adrenal bodies in, 110

anatomy of thyroid in, 258-260
branchial bodies in, 255, 259-60
thymus in, 325

Apocodeine, effects of, 180-81
Arachnodactyly, 409
Artefacts in thyroid gland, 271
Arteries, effects of adrenal extracts

on, 165-177
Arterioles, contraction of, following

adrenal extracts, 166, et seq.
Arteriosclerosis, hyporplasia of

adrenals in, 139
Arthritis deformans and acromegaly,

376

Asthenia in Addison's disease, 130
Asthma, adrenal preparations in, 206
Ateleiosis, 381
Atheroma from adrenin injections,

176-7

Athyrosis, foetal and maternal, 294-5
Atropine, action of liver on, 38

choline and, 26-30
Autocoid substances, 35
Autolytic processes due to enzymes,

8, 9

Autonomic nerves, stimulation of,
actions of adrenin compared with,
187, 191

Autonomin, 36
Autoplastic, definition of, 78
Aves. See Birds

Badger, thyroid extirpation experi-
ments in, 303
Basal metabolism, influence of

thyroid on, 291
Basedow's disease, 290-293
Bdellostoma, adrenal bodies of, 98
Bile, secretion of external and

internal, 13, 61

Birds, adrenal bodies of, 112, 114
adrenal extirpation in, 1.">1
parathyroid in, 261
post-branchial body in, 262
thymus in, 325
thyroid in, 260
Biuret reaction, 272
Bladder, diseases of, adrenal pre-
parations in, 206
effect of pituitary extract on, 352
Blood, changes in, in Addison's

disease, 130
destruction of activity of adrenin

in, 201
glands, 4
Blood-pressure, after extirpation of

adrenal bodies, 145
effect of adrenal secretion
on, 165-177

of choline on, 25-30
of clamping adrenal

vein, 221-223
of injection of paired
bodies of Elasmo-
branchs, 99, 102
of injections on, 24-31
of injection of blood of

adrenal vein, 217
of pituitary extract on,

347-351
of renal extract on,

25, 52

of thymus on, 336
of thyroid extract on,

314
fall of, from small doses of

adrenin, 175

in Addison's disease, 130
not maintained by chroma-
phil tissues, 221-224, 248
Blood-stream, adrenal secretions

poured into, 216-238
internal secretions passed

into, 4, 14

Blood-vessels, actions of adrenin
on, compared with nerve
stimulation, 187-191
action, animal extracts on,
24-31

I

INDEX

413

Blood-vessels, pathological results

from adrenin injections, 176-7
Bone, condition of, in acromegaly,

371-2
growth of, influence of testis on,

73

thyroid on, 307

Brain, adrenal insufficiency and, 138
blood-supply of, 174, 299-300
extracts, chemistry of, 30

effect on blood-pressure, 26,

27, et seq.

relation of pituitary to, 338, 345
sand, 387
Branchial bodies, 255

of anura, 255, 259-60
organs, development of, in

mammals, 279-281
Breast. See Mammary
Bufagin, 200

Cachexia hypophysipriva, 361-364
strumipriva, 289-290
thyreopriva, 289-290
Calcium, deficiency of, as cause of

experimental tetany, 323
output after pituitary feeding,

358

Cancer cells, resistance to, 19
Carbohydrate metabolism, 46

influence of internal secre-
tions on, 220
tolerance in pituitary disorder,

381-83

tests for, 381-382
Carcinoma of thyroid in Elasmo-

branchs, 283
in Telcosts, 257
Carnivora, thyroid extirpation results

on, 300-306
Carotid body, 250-253
Castration, adrenal extirpation and,

144

effects of, 68-74
enlargement of thymus after,

335-6

Catabolic products, 8
Cats, adrenal extirpation experiments

on, 140, 143

thyroid extirpation in, 301-2
Caudal cortical body, 102-6

chromaffin, 123
Cells, chromophile, 339
chromophobe, 339
epithelial of thyroid gland, 270
interstitial of testis. See Inter-
stitial cells of testis
luteal. See Corpus luteum
pineal, 386-8
pituitary, 339-343
relationship of, to secretions, 9

Cells, secretory, epithelial, 12

thymic. See Thymus gland
Chalones, 35

Chelonia, adrenal bodies of, 112
Chemical, stimuli of bodily functions.

16, 17

Chemistry, physiological, 20
Chemotaxis, mechanism of, 7
Choline, atropine and, 26-30
Chondritis, fcetalis, 381
Chondrodystrophia foetalis, 381
Chromaffin and chromaphil, 123, note
Chromaphil bodies, 116-122
abdominal, 117-121
histological appearance of,

119

in teleostean fishes, 106
sympathetic system and,

118, 121, 124-5
cells, in ganglia, 121
tissues, 13. See also Adrenal

medulla

active principle of, ex-
ceptional nature of, 216
chemical nature of active
substance of, 185-6, 192-
200
function of, emergency

theory of, 233, 236, 248
general physiological effects

of, 158-165

hyperf unction of, in inter-
stitial nephritis, 139
internal secretion of, 13,

216-238

in the rat, 147—8
pharmaco-dynamics of ex-
tracts of, 158-185,187-191
atheroma, following in-
jection, 176-7
bleeding from mouth and

nostrils, 160
cardiac inhibition through

vagi, 168
constriction of organs, 166-

168

convulsions, 160
dyspnoea after, 159
early experiments upon, 158
effects of watery or saline
extracts of, 158

on blood vessels of,

165-177
on different animals,

160

heart, 168

respiration, 160, 177-8
skeletal muscle, 178
various involuntary
muscles, 179-185,
187-191

414

INDEX

Chromaphil tissues, effects produced

by " paired supra-renal

bodies" of Elasmo-

branchs, 161

elimination of toxic material

160
fall of blood-pressure from

small doses, 175
effects of, general, 158-165;
special, 165-185, 187-191
hasmaturia after, 160
hypertrophy of islets of

Langerhans after, 162
paresis, 160
partial immunity, 160
pathological effects on

vessels, 176-7
said not be glandular, 13,

216
secretion of. See Adrenal

medulla
and distribution of blood in

body, 230
tonus, theory of, 221-224,

248

tumours of, 139-140
Chromogen adrenal, 185
Chromophile cells, 339
Chromophobe cells, 339
Chvosteks sign, 296
Cocaine, adrenin used with, 204-5
Coccygeal body, 254

function of, 254
microscopic structure of, 254
Cod-liver oil, use of, 39
Colloid, micro -chemical reactions of,

271-3

pituitary, 340-1
thyroid vesicles containing,

271-3

Conarium, 385
Consensus parti um, 5
Conjunctiva, adrenal preparations

applied to, 205-6

Co-ordination, primitive means of,
between different parts of body, 17
Corpuscles, chromaphil, 99-106

of Stannius, 99-106, 108, 109
Corpus luteum, 81-82
Correlative organs, 10
Cortical bodies, accessory, 116

comparative anatomy of,

126
body, cranial and caudal, 102-

106
Cretinism, endemic, 284-286, 304-5,

380

Cretinoid dysplasia, 381
Crocodilia, adrenal bodies of, 112
Cryptorhitic tissues, 35
Curare, action of liver on, 38

Cyclostomata, adrenal bodies of, 98
Cysts, pineal, 392

Cytotoxic sera, in study of internal
secretion, 33

Dalrymple's sign, 290
Deciduomata, artificial, 86, 87
Degeneratio adiposo-genitalis, 379
Dental apparatus, and endocrine

disturbances, 10

Depressor substance, 25, 31, 348
Dercum's disease, 408
Diabetes, 48-51

functional increase of chroma-
phil tissue in, 139
Diabetes insipidus, 382-383
Diabetic, intoxication coma, 50
Diaphysis, 388
Diphtheria, adrenin in, 208
Dipnoi, adrenal bodies in, 107-109

thymus in, 325
Disease, mental, due to changes in

ductless glands, 10
Dogs, adrenal extirpation experiments

on, 140, 143-146
anatomy of thyroid and para-
thyroids in, 264-266
parathyroid extirpation experi-
ments on, 319-323
thyroid extirpation experiments

on, 300-1, 303
Ductless glands, antitoxic function

of, 15

as correlative organs, 10
grouping of, 397-398
hypersecretion of, 10
origin of term, 4
Duodenum, extirpation of, 40

food in and pancreatic secretion,

58

internal secretion of, 57-64
Dwarfism, 9, 379
Dyspituitarism, 370
Dyspnoea, produced by extracts of

chromaphil tissues, 159
Dystrophia adiposo-genitalis, 379

Eels, adrenal extirpation experiments

on, 151-2
Effusion, pleural, adrenalin injections

in, 211
Eggs, without shells after thymec-

tomy, 335
Elasmobranchs, adrenal bodies of,

98-99, 123

anatomy of thyroid in, 256
carcinoma of thyroid in, 283
extirpation experiments in, 152—

3
inter-renal body of, 98-101, 103

INDEX

415

Elasmobranchs, "paired supra-renal

bodies" of, 98-99, 101, 102
pituitary body in, 344
thymus gland in, 325
Emergency theory of function of

chromaphil tissues, 233, 236, 248
Endocrine tissues, 35
Endocrinopathic inheritance, relation

to Mendelian theory, 10
Endostyle in Petromyzon, relation to

thyroid, 255-6
Enzymes, 2

intracellular, 8

Epinephrin, preparation of, 193
Epinine, 199
Epithelial bodies, 42, 43

structure of glands, 4, 12
Erb's sign, 295
Ergograph, use of in Addison's

disease, 130

Eucaine, adrenin used with, 205
Evirati, 68

Excretions, definition of, 14
internal, 14
processes of, 2

Extirpation, experiments, 21-22^
Extracts, subcutaneous injections of,

24

Eye, actions of adrenin on, compared
with nerve stimulation, 188

Fat formation of, effects of castration

on, 73, 74
Fatigue, effect of testicular extract

on, 6, 67, 68
Feeding, experiments in, 23

See Opotherapy and Organo-
therapy
Female characteristics, effect of

ovariotomy upon, 76, et seq.
Ferments, 7
Fishes, adrenal extirpation in, 151-

152

islets of Langerhans in, 43
pituitary body in, 343-4, 369-70
thyroid in, 256-7
Foetus, extract of, mammary growth

caused by, 16

structure of thyroid in, 271
Food, containing iodine, 309

effect on pancreatic secretion, 58
tissue feeding, 23
See Opotherapy and Organo-
therapy

Formative stimuli, 10
Foxes, thyroid extirpation in, 303
Fright, and adrenin secretion, 236
Frogs, adrenal bodies in, 110-112
adrenal extirpation in, 149-151
pancreatic extirpation in, 40,
41

Frogs, parathyroids in, 258-259
post -branchial body in, 260
secondary sexual character in,

71, 72

thyroid in, 258-260
thymus in, 325

ventral branchial body in, 258-
259

Frolichs syndrome, 379

Function, bodily, chemical stimuli of,

Ganoids, adrenal bodies of, 106-107

thymus in, 325
Gastric hormone, 66
Gastric mucous membrane, 65-66
Gastric secretion, 65-66
Generative ferment, 16
Genital organs, internal secretion of,

67-92

relationship of pineal to,
390-394

of pituitary to, 379-380,

406

of thymus to, 335-6
of thyroid to, 318
Genito-adrenal syndroma, 242
Gigantism, 9, 378
Gill clefts, organs derived from, 255,

280-281, 325-337
thymus glands originating

from, 325, 337
Gland alveoli, 4
Glands, 3-4, 12-17; hypertensive

and hypotensive, 25
action of adrenin on, 187-191
effect of pituitary extract on,

353-355
relationship of thyroids and

parathyroids, 276, 399
Gland substance, commercial mode

of preparation of, 23
Glandula insularis cervicalis of pende,

14

Glomeruli caudales, 254
Glomus coccygeum, 254
Glycosuria, after injection of extracts
of chromaphil tissues, 162, 218
pancreatic secretion and, 40,

48-51

pathology of, 40-41, 46-51
Goitre, 282-4

exophthalmic. See Graves'

disease

in teleostean fishes, 257, 283
Gonadin, mammary stimulus due to,

16

Grsefe's sign, 290
Grafting, experiments in, 22
ovarian, 78-79
of thyroid and parathyroids, 317

416

INDEX

Graphic method, 20
Graves' disease, 290-3
Growth, influence of testis on, 72-73
precocious, of sexual organs, 242
Growths, new, hormone theory, 18
Guanidine, as cause of experimental

tetany, 324

Gu.inea-pigs, adrenal extirpation ex-
periments on, 140-5
thyroid and parathyroids in,

266-8

thyroid extirpation experi-
ments, 303

Haemochromogen, in adrenal medulla,

216

Haemolymph organs, 14
Haemoptysis, adrenal preparations in,

207
Haemorrhages, adrenal preparations

in, 206-8
Harmozones, 36
Hassal, corpuscles of, 329
Heart, action of adrenin on, compared
with nerve stimulation, 168,
189

disease, cardiac extracts in, 7
effect of adrenal extirpation on,

154
pituitary extract upon, 347-

50

thyroid extract on, 316
tissue extract on, 26-30
failure, adrenin in, 208-9
inhibition of, through vagi, 168
Heart-beat, effect of pineal extract

upon, 388-389
rate of, after adrenal injections,

168

Heat. See JSstrous cycle
Hemisin, 195
Hermaphroditism and adrenal hyper -

plasia, 242
experimental, 80

Hens, effect of thymectomy on, 335
Herbivora, thyroid extirpation re-
sults on, 304-306
Heteroplastic, definition of, 78
Histamine (/3-Iminazolylethylamine),

31

Homoplastic, definition of, 78
Hormonal, 36
Hormones, 16-18, 35-37
gastric, 66
pituitary, 368-369
vanous, 17, 35
Hormonex, 36
Horns, growth of and castration,

69-70

Horse, anatomy of parathyroids in,
268-269

Humoral, physiology and humours,

6
Hydrazine, action of, on glycosuria,

219-220
Hyperglycaemia and diabetes, 48,

et seq.
Hypernephroma of adrenal bodies,

241-2 ; medullary, 140
Hyperpituitarism, 371, et seq.
Hyperplasia, functional of pituitary,

370, et seq.
ant lobe, 370
post lobe, 370

Hypersecretion and hyposecretion, 10
Hypertension and excessive adrenal

function, 139
Hyperthyroidism, 294
Hypophysis. See Pituitary
Hypopinealism, 390-94
Hypopituitarism, 371, et seq., 378

Inanition, hypertrophy of adrenal

bodies in, 294
" Infant Hercules " type of adrenal

hypernephromata, 242
Infantilism 379-380
Infundibulin, use of, 383
Inheritance, endocrinopathic, 10
Injections, 24-25
Internal excretions, 14
Internally secreting glands, 4
Internal secretion (see Secretion,

internal), 5, 9-10

Interrelations of the organs of
internal secretion, 395-409. See
Table of Contents

Inter-renal body, homologies of, 98-99
of Elasmobranchs, 93-101,

103

physiological effects of ex-
tracts, 99-103
Interstitial cells of ovary, histology

of, 88-89

staining reactions of, 89
of testis, 70-71, 74
nephritis and hyperfunction of

chromaphil tissue, 139
Intestinal internal secretion, 57-64
Intestine, effect of pituitary extract

on, 352
pancreatic juice excited by acid

in, 59

Intraperitoneal injection, 24
Intravenous injection, 24
Invertebrate, adrenal bodies of, 96,

97

Investigation, methods of, 20, 37
Involuntary muscles, effect of pituit-
ary extract on, 351, 353
Iodides, effect on Graves' disease, 292

INDEX

417

Iodine, relation of, to the thyroid,

308-314

thyroid gland and thyroxin, 311
Iodine, treatment of goitre, 284
lodo-thyreoglobulin, 310
Islets of Langerhans. See Langer-
hans, islets of

Katabolic products, formation of, 8

Kephalin, 203

Kidney, effect of pituitary extract on,

355

Kidney, internal secretion of, 52-56
" Kinetic system," 396

Langerhans, islets of, 41-48
Larynx, relation of thyroid to, 298
Lecithin in adrenal cortex, 240
Leucocytes, relation of thymus to,

332
Lipochromes of ovary and corpus

luteum, 83
Lipoids, Ciaccio's method for the

demonstration of, 240
Lipoids of the adrenal bodies, 203
Liver, glycogenic function of, 5, 38
Liver, internal secretion of, 38-39
Lcewi reaction in diabetes, 50
Lungs, vasomoter nerves to, 181
Lutein, 83
Lymphatic glands, internal secretion

of ?, 9, 14
Lymphoid organ, thymus as, 330

Macrogenitisomia prsecox, 393
Male characters, development of,

67-74, 80

induced by ovariotomy, 77

in female, connected with

adrenal hyperplasia, 241-

243

Mammals, adrenal bodies of, 112-123,

125
adrenal extirpation experiments

in, 140-149
anatomy of the pituitary body

in, 338-343

general anatomy of the thyroid
and parathyroids in, 262-281
thymus in, three types of, 328
thyroid extirpation upon, 300-

307
Mammary gland and generative

ferment, 16
effect of extract of foetus on,

16, 88
effect of pituitary gland on

secretion of, 353, 354
" Mammary hormone," 16
Marchand's adrenal bodies, 116
Melanin, formation of, 136

Menopause, ovarian extracts and, 90
Menstruation, disorders of, ovarian

extracts and, 91
enlargement of thyroid during.

See Thyroid
induction of, 85
Mental disease, due to changes in

ductless glands, 10
symptoms in Addison's disease,

131

Metabolic activities of protoplasm, 1
Metabolism, actions of adrenin on,
compared with • nerve stimu-
lation, 187-191
in acromegaly, 373
in Addison's disease, 132
influence of kidneys upon, 56
of organs upon, 218
of ovary upon, 78
of pituitary on, 375-379
of thyroid on, 316-7
stimulated by proteins in food, 8
Methods of investigation, 20-37
Metcestrum, 75, 76
Mice, adrenal extirpation, experi-
ments in, 141
Micromelica, 381
Milk, produced in virgin animals, 16

secretion of, causes of, 84
Mcebus sign, 290
Mongolism, 294
Monkey, anatomy of parathyroid in,

264

thyroid extirpation in, 301-4
Mors thymica, 337
Mucous surfaces, adrenal preparations

for, 205-6

Muscle, action of adrenin on, com-
pared with nerve stimulation,
187-191
voluntary, contraction of, effects

of adrenal extracts on, 178
tissue, depressor substance from,

27

My ome trial gland, 91
Myosthenin, 195
Myxoedema, 286-9

operative, 289-290

Nebenorgan, 117

Negative internal secretion, .16

Nephrectomy, duration of life after

in animals, 54
Nephritis, adrenal hyperplasia and,

139

oedema in, causation of, 55-56
renal extracts in, 56
Nephroblaptine, 56
Nerves, stimulation of, actions of
adrenin compared with, 187, 191
27

418

INDEX

Nervous action, reflex, causing pan-
creatic secretion, 57-58
symptoms in Addison's disease,

131
system, autonomic, divisions of,

180, 181
controlled by chemical

stimuli, 18

effect of adrenal extirpation
on, 145

pituitrin on, 349, 350,

351

evolution and the, 17
incretins, 285
Nervous tissue extracts, effect on

blood-pressure, 26-30
New growths, hormone theory of, 18
Nicotine, liver antitoxic for, 38
Nitrogen, excretion of, influence of

thyroid on, 316-317
output after pituitary feed-
ing, 358

Nose, diseases of, adrenal prepara-
tions for, 206

(Estrus, 75-76

cycle dependent on ovaries,

75-76
Opotherapy, 67, 74

theoretical basis of, 6, 7
Orchitic extracts, medicinal uses of,

74

Organotherapy. See Opotherapy
Organs, glandular, 3

hsemolymph series of, 14
use of, 6
Osmic acid vapor, to show adrenin

granules, 235
Osteitis deformans and acromegaly.

376
Osteomalacia, 92

related to hyperfunction of

ovaries ?, 92

Ovarian medication, 90-91
Ovary, 75-80

hypertrophy of adrenal cortex

after, 244
extracts of, heat produced by,

84-5

physiological effects of, 80
therapeutic value of, 90-1
internal secretion of, 75-92

stimulus to mammary gland,

88

interstitial cells of, 88, 89
oestrus cycle dependent on, 85
relationship between pituitary

and. See Pituitary
Ovulation, 75-6
Oxidation of adrenal extracts, 201

Paired supra-renal bodies, 98-102
Pancreas, diseases of, and diabetes,

48, 49, 50, 51
glycosuria and, 46
internal secretion of, 40-51
Pancreatic duct, 45, 46

juice, excited by acid in duo-
denum, 58
secretion of, 57-64

excited by secretin, 60
table of excitants of, 63
secretion, mechanism of, 60,

et seq.

Paraganglin, 195
Paraganglioma, 139
Paralysis agitans, 296

following adrenal extracts,

158
no true following adrenal

extirpation, 145
Paraphysis, 386
Parasomata, 117
Parathyroids. See Chapter XIII,

Table of Contents
See also Thyroids and Para-
thyroids
accessory, 303-4
comparative anatomy and his-
tology of, 255-269
development of, 279-281
diseases of, 295-297
external, 262-3
extirpation of, results of, 319-

324

functions of, 319-324, 295-7
histology of, 274-7
in birds, 261

chrysemys picta, 260
frogs, 258-9
pseudemys scripta, 260
rana esculenta, 259
testudo groeca, 260
relationship between thyroid

and, 276-7, 399
to other glands, 399
surgery of, 321-2
Parhormones, 36
Pathological methods, 21
Pathology, experimental, 20, 21
Peristaltic hormone, 36
Peristalsis, sluggish intestinal, pitui-
tary extract in, 384
Petromyzon, adrenal bodies of, 98

thyroid in, 255
Phaeochrome, 123
Pharyngeal pituitary, 342
Pharynx, and gill -clefts, organs
derived from, 255, 280-1,
325-337

thyroid connections with, 255-6,
281

INDEX

419

Phosphorus output after pituitary

feeding, 358

Physiological chemistry, 20
Physiology, humoral, 6
Pigment pituitary, 342
Pigmentation, cutaneous following

adrenal extirpation, 141-2
in Addi son's disease, 129
Pineal body, 385-394. See Table of

Contents
teratoma of, 392
tumours of, 392
Pineal eye, 386

syndroma, 393 .
Pisces, adrenal bodies of, 98-109.

See Fishes
Pituitary body, 14, 338-384. See

Table of Contents
diseases of, 370-383
elements furnishing active

substances, 356-7
extirpation experiments on,

21, 361-5

hyperf unction of, 370-378
insufficiency of, 378-383
internal secretion of, 356-7
relationship between gener-
ative organs and,
379-380, 402-404
thyroid and para-
thyroids and, 399 —
400
disorders, carbohydrate tolerance

in, 381-3
extracts, effects of, 347-356.

See Table of Contents
elements of gland fur-
nishing active substance,
356-7

feeding and metabolism ex-
periments with, 357-9
in gynaecology, medicine

and surgery, 383-4
hormone, 368-9
Pituitrin, effects of, 355
Pluriglandular disorders, classifica-
tion of, 408

Polyglandular syndrome, 395, 407-8
Polyuria, caused by pituitary extract,

355

Post-branchial bodies, 255, 279, 280-1
in birds, 262
in chrysemys picta, 260
in frog, 259-60
in toad, 259
in triton, 258
Pregnancy, growth of corpus luteum

during, 88

mammary stimulus during, 88
pituitary changes during, 354,
402-4

Pressor bases, action similar to that

of adrenin, 198-9
substances, 25
of pituitary
tissues yielding, 27
Products, catabolic and synthetic, 8
Progastrin, 66
Progeria, 294, 379, 380
Pro-oestrum, 75-6
Prosecretin, duodenal, 60
Prostate gland, atrophy of, after

castration, 69

internal secretion of, 74-75
Prostatectomy, 74-75
Protein, colloid containing, 272-273
Proteins, of adrenal bodies, 202
Protopterus, adrenal bodies in, 107-

109
Pseudo hermaphroditism and hyper-

plasia of adrenal gland, 241
Pseudorachitism, 381

fcetalis micramelica, 381
Pubertas prcecox, 408
Puberty, effect of castration on,

80-88

gland, 88, et seq.
growth of thymus and, 336
Pupil, dilation of, after adrenalin

injections, 164-180
after local application of

adrenalin, 182
test for adrenin, 182
Putrid meat pressor, principles in, 31
Pyrocatechin, 185-186, 192

Rabbits, adrenal extirpation experi-
ments on, 140-149
anatomy of the thyroid in,

266-267
extirpation of thyroid in, 301-

303, 306

Rachitis foetalis, 381
Rats, adrenal extirpation experiments

on, 147-148
anatomy of the thyroid in,

266-267

extirpation of thyroid in, 301
Rathke's pouch, 344-346
Reptiles, adrenal bodies in, 112-113
anatomy of the thyroid in, 260
islets of Langerhans in, 42
parathyroids and post-branchial

bodies in, 260
thymus in, 325-327
Respiration, cardiac, paroxysmal, 323
effects of adrenal extracts upon,

177-178
of pituitary extract upon,

351

Respiratory centre excited, in as-
phyxia, 8

420

INDEX

Reproductive organs, internal secre-
tion of, 67-92

Salivary glands, extirpation of, 22
Salts in experimental tetany, 323-324
Sarcoma, inoculation with, 18
Scyllium canicula, histology of thyroid

in, 256

Secondary sexual characters, influ-
ence of ovaries on, 75-79
Secretin, effects on islets, 42
gastric, 65-66
pancreatic secretion excited by,

60

production of, 60
Secretion, antitoxic function of,

14-15

and excretion, 2
and internal secretion, 1
definition of, 1-3
external, 5, 13
internal, 1-19

definition of, 13 & ff.

earliest use of the term, 5

gastric, 65-66

hepatic, 38-39

injections and, 24, et seq.

intestinal, 62

methods of investigation,

20-34

negative, 16

of adrenal bodies, 93-249
ovarian, 75-89
pancreatic, 57-64

after severance of

nerve-, 57

passed into blood-stream, 4
physiological relationship
between glands having,
366, 395-409
renal, 52-6
testicular, 67, et seq.
thyroid, 307-308
prostatic, 74-75
psychical, 65
renal, 52-6

reproductive organs, 67-89
testicular, 67-74
Seminal fluid, 69. See Testis

(footnote), 3
Serum, hepatolytic, effect of, 55

nephrolytic, toxic effect of, •"»•"»
Sexual characters, secondary influ-
ence of testis on, 68-73
organs. See Reproductive organs
Sheep, thyroid extirpation experi-
ments in, 304-306
Shell shock, due to adrenal

insufficiency ?, 138
Shock, pituitary preparations in, 383

Skin, action of adrenin on, compared

with nerve stimulation, 188
bronzing of, in Addison's disease,

128-129

condition of, in myxoedema, 288
Sperlerpes ruber, anatomy of thyroid

in, 257-258
Spermatogenesis, effect of extirpation

of prostate on, 74—75
Spermatozoa, 3
Spermin, metabolic effects of, 67-68

(Pcehl), 67, 74
Sphygmogenin, 186
Sopranists, 68 •

Spinal cord extract, effect on blood-
pressure, 27

secretion, due to stimula-
tion of, 57

Splanchnic curve, form of, 224-235
effect of adrenal extirpation

on, 225

tying or clamping ad-
renal veins on, 224-
235

nerve, secretory nerve to ad-
renals, 219, 221, 224-235
Splaiichnics, stimulation of, 223-233
Staining reaction of colloid, 272-3
Stannius, corpuscles of, 99, et seq.
Status lymphaticus in Addison's

disease, 130

Stimulation, chemical means of, 17
Stimuli formative, 10
Stomach, effect of pituitary extract

on, 353-355

" Struma supra-renals," 243
Strychnin, liver antitoxic for, 38
Sugar, pancreatic secretion and pro-
duction of, 46-51
" Summer cells " of adrenal bodies,

243
Suprarenal bodies. See Adrenal

bodies

Suprarenin, 192

Sympathetic nerves, stimulation of,
actions of adrenin compared
with, 187-191
system, chromaphil bodies of,

116-122
Syndroma, geni to -adrenal, 243

pineal, 393

Synthetic products, formation of, 8
Syringomyelia and acromegaly, 376

Teeth and endocrine disturbances, 10
Teleosts, adrenal bodies of, 99-106

extirpation, experiments on,

151-152

anatomy of the thyroid
256-257

in,

INDEX

421

Teleosts, chromaphil cells in, 106
goitre in, 257, 283
pituitary body in, 343-344,

369-370
thymus in, 325
Teratomata, pineal, 392
Testicular extracts, 6, 67, 74
Testis, growth of, as affected by

adrenal feeding, 245
internal secretion of, 67-74.

See Table of Contents
relationship of prostate gland to,

74, 75
Tetania parathyreopriva, 319-324

symptoms, 322-324
Tetany, 295-6 ; endemic, 297
Thymic death, 337
Thymus extracts, physiological effects

of, 336
Thymus gland, 14, 325-337. See

Table of Contents
depressor substances of, 27,

336
enlarged in Graves's disease,

291

epithelial cells in, 331-332
extirpation of, 21
hyperplasia of, in Addison's

disease, 130

types of, in mammals, 328
Thyroglobulin, 310
Thyroid and parathyroids, 255-274.
See Table of Contents. See also
Thyroid gland
Thyroid extracts, effects and medical

uses, 314-7
effect on thymus, 277 et seq.,

401

feeding with, 23
gland, 255-324. See Table of

Contents
accessory, 303-4
action of, on adrenals, 398,

399

on pancreas, 401
on thymus, 401
diseases of, 282-295. See

Table of Contents
extirpation of, 21, 301-307
effect on pituitary body,

399-400
functions of, 255, 318. See

Table of Contents
histology of, 269-273
influence on metabolism,

316-7
internal secretion of, 307-

8
intervesicular cellular tissue

of, 274
not essential to life, 30£

Thyroid gland, pathological con-
ditions of, 282
relationship to generative

organs, 318

between parathyroid

and, 276-7, 399

pituitary and, 399-

400
secretion of, 307-8

artificial renewal of,

314-317

insufficiency, 293
Thyroiodin, 310
Thyroxin (Kendall), 310-14
Timme's disease, 408
Tissue extracts, effects of, 25-32
growth of, and hormone theory,

18

Toad, post-branchial body in, 259
Tonus theory of adrenal bodies,

221-224, 248
Toxins, 7
Transplantation of adrenal bodies,

156-7

ovarian, results of, 80
thyroid, 317
Triton, parathyroid in, 258

post-branchial body in, 258
Trousseau's sign, 295
Tryptophan, preparation of adrenin

from, 247

Tumours of adrenal bodies, 139
Tyrosin, production of adrenin from,
200

Uraemia, nephrectomy producing,

52-55

phenomena of, 53
Urea, ammonia converted in liver to,

38

elimination of, 38
hepatic production of, 38
Ureters, ligature of, effect of, 53
Urinary organs, action of adrenin on,
compared with nerve stimulation,
187
Urine, blood - pressure raised by

substance in, 31
increased after nephrectomy,

56
secretion of, effect of pituitary

extracts on, 355

Urodela, adrenal bodies in, 110-112
anatomy of thyroid in, 257-8
thymus in, 325
Urohypertensin, 31
Uterine mucosa, effect of mechanical

irritation of, 86-87
sensitization of, by corpus
luteum, 86

422

INDEX

Uterus, cyclical changes in, 75-6
effect of pituitary extract upon,
351

Vagus, section of, 172
stimulation of, 57
Vas deferens, ligature of, 71
Vasoconstrictor substances, specific, 9
Vasodilator substances, specific, 9
Vasomotor nerves, effect of adrenal

injections, 229, et seq.
Vasomotor reflexes, effect of adrenin

on, 229-233
effect of pituitary extract

on, 350-351
Vegetative processes, 10

Ventral branchial body of frog,

258-9

Vesicles of thyroid, 255, et seq.
Vesiculae seminales, atrophy of, after

castration, 69
Vividiffusion in study of internal

secretions, 33
Vomiting, in Addison's disease, 130

Waste products, elimination of, 2
White line, adrenal (Sergent), 131
Wolf, prairie, adrenal extirpation
experiments in, 303

Xanthoproteic reaction, 272
Yellow body. See Corpus luteum

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