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THE PHYSIOLOGY

AND PHARMACOLOGY

OF THE PITUITARY BODY

H. B. VAN DYKE

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THE UNIVERSITY OF CHICAGO
MONOGRAPHS IN MEDICINE

Editorial Committee

FRANKLIN C. McLEAN, Chairman

ANTON J. CARLSON

H. GIDEON WELLS

THE PHYSIOLOGY AND PHARMACOLOGY
OF THE PITUITARY BODY

THE UNIVERSITY OF CHICAGO PRESS, CHICAGO

THE BAKER & TAYLOR COMPANY, NEW YORK; THE CAMBRIDGE UNIVERSITY
PRESS, LONDON; THE MARUZEN-KAB USHI KI- K.AI S HA, TOKYO, OSAKA,
KYOTO, FUKUOKA, SENDAI; THE COMMERCIAL PRESS, LIMITED, SHANGHAI

THE PHYSIOLOGY AND
PHARMACOLOGY OF
THE PITUITARY BODY

Volume II
By H. B. VAN DYKE

Head of the Division of Pharmacology, Squibb Institute for
Medical Research, New Brunswick, New Jersey

Honorary Professor of Physiology, Rutgers University

Formerly Professor of Pharmacology in the Universi'y of Chicago
and in Peiping Union Medical College

THE UNIVERSITY OF CHICAGO PRESS
CHICAGO • ILLINOIS

COMPOSED AND PRINTED BY THE UNIVERSITY
OF CHICAGO PRESS, CHICAGO, ILLINOIS, U.S.A.

FOREWORD

DR. VAN DYKE has again rendered a valuable service
to biology and medicine in presenting in this second
volume his critical digest of the experimental and
clinical literature on the pituitary body that has appeared
since 1935. During these four years, while public attention
has been focused mainly on violence and war, on economic
maladjustments and social strife in many lands, and when
myopic men have clamored for a moratorium on science,
biological and medical research in some countries has still
gone on at a rate and of a quality which now calls for a second
review volume on the pituitary body alone. I think this is
clearly on the credit side of our simian ledger, even though
the pace of publication of excellent research and the making
of good scientific books bid fair to exceed our capacity for
memory and mental digestion.

The pituitary body is still the "master" among the
endocrine glands. The four additional years of research have
detracted very little from its prestige, while it has extended
its significance in several directions. A few pituitary hor-
mones have become more hypothetical than they were four
years ago, a few appear to have become more firmly estab-
lished, but, with the possible exception of the lactogenic
hormone, their chemical identity still eludes us. In fact, all
the fundamental questions anent the pituitary body, in health
and in disease, are still beyond the horizon. The role of this
gland in the normal physiology of aging has scarcely even
been formulated as a problem. The author's present winnow-
ing will help to direct the next advance on many fronts.

A. J, Carlson

February 1939

Vll

PREFACE

THE stream of reports on the functions and interrela-
tionships of the pituitary body now flows at the rate
of approximately 750 articles yearly. Since 1934 re-
search has been especially active; while new and useful con-
tributions are much less numerous than the volume of data
offered would lead one to expect, nevertheless, notable ad-
vances have been made in clarifying certain aspects of the
complex functions of this organ. In this respect, several fields
deserve particular mention — i.e., the physiological signifi-
cance of the pars neuralis, the importance of the anterior
pituitary in carbohydrate metabolism, the physiology of the
breasts in relation to the anterior pituitary, and the correla-
tion of anatomical changes in the gland with alterations of
function and morphology elsewhere in the body. The great
interest shown in the gonadotropic hormones appears not to
have led to a commensurate return. Investigation of the thy-
rotropic hormone probably has been least fruitful recently.
In the present volume I have undertaken to meet the need
of sifting and classifying the new data and concepts and of
modifying the old by endeavoring critically to review recent
work on the physiology and pharmacology of the pituitary
body. A brief summary of my opinion of the present state of
our knowledge has been added to each chapter. The first
volume included part of the reports of 1935; the present
volume is believed to include references to all important ex-
perimental work published during the remainder of 1935 and
during the years 1936 and 1937. In addition, some reports of
1938 are reviewed. The Bibliography (1,418 titles) represents
78 per cent of the articles which were considered.

I wish here to record my thanks to a number of colleagues
who have given me the benefit of expert and critical advice.

PREFACE

Dr. R. O. Greep kindly assembled for me the information
which appears in the Appendix. I am grateful to the authors
and publishers — American, British, French, and German —
who gave me permission to reproduce illustrations and tables.
These all receive acknowledgment where the material ap-
pears.

H. B. VAN Dyke

New Brunswick, New Jersey
February 1939

TABLE OF CONTENTS

PAGE

List of Illustrations xiii

CHAPTER

I. The Anatomy of the Pituitary Body i

II. The Regulation of Growth by the Pituitary Body . 32

III. The Gonadotropic Hormones of the Pituitary Body . 47

IV''. The Gonadotropic Hormones Associated with Pregnancy

OR Certain Neoplasms 124

V. The Pars Glandularis of the Pituitary Body in Rela-
tion TO THE Development of the Breasts and the Secre-
tion OF Milk i^i

VI. The Thyrotropic Hormone 174

VII. The Interrelationship between the Pars Glandularis
and the Adrenal Glands; the Influence of the Pars
Glandularis on the Metabolism of Carbohydrates,
Lipoids, Proteins, and Minerals (with Remarks on the
Pituitary-Parathyroid Interrelationship) .... 198

VIII. The Pituitary Body in Relation to the Regulation of

the Distribution OF Pigment IN Chromatophores . . . 244

IX. New Observations on the Chemistry and Pharmacology

OF Extracts of the Pars Neuralis 258

X. The Pars Neuralis as a Gland of Internal Secretion . 274

Appendix. The Structural Formulas and Principal Actions

OF Hormones of Natural Origin 293

Bibliography 298

Index 385

51955

LIST OF ILLUSTRATIONS

FIGURE PAGE

I. The Blood Vessels OF THE Human Pituitary Body ... 3

The Relation of the Meninges to the Pituitary Body of
THE Dog <;

The Innervation of the Pituitary Body according to

ROUSSY AND MoSINGER ~j

Diagram of the Hypothalamico-hypophysial Fiber System

OF the Monkey 8

5. Colloid-Formation in Neurons of the Supraoptic and

Paraventricular Nuclei 9

6. Diagrams Illustrating Views of Different Authors on

the Relationships of Cells of the Pars Glandularis . . 14

7. Diagram of the Relationship of the Cells of the Human
Pars Glandularis /^r/;?^ 15

The Effect of Prolonged Treatment by Oestrone on the
Gross and Microscopic Appearance of the Pituitary of
THE Mouse 20

9. The Action of Pituitary Gonadotropic Hormone on the

Urogenital Tract of the Female Chick Embryo ... <^4

10. The Action of Pituitary Gonadotropic Hormone on the
Size of the Testis and the Color of the Bill of the Eng-
lish Sparrow n^S

11. The Action of Pituitary Gonadotropic Hormone on the
Ovary AND Oviduct OF the English Sparrow c^-j

12. Changes in Ovarian Weight and in the Number, Size, and
Appearance of the Ovarian Follicles Following Hypophy-
sectomy in the Immature Rat 63

13. Differences in the Response of the Ovary of the Imma-
ture Rat to the Pituitary of Horses Differing in Sex and
Age 68

14. "IThe Relationship of the Dose of Follicle-stimulating
and>HoRMONE and the Response of the Ovaries and Uterus of

15. JTHE Immature Mouse 108, 109

16. Diagram Illustrating the Failure of the Hypophysec-
tomized Rat To Form Antihormone in Response to
the Excessive Secretion of Gonadotropic Hormone by a
Spayed Partner IN Parabiotic Union 114

f xiii 1

LIST OF ILLUSTRATIONS

FIGURE PAGE

17. Potentiation of the Action of Gonadotropic Extract as a
Result of the Addition of "Merthiolate" to the Solution
BEFORE Injection 119

18. The Excretion of Gonadotropic Hormone in the Urine
during Pregnancy 126

19. The Rate of Disappearance of Gonadotropic Hormone of
Pregnant-Mare Serum Following Intravenous Injection
into the Rabbit I47

20. The Effects of Oestrogen, Corpus Luteum Hormone,
AND Lactogenic Hormone on the Breasts of the Castrated
Rabbit ii;j

21. The Relationship between the Dose of Lactogenic Hor-
mone and the Growth of the Crop-Gland of the Pigeon . 170

22. The Effect of Hypophysectomy and of the Injection of
Anterior Pituitary Extract ON THE Thyroid of the Newt . 177

23. The Effect of Hypophysectomy on the Concentration of
Sugar in the Blood of the Fasting Monkey .... 206

24. "I Diagrams Illustrating the Production of Diabetes Mel-
andi-LiTUS by the Injection of Anterior Pituitary Extract

25. J INTO the Dog. The Effect of Insulin Also Is Shown . 222-23

26. The Effect of Hypophysectomy on the Distribution of
Pigment in the Melanophores of THE Angel Shark . . 246

27. A Position of Bilateral Lesions Which Produce Diabetes
Insipidus IN THE Cat 281

28. Hypertension Caused by Renal Ischemia in Relation to

THE Pituitary Body 280

CHAPTER I
THE ANATOMY OF THE PITUITARY BODY

IN RECENT years the majority of the reports concerned
with the anatomy of the pituitary body have dealt with
its physiological aspects. The pituitary's largest and
most important division — the pars glandularis — has received
the greatest attention. Unfortunately the quality of the work
published varies greatly, so that many of the findings scarcely
deserve mention and serve only further to confuse any pres-
entation which attempts completeness. To a varying extent,
of course, the same remark is true of other pituitary investi-
gations which are non-morphological.

The recent additions to our knowledge of the embryology
of the pituitary body are few. The morphological and func-
tional development of the pars buccalis in larvae of anuran
amphibia {Rana pipiens^ R. syhatica) can take place without
contact with nervous tissue contrary to the views of some
embryologists (Atwell, 1937). This statement may not be
true so far as the pars tuberalis is concerned. On the other
hand, x'^twell's experiments with larvae of a salamander
{Amblystoma punctatum) suggested that similar development
of the pars buccalis in this animal requires the presence of
nervous tissue near by. Schliefer (1935) studied the develop-
ment of the pituitary of the toad {Bufo vulgaris), especially as
it is related to metamorphosis. He found that development
is not complete until toward the end of metamorphosis. Also
he stated that the administration of pars neuralis extract
C'hypophysin-feeding") is associated with some retardation
of metamorphosis, an increased rate of growth, and altera-
tions in the cells and pigment of the pars intermedia; it
appears fruitless to attempt to interpret these observations.
Tilney (1936) has recently made a detailed study of the de-

[il

THE PITUITARY BODY

velopment of the human pituitary which, he emphasizes, fol-
lows a typical mammalian pattern such as that of the cat.
According to Tilney, the pars glandularis (which he terms the
pars distalis) develops as a medullary core almost entirely
surrounded by a cortical envelope; he believed that the func-
tional anatomy of these developmental divisions should be
carefully investigated.

There have appeared recently several contributions to the
comparative anatomy of the pituitary body, particularly in
fishes and amphibia. Among the fishes studied were several
species of skates (Rata maculala, R. clavata, and R. brachyura
[Howes, 1936]), various selachians (Ranzi, 1937), and a num-
ber of species of bony fishes (particularly Silurus glanis
[Lange, 1936]), including the eel, Anguilla vulgaris (Hagen,
1936). Some of the studies embraced physiological correla-
tions. For example, Lange described the yearly cyclic changes
in the pituitary of S . glanis. Ranzi found that bv the his-
tological appearance of the pars glandularis and pars inter-
media it was possible to decide whether the pituitary had
been removed from an immature, a normal adult, or a preg-
nant selachian. Hagen pointed out that the pars glandularis
of the eel is largely made up of oxyphils. The volume and
vascularity of the pituitary markedly increases during meta-
morphosis. Sato (1935) studied several anuran amphibia.
Among studies in birds that of Schildmacher (1937) is best
mentioned here. He investigated the histology of the pitui-
tary in the blackbird {Turdus merula) in males and females at
times of annual flights (spring and autumn).

THE BLOOD VESSELS OF THE PITUITARY BODY

Wislocki and King (1936) have made an important con-
tribution to our knowledge of the vascular connections of the
pituitary body and adjacent tuber cinereum. Their results
indicate that the description of Popa and Fielding, especially
of the hypophysio-portal system, requires extensive modifica-
tion. The pars glandularis is furnished with blood by two

THE ANATOMY OF THE PITUITARY BODY

routes: aiferent arteries and afferent portal veins which origi-
nate in the region of the stalk from a plexus both surrounding
and penetrating the infundibular stem (see Fig. i). The ter-
minal parts of these arteries and veins unite to form the

Fig. I. — The blood vessels of the human pituitary body as revealed by a dissec-
tion of the base of the brain, s.fi.a.: superior hypophysial arteries, anastomosing
arteries supplying the pars neuralis, pars intermedia, and pars glandularis, p.v.:
portal veins on the stalk, b.v.: basilar veins, into which blood only from the floor
of the hypothalamus flows. (From Wislocki and King, Amer. J. Anat., 58, 421-72
[1936].)

sinusoids characteristic of the pars glandularis. Blood leaves
the pars glandularis in veins passing from the lateral poles of
the anterior lobe to the cavernous sinuses. The eminentia
saccularis, infundibulum (pars neuralis), and pars intermedia
are supplied with arteries and drained by veins which are

[3]

THE PITUITARY BODY

almost independent of those of the anterior lobe. These ves-
sels enter and leave by the posterior pole of the pars neuralis.
Contrary to Popa and Fielding, as well as many other in-
vestigators, the authors concluded that the hypophysio-por-
tal veins receive no blood from the anterior or posterior lobes
and that the hypothalamus in a vascular sense is inde-
pendent of the pituitary body. On the other hand, the ter-
minal basal portion of the tuber cinereum — the eminentia
saccularis — appears from its vascular supply as well as from
the readiness with which it takes up vital dyes to be one part
of a unit composed of the eminentia saccularis, the stalk, and
the pars neuralis. In respect of their avidity for vital dyes
and their unusually rich and complex blood supply, the
supraoptic region of the diencephalon and the area postrema
of the "hindbrain" also appear to be tissues similar to those
of the unit just described.

It is emphasized by Wislocki and King that the foregoing
description is particularly true of the monkey (and probably
human)' pituitary and hypothalamus. It should again be em-
phasized that their results indicate that blood flows from the
hypophysio-portal vessels to the pars glandularis and not in
the reverse direction, as was the contention of Popa and Field-
ing as well as others. The description of Wislocki and King,
moreover, denies the assumption of many authors that secre-
tions of the pituitary body have ready access to and specifi-
cally affect hypothalamic "vegetative centers."

The blood vessels of the diencephalic-hypophysial region
in the cat are, in most respects, like those in the monkey;
however, the eminentia saccularis is less well vascularized in
the cat (Wislocki, 1937). In the cat, also, Stevens (1937)
measured the total lengths and average diameters of the
capillaries per unit volume of tissue of the various parts of
the pituitary body. She concluded that the pars tuberalis is
supplied with sinusoids even more richly than the pars glan-
dularis. The latter was found to have a vascular bed about

' See also the report of Wislocki (1937).

[4I

THE ANATOMY OF THE PITUITARY BODY

six times as large as that of the pars neurahs which, in this
respect, resembled the motor nucleus of the seventh nerve.
The pars intermedia contained the smallest number of capil-
laries.

THE MENINGES OF THE PITUITARY BODY

New studies of the meningeal relations of the pituitary-
body in the dog (Schwartz, 1936) and in a number of mam-

Srain

Post, clinold
process
.u ♦„. p,g..

arachnoid

Subdural
space

. Dura

\>ur(x \yn&

Pars '

Peceding collar of

capsule

Splieooid bor>«

tubaralLs

arachnoid

Mypophyais

Fig. 1. — -The relation of the meninges to the pituitary body of the dog. Note that
the pia-arachnoid surrounds the stalk and pars tuberalis but not the remainder of
the pituitary body. (From Schwartz, Anat. Rec, 67, 35-44 [1936].)

mals, including man and the human embryo (Wislocki,
1937), have been reported. The subarachnoid space encircles
the infundibular stalk but does not surround the pituitary
body proper, although it may penetrate into the sella turcica
a short distance in the cat and dog (see Fig. 2). The dura
mater extends throughout the sella turcica and constitutes
one layer of a fused structure consisting of periosteum, in-
trasellar dura, and pituitary capsule. Therefore there is no
subdural space.

[5]

THE PITUITARY BODY

THE INNERVATION OF THE PITUITARY BODY

It has been known for many years that the pars glandularis
receives sympathetic nerve fibers from the carotid plexus. In
the cat these non-myelinated fibers accompany the arteries
and terminate chiefly in the pars glandularis and the pars
neuralis. Not all the nerve fibers degenerate after cervical
sympathectomy, and some may be parasympathetic in origin
(Hair, 1938). The functional significance of this innervation,
however, has not yet been adequately explored. Evidence of
a nervous regulation of the pars glandularis is slowly ac-
cumulating.^ Concerning the pathways involved, however,
little is known. The physiological importance of the nerve
supply of the pars intermedia has been clearly suggested by
experiments in amphibia and certain other cold-blooded ani-
mals. Here again, however, not much is known about the lo-
cation of the innervating (efferent) neurones, although Hair
found that some fibers of the supraoptico-hypophysial tract
can be traced to the pars intermedia in the cat. Our best in-
formation deals with the nerve supply of the pars neuralis.
Especially in recent studies employing physiological and
morphological technics it has been possible to demonstrate
the great dependence of the pars neuralis on certain hy-
pothalamic nuclei, particularly the paired supraoptic nuclei.
Necessarily, then, the greater part of the discussion will be
concerned with the pars neuralis. Much of the review of the
physiological experiments, together with an additional dia-
gram of the nervous connections between the hypothalamus
and the pars neuralis, will be found in chapter x.

The diagram reproduced as Figure 3 represents the opinion
of Roussy and Mosinger on the innervation of the pituitary

^ Such as the effect of light on the secretion of gonadotropic hormone in birds
and in one mammal, the ferret. Strong, diffuse electrical stimulation causes the
liberation of gonadotropic hormone (ovulation) in the rabbit. See also the report
of CoUin and Hennequin (1936) on changes in the pars glandularis of the rabbit fol-
lowing bilateral extirpation of the superior cervical ganglia (see also chap. iii).

[6]

THE ANATOMY OF THE PITUITARY BODY

body. Some of the interconnections depicted represent pos-
sibilities rather than probabihties inferred from correlated

Fig. 3. — The innervation ot the pituitary body according to Roussy and Mo-
singer. (From Presse med., 44, 1521-23 [1936].)

Band, opt.: optic tract; Carot.: carotid artery; Chaine Int.: cervical sympa-
thetic; Cps. mam.: mammillary body; Gg. cerv. sup.: superior cervical ganglion;
Lobe ant.: pars glandularis; Lobe int.: pars intermedia; Moelle cerv.-dors.: cervico-
thoracic portion of spinal cord; Vj": third ventricle; V^*^: fourth ventricle; Tuber:
tuber cinereum.

/, Amygdalo-tangential* tract (olfactory-pituitary reflexes). 2, Retino-tan-
gential* tract (optico-pituitary reflexes), j, Pars tuberalis. ^, Pathway by which
pituitary can be influenced by corpus striatum and globus pallidus. 5, Subependy-
mal network of sensory nerves. 6, "Neurocrinie hypophyso-hypothalamique." 7,
Islet of glandular cells in pars neurahs. S, Tubero-hypophysial tract, g, Mammillo-
hypothalamic tract. 10, Thalamo-hypothalamic pathways. //, Cortico-hypothal-
amic pathways. I3, Decussation of descending hypothalamic pathways, /j, Hypo-
thalamico-hypophysial tract. //, Zone of transition. 75, Central sensory pathways.

* Tangential or supraoptic nucleus.

morphological-physiological experiments. An example of

a diagram based upon such experiments is that of Figure 4.

The function and, indeed, the morphological maintenance

of the pars neuralis depends upon the normal flow of im-

THE PITUITARY BODY

pulses from certain nuclei in the hypothalamus to the neural
lobe. (The most complete experiments have been performed
in cats by Fisher, Ingram, and Ranson.) The important nu-
clei are the paired supraoptic nuclei which supply most of the
nerve fibers of the pars neuralis as well as a few fibers to the
different divisions of the pars buccalis. Both of the nuclei
must be destroyed or cut off' from the pars neuralis before the
latter undergoes atrophy and ceases to elaborate its hor-
mones. The neurones of the supraoptic nuclei degenerate and

Fig. 4. — Diagram of hypothalamico-hypophysial fiber system of the monkey.
(From Ingram, Fisher, and Ranson, Arch, intern. Med., 57, 1067-80 [1936].) Diabe-
tes insipidus can be produced by lesions in the circumscribed region L. IS: stalk;
M: mammillary body; OC; optic chiasm; P/^.- pars glandularis; PP; pars neuralis;
PT: pars tuberalis; SHT: supraoptico-hypophysial tract; SO: supraoptic nucleus;
VM: ventromedial component of supraoptic nucleus; TC: tuber cinereum; THT:
tubero-hypophysial tract. As indicated by a broken Hne, it is possible that fibers
of the supraoptico-hypophysial tract pass through the optic chiasm.

disappear after hypophysectomy — i.e., in the dog or rat
(Hare, 1937; Rasmussen, 1937) or after interruption of the
supraoptico-hypophysial tract. The filiform or paraventricu-
lar nuclei perhaps also directly or indirectly — i.e., by way of
interposed synapses with neurones of other nuclei — innervate
the pars neuralis. The morphological evidence for this inter-
pretation is, however, better than the neurological.-'

3 The following are recently published references to authors who have made ob-
servations on other parts of the pituitary and its possible central connections: Col-
lin (1935), Collin and Fontaine (1936), Collin and Hennequin (1936), and Roussy
and Mosinger (1935-36).

[81

THE ANATOMY OF THE PITUITARY BODY

Hair (1938) described knoblike enlargements projecting
from nerves distributed in the pars glandularis, pars inter-
media, and pars tuberalis of the cat's pituitary body. These
enlargements lay in contact with the epithelial cells. In the
pars neuralis the nerves terminated in bulblike structures
similar to those described by others in the neural lobe of the
ox and of man.

Fig. 5. — Colloid-formation in neurones of the supraoptic and paraventricular
nuclei. (From Peters, Z. Neur., 154, 331-44 [1936].) Colloid a as fine drop-
lets, b diffusely distributed, and c and d as large accumulations believed to follow
coalescence of smaller droplets. Vacuoles may appear to be empty, A o( e, or partly
filled, C of/, or completely filled, B oi e, with colloid.

A number of French and German authors'* have called
attention to the peculiar morphology of the neurones of cer-
tain hypothalamic centers. Some of the morphological varia-
tions which may occur in the cells of the supraoptic and para-
ventricular nuclei are illustrated in Figure 5. The formation
of colloid by these or homologous neurones is said to be recog-
nizable not only in man and other mammals but also in other
vertebrates such as reptiles, amphibia, and fishes, as well as in

■t Collin and collaborators (see the earlier volume), Scharrer (1933-35), Gaupp
(1935), Gaupp and Scharrer (1935), Peters (1935), and Roussy and Mosinger (1935-
36). Florentin (1937) discusses changes related to secretory activity of the pars in-
termedia (toad). Roussy and Mosinger (1937) also review anatomical evidence for
the secretion of pituitary hormones into the cerebrospinal fluid.

THE PITUITARY BODY

one invertebrate, the snail. Other morphological characteris-
tics which have been described in these nuclei are multinu-
clear cells, endocellular capillaries, and degeneration and dis-
integration of the cells. All these observations seem to place
the neurones of the supraoptic and paraventricular (and per-
haps the tubero-mammillary) nuclei in a category different
from that of other cells of the central nervous system, al-
though Peters found colloid inclusions in cells of certain nu-
clei of the medulla oblongata.

The evidence that such cells secrete colloid and are to be
considered a "diencephalic gland" is morphological and does
not deserve acceptance at this time. The "secretory activity"
of these cells appears to be slight in childhood; it is not other-
wise correlated with age and is not altered as a result of
nervous or endocrine diseases.

THE PARS INTERMEDIA, THE PARS NEURALIS
AND THE PARS TUBERALIS

It has again been emphasized that the pars intermedia of
man and the anthropoid apes is a structure so rudimentary in
appearance that it appears to have no important function
(Berblinger and Burgdorf, 1935; Plaut, 1936; and Scriba,
1936). Frequently, also, the human pituitary contains no re-
sidual cleft of Rathke's pouch. In the pituitary of the por-
poise^ and the whale,^ the pars glandularis is completely
separated from the pars neuralis by a leptomeningeal-dural
fold. The embryologic development of the organ in the por-
poise and whale is therefore apparently different from that in
other mammals. No pars intermedia can be recognized in the
cetacean pituitary.^ According to Benjamin (1935), the de-
posits of pigment in the pars intermedia and in the pars
tuberalis of wild and hooded rats — but not present in pure

5 Tursiops truncatus.

* Balaenoptera physalus, B. sibbaldi, and Physeter megalocephalus (see Gelling,
1935; and Wlslockl and Gelling, 1936).

' Whether or not a pars intermedia can be identified in the bird's pituitary is still
undecided (see the discussion of Wislocki and Gelling).

f 10]

THE ANATOMY OF THE PITUITARY BODY

albinos — originates in the leptomeninges and, after develop-
ment, is found in the connective-tissue septa.

The cells of the pars intermedia secrete the chromatosome-
dispersing hormone. If, however, the pars intermedia is rudi-
mentary and perhaps non-functional (man) or absent (fowl.^
cetacean), the hormone is still formed by cells of the pars
glandularis.

The basophilic cells of the pars neuralis have been care-
fully studied by numerous authors because of their possible
relationship to clinical disorders such as hypertension — a
view particularly emphasized by Gushing. These cells are
probably derived from the pars intermedia (Andreis, 1935;
and Rasmussen, 1936) and, it is generally agreed, increase in
numbers particularly after middle age, when, of course, essen-
tial hypertension is more frequently present. However, it ap-
pears clear that there is no convincing correlation between the
development or presence of hypertension and the ingrowth
(and hyperplasia) of basophilic cells in the pars neuralis. The
association of hypertension and this morphological change
is fortuitous (Marcano, 1935; Hawking, 1936; Rasmussen,
1936; and Scriba, 1936). Likewise these basophilic cells prob-
ably have nothing to do with the elaboration of the oxytocic
and pressor-diuresis-inhibiting hormones of the pars neura-
lis. The cetacean pars neuralis is entirely separated from the
pars buccalis by meninges and yet contains the character-
istic pars neuralis hormones (Geiling, 1935). In the cat, after
sufficient injury of the supraoptico-hypophysial nervous con-
nections, the amount of oxytocic and pressor hormones in the
pars neuralis is markedly reduced in association with atrophy
of the pars neuralis; yet there is little change in the pars
intermedia (Fisher and Ingram).

The hyaline bodies of Herring, which can be found in the
pars neuralis of the whale (Wislocki and Geiling, 1936), are
therefore not derived from juxtaposed cells of the pars
buccalis (pars intermedia) as has been suggested from studies
of the pituitary of other mammals. In fact, Gersh and Tarr

[II]

THE PITUITARY BODY

(1935) offer good evidence that such hyaHne bodies are fixa-
tion artefacts and are unrelated to the amount of pressor hor-
mone in the pars neuraHs. Gersh and Tarr studied the pars
neuraHs of six mammals and of the fowl. True secretory cells
have long been sought in the pars neuralis. Recently Gersh
(1937) described parenchymatous "glandular" cells more or
less uniformly distributed in the pars neuralis and containing
granules or lipoid droplets. They could be identified in the
neural lobe of nearly all mammals and of two birds (fowl and
pigeon). They appear to be supplied with nerve fibers passing
down the stalk and probably secrete the diuresis-inhibiting
(vasopressor) hormone. They were found to undergo degen-
eration after section of the stalk and to increase in number
and size if water was withheld. The brown and black pig-
ment of the human pars neuralis has been studied recently by
Roussy and Mosinger (1935). Trossarelli (1935) investigated
the connective tissue and nerve fibers of the pars neuralis.
He confirmed Tello's earlier description of the club-shape of
some of the nerve endings of the pars neuralis. Although true
nerve cells heretofore have not been identified in the pars
neuralis, Kasahara (1935) stated that nerve cells with grow-
ing fibers could be found in his cultures of pars neuralis tissue
obtained from young rabbits. The distribution of mast cells
in the infundibulum and pars neuralis of the ox, the cat, and
man has been studied by Gray (1935). The mast cells often
appeared to be closely associated with the primary capillary
network of the hypophysio-portal system.

There have been no important additions to our knowledge
of the morphology of the pars tuberalis. Its functional im-
portance is still unknown, although Biggart believed that it
secretes the diuresis-inhibiting hormone.

THE PARS GLANDULARIS

As has already been mentioned, the majority of the recent
reports dealing with the anatomy of the pituitary body are
chiefly concerned with the physiological anatomy of the pars

[12]

THE ANATOMY OF THE PITUITARY BODY

glandularis. In addition, there are a few miscellaneous re-
ports which will be considered at the end of this section.
Some of the most interesting interpretations are the result of
studies of human pituitaries. Furthermore, confidence in the
validity of the conclusions reached is possible because, in the
best of these reports, actual cell-counts rather than impres-
sions were used in gathering data. Likewise, in a number of
reports of an experimental nature this technic has been used.
Finally, it is unfortunately also true that morphological in-
vestigations of the pars glandularis — whether of man or of
animals — in which conclusions of a quantitative character are
reached without any recognition of the necessity of founding
these on a technic quantitatively sound are often the prin-
cipal means of confusing efforts to make a modest start in
satisfactorily picturing the function(s) of the cells of the
anterior pituitary.

There still is no agreement in reference to the relationship
between the reserve cells and the chromophil cells. ^ Franck,
in several reports pubHshed in 1935-37, concluded, as many
authors have before him, that the chromophil cells are de-
rived from the reserve cells. He believed that there exist sev-
eral varieties of oxyphils and basophils, and that the latter in
turn are derived from oxyphils. Kirkman (1937), like Franck,
also used the guinea pig. Kirkman's elaborate study included
a careful analysis of previous reports and should be read by
those particularly interested in the physiological anatomy of
the pars glandularis. He studied the anterior pituitary of
guinea pigs during the oestrous cycle, in pregnancy, post-
partum, after gonadectomy, in fetal life, etc. Figure 6 is re-
produced from a report by Severinghaus and indicates, in
diagrammatic form, some views which have been held as to
the relationship between the reserve cells (chromophobes)
and the chromophils (oxyphils or acidophils and basophils).
This author (1937) has recently reviewed the relationship of

'The report of Collin and Stutinsky (1937) contains a description of cellular
peculiarities of the anterior pituitary of the frog.

[13]

\l/

Mothw
Czll

SmnJ gE-MY

3e/NDA

COLLI/^

Acbit
Giaad

On tumor?)

^^/

tmbrgonic
Gland

\(aA\js

a • acioophile-
6 • Basophilc

St:V&IZI<SGUAUS

0?d'', D*^- De<je/seBAri/NG Cells

E • Cell smoww gca^ulac ELiMKNAficy^

T- TeA/SSipONAL (UBtCGA/SGZELL)

C° C • Acidophilic a/^d Basophilic cmbomopucxjes etSPECfivc-LY

Fig. 6. — Diagrams illustrating views of different authors on the relationships of
cells of the pars glandularis. (From Severinghaus, Physiol. Rev., 17, 556-88 [1937].)

Fig. 7. — Diagram of the relationship of the cells of the pars glandularis. (From
Crooke and Russell, J. Path. Bact., 40, 255-83 [1935].) Staining by authors'
differential method. /, Reserve cell. 2, Transitional basophil, j, "Adult" basophil.
^ and 5, Oxyphils in early and later transition. 6, "Adult" oxyphil. 7, Exceptionally
large reserve cell.

THE ANATOMY OF THE PITUITARY BODY

the cellular morphology of the pars glandularis to the gland's
physiological activity. The view of Crooke and Russell
(1935) as to the cellular relationships in the human anterior
pituitary is illustrated in Figure 7.

Dawson (1937) has named a specialized portion of the pars
glandularis the "zona tuberalis" because of its location. In
the cat and rabbit this part of the anterior pituitary consists
largely of reserve cells and basophils, the proportions of which
vary greatly in response to changes in the reproductive cycle,
gonadectomy, adrenalectomy, etc.

According to Sanchez-Calvo (1937), if guinea pigs or rab-
bits are kept in a dark room, there occurs, among other
changes, a marked increase in the proportion of oxyphils in
the anterior pituitary. The maximum change was observed
after the animals had been kept for 72 hours in darkness.

The relationship between the reproductive organs or their inter-
nal secretions and the anatomy of the pars glandularis. — The re-
lationship between normal sexual activity and the morphology
of the pars glandularis recently has been studied in the frog
(Zahl, 1935) and pigeon (Marza and Blinov, 1936). Zahl con-
cluded that the important changes which can be correlated
with the annual sexual cycle of several species of Rana involve
the oxyphil and reserve cells. (The small basophils appeared
to be unimportant.) During the winter months the number
of oxyphils containing "fuchsinophil" droplets*^ increases at
the expense of the reserve cells and reaches its peak in the
spring. Following the breeding season, the number of oxy-
phils undergoes a gradual reduction and is lowest in the late
summer and autumn. xAccording to Marza and Blinov, the
pituitary of the female pigeon enlarges at about the time of
ovulation without, however, any apparent change in the
number of reserve or basophil cells. Their technic did not
permit them to draw any conclusions concerning the oxy-
phils.

Opinions on the histological appearance of the pars glandu-

' Zahl also speaks of fuchsinophil droplets in cells "otherwise chromophobic."

[Kl

THE PITUITARY BODY

laris of mammals like the rat at different stages of the
oestrous cycle vary greatly. The recent careful study of
Wolfe (1935), who used both qualitative and quantitative
technics, led him to conclude that in the female rat the pro-
portion of none of the cells — disregarding finer qualitative
details such as the content of granules — varies at different
stages of the oestrous cycle.'" He believed that the only clear-
cut cyclic change is in the granules of the basophils. These
granules are most numerous in pro-oestrus and rapidly dimin-
ish in number during oestrus and metoestrus. Pfeiffer (1937)
supplemented his other experiments designed to alter the
sexual characteristics of pituitary function in rats (see chap.
iii) by anatomical studies. The distribution of cells typical
of the male or female pituitary could be produced by trans-
planting testes into spayed females or ovaries into castrated
males. The anterior pituitary of animals with both ovarian
and testicular grafts tended to be of the male type. After
puberty and, therefore, after sexual differentiation of the pars
glandularis, the distribution of cells could not be altered.

The alterations in the pituitary accompanying parturition
and the onset of lactation have interested several investiga-
tors. Collin and Florentin (1935) who used guinea pigs, as
well as Weis (1935) who used rats, stated that an unusual and
marked predominance of reserve cells is observed at parturi-
tion and for about 24 hours later. They beheved that this
change is related to the initiation of lactation. Collin and
Florentin also concluded that the oxyphil is the more numer-
ous chromophil during the first half of pregnancy, whereas
the basophil predominates toward the end of pregnancy.
Desclin (1936) was interested in the significance of the corpus
luteum in maintaining the pituitary's lactation morphology
in the rat. He found that the latter persists after ovariec-
tomy, provided that the young continue to suckle. If, how-

'° The proportions of the different cells confirmed Wolfe's previous report. The
means and standard deviations were: basophils, 4.1 + 1.3 per cent; oxyphils,
34.2 ± 4.3 per cent; reserve cells, 61.8 + 4.4 per cent.

f 16I

THE ANATOMY OF THE PITUITARY BODY

ever, the young are removed, the pars glandularis assumes
the appearance characteristic of gonadectomized animals (in-
creased numbers of basophils, "castration-cells"). Kraus
(1935) has advanced the opinion that the "pregnancy-cells"
of the pars glandularis, growing initially because of placental
stimulation, secrete the lactogenic hormone which is released
into the circulation after the expulsion of the placenta. He
believed that suckling is the stimulus responsible for the con-
tinued secretion of the lactogenic hormone by these cells.

Characteristic changes in the anterior pituitary following
gonadectomy can be consistently observed in the rat and
have already been described in the former volume. These
changes chiefly involve the basophils which increase in num-
ber and later hypertrophy and become vacuolated. Such
basophils containing a single large vacuole have been named
castration-cells. In other animals, such as the guinea pig,
contradictory descriptions of the changes in the pars glandu-
laris following gonadectomy continue to appear. Unlike
Severinghaus, Nelson (1935) declared that gonadectomy (or
cryptorchidism) is followed by a slight but definite increase
in the percentage of basophils in the guinea pig's anterior
pituitary; however, Nelson agrees that castration-cells of the
murine type are rare. An increased amount of colloid has
been described in other studies of the pituitary of gonadec-
tomized animals. Nelson mentions that thyroid-like follicles
containing colloid are prominent in the anterior pituitary of
gonadectomized or cryptorchid guinea pigs. Tuchmann
(1937), who also studied the pituitary of gonadectomized
guinea pigs, observed an entirely different change — i.e., a
progressive, marked increase in the proportion of oxyphils.
Both Nelson and Tuchmann were able to reverse the changes
caused by gonadectomy by injecting oestrin. The reader is
referred to the earlier volume for a description of anterior
pituitary changes attributed to gonadectomy or injury of the
gonads in man and other mammals.

The other recent reports deal with the correction or re-

[17]

THE PITUITARY BODY

versal of castration changes in the pituitary of the rat." It
is well known that several oestrogens and androgens cause
reversal of the changes, so that the pituitary may assume a
normal appearance both grossly and microscopically. Hohl-
weg (1935) insisted that progesterone alone (0.54 mg. daily
for 15 days to adult or immature spayed rats) does not alter
the changes in the pituitary due to gonadectomy. The results
of Migliavacca (1936) agreed with those of Hohlweg. There-
fore the findings of Clauberg and Breipohl to the contrary
lack confirmation. Nelson and Gallagher (1935-36), in agree-
ment with others, found that male hormone whether from
urine or testis prevents castration changes in the rat's pitui-
tary. Similar effects with two pure androgens, androstane
diol and androstene dione, were also described.'^ Carcino-
genic substances (benzpyrene and a dibenzanthracene diol)'^
can prevent the pituitary changes due to gonadectomy
(Wolfe, 1936; and Tuchmann, 1937).

The effects of oestrogenic and androgenic substances on
the pars glandularis are, of course, not limited to the correc-
tion of gonadectomy changes. In the past few years several
authors have reported on the changes appearing in the pitui-
tary of normal animals, both immature and adult (mouse, rat,
guinea pig, and rabbit), particularly after the injection of
oestradiol benzoate or oestrone.'^ The alterations about to
be described vary, depending upon dosage, preparation used,
duration of injections, sex, age, etc. The variations for the
purpose of this review, however, are not sufficiently impor-

" The relative importance of the interstitial cells and the germinal epithelium
in preventing "castration" changes in the pituitary remains undecided. De Fremery
(1936) minimizes the importance of the "sex hormones."

"Other experiments with androgens have been reported by Allanson, Hohlweg,
Wolfe and Hamilton, and Yanagita.

'3 See also the report of Tuchmann and Demay (1936).

'•< 1935: Nelson, Wolfe, Wolfe and Phelps; 1936: Halpern and D'Amour, Wolfe,
Wolfe and Chadwick; 1937: Wolfe. It appears that luteinization of the ovaries is
definitely associated with the pituitary changes in female rats. Martins (1936) could
detect an increased vascularity of the pituitary, transplanted to the anterior cham-
ber of the eye, 24-48 hours after the injection of a large dose of oestradiol benzoate.

I18I

THE ANATOMY OF THE PITUITARY BODY

tant to justify a detailed description. Often the dose of the
oestrogen has been large (e.g., 200 rat-units of oestradiol
benzoate daily for 10 days ), so that the effects may be such
a distortion of the physiological as to be chiefly of phar-
macological importance. The first and most important
change is a loss of granules from the basophils; in addition,
the percentage of basophils is reduced. Especially after large
doses, a similar loss of granules occurs in the oxyphils. Owing
to hypertrophy of the anterior pituitary, the proportion, but
probably not the number, of these cells diminishes. Several
of the authors concluded that "degranulated" basophils are
transformed into reserve cells. Such a transformation only in
a small part accounts for a simultaneous marked increase in
the percentage and total number of the reserve cells in which
numerous mitoses can often be observed. The hypertrophy
of the pars glandularis is due to the hyperplasia of reserve
cells. '5

Usually the injection of a large dose of an oestrogen pro-
duces a considerable hypertrophy of the anterior pituitary
(2-3 times normal size). Enormous doses of an oestrogen may
correspondingly accentuate the change, so that the hyper-
plasia of the reserve cells is indistinguishable from a neoplasm
(reserve-cell adenoma). A change of this sort was first pro-
duced by Cramer and Horning (1936) in mice (see Fig. 8),
The authors were primarily interested in the production of
mammary carcinoma by the application of a solution of
oestrone (o.oi per cent dissolved in chloroform) to the skin,
through which the hormone was readily absorbed. In several
mice with large hemorrhagic adenomata composed almost en-
tirely of reserve cells, there were cachexia and degenerative
changes in the adrenal cortex, in addition to the expected
regressive alterations in the gonads. The authors suggested
that the mice with pituitary adenomata were suffering from

'5 The response of the transplanted pituitary is similar; so it is not likely that the
effects depend to an important extent on the nervous system, as some authors have
asserted (Desclin and Gregoire, 1936}.

[19]

THE PITUITARY BODY

a marked hypophysial deficiency, probably because of the
disappearance of the chromophilic cells. Confirmatory ex-
periments in rats have been reported by McEuen, Selye, and

Fig. 8. — The action of large doses of oestrone, administered over a period of
6 months, on the pituitary of the mouse. (From Cramer and Horning, Lancet,
230, 247-49 [1936].) /, Gross appearance of normal pituitary and optic nerves.
2, Pituitary of treated male mouse illustrating marked congestion of the pars glandu-
laris and compression of optic nerve. J, Photomicrograph of pars glandularis of
treated mouse (i") showing large hemorrhagic areas. 4, Photomicrograph of glandu-
laris of normal mouse at a slightly higher magnification than j.

Collip (1936) and by Zondek (1936). It has not been con-
vincingly shown — as Zondek believed — that such pituitary
adenomata are produced much more readily in male than in
female rats. Lacassagne and Nyka (1937) concluded that the

f20l

THE ANATOMY OF THE PITUITARY BODY

effect of an oestrogen on the pituitary varies in different
strains of mice.

Selye, Browne, and Collip (1936) injected 4 mg. of pro-
gesterone into young, mature female rats for 12 days. This
treatment was followed by some reduction in the size of the
ovaries (23 per cent) and some increase in the pituitary's
weight (29 per cent). In the pars glandularis of the injected
animals there was found "a great number of small cells with
relatively dense chromatin."

Testosterone (or its propionate) causes no pituitary hyper-
trophy (McEuen, Selye, and Collip, 1937) and in this respect
differs from oestradiol or oestrone. However, like the oestro-
gens it brings about a degranulation of the basophils (Wolfe
and Hamilton, 1937).

Wolfe (1935) and Wolfe and Phelps (1935) reported that
the effects of prolan on the pars glandularis of the adult rat
resemble those of an oestrogen — i.e., loss of granules from
basophils (and oxyphils) and hyperplasia of reserve cells. Ap-
parently these changes are due to the liberation of oestrogen
or androgen from the gonad stimulated by prolan. In 1937
Wolfe stated that prolan prevented some of the similar effects
of oestradiol in immature female rats. In comparison with
the pituitary of animals given only oestradiol, that of animals
receiving both prolan and oestrogen was less hypertrophied
and contained more basophils which were normal in respect
of granules.

The relationship between other glands of internal secretion and
the anatom y of the pars glandularis . i . The thyroid. — -The pars
glandularis of the rabbit increases about 50 per cent in weight
after thyroidectomy performed 159-333 days previously (van
Dyke and Chen, 1935). Franck (1936) stated that the ad-
ministration of thyroid extract or thyroxin (and, to a less
extent, adrenal cortical hormone) to guinea pigs causes a re-
duction of the number of granules in the oxyphils. The num-
ber of basophils containing granules was thought also to be
reduced. Franck also stated that an extract containing thyro-

[21 1

THE PITUITARY BODY

tropic and adrenotropic hormone caused similar changes.
Iodine, KI, or diiodotyrosine were found to lessen the effects
(Franck, 1937).

There has been some discussion as to the nature of the
changes in basophils in thyroidectomized as compared with
gonadectomized animals. Nelson and Hickman (1937), al-
though affirming that they could distinguish between the
alterations in basophils due to thyroidectomy or gonadec-
tomy, contended that the same basophils are affected by
either operation. They found that changes due to thyroidec-
tomy, except degranulation, could be corrected by the ad-
ministration of oestrone. Guyer and Claus (1937) believed
that the formation of vacuoles in the basophils is due to ac-
cumulation of secretion after gonadectomy, whereas after
thyroidectomy it is the result of cellular degeneration. Zeck-
wer (1937) particularly supports the view that the thy-
roidectomy and gonadectomy cells of the anterior pituitary
are different and can be identified morphologically.

2. The adrenals. — Lippross (1936), using rats instead of
guinea pigs, found no significant changes in the morphology
of the pituitary — and adrenals and gonads — after the pro-
longed administration of adrenal cortical hormone or epin-
ephrine. Therefore, his findings did not confirm those of
Franck.

The compensatory hypertrophy of an adrenal gland after
the extirpation of its mate depends chiefly upon the secretion
of an adrenal cortical stimulating hormone by the pars
glandularis. Zeckwer (1937-38), taking into account the
changes occurring in both adrenals following thyroidectomy
or gonadectomy, studied the effects of these operations on
compensatory adrenal hypertrophy in relation to the his-
tology of the pituitary. She concluded that the oxyphils,
which tend to disappear after thyroidectomy, do not secrete
the adrenotropic hormone. Also, this hormone was thought
not to be secreted by the thyroidectomy-cells or castra-
tion-cells, inasmuch as the degree of compensatory hyper-

THE ANATOMY OF THE PITUITARY BODY

trophy could not be correlated with the number of either
cell type. Therefore, she surmised that the adrenal cortical
stimulating hormone is secreted by the basophils (see also
pp. 15, 21-22).

The change in the morphology of the pituitary character-
istic of adrenal insufficiency is a reduction, sometimes very
marked, in the percentage of basophils. Grollman and Firor
(1935) found that this change, accompanied by an increased
vascularity of the pituitary, is very marked in the dog. In the
rat the reduction of the number of basophils is less promi-
nent; however, the staining of these cells is "very abnormal."
Recently, the cells of the hypophyses from patients with
severe adrenal insufficiency (Addison's disease or atrophy of
adrenals) have been counted by several investigators (Crooke
and Russell, 1935; Hawking, 1936). The percentage of baso-
phils was found to be greatly reduced (e.g., 0.06-0.5 per cent
compared with 7-1 1 per cent in a normal series).'^ A con-
siderable number of abnormal transitional basophils was en-
countered in the series of Crooke and Russell. The propor-
tion of oxyphils also was abnormally low, whereas the propor-
tion of reserve cells was abnormally high.

3. The pancreas. — After repeated injections of insulin into
guinea pigs, the pars glandularis is said to be composed of an
increased number of oxyphils with a corresponding diminu-
tion in the number of reserve cells (Kahn, 1935). On the
other hand. Gentile and Amato (1936) stated that pan-
createctomy in the dog is also followed by an increase in the
proportion of oxyphils which, however, appear relatively
nongranular. The volume of all the cells was found to be
increased. Kahn and Waledinskaja (1936) concluded that
partial pancreatectomy in the rabbit is followed by degenera-
tive changes in the oxyphils and that the magnitude of these
changes depends upon the degree of pancreatic insufficiency.
An investigation of the pituitary of normal cats and of cats

'* Confirmatory reports without cell-counts have been published by Andreis
(1935) and Meesen (1935).

[23]

THE PITUITARY BODY

sacrificed at various intervals after complete pancreatectomy
was made by Fichera and Ferroni (1937), The authors be-
lieved that the pituitary undergoes hypertrophy and that a
marked increase in the proportion of reserve cells at the
expense of the oxyphils takes place as a result of the opera-
tion.

4. The parathyroids. — The pituitary of male rats after
parathyroidectomy or repeated injections of parathyroid hor-
mone or a solution of CaCU was studied by Takahisa (1936).
It was his belief that the principal alteration is in the oxy-
phils— the proportion increasing with parathyroid deficiency
and diminishing if there is an excess of parathyroid hormone
in the body's circulating fluids. The administration of a solu-
tion of CaCL appeared to cause changes resembling those of
parathyroid deficiency.

5. The thymus. — Clark, Steinberg, and Rowntree (1936)
investigated the effects of a thymus extract on the distribu-
tion of cells in the pars glandularis of the rat. Especially in
very young male rats growing at a precocious rate (age:
0-13 days) the percentage of oxyphils was almost twice that
in the anterior pituitary of control animals. The authors cor-
relate this change with the rapid growth observed. In female
rats of a corresponding age, however, the increase in the pro-
portion of oxyphils was only about 25 per cent. In older rats
(age: 13-45 days) no differences were found.

6. Attempts to correlate changes in the human pituitary with
alterations in other endocrine glands or with disease syndromes.
— The syndrome of Gushing, which he named pituitary
basophilism, now appears not to be related to a basophil
adenoma of the pars glandularis as Gushing first believed.
Susman (1934) found adenomata in 8 per cent of 260 human
pituitaries which he examined. Nearly half the adenomata
(eight of seventeen) were basophilic; yet Gushing's syndrome
was not present. On the other hand, the syndrome may be
present in the absence of a basophil adenoma. Grooke (1935)
made the important observation that a hyaline change in the

[24]

THE ANATOMY OF THE PITUITARY BODY

basophils of the anterior pituitary invariably is associated with
typical pituitary basophilism'^ in the absence or presence of
basophil adenoma, a neoplasm of the thymus, or a hyperplasia
of the adrenal cortex. A similar hyaline change in a few cells
was found in 9 of 350 hypophyses of individuals without Cush-
ing's syndrome. Another careful investigator of the pitui-
tary, Rasmussen (1936), has fully confirmed Crooke's obser-
vations in three additional cases. Rasmussen also agreed
that such hyaline changes in the basophils are rare in other
diseases such as essential hypertension, eclampsia, etc.

Hawking (1936) as well as Rasmussen (1936) have made
actual counts of the various cells occurring in the pars glandu-
laris of patients afflicted with various chronic diseases. As a
result, it was concluded that no convincing change in the
morphology of the pars glandularis occurs as a result of essen-
tial hypertension, diabetes mellitus, and Graves's disease.
Using less exact methods, Kraus (1935)'^ and Spark (1935)
came to a similar conclusion regarding hypertension and
eclampsia. Miiller (1936) stated that he discovered twelve
adenomata of the anterior pituitary (mostly reserve-cell
adenomata) in twenty cases of adiposity but only two in
twenty control cases (normal or of cachexia). Apparently the
excretion of gonadotropic hormone in the urine, revealed by
the production of ovulation in rabbits, may or may not be
associated with various neoplasms of the pars glandularis
(McCullagh and Cuyler, 1937). According to Susman (1935),
a diminution in the number of oxyphils is characteristic of the
pituitary of patients dying largely as a result of shock. Also
without making cell-counts, Meesen (1935) believed that
there is some correlation between basophilic invasion of the

'7 AH twelve patients from whom Crooke's material was obtained had the follow-
ing symptoms: an adiposity of the face and trunk; a plethoric, florid, or dusky com-
plexion; a persistently high blood pressure; amenorrhea or impotence (if past pu-
berty). In nearly all there were cutaneous striae of the abdomen or thighs and gly-
cosuria or lowered sugar tolerance. In some there was a severe osteoporosis.

'* Kraus suggested that an apparent increase in the proportion of basophils in
renal disease and other conditions, including advancing age, may be of some ill-
defined compensatory nature.

[25]

THE PITUITARY BODY

pars neuralis and essential hypertension, as well as between a
proliferation of the oxyphils (secreting growth-promoting
hormone?) and the growth of sarcomata.

Erdheim (1936) suggested that pregnancy-cells, which
clearly are not the source of prolan, secrete a hormone pro-
moting the growth of the fetus and some of the maternal
parts. He regarded the similar cells appearing in the pituitary
of patients with congenital aplasia of the thyroid as the
pituitary's attempt to compensate for the harmful effect of
thyroid deficiency on body-growth.

The reduction in the percentage of basophils, as well as a
similar but less prominent change in the oxyphils, in the
pituitary of patients with Addison's disease has already been
described.

Miscellaneous observations. — Andersen, Prest, and Victor
(1937) investigated the metabolism of the isolated pars
glandularis of the rat at different stages of sexual activity,
including pregnancy and lactation. They concluded that the
metabolism of the gland could not be correlated with the
percentage of basophils as determined by Wolfe and his col-
leagues. The pars glandularis was found to be heaviest dur-
ing oestrus.

Several authors have reported their impressions of the
changes in the pars glandularis due to administration or
deficiency of various vitamins. Gi^dosz (1935) stated that
repeated subcutaneous injections of a solution containing
vitamin A into rabbits bring about an increase in the num-
ber of oxyphils and, to a less extent, in the number of
basophils. Intravenous injections of a solution of vitamin C
were followed by similar changes. The pituitary of vitamin
Bi deficiency (six human cases of beriberi) was investigated
by Marburg and Wenckebach (1936). The pars glandularis
frequently contained necrotic areas; the oxyphils and baso-
phils often were separated into adenoma-like groups. They
suggested that apparent holocrine degeneration of the baso-
phils of the pars neuraHs might be related to the circulatory

[26I

THE ANATOMY OF THE PITUITARY BODY

disorders of the condition. ^According to Nitzescu and Bra-
tiano (1936), changes in the oxyphils follow the administra-
tion of enormous doses of vitamin D to the dog. Stein (1935)
reviewed the literature dealing with alterations in the pitui-
tary as a result of a deficiency of vitamin E. He himself could
find no difference in the size or weight of the various lobes or
in the percentage of different cells by comparing the hypoph-
yses of female rats cured of a vitamin-E deficiency with
those of rats on a vitamin-E deficient diet. Confirmatory re-
sults were obtained by Miiller and Miiller (1937). However,
in three male rats (on a diet free from vitamin E for 280 days)
the authors found moderate castration changes in the ante-
rior pituitary.

The pituitary has been successfully transplanted into the
anterior chamber of the eyes of rabbits and guinea pigs by
Haterius and his colleagues. ^^ Such grafts become attached to
the iris and, like similar homoplastic grafts attached to the
subconjunctival tissue, are composed mainly of basophils
about two months after transplantation. The ocular grafts in
hypophysectomized guinea pigs caused an increase in the
number of ovarian follicles with uterine hypertrophy and
persistent oestrus. No atrophy of the thyroid or adrenals oc-
curred. The authors point out that inadequate vasculariza-
tion and the absence of a nerve supply may account for the
lack of a secretion of luteinizing hormone (no complete fol-
licular maturation or ovulation or corpus luteum formation).
Martins (1936) found that pituitary transplants (in kidney
or in anterior chamber of eye) had little effect on the symp-
toms of hypophysial deficiency in five rats receiving the
transplants 16-100 days after hypophysectomy. Also he
transplanted the pituitary into gonadectomized nonhypo-
physectomized rats. Castration-cells could be found in the
pituitary in situ but not in the grafts 1-3 months later. The

"Haterius, Schweizer, and Charipper (1935) and Schweizer, Charipper, and
Haterius (1937).

[27]

THE PITUITARY BODY

pars intermedia, which is the least vascular part of the pitui-
tary, survived transplantation best.

Kasahara (1935) has studied the changes in the cells of the
rabbit's pars glandularis when cultures are made of the latter.
He found that the proliferating cells were neither chromo-
philic nor chromophobic. He described the cultured cells as
"deflected epithelium" in distinction from Champy's term
"dedifferentiated epithehum." Gaillard (1937) cultured jux-
taposed slices of the pars glandularis and the pars neuralis of
rats. He observed at the line of contact structural alterations
including cysts, which led him to suggest that a similar rela-
tionship in vivo accounts for the morphological peculiarities
of the pars intermedia. The same author described in another
report (1937) cultures of the pars glandularis and other
tissues removed from rabbits. Under proper conditions he
could recognize oxyphils. He believed that suitably cultured
anterior pituitary increases the rate of growth of osteoblasts.
Anderson and Haymaker (1935) found that only the chromat-
osome-dispersing hormone from the pars intermedia is formed
in cultures of the pituitary of rats eight days old. There was no
evidence of new secretion of the diuresis-inhibiting hormone
(pars neuralis) or of gonadotropic, thyrotropic, or adrenal
cortical stimulating hormones (pars glandularis). Their re-
sults agree with those of Engel and Werber (1937) but not
with those of Nagayama (1937), who was interested only in
the formation of gonadotropic hormones. The observations of
Gelling and Lewis (1935) are discussed in chapter viii.

SUMMARY

The blood supply of the pituitary body is complex. The
hypophysio-portal veins, concerning which so much has been
written, now appear to be afferent rather than efferent as
thought formerly. They correspond, as far as the pars glan-
dularis is concerned, to the hepatic portal veins. Also, like
the liver, the anterior lobe is furnished with arterial vessels.
The bloodsupply of the pars glandularis is quite independent

[28 1

THE ANATOMY OF THE PITUITARY BODY

of that caring for the pars neurahs. At least in mammals hke
the monkey and man, it is now beheved that there is no close
vascular connection between the pituitary body and the
hypothalamus. There is, therefore, little basis for postulating
important effects of pituitary hormones on diencephalic cen-
ters.

However, certain hypothalamic centers, particularly the
supraoptic nuclei, supply efferent fibers to the pars neuralis.
If this innervation is completely severed, the pars neuralis
atrophies and ceases to secrete its hormone in some if not all
mammals. The cells of nuclei like the supraoptic nuclei mor-
phologically are very different from most neurones but can-
not yet be described as glandular cells of the diencephalon.
The innervation and especially the central connections of the
pars glandularis and pars intermedia are matters requiring
intensive investigation.

The function and therefore the morphological significance
of the pars tuberalis are unknown.

The pars intermedia, the source of the chromatosome-dis-
persing hormone in many animals, is, of course, a part of the
pars buccalis. In certain animals lacking a pars intermedia,
either because of its failure to differentiate or because of its
regression in later life, the lobe's characteristic hormone is
secreted by the pars glandularis.

The oxytocic and vasopressor hormones of the pars neuralis
probably are not secreted or derived from cells of the pars
buccalis such as invading basophils. Such invasion of the pars
neuralis is not etiologically related to diseases like essential
hypertension or eclampsia. Certainly, the hyaline bodies of
Herring do not represent the hormones either actually or in a
preformed state. A newly described glandular cell in the pars
neuralis appears to be the source of the diuresis-inhibiting
(vasopressor) hormone.

A great variety of changes in the pars glandularis has been
related to the endocrine equilibrium of the animal, whether
occurring normally or owing to a deficiency or to the injec-

[29]

THE PITUITARY BODY

tion of hormones. Generally accepted changes in the pitui-
tary due to a hormone-deficiency are the appearance of thy-
roidectomy-cells following thyroid extirpation and the ap-
pearance of castration-cells following gonadectomy. In ad-
dition, there is good evidence that a deficiency of adrenal
cortical hormone is accompanied by a marked reduction in
the percentage of basophils. The morphological changes in
the pituitary caused by gonadectomy can be corrected by
oestrogenic and androgenic substances, but not by proges-
terone. Injected into normal animals, large doses of male or
female hormone cause a depletion of the granules of the
basophils. Very large doses of an oestrogen like oestrone
bring about hypertrophy of the pars glandularis because of a
hyperplasia of the reserve cells. This change may culminate
in the formation of a reserve-cell adenoma.

Considerable progress has been made in relating the mor-
phology of the pituitary to disease in man. Adrenal insuf-
ficiency is clearly accompanied by a marked reduction of the
percentage of basophils. The syndrome of Gushing (pituitary
basophilism) is invariably associated with hyaline changes in
the basophils. xA basophil adenoma is not necessarily present.
The best-known syndrome etiologically related to the pitui-
tary is acromegaly (and giantism); the change here observed
is the development of an adenoma composed of oxyphilic
cells. Hence oxyphils are thought to secrete growth-promot-
ing hormone. The opinion of the most careful investigators is
against the view that pituitary changes (especially in the
basophils sometimes in relation to their growth into the pars
neuralis) are characteristic of essential hypertension, eclamp-
sia, Graves's disease, or diabetes mellitus.

ADDENDUM

There appeared to be no great need in this volume for a
chapter dealing only with the effects of hypophysectomy,
inasmuch as almost all the topics would require reconsidera-
tion in the succeeding chapters. All the various effects of hy-

I30]

THE ANATOMY OF THE PITUITARY BODY

pophysectomy are referred to in the Index. However, there
are a few reports which should be mentioned here. Abram-
ovitz (1937), Thomas (1937), Miyagawa (1936), and Harris
and Popa (1938) have discussed the technic of hypophysec-
tomy in teleost fishes, in the mouse, and in the rabbit. A
brief description of the effects of hypophysectomy in the
mouse (in male and in normal, pregnant, and lactating fe-
male) will be found in the report of Leblond and Nelson
(1937). Observations on the effects of radon or X-rays on the
pituitary of various animals have been published by Ber-
tolotto (1935), Cucchini (1934), Fehr (1936), Lacassagne and
Nyka (1934-35), and Franck (1937). Karlik and Robinson
(1935) gave a detailed description of the changes in the cen-
tral nervous system as well as the other better-known altera-
tions in the organs and their functions appearing in a dog
during and after a five-year period following hypophysec-
tomy. According to Robinson (1937), hypophysectomy in the
pig is followed by characteristic atrophic changes in all the
glands of internal secretion except the adrenal cortex. Cer-
tainly this observation requires confirmation.

The relationship of the hypothalamus to the pituitary
body likewise is discussed in the appropriate chapters, espe-
cially in chapter x. Readers who are particularly interested
in this relationship are referred to the review of Raab (1936).
Raab's enthusiasm, however, has led him to many conclu-
sions lacking a sound foundation.

CHAPTER II

THE REGULATION OF GROWTH BY THE
PITUITARY BODY

NO INVESTIGATOR has succeeded in preparing a
satisfactorily "pure" growth-promoting extract of
the pituitary body. There is general agreement that
the pituitary, among endocrine glands, is the most important
regulator of growth; but whether this regulation is effected
by a specific "growth-promoting hormone" or by direct or
indirect combined effects of other pituitary hormones, such
as the lactogenic and the thyrotropic hormones, remains an
undecided issue.

Particularly Riddle and his colleagues oppose the view
that a specific growth-promoting hormone is secreted by the
anterior pituitary. They suggest that the combined action
probably of the thyrotropic and lactogenic hormones ac-
counts for the principal somatic effects of growth-promoting
extracts and have put forward suggestive but not conclusive
evidence in favor of this view. All the potent extracts which
they have examined contained both of these hormones to
which they attribute any calorigenic effects such extracts
may have (Riddle and others, 1936). Bates and his co-
workers (1937) found that the injection of "relatively highly
purified preparations" of the lactogenic hormone into hypo-
physectomized pigeons caused body-growth as well as a
marked increase in the weight of the liver.' Similar effects
together with a growth of the intestine were observed in
normal pigeons. The only studies which have been consid-

' Effkemann and Herold (1935) concluded that extracts of organs other than
the pituitary may cause moderate or marked hypertrophy of the Hver in the pigeon
and rat without striking associated changes in body-weight. However, they believed
that pituitary extract brought about specific morphological changes.

REGULATION OF GROWTH

ered successful in mammals were made in mice with heredi-
tary dwarfism. According to Riddle (1935), and Bates,
Laanes, and Riddle (1935), growth in such mice can be pro-
duced by thyrotropic extracts or, much less effectively, by
lactogenic extracts. They observed a marked synergism of
the effect if both extracts were administered. "Follicle-stimu-
lating hormone," from the blood of the pregnant mare, was
without action. Kemp and Marx (1936) agreed that lacto-
genic extracts produce a definite growth of mice with heredi-
tary dwarfism. They found thyroxine more effective than
thyrotropic hormone, especially in combination with a pitui-
tary growth-promoting extract. It is of interest that the
degenerative changes in the gonads of such mice were cor-
rected and that normal gonads were maintained by a variety
of treatments — growth-promoting extract or lactogenic ex-
tract or thyrotropic extract or thyroxine.

However, there are numerous objections to the view that
the thyrotropic hormone or the lactogenic hormone or both
account for the principal effects of growth-promoting ex-
tracts. Conclusions drawn from experiments in pigeons prob-
ably have only a limited significance in mammals. Thyro-
tropic hormone antagonizes the growth-promoting effect of
the lactogenic hormone in pigeons (Bates, Riddle, and Lahr,
1937)5 whereas the two hormones were found to have a syner-
gistic effect on growth in the dwarfed mouse. Hypophysec-
tomized rats are very sensitive toward pituitary growth-
promoting extracts; yet no investigator has succeeded in
causing such animals to grow by administering either lacto-
genic hormone or thyrotropic hormone or a combination of
the two. Although it must be admitted that partially refined
growth-promoting extracts are usually more certain and more
persistent in their action than highly purified preparations,
the same remark applies to comparisons of the action of such
partially refined extracts with that of the combined adminis-
tration of lactogenic and thyrotropic hormone to mice with
hereditary dwarfism. Bates, Laanes, and Riddle (1935) ob-

[33]

THE PITUITARY BODY

served that the maximum effect on the growth of dwarfed
mice was obtained by administering a growth-promoting ex-
tract ("Phyone") which had been only partially purified and
contained lactogenic, thyrotropic, and gonadotropic hor-
mones. Moreover, some authors have reported success in ex-
tracting from the anterior pituitary a growth-promoting prin-
ciple free from gonadotropic hormone (Evans and others) or
gonadotropic and thyrotropic hormones (Collip, Selye, and
Thomson) or lactogenic and thyrotropic hormones (Dinge-
manse and Freud, 1935).

Some years ago Smith pointed out that the growth which
occurred in hypophysectomized rats following the adminis-
tration of a crude anterior pituitary extract was accompanied
by no betterment of the atrophic changes in the thyroid,
adrenal glands, and gonads. Also, it is agreed that the growth
response to pituitary extract is not reduced as a result of
thyroidectomy; in fact, acromegalic-like changes in the bones
and joints of guinea pigs receiving anterior pituitary extract
may be more pronounced in thyroidectomized than in normal
animals (Silberberg, 1936; Silberberg and Silberberg, 1937).
Mortimer's observations (1937) suggested that thyroid ex-
tract or thyrotropic hormone tends to cause a loss of minerals
from certain bones, whereas growth-promoting extract may
bring about a sclerosis. According to Moon (1937), suitably
large doses of adrenotropic extract inhibit the somatic growth
of gonadectomized animals without clearly affecting the
growth of the spleen, kidneys, liver, and gastrointestinal
tract; therefore, his results are in agreement with the view
that effects on the adrenal cortex play no positive role in
the general growth-promoting effect of a pituitary extract.

The only sensible verdict to render in answer to the plea
that the anterior pituitary elaborates (or does not elaborate)
a specific growth-promoting hormone is the Scotch verdict
of "not proved." Although the thyroid, gonads, and adrenals
undoubtedly are important in the regulation of growth, it ap-
pears unlikely that changes in the secretory performance of

[34]

REGULATION OF GROWTH

these glands account for the growth-promoting eifects of an-
terior pituitary extract. Future worlc must decide the sig-
nificance of the lactogenic hormone in growth, as far as
growth is affected by the pituitary body. Also, without con-
firmation, it is hazardous to affirm or deny either that
"growth-hormone" free from lactogenic (and other) hormone
can be prepared or that a suitable combination of anterior
pituitary "hormones," with little effect separately, can imi-
tate all the growth-promoting effects of a suitable anterior
pituitary extract. Therefore, the reader should recognize
that the use of the term "growth-promoting hormone" in
other parts of this chapter and book is dictated by conven-
ience rather than by a belief that it deserves more than a
qualified acceptance.

Recent reports on visceral or somatic abnortnalities caused by
hypophysial deficiency. — Schofield and Blount (1937) ob-
served that the removal of the anterior pituitary from larvae
oi Ambly stoma punctatiim is followed by a general reduction in
growth, including the growth in length of the digestive tract.
They believed that the latter change is causally related to the
former. The reports of other investigators, previously re-
viewed, indicated that hypophysectomy in larval or imma-
ture salamanders of a closely related species i^A. tigrinum)
does not significantly affect growth. Aubrun (1935) removed
the pars glandularis or the neurointermediate lobe from Bufo
arenarum and observed cutaneous changes — hyperkeratosis
and lessened secretion, or paling and capillary dilatation — re-
sembling those previously described by Giusti and Houssay.

Only a few reports dealing with mammals need be con-
sidered here. Houssay and Lascano Gonzales (1935) studied
the effects of hypophysectomy on the dog's spleen. In the
young dog, splenic growth was reduced; in the adult dog,
splenic atrophy appeared to be associated with an increase
in the size of the splenic follicle and an increase in the number
of malpighian corpuscles. The authors considered that the
changes resembled those characteristic of senility. The re-

[35]

THE PITUITARY BODY

port of Freud (1935) on the rapidity of atrophy of certain
endocrine organs after hypophysectomy is of interest to in-
vestigators. According to this author, complete hypophy-
sectomy in the rat is followed by a maximum atrophy of the
gonads in 8-10 days, of the secondary sexual organs in 8-25
days, of the thyroid in 10 days, and of the adrenals in 14-18
days. Liith's report (1937) indicated that spontaneous hypo-
physial deficiency in man (Simmonds' disease) may occur in-
dependently of genetic constitution. He discovered cases of
apparent hypophysial deficiency in individuals with normal
identical twins.

The ejects of growth-promoting hormone {anterior pituitary
extract or tissue). — There is a number of recent observa-
tions, some clear cut, some difficult to classify otherwise,
which bear on the physiology and pharmacology of the
growth-promoting hormone. Murayama, Gurchot, and Gut-
tentag (1937) concluded that a high concentration (2-4 per
cent) of a commercial growth-promoting extract inhibits the
root-growth of seedHngs of Lupinus albus; nothing in the re-
port indicates that this is a specific effect either of growth-
promoting or, indeed, of anterior pituitary extracts. Fresh
fowl pituitary was inserted into incubating hen's eggs by
Pighini (1937) on the third to the fifth day of incubation. The
tissue was absorbed and appeared to favor embryonic growth
(seventeenth day of incubation). However, Wolff and Stoll
(1937) beheve that embryonic growth and differentiation,
including the endocrine organs, takes place in the fowl in the
absence of a functional pituitary body. All the other experi-
ments were performed in mammals. Several investigators
have found that the administration of anterior pituitary ex-
tract to pregnant animals, such as the rat, may prolong gesta-
tion and promote fetal growth; however, it usually appeared
that such changes should be attributed to gonadotropic — ab-
normally prolonged secretion by corpora lutea — rather than
to growth-promoting hormone. Recently, Watts (1935) re-
ported that she was able to cause a significant increase in the

I36]

REGULATION OF GROWTH

weight of both fetuses and mother by administering certain
growth-promoting extracts to pregnant rats. Creep (1936)
studied the replacement value of pituitary grafts inserted into
the sella of rats of both sexes immediately after hypophysec-
tomy, which was performed when the animals were four
weeks old. He obtained partial replacement in about three-
fourths of the animals (5 males and 32 females), in that
growth occurred but did not proceed beyond one-half to two-
thirds the normal adult level. The performance of the sexual
glands was often essentially normal and will be discussed in
chapter iii.

Especially among clinicians there has always been con-
siderable interest in the changes in bones and joints attrib-
uted to alterations in the secretory activity of the anterior
pituitary. Recently Coryn (1936) has reviewed from a clin-
ician's viewpoint the etiological relationship between dis-
eases of bones and joints and changes in the endocrine glands.
He concluded that pituitary hyperfunction — e.g., oxyphil
adenoma of acromegaly — accelerates cellular proliferation and
only in this way affects endochondral osteogenesis. He de-
nied that any secretion of the normal or abnormal anterior
pituitary alters hyaline cartilage or causes hypertrophy of
cartilage cells or calcification of osseous tissue. Also, he be-
lieved that ankylosing or deforming arthritides do not result
from a disturbance of pituitary function, contrary to experi-
mental and clinical observations of others. Silberberg (1936),
as well as Silberberg and Silberberg (1936-37), recently have
studied the changes in the bones and joints of guinea pigs re-
ceiving daily injections of an acid extract of the anterior
pituitary of the ox for 1-20 weeks. The authors concluded
that it is thus possible to produce changes in the joints and in
the chondro-osseous junctions of the ribs resembHng acro-
megalic arthropathia and acromegalic rosary. Also, they
found that callus-formation was delayed by the administra-
tion of the extract. All these changes were equally or more
pronounced in thyroidectomized guinea pigs. The reader is

[37]

THE PITUITARY BODY

referred to the authors' pubHcations for a detailed account of
their findings, which include observations of the effects of
such an extract on other phases of bone-growth in normal
and ovariectomized animals. Mortimer (1937) carefully
studied the changes in bones, especially those of the cranium
of the albino rat, resulting from hypophysectomy or from the
administration of growth-promoting extract. His observa-
tions cannot be adequately summarized in a few words, but
should be read in the original communication by those who
are interested in the endocrine phase of bone-growth and
maintenance.

It will be recalled that the principal gross biochemical
changes in the bodies of normal rats, receiving growth-pro-
moting hormone compared with littermates not so treated,
consist of a diminution in the percentage of "fat" and an in-
crease in the percentage of water, protein, fat-free dry tissue,
and ash. Lee and Ayres (1936) have recently studied some of
the similar biochemical aspects of hypophysectomy in sixteen
pairs of littermate rats, one of each pair being hypophysec-
tomized at a weight of about 210 gm. All the animals re-
ceived the same food in the same quantity. The weight loss
of the hypophysectomized rats was about 20 per cent greater
than that of the normal rats; however, the normal animals
lost more fat (60 per cent loss compared with 28 per cent
loss in operated rats).^ There was a 20 per cent loss of body
nitrogen in the hypophysectomized rats, whereas there was
no loss in the normal group. The percentage of creatine and
creatinine in the carcass was the same in both groups. In
general, the changes observed in hypophysectomized rats
were the reverse of those following injections of growth-pro-
moting extract. Lee and Ayres also studied a number of
nitrogenous constituents, both protein and non-protein, of
the liver. The only conspicuous changes were in the total
non-protein nitrogen, amino acids, and urea, all of which were
present in higher concentration in the liver of the hypophy-

^ Substances extracted by ether.

[^8 1

REGULATION OF GROWTH

sectomized animal. According to Reiss, Schwarz, and Fleisch-
mann (1936), the administration of growth-promoting ex-
tract (containing some adrenotropic but no thyrotropic or
gonadotropic hormone) to the starved dog or rabbit causes,
even after a few hours, a considerable fall in the "rest" N
(10-49 P^^ cent) and free arginine (19-43 per cent) associated
with a rise of 21-66 per cent in the urea N of the blood. Their
results are not fully in accord with those previously reported
by others. In a study of the phosphatase activity of bone and
kidney, Wilkins and others (1935) were unable to detect any
significant difference in adult female rats, some of which re-
ceived injections of a potent growth-promoting extract.
Body, bone, and kidney weights were all increased as a result
of the treatment.

The relationship between the growth-promoting hormone and
other glands of internal secretion, i. The gonads J — Perhaps
the simplest interpretation of the effect of gonadectomy on
growth in certain animals is that the effect is principally due
to a change in the secretory activity of the anterior pitui-
tary. Recently, studies of growth-alterations following gonad-
ectomy in the rat have been reported by Holt, Keeton,
and Vcnnesland (1936), Billeter (1937), Freudenberger and
Hashimoto (1937), and Freudenberger and Howard (1937).
Castrated and normal male rats gow at about the same rate;
however, the normal male tends to grow larger. The spayed
female rat clearly grows more rapidly and maintains its
weight better than the normal female. The difference is not
due to the deposition of fat and may amount to 20 per cent
at an age of 13 weeks (9 weeks after spaying). The glands of
internal secretion as well as other viscera are heavier; the
most striking change is in the thymus which may be 75 per
cent heavier than that of the normal female.

iAt least in the case of the female rat, the internal secre-

i Growth-promoting extract, like others derived from the anterior pituitary, may
contain a substance inhibiting certain gonadotropic effects. This substance has been
named "pituitary antagonist" by Evans and is discussed in chap. iii.

[39]

THE PITUITARY BODY

tions of the ovary appear to inhibit the secretion of growth-
promoting hormone by the pituitary. This behef is further
strengthened by the observation of Spencer, D'Amour, and
Gustavson that the repeated injection of oestrone into grow-
ing rats significantly inhibits growth. Their experiments have
been extended by Zondek (1936-37), Billeter (1937), and
Freudenberger and Clausen (1937).'* Small doses of oestrone,
such as 3 rat-units daily, inhibit the growth of spayed rats
so that they may weigh less than non-injected spayed rats
and, often, less even than normal non-injected rats. How-
ever, such small doses must be given from an early age and
have little effect if first injected when growth is nearing com-
pletion. The inhibition of growth due to larger doses of
oestrone (e.g., 0.02 mg. on alternate days) affects the glands
of internal secretion and, with the exception of the hver, al-
most all the other viscera including the central nervous sys-
tem. Zondek used large doses of oestradiol benzoate in his ex-
periments (e.g., 180,000 mouse-units of "Dimenformon" in
18 weeks). He concluded that the dwarfing of rats by this
treatment was caused by a marked hypophysial deficiency,
which in some cases was complete, inasmuch as no further
growth occurred after treatment was stopped, unless anterior
pituitary growth-promoting extract was injected. Zondek,
also, performed experiments with fowls in which he observed
osteosclerosis (femur, tibia, and fibula). ^

2. The thyroid. — The possible importance of the thyro-
tropic hormone as a participant in the growth effects of an-
terior pituitary extract has already been discussed. There
can be no question concerning the inhibition of growth which
may appear if complete thyroid deficiency is produced early
in life — a statement again emphasized by the recent study of

'^ Shumacker and Lament (1935) were unable to detect any change in the growth
of 6 rats receiving 9 rat-units of oestrone daily between the ages of 23 and 90 days.

s Numerous other observations on the effects of oestrogens on the pituitary and
its secretions are discussed elsewhere (particularly chaps, i and iii). Lauson, Heller,
and Sevringhaus (1937) studied the effects of an oestrogen in the mature spayed
rat. They particularly investigated the pituitary, adrenals, and thymus.

[40I

REGULATION OF GROWTH

Binswanger (1936), who performed his experiments in dogs.
There is real doubt, however, that the thyrotropic hormone
which may be found in growth-promoting extracts is of great
importance so far as growth effects are concerned.^

3. The adrenals. — Moon (1937) found that the injection of
the anterior pituitary hormone stimulating the adrenal cortex
inhibits somatic growth in young rats of both sexes (the au-
thor administered 13-4- "units" over a period of 2-4 weeks).
There was little or no effect on the growth of the spleen, liver,
kidneys, and alimentary canal. Swingle and others (1936) in-
creased the period of survival of adrenalectomized cats by
administering a growth-promoting pituitary extract; how-
ever, they attributed the beneficial effect of the extract to
gonadotropic hormone rather than to a growth-promoting
hormone.

4. The thymus. — The more recent observations suggest
that an internal secretion of the thymus promotes growth
and development. However, there are no observations indi-
cating to what extent such an action may be related to the
secretion of a growth-promoting hormone by the pituitary.
Rowntree, Clark, and Hanson (1935) reported that the ad-
ministration of an extract of the thymus to rats through sev-
eral generations finally led to precocious growth and develop-
ment which might be very marked early in life. The reverse
experiment, thymic deficiency by thymectomy, produced
after 2-3 generations a retardation of early growth, especially
marked at an age of about i month (Einhorn and Rowntree,
1936). The rate of development appeared not to be affected.
Parhon and Coban (1936) also found that thymectomy re-
tards the growth of fowls (Leghorn and Rhode Island vari-
eties). They removed both lobes of the thymus when the
birds were about 3 weeks old; at an age of 6 months the thy-
mectomized fowls weighed about 30 per cent less than the
nonoperated controls.

*The growth of the liver in the duck in relation to the thyroid, gonads, and hy-
pophysis is discussed by Benoit (1937).

[41]

THE PITUITARY BODY

5. The epiphysis. — Engel(i936),as well as Kup (1936), con-
tinues to champion the view that a pineal secretion inhibits
the growth-promoting effects of anterior pituitary secretion.
However, the evidence which they are able to assemble does
not enable one to attach even hypothetical value to this be-
lief. Some observations suggest the opposite effect. For ex-
ample, Takacs (1935) fed dried calf epiphysis to young fowls
(10-35 ^^^g- P^^ day). The birds receiving epiphysis for 4
months weighed more than 200 per cent more than the con-
trols. The excess weight was striking (102 per cent) but less
pronounced after 5 months' feeding, when the experiment was
terminated.

Deficiency of vitamins or minerals and the growth-promoting
hormone. — It appears that failure of growth due to a deficien-
cy of vitamin A or of the "growth factor" of casein cannot be
attributed to a failure in secretion of growth-promoting hor-
mone. This is indicated by the experiments of Margitay-
Becht and Wallner (1937). The authors produced growth
stasis in young rats by diets deficient either in vitamin A or
in the alcohol-ether extract of casein. In neither case did the
administration of anterior pituitary growth-promoting ex-
tract cause a resumption of growth. There remains, of course,
the possibility that the dietary deficiency had rendered the
tissues refractory toward the hormone.

Orent-Keiles, Robinson, and McCoUum (1937) concluded
that a sodium-deficient diet, more than diets deficient in CI
or NaCl, interferes with growth in the rat. Whether or not
this change as well as others, particularly in the female or-
gans of reproduction, depends to an important extent on
changes in the anterior pituitary is not known. According to
Hove, Elvehjem, and Hart (1937), zinc appears to be an im-
portant factor in the secretion or peripheral action of a pitui-
tary hormone controlling (favoring) the movement and tone
of the digestive tract of the rat. With a deficiency of zinc in
the diet and therefore with a deficiency of this hypothetical
hormone, intestinal absorption is delayed and reduced so

REGULATION OF GROWTH

that growth is retarded. The protein phase of metabolism ap-
peared particularly to be reduced. The authors' dismissal of
the growth-promoting hormone as the important factor is
largely based on the greater effect of whole pituitary implants
in comparison with that of a growth-promoting extract
("Antuitrin G"). However, the comparison was made under
different conditions as to the age of the rats and the duration
of zinc-deficiency. Therefore, until growth-promoting hor-
mone or other better-defined anterior pituitary hormones
have been clearly excluded, it is undesirable to identify a new
pituitary hormone on so slender a basis.

The effect oj growth-promoting hormone on the growth of yteo-
plasms. — Engel (1935) has made further observations on the
relationship of the pituitary and of gonadotropic hormones
(prolan, gonadotropic hormone of pregnant-mare serum) to
the growth of transplants of EhrHch's adenocarcinoma in
mice. He concluded that gonadotropic hormones may have
some inhibiting effect on the growth of the tumor and that
pineal extract may have a marked inhibitory effect. He be-
lieved that the depressing effect of pineal extract is indirect
and due to a secretory inhibition of, or antagonism toward,
the growth-promoting hormone. Several recent authors
agree that hypophysectomy retards the growth of malignant
neoplasms, especially if transplantation is delayed several
weeks after operation (Walker mammary carcinoma: Sam-
uels and Ball, 1935; neoplasm due to i :2:5:6 dibenzanthra-
cene: Ball and Samuels, 1936; transplanted neoplasm: Reiss,
1936). Reiss found that the oxygen-consumption of such
tumors is low, but that aerobic glycolysis remains unchanged
or increases. Emge and Murphy (1936), investigating the
growth of autogenous sarcoma in the rat, observed no striking
effect of hypophysectomy on tumor-growth except when
transplantation was undertaken some time after operation.
They could detect no increased rate of tumor-growth as a re-
sult of the administration of growth-promoting extract to
tumor-bearing normal or hypophysectomized rats. Likewise

[43]

THE PITUITARY BODY

Zondek (1937) concluded that the secretion of growth-pro-
moting hormone does not influence the growth of a sarcoma
due to benzpyrene; for the tumor grew no better in normal
rats than in rats dwarfed because of the injection of large
doses of oestradiol benzoate.

Druckrey (1936) believed that pituitary gonadotropic hor-
mone inhibits tumor-growth in the rat. As malignant neo-
plasms he used the Flexner-Jobhng carcinoma and the Jensen
sarcoma. Shortly after castration, tumor-growth appeared
to be unusually rapid. Later, however (4-6 months after
castration), when the gonadectomized animal's pituitary
contains and secretes the maximum amount of gonadotropic
hormone, inhibition and even failure of tumor-growth ap-
peared. Largely from this finding Druckrey reached the con-
clusion stated above.

Both recent and older observations permit the drawing of
only Hmited conclusions as to the control of the growth of
neoplasms by the anterior pituitary. If there is a complete
pituitary deficiency, the initiation of neoplastic growth is
more difficult; if the deficiency is produced after neoplastic
growth is under way, further growth may take place at a
slower rate. Certainly the pituitary appears not to be an im-
portant regulator of cellular proliferation in tumors. The
conclusion of Engel — that pineal extract inhibits the growth
of a carcinoma by acting on the pituitary — as well as the in-
ference of Druckrey — that the growth of a sarcoma or car-
cinoma is inhibited by the secretion of gonadotropic hor-
mone— hardly deserve acceptance without data from more
complete experiments.

The assay of growth-promoting extracts. — Several matters of
technic must be mentioned in connection with the assay of
growth-promoting extract. Evans, Pencharz, and Simpson
(1935) pointed out that crude rather than purified extracts
seem to have more certain efi^ects and may be active if given
to animals no longer responding to a purified extract. Also,
Mortimer (1937) found "resistance" appeared later toward

t44l

REGULATION OF GROWTH

crude extracts than toward more purified extracts. It is diffi-
cult to correlate these observations with the conception of
"antihormones."

Evans and his colleagues found that if hypophysectomized
rats failed to respond to an extract, there might occur a strik-
ing response if glucose solution was also administered paren-
terally.^

Factors influencing the assay of growth-promoting hor-
mone have been studied in normal and hypophysectomized
rats by Chow, Chang, Chen, and van Dyke (1938). In nor-
mal rats, in confirmation of the work of others, they found the
young adult female rat most suitable. Sex does not affect
the response of hypophysectomized rats which, in terms of
the percentage change in weight, is at least twice as great as
that of normal rats. Rats with a hypophysial deficiency of
8-10 months are less sensitive than those hypophysectomized
1-6 months before assay. Differences in response in relation
to dosage are more easily recognized in hypophysectomized
rats, whereas in normal rats a doubling of the dose may not
be followed by a change in response which is convincingly
greater. In either normal or hypophysectomized rats the
optimum period of injection probably is not longer than 10
days. Even 6 weeks after the use of rats for assay, their re-
sponse to a second course of injections is reduced.

The preparation and purity of growth-pro?noting extracts of
the anterior pituitary. — The only recent attempts to purify
growth-promoting extracts are those of Dingemanse and
Freud (1935). They stated that their preparation contained
neither lactogenic nor thyrotropic hormone and that 0.025
mg. administered intraperitoneally once daily to hypophy-
sectomized rats (120-80 gm.) caused an average gain of
weight amounting to 7 gm. following administration for one
week. The method they described required the following

'According to Shelton, Cavanaugh, and Long (1935), the effect of growth-pro-
moting extract in adult female rats is potentiated by the injection of 0.5 cc. of hu-
man serum 3-6 weeks previously.

[45]

THE PITUITARY BODY

steps: adsorption on norit from a weakly alkaline solution,
elution of the hormone by phenol, and subsequent precipita-
tion by a solution of one part of alcohol in two parts of ether.
The authors also concluded that the hormone could dialyze
through collodion membranes and that the nitrogen content
of the material in the sac was higher than that of the dialyzed
material. The dialysis was performed at a very high pH
(o.oi NNaOH).

Summary. — The clear-cut identification of a growth-pro-
moting hormone in the anterior pituitary is perhaps the prob-
lem of greatest immediate importance to those interested in
this aspect of the physiology of the pituitary body. On the
other hand, if such a hormone is not secreted by the gland,
new interpretations of much satisfactory data will have to
be made. It is still possible, however, provisionally to use the
term "growth-promoting hormone."

Few of the recent observations require reference in this
summary. Experimentally, changes in bones and joints,
some resembling those of acromegaly, have been more exten-
sively studied. Additional data on general biochemical
changes due to hypophysectomy have been secured. As far
as other glands of internal secretion are concerned, there is
additional evidence, at least in the rat, that the oestrogenic
secretion of the ovary may act as a brake on general growth.
Endocrine glands such as the thyroid, adrenals, thymus, and
epiphysis may affect growth — sometimes positively, some-
times negatively. How such effects are related to excessive or
reduced secretion of the growth-promoting hormone in no
case has been convincingly demonstrated. The growth of
malignant neoplasms may be slightly favored by anterior
pituitary secretion; this effect, however, appears not to be im-
portant. Recently little attention has been paid to the purifi-
cation of the growth-promoting hormone. This may prove
to be an impossible task made even less attractive by the dif-
ficulties of accurate assay.

CHAPTER III

THE GONADOTROPIC HORMONES OF THE
PITUITARY BODY

IF THE number of articles published were acceptable as
a safe basis of judgment, it could easily be concluded
that the gonadotropic hormones are the most important
secreted by the anterior pituitary. This field of inquiry is
attractive not only because of its inherent importance but
also because the probability of securing fruitful results is
great. There can be no doubt that the anterior pituitary
secretes gonadotropic hormone(s) essential for the normal
functioning of the gonads of mammals and other vertebrates.
As a result, nearly every investigator interested in the physi-
ology of the gonads has quickly entered or wandered into
the rich and diversified field of pituitary-gonad interrelation-
ships— sometimes without reaHzing he is there. Furthermore,
work may be greatly facilitated by the fact that the assay
of the hormones with a fair degree of accuracy is often, but
not always, easily accomplished.

Despite all the labor represented by a vast number of re-
ports during the past few years, it is not yet possible to
enumerate satisfactorily the gonadotropic hormones of the
pituitary. Separate follicle-stimulating and luteinizing hor-
mones are generally believed to exist; it is by no means cer-
tain that the former specifically maintains the mammalian
seminiferous tubules, whereas the latter insures the normal
secretion of testicular hormone by the interstitial cells. It
has been reported that principles synergizing with or an-
tagonizing gonadotropic hormone have been extracted from
the pituitary; however, their physiological importance is
largely postulated from deduction. Several authors have rec-
ognized the great importance of excluding the animal's own

[47]

THE PITUITARY BODY

pituitary in determining accurately qualitative and quantita-
tive effects of extracts. The increased accuracy of interpre-
tation more than justifies the great increase of labor required.
Final judgment on the effect(s) of an extract should be
based upon experiments with hypophysectomized animals.

The follicle-stimulating hormone often excreted in human
urine in considerable amounts after spaying or castration or
after the menopause probably originates in the anterior pitui-
tary. On the other hand, the gonadotropic substances dis-
cussed in chapter iv appear not to be secreted by the hy-
pophysis. These substances are prolan (from the chorionic
cells of the human pregnant uterus), the gonadotropic hor-
mone characteristic of pregnant-mare serum (likewise prob-
ably secreted by chorionic orendometrial cells), and the gonad-
otropic hormones of neoplasms such as hydatidiform mole,
chorionepithelioma, and testicular tumor (from the cells of
the neoplasms).

In this chapter a systematic account of pituitary-gonad
interrelationships, especially as these are understood from
later work, will be attempted. It is hoped that the reader will
recognize the diversity of the literature both in subject mat-
ter and in quality. Diversity in the former often makes ar-
rangement difficult. Diversity in the latter may lead to defi-
nite conclusions, either sound or wrong. Sometimes, however,
the only reasonable position to take is one of suspended
judgment, unwelcome as this may be to many readers.

THE BIOLOGY OF THE GONADOTROPIC
HORMONES IN VERTEBRATES

Fishes. — Using an extract of ox pituitary. Young and
Bellerby (1935) were unable to produce either significant
changes in the gonads or metamorphosis in the lamprey
{Lampetra planeri). However, changes in body-shape and
marked cloacal swelling, both secondary sexual characteris-
tics of the period preceding spawning, appeared. In earlier
reports several authors had succeeded in producing spawning

[48]

THE GONADOTROPIC HORMONES

or hypertrophy of the gonads in other fishes. Usually changes
in the gonads or secondary sexual organs of fishes, including
spawning, can be produced by fish pituitary but not by
mammalian pituitary or by extract of the mammalian pitui-
tary. However, dosage may not have been adequate. De-
scriptions of experiments and references to other work can
be found in the reports of Gerbilsky and Kashchenko (1937)
and of von Ihering and de Azevedo (1937). ArtemofF (1936)
successfully used the pituitary of the frog.

Amphibia. — The majority of the reports previously re-
viewed indicated that the amphibian pituitary has an im-
portance in the maintenance of the gonads corresponding to
that in mammals. The most that will be attempted here is
to bring the references up to date by citing the work of recent
authors.

I. Anuran amphibia. — Several aspects of the biology of
gonadotropic hormones have been studied in six species of
frogs {Bombinator igneus^ Hyla arborea^ Pelobates Juscus^^
Rana esculenta^ R. pipiens^ and R. tempot^aria^'"^). Several
authors have studied ovulation or oviposition or both. Ros-
tand administered the extract of 6-20 pituitary glands of the
same species to R. esculenta^ R. temporaria., or Bujo vulgaris.
He found that ovulation could be produced 5 months before
the normal time. It was more difficult to induce ovulation
earlier; moreover, the ova then were often not mature and
could not be fertilized. Similar results were reported by Gal-
lien who used R. temporaria. The number of eggs extruded
appeared to be proportional to the dose of frog pituitary
(6-9 glands as a saline extract) or beef anterior lobe (1.6-3
gm. as an alkaline extract). The very low potency of the
pituitary of the ox was previously reported by others (e.g.,
Rostand using H. arborea). Gallien observed no effect from
the injection of urine of spayed women (3-8 cc.) or urine of
pregnancy (7-9 cc). According to Rostand, extract of the
pituitary of R. esculeyjta or Bujo vulgaris can readily induce

' Rostand (1934-35). ' Rugh (1937). 3 Gallien (1937). " Shapiro (1937).

[49]

THE PITUITARY BODY

ovulation in H. arborea but not in Bombinator igneus^ unless
the ovary contains ripe ova. He found P.fuscus, even when
the ovaries contained ripe ova, very insensitive toward either
type of pituitary extract. ^

Rugh concluded that the anterior pituitary of the male frog
{R. pipiens)^ although somewhat heavier than that of the
female, contains little more than half the amount of ovula-
tion-inducing hormone. He stated that usually within 24
hours oviposition in mature frogs followed the intraperitoneal
administration of the pars glandularis of two adult females or
four adult males. In the hibernating male frog of the same
species, Rugh found that about 16 hours after the administra-
tion of anterior pituitary gonadotropic hormone, amplexus
(with an ovulating female of the same species only) and the
release of all mature spermatozoa could take place. Sperma-
tozoa were found in the lumen of seminiferous tubules, in
Bowman's capsule, the renal tubules, and the ureter. In an-
other article, Rugh reported on seasonal changes in ovarian
and pituitary weight and the relationship of such changes to
alterations in pituitary gonadotropic effects. Shapiro (1936-
37) has particularly studied the clasping reflex in R. tempo-
raria and Xenopus laevis (a toad). He decided that secretions
of both the pars glandularis and the testis or ovary are neces-
sary for the initiation of the reflex. The reflex, followed by
ovulation, oviposition, and fertilization, could be produced
in Xenopus by the injection of pregnancy-urine extract or an
acid extract of the pars glandularis of the sheep or goat. In
B. arenarum the removal of the pars glandularis a few days
after subtotal extirpation of testis tissue prevents the marked
compensatory growth of the latter (Houssay and Lascano-
Gonzalez, 1935).

The implantation of pituitary tissue of the frog or toad can
cause ovarian stimulation in the immature mouse (Benazzi,
1937; and Zwarenstein, 1937). However, the potency of am-
phibian pituitary is much less than that of mouse pituitary.

5 See also Osima (1937).

[50]

THE GONADOTROPIC HORMONES

Shapiro (1937) attributed the inhibiting or stimulating effects
of an extract of sheep pituitary, used chiefly for its lactogenic
effects, to contaminating gonadotropic hormone. The author
studied the extract's effects on the amphibian testis.

2, Urodele amphibia. — Adams and Mayo (1936) investi-
gated the effects of homo-implants on oviposition in a sala-
mander, Triturus viridescens. They were able to produce
oviposition in the nonbreeding months stretching from Oc-
tober to early March. The effect appeared earlier at 20°
than at 14° C. (resembling the observation of Bellerby in
X. laevis; Bellerby used beef anterior-lobe extract). The male
pituitary was perhaps the more potent; the pituitaries of
animals gonadectomized 4-98 days previously were possibly,
but not definitely, more potent than normal glands. Klein-
schmidt (1937) studied the changes in the male gonads of
hypophysectomized larvae of T. vulgaris for many months
postoperatively. Although regressive changes in the germi-
nal cells of the testis were clearly marked, especially 3-10
months after hypophysectomy, yet 20 months postopera-
tively islands of healthy cells with spermatogonia, resembling
normal testicular tissue of animals four months old, could be
found. The Wolffian and Miillerian ducts were both well de-
veloped; however, the latter was not joined to the cloaca.
Some degenerative changes in the follicle-cells of the testis
were found. The fat body was not altered until an age of
1 4 months, after which it underwent hypertrophy because of
hyperplasia.

Reptiles. — According to Evans (1935), the gonads of imma-
ture young lizards {Anolis carolinensis) of either sex could
be stimulated by prolan or by extract of whole sheep pitui-
tary. In the male the same effects were produced by either
extract: testicular hypertrophy, hypertrophy of the hemi-
penis, epididymis, and vas deferens, spermatogenesis, eleva-
tion of the dorsal crest, frequent molting, behavior changes,
etc. In female animals prolan brought about hypertrophy of
the ovary and oviduct as well as more frequent molting and

[5']

THE PITUITARY BODY

behavior changes. Only sheep pituitary extract caused, in
addition to these changes, maturation of ova or ovulation
and oviposition. MelHsh (1936) investigated pituitary-gonad
interrelationships in the horned lizard, Phrynosoma cornutum.
Prolonged illumination of animals furnished abundant food
and kept at a high temperature (35° C.) for six weeks during
winter had little effect on the gonads (control lizards hiber-
nating at 5° C). On the other hand, if the experimental ani-
mals were also given the equivalent of 3 gm. of whole pitui-
tary of the pig, the gonads of both sexes were stimulated so
as to resemble those of animals early in the breeding season.
Other experiments in similar lizards have been reported by
Mellish and Meyer (1937). hw increased ovarian weight,
largely due to an increased deposition of yolk, was produced
by the administration of various anterior pituitary extracts
or pregnant-mare serum. The animals were well fed and
kept at 32° C. under continuous artificial illumination. None
of the animals was hypophysectomized. An unfractionated
anterior pituitary extract did not affect the ovaries of ani-
mals hibernating at 5° C. At that temperature there ap-
peared to be only partial absorption of the extract.

Forbes (1937) investigated the action of an alkaline extract
of whole pituitary of sheep in immature alligators (4-18
months after hatching). Some hypertophy of the ovaries to-
gether with marked growth of the oviducts occurred in fe-
male animals. There was no effect on the Wolffian ducts. In
males a marked hypertrophy of the testes, without sperma-
togenesis, was produced. The size of the mesonephron in
males receiving the extract was reduced.

Birds. — In the past few years there has been reported a
considerable number of new or more detailed observations
on the physiology of gonadotropic hormones in birds. Almost
all deal with hormones of pituitary origin.'' An interesting as-

* Later reports also support the conclusion that prolan has no significant effect
on the gonads of birds (Hill and Parkes, 1935; Witschi and Keck, 1935; Uhl and
others, 1937). Breneman's results (1936) apparently were inconclusive. Koch
(1935) could not confirm his earlier report that prolan brings about an increase in
the egg-laying performances of hens.

THE GONADOTROPIC HORMONES

pect of work in this field is the manner in which the duration,
intensity, and quaHty of light may affect the reproductive
organs of both birds and other vertebrates. There is every
likelihood that such effects of light are mediated through the
pars glandularis; moreover, such effects are additional evi-
dence in favor of the physiological importance of efferent
secretory fibers, innervating the anterior pituitary. In the
account which follows, recent general work in birds will be
considered first. At the end of this section the effects of light
on the sexual organs of other vertebrates, including mam-
mals, will be discussed.

Domm and Dennis (1937) caused definite changes in the
gonads of chick embryos by administering sheep pituitary
extract (see Fig. 9). Five rat-units were administered daily
during the 5-9 days of incubation, the embryos being re-
moved later (e.g., the eighteenth day). In female embryos
there occurred hypertrophy of the ovary (chiefly of the
medulla) and rudimentary right gonad. (Injections during
post-embryonic life did not produce the latter effect.) Testic-
ular hypertrophy in male embryos was less frequent and
less pronounced; when present it was due principally to a
change in interstitial tissue. Alterations of the Miillerian or
Wolffian ducts or of the head furnishings did not occur. Hy-
brid embryos responded better than pure-bred Leghorns.
Breneman (1936) studied the effects of follicle-stimulating
and luteinizing hormones on the gonads of chicks 5-15 days
after hatching.^ The author's experiments were often com-
plex, and some of his conclusions appear not to be firmly es-
tablished. Maximum gonad-stimulation was produced by pi-
tuitary foHicle-stimulating hormone or pregnant-mare serum.
He believed that, as in the mammal, the follicle-stimulating
hormone affected the tubules of the testis, whereas the lutein-
izing hormone acted on the testicular interstitial cells. Also,

^ The lactogenic hormone, which according to Riddle and others brings about a
reduction in the weight of the male or female gonads of fowls or pigeons, was without
effect in the very young chicks.

[S3]

/T. TodcL 'd5

Fig. 9. — The action of pituitary gonadotropic hormone on the urogenital tract of the female
chick embryo. (From Domm and Dennis, Proc. Soc. Exp. Biol. Med., 36, 766-69 [1937].)

Lejt: control; right: treated embryo which received 5 rat-units of sheep pituitary extract for
5 days (fifth to ninth day of incubation); incubation of both embryos continued until the
eighteenth day. rr: right rudimentary gonad; lo: left ovary; wb: Wolffian body; wd: Wolffian
duct; Im: left Miillerian duct; rm: remnant of right Miillerian duct; a: adrenal; c: cloaca;
m: kidney; u: ureter.

THE GONADOTROPIC HORMONES

he concluded that the action of folhcle-stimulating hormone
(of the pig's pituitary) is inhibited if, prior to injection, it has
been mixed with luteinizing hormone, lactogenic hormone,
or an extract of pregnancy-urine.

Compensatory hypertrophy of the testis as well as several
other phases of the pituitary-gonad interrelationship was
studied in Leghorn cockerels by Belsky (1936). The author
concluded that the compensatory hypertrophy in young birds
is associated with pituitary hypertrophy. Under other condi-
tions hypertrophy of the pituitary is associated with an ab-
sence or diminution of gonad function (castration or times
of seasonal rest of the gonads).

Brown Leghorn hens were hypophysectomized by Hill and
Parkes (1935). The expected reversion of the feathers to the
male (asexual) type was observed only in the neck hackles.
Plumage changes characteristic of thyroidectomy appeared
in the hypophysectomized cock. These changes as well as
atrophy of the testis and comb could be lessened only for a
few days by the injection of beef anterior pituitary extract.
The administration of testicular hormone, but not of oestrone,
caused growth of the atrophied comb.

Witschi and Keck (1935) investigated the action of extract
of the pituitary of the horse and ox on the gonads of the
English sparrow. Preliminary observations indicated that
great seasonal variations occur in both sexes — marked growth
of the gonads occurring in spring and early summer and rapid
involution taking place in July and August.^ Secondary sex-
ual characters such as the color, shape, and texture of the
bill underwent corresponding alterations. The daily adminis-
tration of pituitary gonadotropic hormone (e.g., 2 rat-units
for 16-33 days) could cause a sixty-fold increase in the size
of the testis or ovary of birds with resting gonads. The antic-
ipated alterations in secondary sexual characters, such as

^ During involution the testis might regress to one-thousandth its previous size;
the ovary might atrophy to the size of that of an immature bird 2-3 months old.

[55]

THE PITUITARY BODY

the color of the bill and the size of the oviduct, were observed
(see Figs. lo and 1 1).

The pituitary of birds contains gonadotropic hormone cap-
able of stimulating the mammalian ovary (Leonard, 1937,
fowl pituitary, ovulation in the rabbit, or ovarian hyper-
trophy in the normal or hypophysectomized rat; Witschi,
Stanley, and Riley, 1937, turkey pituitary, ovarian hyper-
trophy in the normal or hypophysectomized rat). Leonard
concluded that the fowl's pituitary contains luteinizing hor-
mone as well as the hormone stimulating the adrenal cortex.

Fig. 10. — The effect of daily injections of 2 rat-units of pituitary gonadotropic
hormone on the size of the testis and the color of the bill of the English sparrow.
(From Witschi and Keck, Proc. Soc. Exp. Biol. Med., 32, 598-603 [1935].)

A few other observations were made, chiefly in male birds.
Evans and others (1936) concluded that the apparently
great sensitivity of the immature pigeon's testis toward pi-
tuitary gonadotropic hormone depends upon the lack of ef-
fect of pituitary "antagonist." If the latter is first removed
from a pituitary extract, the ovary of the immature rat is
equally sensitive. Riddle and Schooley (1935), basing their
assays on the testicular response of the immature ring dove,
studied the gonadotropic potency of the pituitary of the
pigeon and the rat. The pituitary of pigeons or ring doves,
1.8-2.5 months after hatching, contained no gonadotropic

[56]

THE GONADOTROPIC HORMONES

(follicle-stimulating) hormone. The pituitary of the adult
pigeon was more potent than that of the immature rat. Clark,
Leonard, and Bump (1937) reported that the testis of the
immature pheasant responds well to the administration of
sheep pituitary extract. A study of the changes in the testis
and comb of chicks receiving injections of male hormone
(extract of male urine, dihydroandrosterone benzoate, testos-
terone, or its propionate) was made by Breneman (1937).
In some instances testicular growth was prevented during

Fig. II. — The effect of i6 daily injections of 2 rat-units of pituitary gonado-
tropic hormone on the ovary and oviduct of the English sparrow. (From Witschi
and Keck, Proc. Soc. Exp. Biol. Med., 32, 598-603 [1935].) Lejt: largest of con-
trols; right: injected bird.

the period of injection (5-10 day after hatching) but in-
creased markedly during the three following weeks. Bagg
(1936) was interested in the production of teratomata in the
fowl's testis by injecting into the gland 0.3 cc. of a 5 per cent
aqueous solution of ZnCL. His injection schedules were most
varied and his results permit only the following conclusions:
(i) previous treatment with sheep pituitary extract made
possible the production of teratoma testis in 2 of 26 birds
(one in June, the other in August), resembling the effect of
zinc chloride solution alone (2 of 20 birds in the spring); (2)

[57]

THE PITUITARY BODY

at seasons other than spring, this effect is not produced by
zinc chloride solution (200 birds); (3) although prolan was
used, there is no evidence that it had any effect.

The effects of light on the activity of the gonads has re-
ceived increased attention since 1934.'' In certain vertebrates
in which sexual activity is cyclic, i.e., varies with the season,
light-variation appears to be the principal environmental
change responsible for the growth or decay of activity of the
reproductive organs. It is reasonable to conclude that the
stimulus of light reflexly initiates the secretion of gonado-
tropic hormones by the anterior pituitary."* What Bisson-
nette termed "sexual photo-periodicity" probably depends up-
on the effect of radiations of different wave-lengths on an
opticohypothalamo-hypophysial, nervous glandular mechan-
ism. The most convincing data have been secured in birds
and mammals.

According to Hoover (1937), precocious ovulation and
spermatogenesis occur in rainbow trout {Salmo irideus), if
the fish are subjected to prolonged illumination during the
period of sexual inactivity. Such trout normally spawn in
March (New Hampshire). In brook trout {Salveliniis foriti-
nalis) spawning takes place when the hours of daylight are
diminishing (October to December). Hoover produced in
this species ovulation and spermatogenesis three months
earlier than normal by increasing and then diminishing the
duration of illumination. In the horned lizard, Phrynosoma
cornutum^ increased light and a higher temperature did not
modify the size of the sexual organs during hibernation
(MelHsh, 1936).

Direct evidence that light may control cyclic sexual activi-
ty in birds and mammals is furnished by studies of the
morphology of the gonads or of the effects of their internal

9 For recently published, general articles, see Bissonnette (1936) and Marshall
(1937)-

" Marshall (1937) cited evidence that in a few animals increased activity of the
gonads is associated with reduced solar illumination. This also appears to be true
of the macaque monkey in captivity.

[5«]

THE GONADOTROPIC HORMONES

secretions on behavior or on secondary sexual characters.
The inference that these changes represent the effects of a
reflex release of anterior pituitary gonadotropic hormones ap-
pears to be justified, because (i) the pars glandularis is as
necessary for the maintenance of the avian gonads as for
the mammalian, (2) the administration of pituitary gonado-
tropic hormone may markedly stimulate the immature or
resting gonads of birds or mammals, (3) in some experiments
(in the drake, Benoit, 1936; in the ferret, Bissonnette, 1935)
it has been shown that the removal of the pars glandularis
prevents gonad-stimulation, otherwise occurring as a result of
increased illumination, and (4) the anterior pituitary con-
tains nerve fibers, probably secretory in character, which
have a likely origin in hypothalamic nuclei. To Rowan
(1915) belongs the credit for making the first experimental
observations in birds. He concluded that prolonged artifi-
cial illumination of the junco {Junco hy emails) leads to pre-
cocious testicular development during the period of sexual
inactivity. Recent studies bearing on the effect of light or
the mechanism of this effect have been made in game birds"
and in the sparrow and duck.

In the English sparrow {Passer domesticus) the "ration of
light" may largely determine testicular growth so that in
midwinter increased illumination may cause precocious testic-
ular hypertrophy with spermatogenesis and blackening of
the beak. Temperature, as Rowan concluded from his study
in the junco, is of little importance. In the spring, however,
reduced illumination may partially but not completely sup-
press normal testicular development (Kirschbaum and Rin-
goen, 1936). From later studies, the authors (Ringoen and
Kirschbaum, 1937) concluded that the testicular response to
light depends almost entirely upon a "stimulus through the

" Observations of Clark, Leonard, and Bump (1937) in the grouse, pheasant, and
quail. The authors suggested that regression of the gonads in the presence of an
apparently adequate photostimulus is due, for unknown reasons, to a lessened
anterior pituitary secretion, inasmuch as gonad-stimulation by injected extract can
still be produced.

[59]

THE PITUITARY BODY

ocular region." In contrast to this view, Ivanowa (1935) be-
lieved that an important part of the effect is due to the action
of light on the whole body surface. According to Benoit
(1935), neither section of the optic nerves nor enucleation of
the eyes prevents precocious testicular growth caused by arti-
ficial light in the immature drake. Apparently the light had
to reach the empty orbits; for if hoods were placed over the
latter, testicular development was prevented. Experiments
like those just cited indicate the urgent need for more obser-
vations on the afferent pathways of reflex photostimulation
of the pituitary in birds. Ivanowa's experiments are open
to the objection that the birds' eyes may not have been ade-
quately hooded. It is difficult to believe that there is an im-
portant peripheral afferent arc other than the optic nerve.

Benoit (1935-37) has made a number of other observations
in drakes either immature or during the period of normal
regression of the testis. (The effects on the gonad of the fe-
male are slight and appear much more slowly.) The testicular
response depends not only upon the duration of illumination
but also upon the wave-lengths (quaHty)" used and the dis-
tribution of "light-dosage." Testicular growth ceases if, dur-
ing artificial illumination, the drake's anterior pituitary is
removed. The gonadotropic potency of the drake's pituitary
in immature mice may be increased if the hours of illumina-
tion are experimentally lengthened. Such experimental de-
velopment of the testis and penis, for some weeks at least,
was found to be lessened greatly by thyroidectomy. How
thyroid deficiency acts, whether by interfering with secretion
by the stimulating organ (anterior pituitary) or by diminish-
ing the response of the end organ (testis), is not clear. The
feeding of thyroid extract or the injection of thyroxine acceler-
ates the rate of testicular growth.

Light has been shown to influence greatly the development
of the gonads or secondary sexual characters including be-

■^ In one report, Benoit states that red and infrared radiations are especially
effective.

I60I

THE GONADOTROPIC HORMONES

havior in mammals with yearly sexual cycles. Oestrus and
the conditions necessary for its production by artificial illumi-
nation have been repeatedly studied in the ferret.'-' Both the
"quantity" and the wave-length of light are important. Vari-
ations in duration, the quantity of light remaining unaltered,
do not influence the rate of acceleration of oestrus (Marshall
and Bowden). These authors also concluded that, whereas in-
frared rays had little effect, ultraviolet rays caused a pre-
mature appearance and abnormal persistence of oestrus. Bis-
sonnette found that the light and hair cycles of the ferret de-
pended upon an intact pituitary, Hypophysectomy pre-
vented both oestrus and its associated hair cycle even in ani-
mals artificially illuminated. Apparently the effect on hair-
growth may be due to the direct action of a pituitary hor-
mone, inasmuch as cyclic changes in hair-growth are not in-
fluenced by gonadectomy. Hill and Parkes were not able to
prevent or delay the onset of oestrus and gonad development
at the usual time of breeding by keeping animals in darkness.
Although the authors agreed that the effect of light on the
anterior pituitary probably explains how oestrus is initiated
in the anoestrous season by increased illumination, they de-
nied that the increasing length of daylight is responsible for
normal oestrus. Bissonnette stated that the latter may be de-
layed or made to persist by severing both optic nerves. Fer-
rets in precocious oestrus have been successfully bred by Bis-
sonnette and Bailey.

In a preliminary report, Whitaker (1936) reported that
white-footed mice {Peromyscus leucopiis noveboracensis) went
into oestrus 6-8 weeks early if they were treated with a com-
mercial ultraviolet lamp. By the increase of the daily ration
of artificial illumination a similarly precocious oestrus with
pregnancy was produced in the raccoon {Procyon lotor) by
Bissonnette and Csech (1937). In the female rat, reversed
illumination (light by night, darkness by day), darkness, or

'^ Late reports are those of Hill and Parkes (1934), Bissonnette (1935), Bisson-
nette and Bailey (1936), and Marshall and Bowden (1936).

[61I

THE PITUITARY BODY

a constant auditory stimulus does not affect the periodicity
of the oestrous cycle (Browman, 1937). However, the au-
thor found that constant illumination might cause a per-
sistence of oestrous smears of the vaginal epithelium from
a few days to several weeks. Normal cycles of oestrus, as
would be expected, were present in animals bhnded by cut-
ting the optic nerves or enucleating the eyeballs. Either op-
eration caused a resumption of normal cycles in animals in
constant oestrus because of continuous illumination or pre-
vented the development of persistent oestrus in similarly
treated animals. '"*

Mammals. — In this section, recently acquired general in-
formation concerning the gonadotropic hormones of the pitui-
tary body will be discussed. There will be no further con-
sideration of the effects of light on the secretion of gonado-
tropic hormones; these are referred to in the preceding section.

I. Female mammals. — There is a number of new reports
chiefly concerned with the effects of hypophysectomy on the
female gonads.'^ Swezy (1936) has again affirmed that the
rate of ovogenesis is accelerated in the rat's ovary as a result
of hypophysectomy. However, degeneration of the follicle
appears after growth has proceeded to a depth of 6-8 rows
of cells. She pointed out that this is the sole example of a

■■" See also Hemmingsen and Krarup (1937).

'5 Lacassagne (1935) concluded that the cells of the pars glandularis and other
parts are quite insensitive toward radon or X-rays. His experiments were performed
in rabbits. Although he was able, by the insertion of a tube containing i mg. of
radium, to cause destruction of the gland for a distance of 1.5-1.8 mm. accompanied
by the characteristic secondary changes in the ovary in about a week, he doubted
that radiation of the pituitary has therapeutic possibilities so far as ovarian function
is concerned. Even after complete destruction of the pars intermedia and pars
neuralis together with destruction of two-thirds of the pars glandularis, ovarian
function is not affected. His estimate that adequate anterior pituitary secretion is
maintained by one-third of the pars glandularis agrees well with the estimates of
Aschner (dog) and Smith (rat).

Newell and Pettit (1935) found that irradiation (X-rays directed toward each
temple in small doses for 5 weeks) led to improvement in the subjective symptoms
of two-thirds of a group of women with dysmenorrhea (26 patients). Sham irradia-
tion had the same effect in half the proportion of a group with similar symptoms
(i.e., in one-third of a group of 15 patients).

[62]

THE GONADOTROPIC HORMONES

biological process undergoing acceleration as a result of an-
terior pituitary deficiency. Some dilute acid extracts of the
pars glandularis produced the same effect — suggesting that

-^1.45

.0^13.9

o ^250

9^25

10 10 iO

DAY^ AFTLR hYPOrHySCCTOMY

Fig. 12. — Variations in the weight, total follicle-count, mean diameter of the
largest follicles, and per cent of vesicular follicles of the ovary of the rat following
hypophysectomy at an age of 28 days. Each point represents the mean of deter-
minations from 3 rats. (From Lane and Creep, Anat. Rec, 63, 139-46 [1935].)

this action was due to inhibition of anterior pituitary secre-
tion. Lane and Creep (19.35) studied in detail the follicles
and the weight of the ovary of the rat hypophysectomized
at an age of 28 days. A graph summarizing their results is
reproduced in Figure 12. It will be noted that groups of

[63]

THE PITUITARY BODY

animals were studied for more than 6 weeks after hypophy-
sectomy. These results are of interest to everyone employing
hypophysectomized immature female rats for the assay of
gonadotropic hormone. The belief that a rise in ovarian
weight takes place about 4 days postoperatively requires
confirmation. The authors found that the injection of fol-
licle-stimulating hormone into hypophysectomized rats
caused an increase in the total number of follicles with a de-
crease in the proportion of those which were vesicular. The
proportion of vesicular follicles — without any effect on the
total number — was increased by the injection of luteinizing
hormone.

Because of the monkey's closer biological relationship to
man, the experiments of Smith, Tyndale, and Engle (1936)
are of unusual interest. These authors found that marked
atresia of follicles, especially of those medium sized or large,
followed hypophysectomy in the macaque {Macaca mulatto).
Involutionary changes in the endometrium and vagina were
as great as or greater than those following spaying. Uterine
bleeding for 3-6 days occurred 2-4 days after hypophysec-
tomy in the middle of the cycle (stage of follicular growth or
proliferation) but was prevented by the daily administration
of oestrin. No prolongation of bleeding followed hypophysec-
tomy during menstruation. The usual changes in the uterine
mucosa were produced by oestrin or progesterone. Uterine
bleeding was delayed but usually followed (8 of 10 monkeys)
"oestrin-deprivation"; therefore, the authors' results speak
strongly against Hartman's view that such bleeding requires
a secretion of the pars neuralis.

In the hypophysectomized and ovariectomized rabbit, the
injection of progestin (i rabbit-unit) neither prevents the
motility-increasing effect of oestrone on the uterus nor renders
the latter oxytocin-insensitive as in spayed rabbits. To pro-
duce these effects in the doubly operated animals, the dose
of progestin must be increased to 4 rabbit-units (Reynolds,
Firor, and Allen, 1936).

[64]

THE GONADOTROPIC HORMONES

xAccording to Bachman (1936) interstitial stroma may
make up a large part of the ovary of the mature rabbit but
largely disappears after hypophysectomy."' Robson's experi-
ments in the rabbit (1937) illustrate how rapid regressive
changes in the ovaries may render the latter almost unre-
sponsive to gonadotropic hormones — i.e., extract of rabbit
or horse pituitary or of human pregnancy-urine. A week or
more after hypophysectomy, the injection of these hormones
had little or no effect on the ovaries, whereas if injections
were begun at once, small doses of gonadotropic hormone
maintained ovarian function as shown by functional per-
sistence of the corpora lutea of pseudopregnancy (8 days)
and by ovulation in response to gonadotropic hormone (12
days). Other experiments led Robson to conclude that both
the pituitary and the ovary are essential for maintaining
pregnancy in the rabbit. However, he was able to maintain
pregnancy in the hypophysectomized rabbit, for some time
at least, by injections of progesterone. The rate of atrophy
of the corpora lutea apparently was not affected. It appears
that among mammals, the mouse and rat are exceptional in
that the corpora lutea in the latter part of pregnancy require
no pituitary luteinizing hormone for their maintenance.''

Emery (1936) reported that homo-implants of the pituitary
in the peritoneal cavity or skeletal muscle of rats apparently
lived from several days to a week. Often such grafts became
vascularized, retained some gonadotropic potency, and ap-
peared nearly normal histologically. Other observations on
the secretory capacity of implants or transplants have been
made in hypophysectomized mice, rats, and guinea pigs.

''The observations of Westman and Jacobsohn (1936) on the effects of hy-
pophysectomy in the rabbit are largely confirmatory of earlier work.

■' Houssay (1935) has confirmed the finding that hypophysectomy in the preg-
nant dog is followed by abortion or fetal resorption. He stated that even in late
pregnancy abortion might appear in 1 days.

Bellerby (1935) found that the intravenous injection of anterior-lobe extract
into pregnant rabbits almost always was followed by abortion or fetal resorption.
Ovulation was often produced; hemorrhagic follicles were more frequently produced
early or late in pregnancy.

[65I

THE PITUITARY BODY

According to Hill and Gardner (1936), successful homo-
transplantation of the pituitary into the testis can be made
in mice which are homogeneous genetically. They showed
that mice carrying such grafts could be hypophysectomized,
yet spermatogenesis, normal testicular germinal epithehum,
and normal adrenal cortex (at least the zona fasciculata)
were all maintained. If both the pituitary and ovary were
transplanted, ovarian secretion was elaborated and even
caused development of the branched ducts of the mammary
gland. Like Hill and Gardner, Greep (1936) found that the
sex of the donor of a pituitary transplant had little or no
significance. For example, the male reproductive organs were
as well maintained by a female pituitary as by a male gland.
Greep hypophysectomized male and female rats 4 weeks old.
He inserted the graft into the empty sella immediately after
operation and was able to secure quite complete replace-
ment effects in three-fourths of the animals. Oestrous cycles
in the females were usually a little prolonged (5-7 days) be-
cause of a longer dioestrus. However, 13 of the rats became
pregnant, delivered normally, and nursed their young. Still
another form of replacement-therapy in the hypophysecto-
mized rat was studied by May (1937), who transplanted the
pituitary of the new-born rat into the anterior chamber of
the eye. Oestrus was first observed 77 days later; there was
some increase in weight over a long period (56-1 19 -gm. in
248 days). Oestrus might disappear after removal of the eye
containing the transplant, with associated atrophy of the
ovary and uterus. Schweizer, Charipper, and Haterius (1937)
made ocular transplants (anterior chamber or lateral sub-
conjunctival tissue) of the pituitary in hypophysectomized
guinea pigs. After about two months the graft clearly seemed
to secrete only one gonadotropic hormone — that stimulating
the follicle. This was shown not only by the abnormal de-
velopment of ovarian follicles and continuous oestrus in the
host but also by the effect of implantation of the graft which
seemed to produce only follicle-stimulation.

[ 66 1

THE GONADOTROPIC HORMONES

Several observations of general interest should also be men-
tioned. Lipschiitz (1936) reported additional studies in
guinea pigs from which about three-fourths of the total
ovarian tissue had been removed. If the operation was per-
formed in new-born animals, it produced little disturbance
of the development and function of the genital tract owing,
the author concluded, to the great reserve of primordial fol-
licles. Sometimes months after the same operation was per-
formed in immature animals (13-28 days old), the vagina
remained open for abnormal periods and the uterine changes
(cystic hyperplasia of the endometrium, etc.) resembled those
of metropathic hemorrhage in man. It is not clear to what ex-
tent the responsibility for these changes must be attributed
to the ovary or to the anterior pituitary or to both. Hamlett
(1935) investigated the effects of whole pituitary extract and
prolan ("xAntuitrin S") on the genital tract of the armadillo
{Dasypus tjovemcijictus). In this animal the blastocyst — i.e.,
fertilized ovum which has undergone cleavage — lies free in
the uterine cavity for four months ("free vesicle period").
Neither hormone hastened implantation; prolan (4 cases)
but not pituitary extract (2 cases) caused abortion or re-
sorption of the unimplanted blastocyst. Either hormone was
found to cause follicle growth, luteinization, and, occasion-
ally, ovulation. According to Lipschiitz and Oviedo (1935),
the gonadotropic potency (immature rat) of the pituitary of
the ratlike South American mammal Myocastor {Myopota-
mus) coypu is even lower than that of the female guinea
pig despite the animal's size (body-weight as great as 4.5 kg.).
Its young, like those of the guinea pig, are well developed
when born. Hellbaum's demonstration of differences in the
qualitative and quantitative effects of the equine pituitary
in the immature rat is of great interest (see Fig. 13). If
judgment be based upon ovarian hypertrophy (weight), the
concentration of gonadotropic hormone is highest in the pitui-
tary of the aged mare and lowest in that of the stallion, fetus,
and colt. The potency of the pituitary of the gelding and

[67]

THE PITUITARY BODY

mare (both pregnant and non-pregnant) is high. The quahta-
tive eifects, which are illustrated by the reproduced figure,
suggest that principally follicle-stimulating hormone is pro-
duced by the pituitary of the stallion and of the aged mare
and gelding, whereas luteinizing hormone also is secreted by
the pituitary of the fetus, colt, young gelding, and adult preg-

,'^

.j^

^v,4

»o

^35.

Fig. 13. — -Photomicrographs illustrating the response of the ovary of the rat to
equal quantities of pituitary powder from glands of horses. The magnifications
are the same in all cases. (From Hellbaum, Anat. Rec, 63, 147-57 [i935]-)

/, Normal mare of reproductive age. 2, Old mare. J, Fetus. ^, Stallion. 5,
Young gelding. 6, Old gelding.

nant or non-pregnant mare. Those interested in a recent
study of the gonadotropic effects of the anterior pituitary
of whales (finback, Balaenoptera physalus; sperm, Physeter
megalocephalus) are referred to the report of Ceiling (1935).
Cyclic changes in the pituitary in relation to those of the
gonads have again been studied by several investigators.
Cole and Miller (1935) could detect no change in the gonado-

[68 1

THE GONADOTROPIC HORMONES

tropic potency (rabbit-ovulation test) of the ewe's pituitary
during this animal's oestrous cycle. Schmidt (1937) found
that, as tested in the immature female guinea pig, the gonad-
otropic potency of the adult female's pituitary is least dur-
ing oestrus and greatest during pro-oestrus. Also she made
a similar study of the pituitary of female adults receiving a
minimal sterilizing dose of X-rays. The gonadotropic po-
tency of the pituitary did not always correspond to the nor-
mal sexual cycle as judged by the vagina. For example, the
pituitary, although removed from an animal in prolonged
oestrus, might contain much gonadotropic hormone. The
metaboHsm of the pars glandularis of the rat in different
phases of reproductive activity has been investigated by Vic-
tor and Andersen (1936) and Andersen, Prest, and Victor
(1937). Their results can be summarized as follows:

Oxygen-consumption :

Pro-oestrus > oestrus > dioestrus or spayed

Parturition > lactation > pregnancy
Aerobic glycolysis:

Spayed > dioestrus
Anaerobic glycolysis:

Pro-oestrus or oestrus > dioestrus or spayed

The highest oxygen-consumption was found in parturient
animals, the lowest in spayed animals. It was about the
same in lactating rats and rats in pro-oestrus. There were
no significant differences in the aerobic and anaerobic glycoly-
sis of pregnant, parturient, and lactating rats.

The effect of pregnancy on the assay of gonadotropic hor-
mones has been investigated by Rowlands (1935), who used
rabbits and expressed dosages in terms of the amount of ex-
tract causing ovulation in 50 per cent of each group. Table i
is a summary of Rowlands' results.

These observations suggest the following conclusions: (i)
The "ovulating dose" of a gonadotropic hormone is higher
in pregnancy than in oestrus. (2) Pituitary extracts, but not
prolan, may vary enormously, depending upon their source,

[69]

THE PITUITARY BODY

in their relative gonadotropic potency in rabbits and rats.
These observations are not new but are here more accurately
confirmed. It is not possible exactly to state how difFerences
are related to the distribution of various pituitary gonado-
tropic hormones in the extracts. Ox pituitary extract is prob-
ably much less potent in follicle-stimulating hormone and
richer in luteinizing hormone; perhaps it contains more
gonadotropic hormone "antagonist," the effects of which
would be more marked in the rat (repeated subcutaneous in-
jections) than in the rabbit (single intravenous injection).
The reader is also referred to later discussion (pp. 1 15-17).

TABLE 1

Relative Dose Causing

Extract of

Ovulation

n 50 Per Cent of Rabbits in

Oestrus

Pregnancy of Duration of

Ovarian Hyper
trophy to 40 Mg.

IS Days

25 Days

Rats

Anterior lobe (ox)

Whole pituitary (horse).

Pregnancy-urine i

2
70

5
60

100
100
100

100

One other report, unrelated however to pregnancy, may be
mentioned here. Bachman (1936) observed that in very
young or juvenile rabbits (15-90 days old) the outstanding
ovarian change in response to sheep pituitary extract or
prolan might be Hmited to the interstitial stroma in which
there appeared large polyhedral cells taking lipoid stains. If,
on the other hand, prompt and extensive luteinization of the
membrana granulosa occurred, there might be no change in
the interstitial tissue. Also, in very young rabbits gonado-
tropic hormone could cause the formation of corpora lutea
without associated progestational changes in the uterus.

According to Morgan (1935), extract of beef anterior lobe
or prolan alters the motility of the uterus of the nonanesthe-

[70]

THE GONADOTROPIC HORMONES

tized rabbit according to the predominant change in the ova-
ries. Increased motiHty is associated with follicle growth; the
change is in the opposite direction, if ovulation and corpus
luteum formation occur. '^ Several other possible interrela-
tionships between the uterus and gonadotropic hormones
have been studied.''^ Gillard (1937) concluded that hyster-
ectomy in the rabbit delays degeneration of the corpora lutea,
thus prolonging pseudopregnancy with hyperemia of the
mammary gland. In his experiments, pseudopregnancy last-
ed about 25 days instead of 18 days in normal animals.
Krane's (1937) observations in hysterectomized women,
some of whom had been studied as long as 6 years postopera-
tively, indicated that in the absence of the uterus there may
be cyclic excretion of oestrogen, resembling that in normal
women, without any increased excretion of gonadotropic hor-
mone. Therefore, hysterectomy is not necessarily associated
with a disturbance of the pituitary-gonad interrelationship.
In conclusion, data bearing on the number of gonadotropic
hormones or their specific effects will be briefly considered.
Loeb and his collaborators,^" who performed most of their
experiments with immature female guinea pigs, describe the
following principal gonadotropic effects: (i) the production
of follicular atresia or destruction by "atresin," (2) luteiniz-
ing effects on the cells of the theca interna or premature lu-
teinization of these cells or maturation of the granulosa of
immature follicles, and (3) maturation of the granulosa of
large follicles. From a study of the effects of pituitary glands
of various animals, of serial implantation, etc., they suggested
that these effects might be due to at least three different
gonadotropic hormones. More often it is assumed that the

'' Morgan found that no effects were produced in spayed rabbits. The earlier
work of Reynolds indicated that a reduction of motility is to be expected in normal
or spayed rabbits after the injection of beef pituitary extract. However, Reynolds
referred to tests made 5-7 hours after injection.

'' See also Hauptstein and Biihler (1936).

^° Kunkel and Loeb (1935); Loeb, Saxton, and Hayward (1936); Saxton and Loeb
(1937).

[71]

THE PITUITARY BODY

important gonadotropic hormones are the folHcle-stimulating
and luteinizing hormones. Fevold and Hisaw and their co-
workers have emphasized that the production of ovulation
requires both hormones. Other experiments indicate that the
secretion of luteinizing hormone in appropriate amount and
at the proper time following follicle growth also is essential
for normal oestrus, so that without this hormone, ovulation,
mating, corpus luteum formation and maintenance^ — and
hence pregnancy — cannot occur (Casida, 1934; Witschi and
Pfeiffer, 1935; Dempsey, Hertz, and Young, 1936). Casida
suggested that atretic corpora lutea are due to the adminis-
tration of an excessive amount of luteinizing hormone. Rid-
dle and others (1936), unable to demonstrate augmentation of
the ovulation-producing effect of follicle-stimulating hormone
by luteinizing hormone, concluded that the latter is not neces-
sary for ovulation. Inasmuch as their experiments were not
performed in hypophysectomized rabbits, this conclusion
does not appear to be warranted. The difficulty of the experi-
mental production of ovulation in the oestrous cat was em-
phasized by Foster and Hisaw (1935), who concluded that at
least some luteinizing hormone — even in minute amount rela-
tive to the dose of follicle-stimulating hormone — must be
administered to cause ovulation. The authors also studied
the duration of pseudopregnancy which persisted 40-44 days.
In the cats of van Dyke and Li (1938) pseudopregnancy per-
sisted only about 20 days; however, they produced a much
smaller number of corpora lutea than did Foster and Hisaw.
Van Dyke and Li used prolan also. Experiments in the im-
mature monkey have been described by Hisaw (1935).

Pfeiffer (1937) believed that the male rat pituitary secretes
or is able to release much less luteinizing hormone than the
female. According to Bunde and Creep (1936), luteinizing
hormone or some substance associated with it can cause the
rapid regression of corpora lutea in hypophysectomized young
adult rats. The earlier experiments of Smith demonstrated
how remarkably long the corpora lutea persist after hypophy-

[72]

THE GONADOTROPIC HORMONES

sectomy in the rat. According to Lane and Greep (1935),
the effects of separated pituitary hormones in immature
hypophysectomized rats are as follows: follicle-stimulating
hormone causes an increase in the total number of follicles
(numerous small primary follicles) and a decrease in the per-
centage of vesicular follicles; luteinizing hormone has no ac-
tion on the total number of follicles but brings about an in-
crease (35-112 per cent) in the proportion of vesicular folli-
cles.

2. Male mammals ."-"^ — A study of the rate of regression of
the testes and accessory organs following the removal of the
pituitary from 9 guinea pigs has been made by Allanson,
Hill, and McPhail (1935). They concluded that maximum
atrophy of the testes, epididymides, prostate, and seminal
vesicles occurred after about 45 days, although there was
marked atrophy of the seminal vesicles after 20-25 days.
xAtrophy of the secondary sexual organs occurred at about the
same rate after castration. According to Leonard and Ham-
ilton (1937), the testis which has been made cryptorchid ex-
perimentally degenerates more rapidly (peak at 6 days after
operation instead of 10 days), if hypophysectomy is also per-
formed. The authors used rats.

Wells and Moore (1936) found that in the adult or young
male ground squirrel {Citellus tridecemlineatus) ^^"^ kept in the
laboratory, spermatozoa were produced in December and
January. Precocious spermatogenesis and full development
of the accessory organs were produced weeks or months in ad-
vance of the normal time by gonadotropic substances (pitui-

^' Koch, Schreiber, and Schreiber transplanted pituitary and testis of immature
animals into the anterior chamber of the same eye. They observed, in comparison
with control experiments, a definite effect on the germinal epithelium. Guinea pigs
were used.

Bastenie and Zylberszac (1937) injected an anterior pituitary extract into male
or female guinea pigs, which also were given colchicine to arrest the mitoses. There
were no striking changes in the gonads. Mitotic division was markedly increased
in the epithelium of the seminal vesicles and the uterine mucosa.

^* Wells and Gomez (1937) describe a technic of hypophysectomy in this
animal as well as the effects of the operation in males.

[73]

THE PITUITARY BODY

tary implants, prolan, or pregnant-mare serum) or by andro-
gens (androsterone or extract of male urine or bull testis) . Why
androgens should have this effect on spermatogenesis is not
known; in view of other work in the rat it is reasonable to be-
lieve that an action on the testicular germinal epithelium is
important. Recent studies of the action of gonadotropic sub-
stances^-' in immature rats have been made by Moore (1936)
and Price (1936). Price compared the effects of pituitary im-
plants and prolan in very young rats. The indirect effect on
the seminal vesicles was accompanied by less change in the
apparent amount of interstitial tissue after pituitary im-
plants than after prolan. Prolonged injection of the latter
caused damage to the germinal epithehum. Moore found
that sheep pituitary and pregnant-mare serum, like prolan,
brought about no precocious spermatogenesis in normal im-
mature rats. The most marked effects were on the inter-
stitial cells and secondary organs; although the seminal vesi-
cles might weigh fifty times as much as those of non-injected
rats, the testicular weight was never more than doubled.
Little change of either type was produced in adult animals.

Follicle-stimulating extract (from the urine after gonad-
ectomy or after the menopause) was injected by Huberman,
Israeloff, and Hymovitz (1937) into men with sterility caused
by an endocrine disturbance (300-2,000 rat-units as 50 rat-
units twice weekly). The treatment appeared to cause an in-
crease in the number and motility of the spermatozoa but
did not correct the sterility.

Using normal rats 21 days old and hypophysectomized rats
2^ days old (7 days after hypophysectomy), Creep, Fevold,
and Hisaw (1936) compared the effects on the male reproduc-
tive organs of follicle-stimulating extract and luteinizing ex-
tract made by them from sheep pituitary. They concluded
that the follicle-stimulating extract had no effect on the inter-
stitial tissue but caused increased mitotic division of the cells
of the germinal epithelium so that spermatogenesis could be

^^ Pituitary homo-implants, sheep pituitary, prolan, and pregnant-mare serum.

[74I

THE GONADOTROPIC HORMONES

carried as far as the secondary spermatocyte stage. The lu-
teinizing extract brought about growth of the interstitial tis-
sue but left the germinal epithelium as "degenerate" as in
control animals. Increased diameter of the tubules in rats
receiving luteinizing extract was believed to be the result of
generalized swelling of the tubules partly owing to the accu-
mulation of fluid in the lumen. The administration of a mix-
ture of the two extracts apparently produced an augmented
effect on the secondary organs. The general results are in
agreement with the views of many authors: a pituitary folli-
cle-stimulating hormone maintains gametogenesis in the male;
a pituitary luteinizing hormone is essential for the normal
functioning of the interstitial tissue. However, proof to si-
lence all arguments to the contrary awaits the isolation of the
hormones in pure form.

Pfeiffer (1936-37) offered experimental evidence that the
pituitary of the male rat secretes only follicle-stimulating
hormone, whereas the female pituitary secretes both follicle-
stimulating and luteinizing hormone. His conclusions are
supported by a different type of data — i.e., effects of extracts
or implants of the pituitaries of male or female rats — gath-
ered by others. Thus it would appear that follicle-stimulat-
ing hormone alone maintains both the germinal epithelium
and the interstitial cells of the testis of the normal rat. Greep
has suggested that minute continuous secretion of luteinizing
hormone (the male rat's pituitary does contain a very small
amount of this hormone) by the male pituitary may be suffi-
cient for the needs of the interstitial cells, which probably
secrete continuously rather than in a cyclic fashion. The
cyclic course of ovarian activity as well as the action of
oestrogen on the pituitary might account for the much larger
amount of luteinizing hormone secreted by the female pitui-
tary. A later report of Greep and Fevold (1937) further com-
plicates discussion. Follicle-stimulating hormone or luteiniz-
ing hormone was administered to adult hypophysectomized
male rats. Spermatogenesis could be maintained by either

[75]

THE PITUITARY BODY

extract, whereas regression of the interstitial cells was pre-
vented only by luteinizing hormone.

SPECIAL CONSIDERATIONS

The secretion of gonadotropic hormones in relation to sex and
the internal secretions of the gonads, i . T)iferences related to
sex and age. — McQueen-Williams (1935) studied the gonado-
tropic potency of the pituitary of rats of different ages and
sexes. Her data supplement those of Clark previously re-
ferred to. McQueen-Williams performed her assays by means
of intramuscular implants in immature female rats, whereas
Clark used immature mice for assay. Both authors found
that the female pituitary is much the more potent in rats
about 3 weeks old, whereas in adult rats the male pituitary
is richer in gonadotropic hormone. One important change en-
countered by McQueen-Williams was a remarkable increase
in the potency of the pituitary of male rats 27-30 days old,
the pituitary then being more potent than at any other age
studied. The gonadotropic potency of the pituitary of male
rats only a week older was again low and did not rise until the
animals were more than four months old.^^ Bates, Riddle,
and Lahr (1935) compared the concentrations of gonado-
tropic hormone in the pituitary of the ox (embryo, calf, adult
steer [castrated male], adult bull, normal cow, and cow in
early and late pregnancy.) Gonadotropic hormone was de-
termined by its effect on the testis of the immature dove. The
authors concluded that the only significant differences were
(i) the low potency of the steer's pituitary (concentration
about 23 per cent less than the average of others) and (2) the
high potency of the pituitary of the cow in early pregnancy
(concentration about 36 per cent more than the average of
others). The low potency of the steer's pituitary is surpris-
ing; also, it might be expected that the pituitary of pregnancy
would be poor rather than rich in gonadotropic hormone. In

'■'^ The pituitaries of rats between the ages of forty-four days and tour months
were not investigated.

[76]

THE GONADOTROPIC HORMONES

TABLE 2

The Gonadotropic Potency of the Anterior Pituitary
IN Relation to Sex*

Animal Serving
AS Donor

Assay Method

Conclusion as to Potency
IN Terms of

Gonado-
tropic
Hormone

Follicle-
Stimu-
lating
Hormone

Luteinizing
Hormone

Adult frog

{Rana pipiens) .

Adult salamander
( Triturus viri-
descens)

Fowl

Adult guinea pig.

Rat: 27-30 days
old

Adult rat

Ovulation in
frog

Oviposition in
T. viridescens

Hypertrophy of

fowl testis
Ovarian effects

in immature

guinea pig
Ovarian change

in immature

rat
Ovarian change

in immature

rat
Ovarian change

in immature

rat

Appearance of
ovarian trans-
plant

Ovarian change
in immature
rat with or
without pro-
lan or extract
of urine of
menopause

&^ 9
d^> 9

'Absent"
in d^
and 9

o^>9

d^>9
9>9

9>c?t

^>9

Rugh (1937)

Adams and

Mayo

(1936)
Domm

(193 1-3.1)
Schmidt

(1937)

Lipschiitz

(1937)

McQueen-
Williams

(1935)*
Lipschiitz
and
Villagran

(1937)
Pfeiffer

(1936)

Leonard

(1937^

* See also Table V, p. 143, of earlier volume.

t In terms of concentration. After castration the male pituitary increases in size. Gonadectomized
animals are indicated by ^ or isf.

tThe author believed that the pituitary of the normal male secretes only follicle-stimulating
hormone.

§ Castrated at birth.

THE PITUITARY BODY

the guinea pig, the presence of a gonad, functioning definitely
but at a low level, appears not to lessen the gonadotropic
potency of the pituitary in comparison with that of gonad-
ectomized animals (Lipschiitz, 1936).

Other observations on the relation of sex to the pitui-
tary's content of gonadotropic hormone have attempted to
distinguish between the follicle-stimulating and luteinizing
hormones. According to Lipschiitz and Del-Pino (1936), man
resembles the rat and guinea pig in that (tested in the imma-
ture rat) the male pituitary causes more formation of lutein
tissue than the female. (The pituitary of women in the first
month of pregnancy caused luteinization of the ovaries; in
the later months this effect diminished or disappeared.)
The opposite view was expressed by Pfeiffer (1936-37), as
well as by others, whose experiments were performed in rats.
According to this author, the male pituitary is capable of se-
creting very little luteinizing hormone. Moreover, Pfeiffer's
conclusion appears to be based on a more "physiological"
method (the behavior of ovarian grafts as affected by the
gonadotropic hormone secreted by the host's pituitary). The
conflicting views expressed in recent reports are summarized
in Table 2. Some of these results will be considered later
when an evaluation will be attempted. Pfeiffer (1936), rely-
ing on the effect on ovarian transplants of gonadotropic hor-
mone released by the rat's pituitary in situ, concluded that
the normal male pituitary secretes follicle-stimulating hor-
mone with little or no luteinizing hormone, whereas the fe-
male pituitary is "bipotential" — i.e., secretes both hormones.
Also he believed that this sexual difference is hormonal rather
than genetic and that after puberty the pattern of pituitary
secretion is practically fixed; Pfeiffer (1936-37) cites other
experiments in support of these views.

1. Experiments with animals in parabiosis.^^ — No attempt

^5 Unless there is a statement to the contrary, all the animals used are rats.
References to other experiments employing the method of parabiosis will be found
both in this chapter and in the Index. 9 refers to a normal female; ^ refers to a

[78]

THE GONADOTROPIC HORMONES

will be made to recapitulate the older experiments with
parabiotic animals; an outline of the results of these experi-
ments will be found in the earlier volume. The outstanding
fact previously demonstrated is that, if a gonadectomized and
a normal animal are joined in parabiosis, an abnormal stimu-
lation of the gonads occurs and persists for months, because,
in all likelihood, abnormal amounts of pituitary gonadotropic
hormone are present in the blood. This is particularly true
of the experiment 9 s^.^^ In the experiment cf sf, the acces-
sory organs of the castrated male remain atrophic. However,
according to McCullagh and Walsh (1935), the injection of a
comb-growth-stimulating hormone ("androtin") prevents
both a gonadotropic effect in the normal male and a regres-
sion of the accessory organs in the castrated male.^^ De
Mello (1936) placed an ovarian graft in the normal male of
the parabiotic pair^ cT. A hypertrophy of the prostate and
seminal vesicles of the normal male, abnormal even for such
an experiment, apparently was caused by the combined ef-
fects of ovarian and testicular secretions. Both the graft and
the testes iri situ were stimulated.

Recently additional observations have been made on the
results of parabiosis between hypophysectomized and normal
or gonadectomized rats. In experiments of the type cTh^,

spayed female; cf refers to a normal male; isf refers to a castrated male; ^ih refers
to a hypophysectomized female, etc. d^htsT would refer to a parabiosis between
a hypophysectomized male and a castrated male.

** In this experiment, the ovaries become cystic and remain in this condition for
months. Coincidently, the changes characteristic of oestrus are observed in the
uterus and vagina. Evans, Simpson, and Pencharz (1935) suggest that the castrated
male pituitary contains (secretes?) but does not release luteinizing hormone. They
implanted the pituitary of castrated male rats into female rats hypophysectomized
at an age of 26 days. Follicle-stimulation followed the smaller dose of pituitary
tissue, whereas corpora lutea were formed after the larger dose (4 glands of young
males 40 days after castration). Four glands of normal males caused only follicle-
stimulation in accordance with the belief of some authors that the normal male
pituitary "releases" only follicle-stimulating hormone.

^' The authors stated that a specific substance in testicular extract ("inhibin")
prevents oestrous cycles in the female rat and causes atrophy of the male accessory
organs,

[79]

THE PITUITARY BODY

both the germinal epitheHum and the interstitial tissue were
stimulated by the gonadotropic hormones of the castrated
rat's pituitary. The effects were much less evident if the
hypophysectomized male rat was joined to a normal rat or a
rat with experimental cryptorchidism (Cutuly and Cutuly,
1937; Cutuly, McCullagh, and Cutuly, 1937). From a study
of the changes in the accessory organs and testes which tend-
ed to be parallel, the authors suggest that the testicle requires
only one gonadotropic hormone, whereas the ovary may re-
quire two. M0ller-Christensen (1935) has published a long
report of his experiments with rats in parabiosis. He has ad-
vanced the view that in the experiment 9 ? , the pituitary
of the normal rat inhibits the activity of its own ovaries. He
cites the experiment 9 h § : cystic ovaries without corpora
iutea are found in the hypophysectomized rat; atrophy of
secondary organs in the spayed female is moderate and not
advanced. ^^ In the experiment 9 9 , of course, the ovaries of
the normal female may become cystic; this change can be
observed more certainly in the experiment 9 sT- The pitui-
tary of the normal female of the partners 9 § or 9 sf under-
goes hypertrophy and contains no gonadotropic hormone
(M^ller-Christensen). x^nother type of parabiosis investi-
gated by the author was that symbolized by 9 h 9 • Normal
oestrous cycles and normal sexual organs were observed in
the normal rat; the gonads and accessory organs of the hy-
pophysectomized rat underwent atrophy. The interpretation
of all these results, especially in terms of an inhibiting effect
of the pituitary on ovarian function, is a suggestion requiring
more supporting data. The contrary effect — increased re-
lease (and diminished utilization) of gonadotropic hormone by
the pituitary after gonadectomy — still appears to be the best
interpretation of most experiments with parabiotic rats.
3. The effects of the internal secretions of the gonads on pitui-

^* Oestrus in the spayed partner is observed more frequently in the experiment
9h'?i than in the experiment 9 ?! (M0ller-Christensen, 1933).

[80]

THE GONADOTROPIC HORMONES

tary function, (a) Hormones of the oestrin groupr'^^^'' — The
effects of hormones of the oestrin group on the secretory per-
formance of the pituitary, aside from their pharmacological
interest, are important because they furnish a basis for inter-
preting the interplay of ovarian and pituitary (gonadotropic)
hormones. This is true although only one member of the
group (oestradiol) probably is a normal secretion of the ovary.
Particularly in the preceding sections, other aspects of this
problem have been mentioned. The experimental data about
to be taken up here extend our knowledge by other technics.
The early experiments of Meyer, Leonard, Hisaw, and Mar-
tin (1930, 1932) demonstrated the diminished gonadotropic
potency of the pituitary of rats which had received injections
of oestrin for 4-10 weeks. The publication of their work was
followed by numerous reports of related phenomena, which,
as far as recent articles are concerned, now require discussion.
Berkowitz (1937) repeatedly added tablets of "Progynon"
(oestrone.^) for a long period to the tank water in which he
kept immature male guppies {Lebistes reticulatus). In size,
shape, and color the fish ultimately resembled females. No
spermatogenesis appeared. The author believed that the
treatment accelerated growth. He was unable to demonstrate
that the tablets had any effect on adult male fish. The injec-
tion of large doses of oestradiol benzoate into the cock causes
regression of the comb and spurs (Zondek, 1936). Bates,
Riddle, and Lahr (1937) concluded that testicular atrophy
occurs if oestrone be injected into adult male ring doves (40
rat-units per day for 10 days). All these effects, like similar
effects in mammals, probably depend upon an interference
with the secretion of gonadotropic hormones by the pituitary
body. Oestrone is said not to affect the egg-laying perform-
ance of the fowl (Unik and Liptschina, 1934).

^' Particularly oestradiol, oestrone, and oestriol, and their esters.

3° According to Miiller (1937), the dose of oestradiol necessary to produce the
vaginal signs of oestrus in the thymectomized or spayed rat is much higher as a
result of hypophysectomy. These results are contrary to those of Smith (1932J,
who used oestrin.

I81I

THE PITUITARY BODY

According to Bokslag (1937), a number of hormones^' re-
duce the gonadotropic potency of the pituitary of rats of
both sexes. However, without critical use, his method of as-
say is objectionable (indirect effects of implants on the uterus
and vagina of immature mice). He believed that gonado-
tropic activity might be increased following the administra-
tion of thyroid extract, but not thyroxine. Other studies in
rats have been made by Biihler (1936), Fischer and Engel
(1936), Halpern and D' Amour (1936), and Emery (1937).
Oestrin was found to cause marked atrophy of the testes
sometimes comparable to that in hypophysectomized rats.^^
Halpern and D'xAmour again reported on the effect of oestrin
on the mammary gland. Robson and Henderson (1936) con-
cluded that the pituitary plays no direct part in bleeding
like that occurring before oestrus in the bitch. Oestrone or
oestriol produced this effect in the absence of the pituitary."
As far as the monkey is concerned, moderate doses of oestrin
(1,265-1,390 rat-units during 28-39 days) cause a decrease
in the number of large follicles and a slight increase in the
rate of follicular atresia. Because of this indirect action of
oestrin on the rate of secretion of gonadotropic hormone by
the anterior pituitary, the damage to the ovary is unimpor-
tant (Allen and Diddle, 1935). Of interest and practical im-
portance to the gynecologist are the experiments which have
been performed in women. Frank and Salmon (1935) re-
ported that menopausal symptoms were associated with the
excretion of gonadotropic hormones. Both the symptoms

3' Such as oestrone, oestrone benzoate, progesterone, testosterone, androsterone,
prolan, etc.

^^ Shumacker and Lamont (1935) found that the administration of 9 rat-units
of oestrone daily for nearly 10 weeks was without effect on the microscopic appear-
ance of the ovary or testis of the rat. Emery's experiments indicated that the secre-
tion of gonadotropic hormone by the young female (130-50 gm.) rat's pituitary
is scarcely affected by doses of oestrone as high as 20 rat-units daily for 6 weeks.
Halpern and D'Amour injected 5 rat-units daily for 3 weeks followed by 20 rat-
units daily for 5 weeks.

33 Oestrin seemed to reduce the reactivity of the uterus to the oxytocic principle
of the pars neuralis. The opposite effect follows the administration of oestrin to
other animals such as the rabbit.

f82l

THE GONADOTROPIC HORMONES

and the excretion of gonadotropic hormones disappeared
after the administration of oestradiol benzoate (4,000-22,000
rat-units; apparently as many as 4,000 R.U, were adminis-
tered at one time). Enormous doses of oestradiol benzoate
have been administered to women-'^ so that the excretion of
gonadotropic hormone is prevented and uterine bleeding may
appear following treatment (500,000-1,500,000 mouse-units
during 20-60 days: Jones and MacGregor, 1936; 200,000
[or more] mouse-units with or without progesterone: Zondek,
1937). According to Zondek (1936), 200,000,-300,000 mouse-
units of "folhcle-hormone" may delay menstruation 6-70
days. He contended that this treatment prevented the secre-
tion of the pituitary luteinizing hormone so that the develop-
ment of the corpus luteum was inhibited. Also he believed
that the treatment increased the rate of secretion of follicle-
stimulating hormone. His results should be compared with
those of others who used animals and thus could control their
experiments better [vide infra) J'"

Other experiments in male animals will be referred to brief-
ly.-^^ Clauberg (1936) believed that a single dose of 5,000
mouse-units of "follicle-hormone" to adult male mice in-
creased their sexual activity and fertility, partly by causing
an increased liberation of gonadotropic hormone by the pitui-
tary and partly by bringing about a hyperemia of the genital
tract. According to Tuchman (1936), the administration of
0.4 mg. of "foUiculin benzoate" (or i mg. of i-2-benzpyrene)
once weekly for 4 weeks causes a cessation of spermatogenesis
and a hypertrophy of interstitial tissue in the male guinea
pig. In male animals oestrogens usually bring about regres-
sive changes in the testes, especially in the germinal epithe-

^■' In the menopause or with primary or secondary amenorrhea or with amenor-
rhea following ovariectomy.

^s Marx, Catchpole, and McKennon (1936) concluded that the uterus retards the
onset of the menopause. For example, the clinical and hormonal disturbances char-
acteristic of the menopause appeared earlier after complete hysterectomy than after
supravaginal hysterectomy.

^^ See also p. 81.

[83]

THE PITUITARY BODY

lium. However, oestrogens are also known to cause hyper-
trophy of some of the male accessory organs. It is probable
that this is a direct effect, although an indirect action on the
testicular interstitial cells may be a participating cause.

The effect of oestrogens on the secretion of follicle-stimu-
lating and especially luteinizing hormones has interested a
number of recent authors. Usually it has been concluded
that enhanced luteinizing effects or abnormally long persist-
ence of corpora lutea already formed may occur as a result of
the injection of an oestrogen. For example, in the adult
mouse, Clauberg (1936) reported that sterility for as long as
29 days occurred after the injection of one or two large doses
of "follicle-hormone." The sterility was attributed to an ab-
normal persistence and growth of corpora lutea which might
be larger than those of pregnancy. In the rat, ovarian hyper-
trophy following the injection of various oestrogens is due to
corpora lutea (Ellison and Burch, 1936; Mazer, Israel, and
Alpers, 1936). Ellison and Burch found that this effect could
be prevented by hypophysectomy. The same conclusion was
reached by Fevold, Hisaw, and Greep (1936) as well as Hohl-
weg and Chamorro (1937), so that it appears that oestrogens
increase the rate of secretion of luteinizing hormone by the
pituitary body." Hohlweg and Chamorro injected 117 of
oestradiol benzoate into immature female rats; the customary
appearance of corpora lutea after this treatment could be pre-
vented by hypophysectomy on the second day after injection
but not if operation was delayed to the fourth day.

The experiments of Fevold, Hisaw, and Greep were de-
signed to detect changes due to injected oestrin, in the
amounts of follicle-stimulating or luteinizing hormone liber-
ated by the pituitary . After the injection of oestrin (0.1-4
R.U.), a constant dose of pituitary follicle-stimulating hor-
mone was administered. The increased ovarian weight, in
comparison with immature animals receiving no oestrin, was

^7 Lipschiitz has again reported that oestrogens lower the luteinizing potency of
the adult male rat's pituitary (e.g., see Lipschiitz, Palacios, and Akel, 1936).

[84]

THE GONADOTROPIC HORMONES

considered to be due to the luteinizing hormone liberated by
the pituitary in situ and to some extent was related to the
size of the oestrin dose.-*^ No such increased effect of follicle-
stimulating hormone after oestrin occurred in hypophysec-
tomized rats. In normal animals, the injection of prolan after
oestrin produced no ovarian hypertrophy greater than after
prolan alone. If prolan be considered a luteinizing hormone,
this result indicates that oestrin does not facilitate the secre-
tion of a synergizing, follicle-stimulating hormone. If oestrin
was injected for 8 days, the ovarian response to pituitary
follicle-stimulating hormone or prolan was reduced in nor-
mal but not in hypophysectomized rats, indicating that this
antagonistic effect is on the pituitary, by which some gonado-
tropic hormone is secreted even in immature animals, and
not on the ovary, x^ll these results suggest the following con-
clusions: (i) oestrin in small doses increases the rate of secre-
tion of luteinizing, but not of follicle-stimulating, hormone;
(2) larger doses of oestrin (8-day injection period) diminish
the rate of secretion of both gonadotropic hormones; and (3)
oestrin appears to have no effect on the ovary. ^"^

Leonard's results (1937) led to a different interpretation as
far as conclusion (2) is concerned; however, he used a differ-
ent method. He estimated the quantity of follicle-stimulating
or luteinizing hormone in the pituitary of the rat receiving
oestrin by determining the effect of a maximum dose of prolan
(50 rat-units) or menopausal urine (equivalent to 100 cc.) and
comparing these effects (i) with those of pituitary tissue from
control animals and animals receiving oestrin and (2) with
the effects of pituitary tissue in addition to prolan or extract
of menopausal urine. The degree of augmentation of the
effect of prolan on the ovary was taken as a measure of the
quantity of follicle-stimulating hormone present in the ad-

3^ The maximum effect apparently was produced by 0.5 R.U. of oestrin.

^' Earlier work had indicated that ovarian regression due to a "sex hormone"
is an indirect result of diminished pituitary function. See, however, the results of
Robson in the rabbit discussed on pp. 86-87.

[85]

THE PITUITARY BODY

ministered pituitary tissue, whereas similar augmentation of
the action of extract of menopausal urine indicated the
amount of luteinizing hormone administered. The author
administered lo rat-units of oestrin daily for lo days. Pitui-
tary tissue in a constant dose of 3.5 mg. dissolved in o.i per
cent NaOH was always given, so that the results refer to the
concentration of a particular gonadotropic hormone. The ad-
ministration of oestrin to adult, spayed fen.ale rats brought
about a reduction in the concentration both of follicle-stimu-
lating hormone and of luteinizing hormone. ■^" Contrary to
the results of Fevold, Hisaw, and Greep, repeated injections
of oestrin into immature rats had no effect on the concentra-
tion of follicle-stimulating hormone present; however, Leon-
ard agreed that the amount of luteinizing hormone was re-
duced. It must be remembered that the pituitary body was
intact in the immature rats used by Leonard for assay — per-
haps constituting a further complicating variable.

Allen and Heckel (1936) reported that pseudopregnancy
in the rabbit can be prolonged to 25 days after a sterile mat-
ing, provided that oestrin be injected; the authors gave no
data on the dosage used. Hidaka (1937) produced pseudo-
pregnancy in rabbits by injecting pregnancy-urine; large
doses of an oestrogen caused a prolongation of the condition
(5,000-10,000 international units of "Gynandol benzoate"
on alternate days). Klaften (1937) injected various doses of
oestrone (sometimes as much as 1,200,000 I.LI.) to produce
corpora lutea. No corpora lueta could be observed in infan-
tile or juvenile rabbits (doses as high as 150,000 I.U.).^' In
adult rabbits there was found, in addition to corpora lutea,
glandular cystic hyperplasia of the uterus with loss of sensi-
tivity to the oxytocic principle of the pars neuralis. Robson's
results (1937) raise the question of the site of action of an

■*" Castration alone caused a marked increase in the concentration of follicle-
stimulating hormone (comparison with normal animals).

■<' Mazer, Israel, and Alpers (1936) stated that mature ovarian follicles could be
produced by the injection of large doses of oestrogens into immature rabbits.

186]

THE GONADOTROPIC HORMONES

oestrogen in causing persistence of corpora lutea. The other
evidence available indicates that the secretion of luteinizing
hormone by the pars glandularis is responsible for the appear-
ance of corpora lutea, when these follow the injection of an
oestrogen. According to Robson, oestrone (107 daily) or
oestradiol (57 daily) maintains the structure and function of
pseudopregnant corpora lutea of hypophysectomized rabbits
for as long as 13 days/^ As in hypophysectomized rabbits re-
ceiving no oestrogen, the ovary of these animals did not re-
spond to gonadotropic hormone. The observations of West-
man and Jacobsohn (1937) are fully in agreement with those
of Robson.

Late in pregnancy in the rat, the administration of 0.5 mg.
of oestrone daily increases the duration of pregnancy to about
24-26 days (Selye, CoUip, and Thomson, 1935). The authors
concluded that this treatment prolongs the life of the corpora
lutea, giving rise to interference with parturition and fetal
death. Pincus and Kirsch (1936) studied the effect of oestro-
gens on ovulation and implantation in the rabbit. As much
as 3,000 rat-units of oestrone, given before mating, did not
prevent ovulation. The administration of oestrone during
the 3-6 days after coitus caused a considerable reduction in
the number of implantation sites. The authors concluded
that ova were killed in the early blastocyst stage but that
cleavage was not affected. Some oestrogens were more harm-
ful than others. Implanted ova, like the fetuses into which
they developed, were normal. The experiments of Courrier
and Gros (1935) in the cat indicated that "folliculin" pre-
vents nidation in the cat if a total dose of 500-1,000 rat-units
be administered on the 5-18 days following coitus. Abortion
was caused by 1,000 rat-units during the 38-43 days, al-
though other doses at other times might not have this effect.

Experiments in parabiotic rats indicate that oestrone inter-
feres with the liberation of gonadotropic hormone by the
gonadectomized partner. Meyer and Hertz (1937) injected

■t^ In one experiment i mg. of testosterone daily was without effect.

[87]

THE PITUITARY BODY

0.05-5.007 of oestrone daily into the gonadectomized part-
ners of the pairs 9 ? and 9 isT-"^ Rats 30-33 days old were
used and received injections for 11 days. The spayed female
appeared to be more sensitive than the castrated male (e.g.,
weight of both ovaries of 9 of 9 9 without injection, 71.0
mg.; similar weight, 9 of 9 9 , if ? received oestrone, 24.0
mg.). This would be expected from the fact that ovarian
changes are usually more pronounced in the female of the
pair 9 sf • Also the authors concluded that by the technic
of parabiosis, a castration change in pituitary function is re-
vealed earlier than by studies of pituitary histology.

According to Victor and Andersen ( 1 937) , oestrone or oestra-
diol causes a significant increase in the oxygen-consumption
of thepituitary of the rat, whether the hormone be added to
the surviving pituitary in vitro or administered to the spayed
rat about 6 hours before the gland is removed. No such
phenomenon was observed in control tissues (liver, kidney).

^) Progesterone^'^ — Progesterone, like oestrone and andros-
terone, may cause regression of the testes in adult ring doves
(Bates, Riddle, and Lahr, 1937). To obtain this effect the
authors injected 0.25 Clauberg-unit each day for 10 days.

According to Hohlweg (1935) the characteristic effects of
gonadectomy on the pituitary are not corrected by the in-
jection of progesterone, despite reports to the contrary.
Hohlweg found that the administration of 0,54 mg. of pro-
gesterone daily for two weeks to adult spayed rats did not
alter the histologic changes in the pars glandularis. He at-
tributed the positive results of other investigators to con-
tamination of their extracts with an oestrogen or an andro-
gen. Large doses of progesterone inhibit oestrus in the rat
(Selye, Browne, and Collip, 1936; Phillips, 1937). Associated
with this effect are moderate ovarian atrophy and some pitui-

« For the meaning of the symbols, see pp. 78-79, n. 25.

'•'' Zwarenstein (1937) concluded that progesterone causes ovulation in the toad
{Xenopus laevis) by its direct action on the ovary. Shapiro previously had found
that testosterone, androsterone, or certain derivatives of these, adrenal cortical
extract, etc., can cause ovulation in this amphibian.

THE GONADOTROPIC HORMONES

tary hypertrophy. There is Httle basis for interpreting these
observations, although Bokslag beHeved that progesterone,
Hke many other substances, lessens the gonadotropic potency
of the pituitary. Moreover, Laroche, Simmonet, and Bom-
pard (1937) found that progesterone''^ lessens the urinary ex-
cretion of gonadotropic hormone in spayed women or women
past the menopause and concluded that its effect therefore
resembles that of oestrone. The corpus luteum hormone ap-
pears not to affect the testis or secondary sexual organs of
immature male rats (Pels, 1936). Pels, however, injected
small doses of progesterone (1.2-1.7 mg. as the total dose
during 1 1-22 days).

A few observations in other animals require mention.
Dempsey (1937) reported that preovulatory swelling and
ovulation are prevented in the guinea pig by the administra-
tion of progesterone (0.05 LU. daily for 20 days). Follicular
growth was not inhibited by the hormone. In the rabbit, also,
the injection of progesterone prevents ovulation after coitus,
although it appears not to diminish the ovulation-producing
effect of prolan-*^ (Makepeace, Weinstein, and Friedman,
1936-37). These observations extend and confirm earlier re-
ports such as that of Mahnert.

c) Androgenic substances such as hormones extracted from
the testes or urine or derivatives of these. '^'^ — Breneman (1937)
studied the effects of androgens on the chick receiving injec-
tions between the fifth and tenth days after hatching. Ob-
servations were continued to an age of 30 days. Substances
such as testosterone or dihydroandrosterone benzoate pre-
vented testicular growth during the injection period. How-
ever, three weeks after injections were stopped, the testes
weighed almost twice as much as those of non-injected chicks.
The author also concluded that dihydroandrosterone ben-

''s Total doses of 25-58 mg. of progesterone as 5-23 injections over 1 1-144 days.

••* In pregnant does, the dose of prolan or extract of the pars glandularis required
to produce ovulation is larger than in oestrous rabbits.

''' Testosterone or androstenedione can cause ovulation by acting on the excised
ovary of the toad, X. laevis (Shapiro and Zwarenstein, 1937).

THE PITUITARY BODY

zoate potentiates the response of the chick's testis to sheep
pituitary extract.

Observations like those of Breneman illustrate the com-
plexity and difficulty of interpreting the reported effects of
"sex" hormones on the gonadotropic phase of pituitary func-
tion. It is necessary to take into account depressant (and
perhaps excitatory) effects'*^ on the secretion of gonadotropic
hormones as well as substitution-effects on the gonad itself
after the removal of the pituitary. For some years the view
that "male sex hormone" may lessen the secretion of gonado-
tropic hormone and thus bring about testicular or ovarian
damage has been accepted and can again be illustrated by re-
cent observations in rats. Oestrus, as judged by the vaginal
smear, may be prevented in the adult female rat by large
doses'^^ of several androgens such as testosterone, androster-
one,^" androstanedione, and androstenedione (Browman, 1 937 ;
Nelson and Merckel, 1937). Androgens may completely pre-
vent ovarian hypertrophy in the female of the parabionts
9 sf, if administered to the castrated male (Hertz and Meyer
1937). The inhibitory effect of three androgens corresponded
to their potency as "male hormones" (e.g., testosterone pro-
pionate > testosterone >dehydroandrosterone). Hain (1937)
concluded that testosterone propionate antagonizes the
oestrogenic effect of oestrone in the spayed rat — a conclusion
not in accord with the usual view that antagonism of the se-
cretion of the intact ovary by a male hormone is the indirect
result of depression of pituitary function. Hain also found
that large doses of androgens such as testosterone or its pro-
pionate, and transandrostenediol cause abortion in the rat

^^ Pfeiffer's results led to the conclusion that the normal internal secretion of the
rat's testis prevents or inhibits the liberation of luteinizing hormone by the pars
glandularis.

'"0.5-5 "ig- daily. Nelson and Merckel usually injected 0.5-1.5 mg. daily for
as long as 30 days.

5" According to Biihler {1936) crystalline "Proviron" (androsterone.'') does not
inhibit the growth of the uterus and ovaries of immature rats receiving 30-50 capon-
units in 8 days.

[90]

THE GONADOTROPIC HORMONES

if injected during midpregnancy or late pregnancy. Oestrone
caused the same effect in 0.003 the dose (or less) of androgen
required. Recently, Moore and Price (1937) studied the
effect of androsterone on the testes and on the gonadotropic
potency of the pituitary of young rats. The daily injection of
0.5-1.5 mg. of the androgen for 20 days inhibited testicular
growth 12-50 per cent and reduced the gonadotropic action
of the injected rat's pituitary. There was no stimulation of
spermatogenesis. The authors concluded that the testicular
damage was the indirect result of pituitary injury. On the
other hand, enormous doses of androsterone (4-6 mg. daily
for 20 days) appeared not to affect the testes of adult rats.

It will be recalled that the gonadotropic potency of pitui-
tary implants increases after gonadectomy. Therefore, the
normal internal secretions of the ovary or testis appear to in-
hibit the secretion (storage) of gonadotropic hormone. Clark
had earher found that, judged by the gonad-stimulating
effect of pituitary implants, secretion of testicular hormone
occurs much earlier than secretion of ovarian hormone in the
rat. In other words, castration at an early age is followed by
an increased gonadotropic effect of the pituitary, whereas
spaying produces no change. Stein (1935) has shown by this
technic that there is considerable testicular secretion even in
the first week of the male rat's life. A confusing exception to
the generalization that gonadectomy is followed by increased
storage or secretion of gonadotropic hormone is that reported
by Bates, Riddle, and Lahr (1935). They found that the
concentration of gonadotropic hormone in the pituitary of the
ox, as indicated by testicular hypertrophy in immature doves,
is lowest in the castrated animal (adult steer), apparently
being lower than in the pituitary of the bull, calf, embryo,
etc.

Another aspect of the problem which can be interpreted as
indicating an inhibiting effect of androgens on pituitary
gonadotropic function is the prevention or correction of cas-
tration changes in the pars glandularis. This has been ac-

[91]

THE PITUITARY BODY

complished in castrated male rats by injecting androsterone
(Hohlweg, 1937) and in spayed females by injecting andros-
terone as well as dehydroandrosterone, androstanedione, or
testosterone (Nelson and Merckel, 1937). All the authors in-
jected large doses of the androgens used. Schoeller, Dohrn,
and Hohlweg (1936) compared the doses of oestradiol ben-
zoate, androsterone, testosterone, and testosterone propio-
nate needed to correct gonadectomy changes in the pituitary
of immature or young adult castrated or spayed rats. Oestra-
diol benzoate (total dose 0.15-0.37) was 200-500 times as
potent as the androgens in immature animals, whereas in
young adult gonadectomized animals of both sexes its poten-
cy was 500-13,000 times greater. In the older animals at
least, testosterone propionate (total dose 1507) was found to
be the most potent of the androgens, its activity being twice
that of testosterone and 10-13 times that of androsterone.
Frank and Salmon (1936) found that androgens affected
symptoms due to castration only slightly and did not influ-
ence the excretion of gonadotropic hormone. Their experi-
ments were performed in two castrated men who received
total doses of androgens such as 20 mg. of androsterone, 25
mg. of dihydroandrosterone benzoate, or 115 mg, of testos-
terone. Apparently androgens are much less potent than
oestrogens in correcting pituitary castration changes, whether
reference is made to altered morphology or to the storage or
rate of secretion of gonadotropic hormones. Salmon's report
(1937) also supports this behef. The injection of 815 mg. of
testosterone propionate over a period of about 4 weeks into a
spayed woman produced effects — i.e., amelioration of meno-
pausal symptoms, disappearance of gonadotropic hormone in
urine — corresponding to those of approximately 4 mg. of
oestradiol benzoate.

Androgens may cause oestrus, prolonged or only length-
ened periodically, in animals with intact ovaries (Nelson and
Merckel, 1937). Hypophysectomy seemed to increase this
effect of dehydroandrosterone. Hohlweg (1937) believed that

[92I

THE GONADOTROPIC HORMONES

corpus luteum formation may result from the injection of
dehydroandrosterone or testosterone into rats. Obviously
suppression of oestrus by an androgen might be related to
such an action. There is no evidence that the anterior pitui-
tary plays an important part in these effects of androgens.
It has been suggested that the ovary may convert an andro-
gen into an oestrogen.

There is good evidence from recently published reports that
androgenic substances also directly affect the testes." Wells
and Moore (1936) found that androsterone or extract of male
urine or bull testis (like gonadotropic extracts) might cause
precocious spermatogenesis in the ground squirrel iCitellus
tridecemlineatus) weeks or months before the germinal epi-
thelium normally becomes active. None of their animals was
hypophysectomized. Confirming the work of Walsh, Cuyler,
and McCullagh, Nelson and Gallagher (1936) as well as
Nelson and Merckel (1937) concluded that "male hormone"
(extract of urine, crystalline androgens) maintains spermato-
genesis in the hypophysectomized rat.^^ Injection must be
started a day or two after hypophysectomy; if there is an in-
terval of 3 weeks between hypophysectomy and initiation of
treatment, spermatogenesis cannot be initiated perhaps be-
cause of irreparable damage to the germinal epithelium. The
treatment does not correct the degenerative changes in the
interstitial cells. Cutuly, McCullagh, and Cutuly (1937) be-
lieved that the maintenance of scrotal function accounted for
the favorable action of androgens on spermatogenesis; how-
ever, Nelson and Merckel pointed out that scrotal function

5' For studies comparing the effect of several androgens on the secondary sexual
organs of normal and hypophysectomized male rats, see Freud (1935) and Laqueur,
Dingemanse, and Freud (1935). For example, although (with a cosubstance) testos-
terone and dihydroandrosterone might produce typical responses in hypophy-
sectomized animals, androsterone was almost without action.

5^ McEuen, Selye, and Collip (1937) concluded that normal testicular structure
in the hypophysectomized rat is not maintained by the injection of testosterone.
Cutuly, McCullagh, and Cutuly (1937) prevented testicular atrophy in hypophy-
sectomized rats by androsterone (1.50 mg. daily) and testosterone (0.45-1.50 mg.
daily) but not by dihydroandrosterone benzoate (1.25 mg. daily).

[93]

THE PITUITARY BODY

but not spermatogenesis may persist in hypophysectomized
rats after the injection of oestrone (i,ooo I.U. daily). The
fact that certain androgenic substances maintain spermato-
genesis in hypophysectomized rats suggests that the normal
pituitary gonadotropic hormone necessary for the testis is
only that stimulating the interstitial cells. If pituitary secre-
tion insures normal function on the part of the interstitial
cells, perhaps the secretion of the latter is all that is needed
to maintain spermatogenesis.

The interrelationship between the secretion of gonadotropic
hormones and the internal secretions of other glands, i . The
thyroid gland. — Reports published after those previously re-
viewed still indicate that only exceptionally does there appear
to be an important interrelationship between the secretion of
gonadotropic hormones and that of the thyroid gland. Gon-
adectomy in the guinea pig may be followed by moderate
proliferative changes in the thyroid according to Kippen and
Loeb (1936). Several authors have studied the effect of thy-
roidectomy on the gonads or their response to gonadotropic
hormone. Leonard and Leonard (1937) found that thyroid
deficiency of about one week's duration probably had no ef-
fect on the number of follicles (including vesicular follicles) of
the immature rat's ovary. According to Friedgood and Can-
non (1936), a marked maturation of the ova in the rabbit's
ovary can be observed several weeks after thyroidectomy.
Another aspect of the problem is the testing of the ovarian
response to gonadotropic hormones after thyroidectomy."
Leonard (1936) tested pituitary or urinary extracts in thy-
roidectomized or normal rats. The extracts themselves were
free from thyrotropic hormone. He concluded that the folli-
cle-stimulating phase of the response is greater in thyroid-
ectomized animals and that thyroid hormone inhibits the ac-
tion of foIHcle-stimulating hormone but not that of luteiniz-

5^ Benoit (19,36) observed that the response of the testes and secondary sexual
organs of the drake to intensive illumination — probably by an indirect neurohumoral
mechanism involving the optic nerves and the pars glandularis — could be pre-
vented by thyroidectomy.

[94]

THE GONADOTROPIC HORMONES

ing gonadotropic hormones such as prolan or pregnant- mare
serum. ^-i The observations of Tyndale and Levin (1937) sup-
port Leonard's conclusions. These authors found that the
ovarian response to foUicle-stimulating hormone (extract of
"menopause urine") may be much greater in hypophysec-
tomized than in normal immature rats. Inasmuch as the in-
jection of thyroxine reduced the ovarian response of similarly
treated hypophysectomized rats, they concluded that poor
function on the part of the thyroid may account for the dif-
ference found. Obviously this suggestion does not exhaust the
list of possible explanations. Thyroid hormone probably pro-
duces an inhibitory effect by its action on the ovary (see also
Fischer and Engel, 1936). On the other hand, the results of
Morrin and Loeb (1935) indicated that the response of the
guinea pig's ovary to implants of the pars glandularis (guinea
pig, ox, rabbit, and rat) was the same whether or not the thy-
roid had been removed previously.

Halpern and Hendryson (1935) reported that dinitro-
phenol, a general stimulant of metabolism, does not signifi-
cantly affect the oestrous cycles of rats and that changes in
the oestrous cycles caused by thyroid extract therefore can-
not be attributed to the stimulating effect of the extract on
metaboHsm.

2. The adrenal glands. — The hormonal variables requiring
attention in a consideration of the interrelationship of the
pituitary (gonadotropic function) and adrenal glands are pi-
tuitary gonadotropic hormones, adrenal cortical stimulating
hormone, and the internal secretions of both the gonads and
the adrenal cortex." Moreover, the internal secretions of the
"end-organs," the gonads and the adrenal cortex, are prob-
ably so similar in structure that, under suitable conditions,

s-t Loeb, Saxton, and Hayward (1936) believed that thyrotropic hormone usually
is associated with luteinizing hormone and "atresin" in the pituitary. The concen-
tration of follicle-stimulating hormone tends to be low if that of the other three
substances is high.

55 Epinephrine, the important medullary secretion, appears to require no con-
sideration.

[95]

THE PITUITARY BODY

they may possess substitutional properties. For example, it
appears that the internal secretion of the corpus luteum,
progesterone, may be a much less potent but fairly satisfac-
tory substitute for adrenal cortical hormone after adrenal-
ectomy. Therefore, experiments dealing with the interplay
of so many variables, to which are added the necessary inac-
curacies of biological work, must be interpreted with reserve.
Complete adrenalectomy may affect adversely sexual and,
presumably, pituitary gonadotropic function. Until there is
better evidence to the contrary, these actions are best inter-
preted as resulting from the general, nonspecific, harmful
effects of a deficiency of the adrenal cortical hormone. Mar-
tin and Fazekas (1937) concluded that salt therapy of bilater-
ally adrenalectomized adult female rats facilitated the normal
cyclic sexual phenomena (normal oestrous cycles in 55 per
cent of animals receiving salt solution in comparison with
normal cycles in 21 per cent of control animals observed for a
much shorter period). What observations they made with
pituitary implants are not of much value as an aid in inter-
pretation. According to Fitzhugh (1937), adrenalectomy in
the rat is followed by a disappearance of oestrous cycles in the
female or atrophy and degenerative changes in the testes of
the male; he reported that both of these changes could be cor-
rected by the injection of adrenal cortical extract. Britton
and Kline (1936) concluded that in the presence of adrenal
insufficiency the female rat is usually sterile; if adrenal in-
sufficiency is produced in pregnant animals, abortion com-
monly occurs and there is no lactation. All these harmful
changes can be prevented by adrenal cortical extract. Fer-
tility also is reduced in the adrenalectomized male rat sur-
viving because of accessory tissue. Friedgood (1937) studied
the effect of adrenalectomy on ovulation in the cat following
coitus. He found that removal of the second adrenal 15-55
minutes after mating was not followed by ovulation (9 cats),
whereas if the operation was delayed until 6 hours after mat-
ing, normal ovulation occurred (3 cats). Bilateral adrenal-

[96]

THE GONADOTROPIC HORMONES

ectomy did not prevent ovulation due to injected pituitary
gonadotropic hormones; however, there appeared to be a re-
tardation of ovulation and interference with the subsequent
formation of corpora lutea (Friedgood and Foster, 1937).

Pituitary implants may markedly prolong the lifeof adren-
alectomized young female rats. It is likely that this effect
is due to an indirect action on the ovaries: luteinization with
abnormal production of corpus luteum hormone occurs (Em-
ery and Schwabe, 1936; Cavanaugh and Gaunt, 1937). ^^

Several authors have declared that extract of the adrenal
glands can cause a moderate gonadotropic effect in rats."
Extract of the adrenal of the gelding or ox in a dose equiva-
lent to 114 mg. of dried gland was found by Deanesly (1935)
to cause oestrous changes in the uterus and enlarged or cystic
follicles in the ovaries of 3 of 10 immature rats. The experi-
ments of xAllen and Bourne (1936) are of little significance be-
cause their female rats were 56-70 days old when used. Fitz-
hugh (1937) believed that extract containing adrenal cortical
hormone causes a slight hypertrophy of the ovaries and uter-
us or a moderate atrophy of the testes of rats. In the female
rat the results were obtained by injecting extract on the 21-44
days of life. Hoffmann (1937) concluded that cortical ex-
tracts containing no cortical hormone cause a gonadotropic
effect or a potentiation of the action of prolan in immature
rats. The maximum effect appeared after 65 hours; the dose
used was equivalent to 600 mg. of dried adrenal cortex; the
substance responsible for the effect was insoluble in lipoid
solvents. Perhaps these effects, elicited with difficulty, are due
to an action on the pars glandularis. Corey (1937) was un-

5* Swingle and others (1937) showed that anterior pituitary extract may prolong
the life of bilaterally adrenalectomized cats independently of sex or the gonads.
Also they found that the bitch during pseudopregnancy requires no adrenal cortical
hormone, although bilaterally adrenalectomized. Their negative results with pro-
gesterone in cats were perhaps due to insufficiently large doses.

57 The secondary sexual organs of castrated, hypophysectomized rats may
respond to adrenal cortical stimulating hormone by a stimulation of growth (David-
son, 1937J.

[97]

THE PITUITARY BODY

able to produce oestrus by injecting potent cortical adrenal
extract into adult hypophysectomized female rats.

3. The epiphysis. — Despite Engel's statement to the con-
trary (review, 1936), there is not yet satisfactory evidence
that pineal secretion antagonizes the gonadotropic secretion
of the pars glandularis. Recent observations are those of
Fleischmann and Goldhammer (1936), Tarkhan (1937), and
Wade (1937). Wade also used prolan and pregnant-mare
serum as gonadotropic substances.

4. The lactogenic hormone of the anterior pituitary .^^^ ^' —
Lactogenic extracts of the pars glandularis, injected into fe-
male rats, may cause a prolonged period of dioestrus (Dresel,
1935). Similar results were obtained by Nathanson, Fevold,
and Jennison (1937) both with pituitary extract and with an
extract of the urine of lactating women. They suggest that
luteinizing hormone rather than lactogenic hormone is re-
sponsible for the effect. ^According to Engelhart (1936), the
lactogenic hormone brings about extensive luteinization of
the rabbit's ovary. However, not all his extracts were free of
gonadotropic hormone. Lahr and Riddle (1936) injected
lactogenic extract into rats and caused a temporary suppres-
sion of oestrous cycles in adult females. Large ovaries con-
taining corpora lutea were present after 8-12 days' treatment.
The authors doubted that progesterone-secretion was respon-
sible for the disappearance of oestrous cycles and suggested
that either an alteration of ovarian function or an interfer-
ence with the liberation of follicle-stimulating hormone ac-
counted for the change produced. Desclin and Gregoire
(1937) transplanted ovaries to the kidneys of female rats
spayed a few days postpartum. Lactation was permitted to
continue in half of the group. A comparison of the ovaries
of the lactating and nonlactating groups 15 days later led the

58 Leblond and Nelson (1936) concluded that the maternal instinct depends
neither on lactation nor on internal secretions of the anterior pituitary, although
these may reinforce or reduce manifestations of the instinct.

59 See also chap. v.

I 98]

THE GONADOTROPIC HORMONES

authors to conclude that the secretion of gonadotropic hor-
mone is inhibited during lactation. According to De Fremery
and Denekamp (1935), doses of pituitary lactogenic hormone,
large enough to initiate the secretion of milk, cause abortion
or fetal death in utero if administered to pregnant goats,
guinea pigs, rabbits, or rats. The lactogenic extract, pro-
lactin, of Bates, Riddle, and Lahr (1937) caused as marked a
regression of the testes of adult pigeons as hypophysectomy.
They believed that the extract did not affect the testes but
interfered with the liberation (or formation?) of "follicle-stim-
ulating" (gonadotropic) hormone.

The statements in the foregoing paragraph can soon be
tested accurately, inasmuch as the isolation of crystaUine,
lactogenic hormone has been announced recently by White,
Catchpole, and Long (1937).

The nervous cont?'ol of the secretion of gonadotropic hormones.
— In the discussion of the effect of light and related radiations
on the gonads it was emphasized that many of the observa-
tions indicate that the secretion of gonadotropic hormones
by the pars glandularis may be reflexly stimulated, the affer-
ent arc being the optic nerves carrying impulses to the hypo-
thalamus, whence secretory fibers pass to the pars glandu-
laris. Here it is proposed to review other data which also
indicate that impulses from the central or peripheral nervous
systems may control the secretion by the anterior pituitary
of gonad-stimulating hormones into the blood stream.

Rosen and Shelesnyak (1937) produced pseudopregnancy
in more than one-half of a group of rats as a result of the in-
tranasal instillation of a solution of silver nitrate. This effect
possibly is related to a reflex effect on the anterior pituitary.
Other investigators have studied peripheral sympathetic
nerves. Friedgood and Pincus (1935) stated that bilateral
faradic stimulation of the cervical sympathetic nerves caused
ovulation in 3 of 6 adult rabbits as well as clear-cut matura-
tion of ova. In later work Friedgood and Cannon (1936) re-
ported that bilateral cervical sympathetic stimulation by a

[99]

THE PITUITARY BODY

condenser-discharge method failed to cause ovulation but
did bring about maturation of ova. They believed that the
cervical sympathetics have only a limited control over the dis-
charge of gonadotropic hormones by the anterior pituitary.
Brooks (1937) was unable to prevent the ovulation following
coitus in the rabbit by removing sense organs or parts of the
central and peripheral nervous systems (such as the olfactory
bulbs or the cerebral cortex or the sacral cord, the abdominal
sympathetics, the uterus, and part of the vagina).

Diffuse powerful electrical stimulation applied to the brain
or lumbosacral cord of the rabbit can cause ovulation, al-
though the latter occurs 7-14 hours later than after coitus
(Marshall and Verney, 1936). Harris (1936) applied a similar
stimulus to the head of the adult female rat; as a result pseu-
dopregnancy occurred in about 70 per cent of the animals.
The same author (1937) was able to produce ovulation, some-
times associated with the formation of cystic or hemorrhagic
folHcles, by applying an electrical stimulus to the hypothala-
mus or pituitary of the rabbit. According to Haterius and
Derbyshire (1937), who used a small bipolar electrode, a
sharply localized area 5 mm. below the surface above and an-
terior to the optic chiasm causes ovulation when stimulated.
There is an associated motor response (flexion of hind legs,
pelvis, and trunk; elevation of tail). The authors used rab-
bits. Cahane and Cahane (1935-36) described histologic
changes in the anterior pituitary and genital atrophy in 2
of 8 rats surviving a lesion made in the infundibulo-tuberal
region of the hypothalamus.

Presumably impulses from the hypothalamus (or thala-
mus) pass down the stalk and provoke secretion of gonado-
tropic hormones when central stimulation is followed by ovu-
lation and pseudopregnancy. However, the evidence is much
less complete than that afforded by similar studies of the se-
cretion of the diuresis-inhibiting hormone of the pars neuralis.
Harris (1937) stated that lesions of the stalk were followed by
genital atrophy in both male and female rabbits. According

f 100 1

THE GONADOTROPIC HORMONES

to Westman and Jacobsohn (1937), this occurs in female rats
as well as female rabbits; the eifects, after section of the
stalk, resemble those of hypophysectomy except that degen-
eration of the cells of the membrana granulosa does not ap-
pear. However, Brooks (1937-38), who used only female
rabbits, concluded that the severing of the stalk, although
preventing ovulation due to coitus and causing atrophy of
the pars neuralis, had no other effect including possible ac-
tions on growth, maintenance of the genital tract, ovaries,
thyroid, adrenal, etc. The ovaries contained ripe follicles
from which ovulation occurred after the injection of preg-
nancy-urine. Brooks emphasizes that operations on the stalk
may also seriously impair the vascular supply of the pituitary
body. According to Keller and Hamilton (1937), breeding,
pregnancy, parturition, and lactation can occur normally in
the dog after the hypophysial stalk has been severed.

Vitamins and minerals in relation to the gonadotropic hor-
mones of the anterior pituitary. — It is natural that the vitamin
considered to be necessary for normal reproductive perform-
ance, vitamin E, should receive the most attention of those
interested in the possible effects of vitamin deficiency on the
pars glandularis. Extracts, such as wheat germ oil, contain-
ing a high concentration of vitamin E, possess no gonado-
tropic action (Verzar and others; Saphir, 1936). Marches!
(1935) stated that adult female rats on a diet deficient in
vitamin E and otherwise sterile became pregnant and deliv-
ered the young normally after a suitable course of treatment
either with anterior pituitary extract or prolan. The young
died shortly after birth. Diakov and Kfizenecky (1935),
however, believed that the vitamin is necessary for the suc-
cessful completion of pregnancy, although the administration
of either prolan or anterior pituitary extract might bring
about follicle growth and ovulation, and make possible fer-
tilization and implantation in female rats receiving no vita-
min E. The gonadotropic hormone(s) causing ovulation in
oestrus rabbits is reduced in amount in the pituitary of the

hoil

THE PITUITARY BODY

adult female rat on a diet contraining no vitamin E (Row-
lands and Singer, 1936). The reduction is comparable to that
occurring on the sixteenth day of pregnancy in normal rats
(50-60 per cent of the normal value). The pituitary of ani-
mals which recover from the vitamin deficiency contains as
much as or more hormone than the normal female gland. Vi-
tamin-E deficiency is accompanied by no conspicuous change
in pituitary weight.''**

According to Orent-Keiles, Robinson, and McCollum
(1937) a sodium-deficient diet brings about, in the female
rat, a delay in sexual maturity and a serious disturbance in
the oestrous rhythm as well as other phases of reproductive
physiology. The animals do not mate. Males, however, re-
main fertile for 2.5-3 months. To what extent pituitary func-
tion is altered is not known.

Riddle and Dotti (1936) concluded that pituitary gonado-
tropic hormone causes an increase in the concentration of
serum calcium in the pigeon (normal, hypophysectomized, or
thyroidectomized) but not after gonadectomy. Other pitui-
tary extracts, not containing gonadotropic hormone, were
without action. They believed that oestrogens but not andro-
gens had a similar action in the pigeon, fowl, and dog (but
not the rabbit); often their results were sufficiently irregular
as not to be convincing. Kozelka and Tatum (1937) found
that the injection of 150 rat-units (total dose.'*) of gonado-
tropic hormone lowered the serum calcium of rachitic dogs
1.7 mg. per cent (from 10. i to 8.4 mg, per cent).

Neoplastic growths and the gonadotropic hormones of the
pituitary body. — Both Katz (1936) and Druckrey (1936-37)
concluded that pituitary gonadotropic hormones antagonize

^° Selye and Collip (1936) reported that rats on a "deficent diet" (50 per cent
ground beans, 50 per cent "Purina") went into permanent dioestrus with ovarian
atrophy. Inasmuch as the ovaries of such animals responded to prolan in a typical
fashion, the authors concluded that the diet led to a failure of secretion of gonado-
tropic hormone by the pituitary.

Teresa (1937) believed that the amount of gonadotropic hormone in the pitui-
tary of the mouse fed a diet lacking vitamin B is less than normal. This observation
is contrary to that of Marrian and Parkes in rats.

[ 102]

THE GONADOTROPIC HORMONES

the growth of malignant neoplasms. Their reasons were the
following: gonadectomy is followed by an inhibition of
growth (including metastases) of such malignant tumors as
tar cancer, the Jensen sarcoma, and the Flexner-Jobling car-
cinoma; this inhibitory effect is at its peak when the amount
of gonadotropic hormone in the gonadectomized animal's
pituitary is highest; the inhibitory effect of gonadectomy
may be somewhat antagonized by an oestrogen; the injection
of a gonadotropic extract (prolan, 5 rat-units on alternate
days) also may inhibit tumor-growth in both normal and
gonadectomized rodents. The report of Bischoff and Maxwell
(1936) directly contradicts this interpretation as far as trans-
planted sarcomata (180 and Rio) are concerned. Although
injections of prolan or pituitary gonadotropic hormone pro-
duced marked changes in the gonads, they did not inhibit
tumor-growth.

The metabolism of the gonadotropic hormones of the anterior
pituitary!''' — Freed (1935), supplementing previous reports,
concluded that gonadotropic hormone, probably originating
in the pars glandularis, is found in the urine of children more
than 4-5 years old. The urine of children 10 years old con-
tains as much hormone as the urine of adults. According to
Frank and Salmon (1935), cyclic variations in the concentra-
tion of both follicle-stimulating hormone and luteinizing hor-
mone can be detected in the blood and urine of normal wom-
en. They reported that the concentration of the hormones in
the blood increased about the 9-12 day of the menstrual
cycle and that a day or two later (10- 14 day) there occurred

'" Engel and Werber (1937), confirming Anderson and Haymaker (1935), found
that tiss' e cultures of the pituitary of the mouse contain no detectable amount of
gonadotropic hormone. The degree of growth of the typical epithelial cells is not
affected by the previous treatment (e.g., gonadectomy) of the mouse furnishing the
pituitary tissue (see also chap. i).

The relationship between the pituitary and the embryonic development of the
gonads in the goat, ox, pig, and sheep was investigated by Daineko (1936).

Saxton and Loeb (1937), using the female guinea pig for assay, studied the
gonadotropic effects of the pituitary of man in relation to sex, age, pregnancy, and
lactation. Those interested should read the original report.

[ 103]

THE PITUITARY BODY

a rise in the urinary concentration of the hormones.*'^ It
must be emphasized that these reports may not be in accord
with those of other investigators. The reports and discus-
sions of Osterreicher (1935) and Fkihmann (1937) should be
read to correct any behef that various authors are in reason-
able agreement as to the concentration of gonadotropic hor-
mones in the blood or the excretion of the hormones in the
urine of both children and adults. This is also true of the
cyclic variations which may be found in the blood and urine
of women.

The daily urinary excretion of gonadotropic hormone by
normal men is probably greater than 6 rabbit-units (Fried-
man and Weinstein, 1937).

Anselmino and Hoffmann (1936) concluded that early in
pregnancy small amounts of pituitary gonadotropic hormone
are excreted in the urine. In the urine of patients with hyper-
emesis gravidarum an increased amount of pituitary gonado-
tropic hormone was believed to be excreted, whereas none
of the hormone could be found in the urine of patients with
eclampsia. These conclusions must be regarded only as sug-
gestions, because detection of the pituitary hormones was
based on the production of ovarian hypertrophy greater than
55-60 mg. in rats 30-35 days old (28-35 gm.). It was assumed
that the prolan present produced a limited hypertrophy. A
total number of only 54 rats was used and the possible syner-
gistic effect of the secretion of the rats' pituitaries was dis-
regarded. According to Tenney and Parker (1937), the urine
of parturient women contains a pituitary-stimulating sub-
stance causing indirect gonadotropic effects. They believed
that this substance could be distinguished from prolan which

''^ The authors as well as Frank, Salmon, and Friedman (1935) performed their
assays in normal rats. Their results should be confirmed (e.g., the presence of
luteinizing hormone) in hypophysectomized rats (see also Guyenot and others,
1936). Evan^and Simpson (1935) produced superovulation and even corpus luteum
formation with extract of "menopause urine." To what extent these phenomena
would have been observed in hypophysectomized rats is not known. Also, they
agreed with others in their description of the synergistic effects of such extracts with
prolan.

[ 104]

THE GONADOTROPIC HORMONES

was completely precipitated by 5 volumes of alcohol, where-
as under similar conditions only 20 per cent of the newly de-
scribed substance could be recovered. Obviously, better data
are needed to establish their conclusion.

Monnier (1936) found that lumbar or ventricular cerebro-
spinal fluid of patients with brain tumor (9 of 20) or other
cerebral disease (3 of 10) stimulated the gonads of male or fe-
male immature mice. Such effects were never produced by
normal cerebrospinal fluid. (Other reports are mentioned in
the previous volume.)

Miscellaneous obs elevations. — Emery (1937) reported that
splenectomy in the rat does not alter various gonadotropic
effects of "minimal strength" pituitary transplants. Gordon
and others had reported differently but used prolan instead
of a true anterior pituitary hormone.

THE PREPARATION, ASSAY, AND SPECIAL EFFECTS OF
GONADOTROPIC PITUITARY EXTRACTS

The preparation and chemical nature of pituitary gonado-
tropic hormones. — The complex effects of pituitary gonado-
tropic extracts have led to equally complex interpretations of
the number of hormones secreted. Even the generally ac-
cepted belief that separate follicle-stimulating and luteinizing
hormones are secreted by the pars glandularis has not been
proved with convincing thoroughness. Therefore, once a
gonadotropic hormone has been isolated as a crystalline,
chemically pure substance, it will be possible rapidly to de-
cide many vexing questions of interpretation.

What data have been published recently still indicate that
pituitary gonadotropic hormone(s) are proteins or substances
of protein-like nature. Tryptic digestion (or heat to a far less
extent) rapidly destroys pituitary hormones, causing ovula-
tion in rabbits or testis-stimulation in immature doves (Rid-
dle and others, 1936). On the other hand, tryptic digestion
under proper conditions appears to bring about destruction of
nearly all the luteinizing action of anterior pituitary extract

THE PITUITARY BODY

in the rat but permits the retention of the extract's follicle-
stimulating effect (McShan and Meyer; Chen and van Dyke).
Rowlands (1935) found that extracts of the beef anterior
pituitary, tested by their ovulation-producing effect in rab-
bits, were not affected by "Merthiolate" (0.02 per cent) but
deteriorated rapidly at room temperature (50 per cent loss
in 9 days, 75 per cent loss in 23 days). Stored at — 2° C, such
extracts lost less than 50 per cent of their activity after a
year. Maxwell and Bischoff (1935), who doubt that there are
two gonadotropic hormones, found that their pituitary ex-
tract was inactivated by o.i N NaOH (3 hours at 37° C.) but
was only partially destroyed by treatment with 0.033 N
NaOH or o.i N HCl under the same conditions. Mild oxidiz-
ing or reducing agents did not affect the hormone(s), whereas
it was partially or completely inactivated by reagents re-
acting with amino, imino, or hydroxyl groups. Formalin
treatment (4-10 per cent at pH 7-8) did not prevent luteiniz-
ing effects. ^^

The extraction procedure of Bates, Riddle, and Lahr (1935)
utilized as an initial solvent 60 per cent aqueous alcohol at a
pH of 9-9.5. Guyenot, Ponse, and Dottrens (1935) described
methods — differential filtration, hydrolysis by acid, autolysis,
peptic digestion — of separating follicle-stimulating ("auxo-
genic") hormone from luteinizing ("crinogenic") hormone.
Evans and others, in two reports published in 1936, described
methods for isolating from pituitary tissue specific extracts
comprising (i) a substance stimulating the interstitial cells
of the ovary or testis, (2) a luteinizing substance, (3) a folli-
cle-stimulating substance which also stimulates the testicular
germinal epithelium, and (4) a substance inhibiting or antag-
onizing the action of the follicle-stimulating substance (or of
prolan or of the gonadotropic hormone of pregnant-mare
serum). Revised methods, including necessary precautions,
of extracting gondaotropic hormones from urine have recent-

^■5 Hayward and Loeb (1937) studied the effects of pituitary tissue implanted
after immersion for hours to days in strong solutions of sucrose, glycerine, or urea.

[106I

THE GONADOTROPIC HORMONES

ly been published by Levin and Tyndale (1935), Thomsen
and Pedersen-Bjergaard (1935-36), Palmer (1937), and Katz-
man (1937).

The assay of the gonadotropic hormones of the anterior pitui-
tary.— The "unit" of a gonadotropic hormone, whether the
assay be performed in the immature rat or in some other ani-
mal, is a term which remains without precision. Recently a
start has been made by the National Institute for Medical
Research (Great Britain) to set up provisional standards and
to determine from the experience of widely separated investi-
gators what methods of assay should be recommended. If
standard preparations for assay and standard procedures of
performing assays are agreed upon and adopted, units of
gonadotropic activity designated by different authors can be
evaluated with far more assurance than at present. Assay is
affected by many factors, the importance of which varies with
the source and nature of the gonadotropic agent. For exam-
ple, the frequency of injection and the route of injection may
greatly modify the response of the immature rat's ovary to
pituitary gonadotropic hormone; however. Bates and Riddle
(1936) found this not to be true of the effect of hormone on
the pigeon's testis.'''' Other obvious factors are the size (or
litter-size)^^ of the immature rat, diet, racial strain, ease with

^"i Bates, Riddle, and Lahr (1935) stated that the response of the immature
dove's testis to gonadotropic extract is not affected by the presence or absence of
luteinizing hormone.

^5 An example of work bearing on this factor is the report of Engle, Crafts, and
Zeithamel (1937). The effect of the rat's rate of growth on the age and body-weiglit
of vaginal canalization was investigated by comparing groups of individuals from
litters of varied size — the rate of growth usually being inversely proportional to
litter-size. The results were as follows:

Litter-Size

Opening ok Vaginal Orifice
(First Oestrus)

Age in Days

Weight in Grams

2-3

4-S

46.5
52.9
77.9
41. 1

lOQ.Q

114,8

127.0

107]

THE PITUITARY BODY

which the preparation used is metaboHzed, possible syner-
gistic or antagonistic effects of substances in the extract, etc.
There is increasing recognition of the inabihty to control the
effects of the anterior pituitary secretion if normal animals
are used for assay. Especially is it necessary to use hypophy-
sectomized animals in testing extracts considered to have
specific qualitative effects.

Investigations of the relationship between dosage of pitui-
tary gonadotropic hormone and the response of the gonads

012 024 03«

Fig. 14. — The effect of various doses of follicle-stimulating hormone of "cas-
trate" urine on the weight of the ovary and uterus of the mouse. (From Levin and
Tyndale, Endocrinology, 21, 619-28 [1937].)

have been made recently by Deanesly (1935), Chow and Liu
(1937), and Levin and Tyndale (1937). Deanesly recom-
mended that the ovarian hypertrophy produced for quantita-
tive assay of pituitary gonadotropic hormone should be repre-
sented by paired ovarian weights within a range of about 30-
80 mg.^'' However, it has become increasingly clear that the
use of ovarian weight as a basis for assay may have only a
limited value. Levin and Tyndale found that the response
of the uterus of the immature albino mouse to the follicle-

^ After fixation in Bouin's fluid and partial dehydration (70 per cent alcohol).

1 108 1

THE GONADOTROPIC HORMONES

stimulating hormone of "castrate" urine to be 5-10 times
greater than that of the ovaries. They obtained data on the
relationship between dose and uterine hypertrophy (see Figs.
14 and 15). In a later report Heller, Lauson, and Sevring-
haus (1938) particularly studied the response of the immature
rat's uterus. According to Bachman (1936), corpora lutea

700-

PCR CtNT iNCREASE =

EXP WT- CONTROL WT
CONTROL WT.

Xioo.

TOTAL DOSE L4II. MILLIGRAMS DRY POWDER.
I I I

UTERINE 0.12
OVARIAN OfiO

024
120

036

L80

0.48
2.40

0.60
3.00

Q72

aeo

Fig. 1 5. — The change in weight of the ovary and uterus of the mouse, in terms of
control weights, following various doses of follicle-stimulating hormone of "cas-
trate" urine. (From Levin and Tyndale, Endocrinology, 21, 619-28 [1937].)

without uterine changes may appear after the injection of
gonadotropic extract (sheep pituitary extract, prolan) into
very young rabbits. No effects are produced in rabbits less
than 1.5-2 months old.

Special efects of gonadotropic pituitary extracts or related
substances, i. The doctrine of antihormones. — Since the pub-
lication of reports by Collip and his collaborators indicating

109

THE PITUITARY BODY

that the prolonged injection of gonadotropic extracts is fol-
lowed by the production, at some unknown site, of "antihor-
mone" which can be detected in the serum, numerous au-
thors have made many further investigations of the phe-
nomenon. The production of antihormone is of practical im-
portance; for, if an injected extract produces antihormone,
successful therapy may be thwarted and the patient's condi-
tion even may be worsened.''' The other important question
is the significance of possible antihormone balance to gonado-
tropic and other hormones secreted by the gland in situ.
Chiefly from experiments in parabiotic animals there is good
evidence against the view that the body may produce its own
antihormone to inhibit excessive secretion by a gland like the
anterior pituitary. Also the evidence from artificially intro-
duced hormone is by no means concordantly in favor of the
antihormone hypothesis.

Usually the prolonged injection of a gonadotropic extract
is followed by progressively less efi'ect, until finally the ovaries
or testes of the injected animals may actually be smaller than
those of animals not receiving treatment. xAntihormone can
then be readily detected in the serum by its inhibitory eff"ect
on the gonadotropic action of the extract when the serum and
extract are injected into fresh animals. An attempt again to
stimulate the gonads of the animals receiving the prolonged
injections after a period of rest either fails or produces only a
slight change. Most investigators are in agreement with
these general statements. However, the interpretation of the
phenomenon is a matter of disagreement which perhaps can-
not be settled from a consideration of the published data.

One obvious basis for the development of antihormone in
response to the long-continued injection of gonadotropic ex-

"' Spence, Scowen. and Rowlands (1938) concluded that the injection into human
beings of prolan (1,000 rat-units weekly) or extract of the pig pituitary (30-50 R.U.
weekly) for varying periods up to 7 months was followed by the appearance of no
"serious amount of iinti-gonadotropic activity" in the serum.

Rowlands and Parkes (1937) suggested that antihormone obtained from serum
of suitably injected animals might be used to lessen the effects of hormones secreted
by the hyperactive pituitary.

tiiol

THE GONADOTROPIC HORMONES

tract is the production of immune bodies by specific or non-
specific protein included in impure extract. Max, Schmecke-
bier, and Loeb (1935), for example, believed that extraneous
protein was responsible for the refractory state of their guinea
pigs to extract injected after 4-6 weeks of treatment. Others
have attempted, without success, to correlate the presence or
development of typical immune bodies with the development
of antihormone. Usually the development of antibodies does
not parallel the development of antihormone (Collip, 1935;
Gustus, Meyer, and Dingle, 1935; Brandt and Goldhammer,
1936). Sulman (1937) who used prolan or pregnant-mare
serum as possible antigens concluded that these substances,
injected into rabbits, behaved neither as antigens (reaction
with antisera, including complement-fixation) nor as hap-
tenes.^^

A great deal of work is represented by investigations of the
species (and source) specificity of antihormones due to the in-
jection of gonadotropic extracts. ^^ If gonadotropic extracts
were highly species specific, this fact would constitute evi-
dence that they are artificially produced by some mechanism
analogous to antigen-antibody reactions. The results are
most varied and indicate that, in the hands of different in-
vestigators— and sometimes in the hands of the same investi-
gator— gonadotropic extracts may or may not be species
specific.'" Chen (1937) found that the ordinary proteins of
sheep or human serum, injected as serum repeatedly into

''* B. F. Chow informs me that failure to secure a complement-fixation re-
action does not necessarily indicate that a substance is not antigenic and that the
antigenic effects of a highly potent antigen (e.g., prolan) may not be recognized un-
less relatively large doses are injected.

^' Gonadotropic extracts, both for producing antihormone and for detecting the
presence of antihormone, have been obtained from the following sources: pituitary
tissue of man, the horse, ox, pig, or sheep; blood, placenta, or urine of human
pregnancy; serum or urine of equine pregnancy; urine of women past the menopause.

'" Parkes and Rowlands (1937) concluded there is at least class specificity toward
antihormones. They were unable to prevent the thyrotropic or gonadotropic effects
of mammalian extracts in fowls by first injecting rabbit serum rich in antihormone
as judged by tests in mammals.

[Ill]

THE PITUITARY BODY

rabbits, do not cause the production of substances behaving
like antihormone toward gonadotropic extracts of sheep or
human pituitary. Several recent authors concluded that vari-
ous gonadotropic extracts from the pituitary, blood, or urine
of different animals could produce antihormone which is not
species specific (Gregerson, Clark, and Kurzrok; Parkes and
Rowlands, 1936; Collip, Rowlands, Thompson and Gushing,
1937). These experiments are the most complete and exten-
sive. However, mixed results may be obtained, so that some
extracts produce antihormone which appears to be partially
or completely species characteristic (Collip, Rowlands, 1937).
Finally, several observers found, at least with their prepara-
tions, that antihormones toward gonadotropic extracts in-
hibit the effect only of extracts of tissue or urine of the animal
of the same species (Fluhmann, 1935; Gustus, Meyer, and
Dingle, 1935; Brandt and Goldhammer, 1936). As far as
pituitary gonadotropic extracts are concerned, the weight
of evidence appears to be against the view that antihormone
is species specific. Perhaps there is true "species specificity"
when extract of human pregnancy-urine (prolan) or preg-
nant-mare serum is used as an "antigen" (Rowlands).
"Source specificity" is believed by Rowlands (1938) to be
complete in the case of pregnant-mare serum, although others
(e.g., Thompson and Cushing) have obtained different re-
sults. It is probable that, if antihormone formation is analo-
gous in some phase or phases to the formation of immune
bodies, the problem is rendered more complex and more diffi-
cult to interpret than most immune reactions, because of the
possibility that the hormone "antigens" are more complex
than is usually suspected (see Rowlands, 1938).''' The con-

'■ The method of detecting antihormone (cf. failure of ovarian hypertrophy in
the rat and failure of ovulation in rabbit) may determine whether the result is posi-
tive or negative. Using an extract of the anterior pituitary of the ox as "antigen,"
Rowlands (1937-38) found that its antihormone antagonized the gonadotropic
action of sheep pituitary extract (ovarian hypertrophy in rats), whereas Parkes
and Rowlands (1936) found this not to be the case when they used the production

[112]

THE GONADOTROPIC HORMONES

sidered opinion of investigators like Rowlands is that an im-
mune-like reaction has been neither proved nor ruled out.

Several attempts to inhibit the effects of gonadotropic hor-
mones secreted by the pars glandularis in situ have been suc-
cessful and constitute evidence favorable to the view that
antihormone-formation is important physiologically, Parkes
and Rowlands (1936) showed that the ovulation which usual-
ly follows coitus in the rabbit can be prevented by the intra-
venous injection, 15 minutes after mating, of rabbit serum
containing a high titer of antihormones toward the gonado-
tropic principles in ox anterior pituitary extract. An exten-
sion of this study by Rowlands (1937) indicated that such
serum containing antihormone, although not interfering with
corpus luteum formation, pregnancy, or lactation in the
mouse or rat, did have the following antigonadotropic effects:
(i) it prevented ovulation in the prepubertal rat, (2) it pro-
duced atrophy of the reproductive organs of the adult male
rat, and (3) it could prevent, in the rabbit, ovulation or cor-
pus luteum formation or, in pregnant animals, implantation
of the blastocyst or fetal survival. According to Collip ( 1 937) ,
antihormone-containing serum prevents oestrous cycles in
rats. Also he believed (1935) that antihormone-like sub-
stances may appear in the blood spontaneously. Thompson
and Gushing (1937) caused marked ovarian atrophy in grow-
ing rats by injecting serum containing antihormone (sheep
pituitary extract as "antigen" for about two months). Hisaw,
Hertz, and Fevold (1936) concluded that, although the con-
tinued injection of sheep pituitary extract might be accom-
panied by a refractory condition of the ovaries in juvenile
monkeys {Macaca mulatto), only temporary effects were pro-
duced in adults. They believed that the antihormone pro-
of ovulation in the rabbit as an indication of gonadotropic effect. However, Parkes
and Rowlands used a saline suspension of the sheep pituitary body.

More clear cut are the experiments of Rowlands (1938) who found that the
serum of an animal receiving a course of injections of pituitary extract might aug-
ment the effects of the extract in immature rats (ovarian hypertrophy) and yet
inhibit the action of the extract in rabbits (ovulation response).

[113I

THE PITUITARY BODY

duced in response to sheep pituitary extract does not inhibit
the action of gonadotropic hormone secreted in situ by the
monkey's pars glandularis.

The strongest evidence against antihormone-production as
a physiological mechanism is afforded by experiments with
animals living parabiotically, as has been emphasized re-

CASTRATE
FEMALE

HYPOPHYSECTOMIZED
FEMALE

Body Weight 250 G
Thyroid 23 MG

Adrenals 64 MG
Access 390 MG

Ovaries

Body Weight 180 G
Thyroid 13 MG

Adrenals 16 MG

Access 1350 MG
Ovaries AI6MG

Fig. 1 6. — Diagram illustrating the ovarian changes which occur as a result of
parabiosis between a hypophysectomized rat with intact ovaries and a spayed rat
which otherwise is normal. No antihormone antagonizing gonadotropic hormone
is produced. (From DuShane, Levine, PfeifFer, and Witschi, Proc. Soc. Exp.
Biol. Med., 33, 339-45 [1935]-)

peatedly both by the author and by other investigators (e.g.,
Doisy, Martins, Witschi). Du Shane and others (1935) there-
fore consider antihormone formation a type of immune-body
reaction. Parabiosis between a spayed or castrated rat and a
normal or hypophysectomied female (e.g., ? 9 , ^ 9 ,
^ 9 h) is accompanied by a marked follicle-stimulating effect
of the gonadotropic hormone secreted principally by the

1114]

THE GONADOTROPIC HORMONES

gonadectomized partner's anterior pituitary. Large cystic
ovaries are developed — a phenomenon which apparently pro-
ceeds indefinitely (e.g., 15 months). In response to this en-
dogenous gonadotropic hormone formed in great excess there
is no compensatory production of antihormone (see Fig. 16).
Finally, it must be realized that potent gonadotropic prepa-
rations, although administered for a prolonged period, do not
necessarily bring about refractoriness of the "end-organ"
(e.g., the ovary) with atrophy as is so commonly the case.
Katzman, Wade, and Doisy (19,37) inserted homo-implants
of the pituitary into female rats for 210-75 days. At the end
of the period of treatment the ovaries still were enlarged, and
there was no gonadotropic (or thyrotropic) antihormone in
the blood. ■'^ Fluhmann (1936) observed that a gonadotropic
extract of the blood of pregnant women still maintained a
marked ovarian hypertrophy in rats receiving injections for
as long as a year," In Thompson's experiments (1937) sheep
received, for six months, injections of a sheep pituitary ex-
tract which readily produced gonadotropic antihormone in
other species of animals. Yet none could be clearly detected in
the blood of the sheep.

2. The inhibition of go?jadotropic effects by substances other
than antihormone s J'' — Extracts of the pituitary body may,
under suitable conditions, antagonize the action of gonado-
tropic substances such as prolan, pregnant-mare serum, and
gonadotropic pituitary extract. To this hypothetical sub-
stance Evans has given the name "pituitary antagonist."
Its inhibition of gonadotropic effect is most characteristically
manifested when administration is intraperitoneal. Evans
and others (1936) have described methods of preparing the
substance free from follicle-stimulating or luteinizing effects.

'^ There was no significant alteration in the weight of the adrenals, thyroid, or
pituitary (see also the similar experiments of Artemov, 1937).

7^ The ovaries contained large corpora lutea, lutein cysts, and developing follicles.
There was hypertrophy of the pituitary with associated histologic changes.

'^ See also the effects of lactogenic extracts (pp. 98-99).

[115]

THE PITUITARY BODY

The authors concluded that it antagonizes the action of folli-
cle-stimulating hormone but not luteinizing hormone and
that it acts independently of the pituitary, thyroid, or adre-
nals. Some of its described effects suggest that it is luteinizing
hormone: it has no action on the ovaries of normal immature
rats, but it causes or permits extensive luteinization of the
ovaries of adult rats and prolongs pregnancy, if injected in
the last half of pregnancy. Evans and his colleagues suggest
that such a substance may be important physiologically. It
is obvious that its presence in extracts may complicate all
studies of the effects of gonadotropic extracts, including in-
vestigations of antihormones (see the following section)."
Leonard, Hisaw, and Fevold (1935) concluded that the in-
hibitory substance is associated with luteinizing hormone,
although follicle-stimulating hormone, also injected intra-
peritoneally, might produce some inhibition. It is the belief
of Jensen (personal communication) that luteinizing hor-
mone, "pituitary antagonist," and "interstitial cell stimulat-
ing hormone" are one and the same principle.

Freud (1937) believed that he had detected an "antiluteo-
genic factor" in extract of the pars glandularis of the ox. He
suggested that the absence of this substance accounts for the
persistence of corpora lutea in hypophysectomized rats.
(Bunde and Greep [1936] considered this to be owing to a lack
of luteinizing hormone or some substance associated with it.)
Two early pregnancies in rats were interrupted by intraperi-
toneal injections of the extract — a fact which the author in-
terprets as supporting his view that the injected substance
antagonized the luteinizing hormone.

3. The augmentation of the ef^ects of gonadotropic extract. —
A variety of substances may potentiate or augment the ac-
tion of a gonadotropic extract. For example, the hypertrophy

"s Evans concluded that the immature pigeon's testis is very sensitive toward
gonadotropic extract, because it is unaffected by "pituitary antagonist" (see also
Bates, Riddle, and Lahr, 1935).

[116I

THE GONADOTROPIC HORMONES

of the immature rat's ovary, caused by a follicle-stimulating
extract, is greatly increased if a luteinizing substance also be
given. A puzzling recent observation of great interest is the
potentiating action, at certain times, of the serum of animals
receiving a prolonged course of injections of gonadotropic
pituitary extract to produce antihormone which, of course,
has the opposite action. This phenomenon has been studied
by Collip (1937), Thompson (1937), and Rowlands (1938).
Thompson's experiments illustrate how this information was
obtained. A horse and two dogs received repeated injections
of sheep pituitary gonadotropic extract. The effects of their
sera on the gonadotropic action of the extract in hypophysec-
tomized or normal immature rats was ascertained at inter-
vals of 7-20 days. Finally, the sera were found to contain a
substance or substances which augmented the action of the
extract on the immature rat's ovary about threefold. Sera
which were obtained 50-80 days after the injections were
started had the maximum augmenting effect. The active sub-
stance(s) was in the pseudoglobulin fraction which also con-
tains immune bodies and antihormones, if these are present.
Thompson suggested that an antihormone to "pituitary an-
tagonist" (see the foregoing section) may have been formed.
Rowlands is inclined to concur with this view and enumerates
reasons in support (specificity of effect for pituitary gonado-
tropic extract only, especially of extracts probably rich in
"antagonist," lack of phenomenon with nongonadotropic
pituitary extracts with other effects, etc.).'^

By direct extraction of the anterior pituitary, a substance
augmenting the action of certain gonadotropic extracts (e.g.,
follicle-stimulating extract as extract of urine of women after
spaying or after the menopause, endometrium of the preg-

"^ In CoUip's experiments (sheep pituitary extract as "antigen" injected into
lambs) antihormone was demonstrated later. Katzman, Wade, and Doisy (1937)
who unusuccessfully attempted to produce antihormone effects by pituitary homo-
implants in rats, remarked that the serum obtained at the end of treatment (7-9
months) augmented the gonadotropic effects of implants.

[117]

THE PITUITARY BODY

nant mare, etc.) can be secured .This was named "pituitary
synergist" by Evans and others. There is not satisfactory
evidence that this substance is different from what others
call "luteinizing hormone." Recent work has been reported
by Evans and Simpson (1935), Saunders and Cole (1935),
and Lein (1937),

A number of substances, if injected with pituitary extract,
is capable of augmenting the action of pituitary gonado-
tropic hormone. In addition to tannic acid (recent studies by
Bischoff, 1937; and Fevold, Hisaw, and Greep, 1937) and
ZnS04 (recent studies by Saunders and Cole, 1935; Fevold,
Hisaw, and Greep, 1936; and Emery, 1937), which were previ-
ously known to have this action, approximately a dozen new
substances have been shown also to be effective. These in-
clude (CH3COO)2Cu and CUSO4 (Fevold, Hisaw, and Greep,
1936-37; Emery, 1937; and Pfeiffer, 1937), "Merthiolate"
(C2HsHgSC6H4COONa), a germicide (Chen and van Dyke,
1938), yeast extract and yeast ash (Fevold and others, 1936),
blood, hemoglobin, or heme (Casida, 1936; McShan and
Meyer, 1937), casein and egg-albumin (Saunders and Cole,
1935), and a miscellaneous group of substances only crudely
characterized (Hellbaum, 1936).

Figure 17 illustrates how strikingly the gonadotropic effect
of an extract may be augmented by a foreign chemical mixed
with the extract before injection. Until there is better evi-
dence to the contrary, it is probable that this group of po-
tentiating substances acts by interfering with the absorption
of hormone, thus decelerating excretion (and possibly de-
struction) and prolonging the action of each dose."

"Fevold, Hisaw, and Greep (19.36) were inclined to believe that CH,COOCu
catalyzes the synergistic effects of follicle-stimulating and luteinizing hormones. In
their earlier work, they reported that the intravenous injection of yeast extract
(10-15 "grams-equivalent") or (CH3COO)2Cu (lo mg.) can cause ovulation in the
rabbit. Pfeiffer (1937) concluded that the injection of a solution of CUSO4 has no
effect on gonadotropic hormone secreted by the rat's pituitary i>i situ.

118

Fig. 17. — The potentiation of the response of ovaries of littermate rats as a
result of the addition of "Merthiolate" to the pituitary gonadotropic extract in-
jected. The rats were 26 days old at death and weighed 68 gm., except D, which
weighed 54 gm. (From Chen and van Dyke, J. Pharmacol, exp. Therap., 62,

333-4S [1938].)

Rat

Total Dose of
Pituitary

Gonadotropic
Extract (Mg.)

Percentage

Merthiolate in

Solution of

Extract

Weight of

Both Ovaries

(Mg.)

2.0
2.0
2.0

0
0

0.02
0,075

17,27
25.71
46 . 90
83.59

THE PITUITARY BODY

SUMMARY

Anterior pituitary secretion is a necessary condition of nor-
mal function of the gonads of all classes of vertebrates. How
this necessary condition is implemented in the living animal
has been of prime interest to a host of biological investigators,
both seasoned and newly recruited. Although experiments
have been performed in all classes of vertebrates — fishes,
amphibia, reptiles, birds, and mammals — there still remain
lamentably great gaps in our knowledge of the physiology of
gonadotropic hormones. It is an unenviable task to sum-
marize the work, because unifying working concepts either
are lacking or may be widely used without equally wide
recognition of their inadequate experimental foundations.

Discussion is difficult if there is not agreement on the prob-
able number of gonadotropic hormones. Yet no investigator
has succeeded in preparing a gonadotropic hormone in pure
form. Partial purification has apparently been achieved and
there continues to be evidence that there are two gonado-
tropic hormones: one facilitating follicle-growth and matura-
tion (follicle-stimulating hormone), the other promoting the
conversion of the cells of the membrana granulosa and thecae
into lutein cells (luteinizing hormone). Both hormones are
said to be necessary to produce ovulation. There is evidence
that what is called follicle-stimulating hormone maintains
spermatogenesis in the testis, whereas luteinizing hormone
nurtures the interstitial cells of Leydig, whence arises "male
hormone."'^ Some authors would lengthen the list further

"' However, other data suggest different interpretations. Observations which
must be reconciled are as follows: (i) follicle-stimulating hormone maintains the
germinal epithelium, whereas the interstitial cells require luteinizing hormone for
normal function (immature hypophysectomized male rats); (2) either hormone will
support spermatogenesis, but only luteinizing hormone maintains the interstitial
cells (mature hypophysectomized male rats); (3) spermatogenesis can take place
normally in the absence of the pituitary, provided that a suitable androgen ("male
hormone") is injected early enough after operation (mature hypophysectomized
male rats); and (4) the pituitary of the normal male rat secretes only follicle-stimu-
lating hormone (at least the secretion of luteinizing hormone has not been detected
in the living animal, although small amounts of luteinizing hormone may be recog-
nized by implanting the male pituitary).

[ 120]

THE GONADOTROPIC HORMONES

with newly named (but not necessarily newly described)
hormones, so that its total would be five or more instead of
two. To recall only the example of the number of "corpus
luteum hormones" once thought to exist before the pure
substance had been isolated is to recognize the continued
need for caution in discussing the number of gonadotropic
hormones secreted by the pars glandularis. At present, there
is probably nothing that will further rational interpretation
and real advancement in this field as much as the isolation
of a gonadotropic hormone of the anterior pituitary in a
satisfactorily pure state.

Much of the recent data requires no reconsideration here.
Descriptions of the effects of destruction or removal of the
pituitary body supplement former reports as to the atrophic
changes which dramatically follow in the ovaries, testes, and
secondary sexual organs. Other experiments have increased
our knowledge of the effects of pituitary tissue or extracts
on the sexual organs of many different animals. It is known
more accurately that even a short period of pituitary defi-
ciency may markedly lessen the sensitivity of the gonads
toward gonadotropic hormone. Also it is of interest that the
persistence of corpora lutea in hypophysectomized rats ap-
pears to be due to the lack of an anterior pituitary hormone.

Physiological evidence of the nervous control of the secre-
tion of gonadotropic hormones has been greatly strengthened
in the past few years. In birds, and at least in some mam-
mals, photic stimuli may elicit the secretion of gonadotropic
hormones, which in turn stir the gonads into activity. Prob-
ably "light" reflexly stimulates the secretory nerves of the
pars glandularis by impulses arising in the optic nerves,
whence they are guided down fibers of the stalk by one or
more groups of neurons in the diencephalon. In animals
without precise seasonal variations in sexual, and hence pitui-
tary, activity photic stimuli do not play such an evident role.
However, diffuse or sometimes sharply localized stimula-
tion of the brain may be followed by the release of gonado-

[121]

THE PITUITARY BODY

tropic hormone from the anterior pituitary as shown by
ovulation in an animal like the rabbit. Other peripheral
nerves like those of the sympathetic system may be part of
an afferent arc, but their significance is not clear.

Great interest has been shown in the hormonal control of
the secretion of gonadotropic hormones, especially as far as
the internal secretions of the ovaries and testes may here be
important. There is much data to suggest that surges or re-
cessions of secretion by the anterior pituitary causing the
growth or decay of gonadal activity (e.g., oestrous cycles)
may be related to the absence or presence of internal secre-
tion (s) of the gonads such as oestrogen from the ovaries.
The regulation of the secretion of gonadotropic hormones by
the pars glandularis may well depend upon a delicate, com-
plex mechanism, partly hormonal and partly nervous. xAlso
it is probable that the relative importance of the nervous
system and of hormones of the gonads varies in different
animals. The reader can easily diagrammatize a self-regulat-
ing physiological unit consisting of the pars glandularis, the
gonads, and the nervous system. However, he cannot safely
picture this unit in any detail. The known hormones char-
acteristic of the gonads vary enormously in their apparent
"regulating" (usually depressing) effect on the formation of
gonadotropic hormone by the anterior pituitary. Oestrogens
far excel androgens in potency; progesterone (from the corpus
luteum) appears to be of slight importance.

The relation of adrenal cortical secretion to the phase of
pituitary physiology under discussion is obscure because so
many variables affect experimentation. Thyroid secretion per-
haps is not of great significance; its usual effect, if any, is
to lessen the action of follicle-stimulating hormone. How
much regulation of the liberation of gonadotropic hormones
by the pars glandularis is effected by the gland's own lacto-
genic hormone can be judged better when experiments have
been performed with the recently isolated lactogenic prin-
ciple.

[122]

THE GONADOTROPIC HORMONES

Much has been written and continues to be written con-
cerning "antihormones." There can be no question that gon-
adotropic extracts, if repeatedly administered in their
present state of impurity, may cause at an unknown site
the production of substances circulating in the blood and
antagonizing the effects of pituitary extracts. Howev^er,
other experiments furnish arguments, so far not refuted,
that such substances are not formed in response to gonado-
tropic hormone secreted by the intact gland.

123

CHAPTER IV

THE GONADOTROPIC HORMONES ASSOCI-
ATED WITH PREGNANCY OR
CERTAIN NEOPLASMS'

GONADOTROPIC hormones associated with preg-
' nancy or with neoplasms are not secreted by the
pars glandularis of the pituitary body. In pregnant
women, as well as in other pregnant mammals in which their
presence has been demonstrated, the characteristic hormone
probably originates in the epithelial cells of the chorion.
Neoplasms, such as certain tumors of the testis, also may
secrete gonadotropic hormones; neoplasms originating in the
chorion almost invariably liberate large amounts of such sub-
stances into the blood stream. The effects of all these sub-
stances differ in one or more ways from those of gonado-
tropic hormones secreted by or extracted from the pars
glandularis.

Most of the published reports deal with the gonadotropic
hormones of the pregnant woman and the pregnant mare.
Presumably, the important function of such hormones in
pregnancy is to insure the maintenance of an ovarian func-
tion favorable to the pregnancy. Inasmuch as the secretion
of the corpus luteum has been shown — especially in the earlier
part of pregnancy — to be vital for the continuance of preg-
nancy in many mammals, the luteinizing effects of the
chorionic hormones have been especially emphasized. In what
mammals, other than man and the horse, is there new evi-
dence for the secretion of chorionic hormone in pregnancy.^
Heretofore there has been doubt as to the presence of gonado-
tropic hormone in the urine of the pregnant monkey. How-

' See also chaps, i and iii or refer to the Index.

[124I

THE GONADOTROPIC HORMONES

ever, Hamlett (1937) has shown that the urine of the preg-
nant macaque about the 19-25 day of pregnancy may con-
tain detectable amounts of gonadotropic hormone. It is prob-
able that gonadotropic principles secreted by the chorion
will be demonstrated in other pregnant mammals by future
investigation.^

No gonadotropic hormone could be found in the serum
of the pregnant ewe (Cole and Miller, 1935) or in the milk
of the pregnant cow (total dose of 1.2 cc. in immature mice
initially 17 days old; Weisman, Kleiner, and Allen, 1935).
These reports supplement those reviewed in 1936.

THE GONADOTROPIC HORMONE (pROLAn) ASSOCIATED
WITH PREGNANCY IN WOMEN

New observations on the metabolism oj prolan? — All the re-
cent observations support the view that prolan is secreted
by the chorionic cells (Bourg and Legrand, 1935; Philipp
and Huber, 1936; Kido, 1937). Most of the experiments were
performed with implants. Kido observed the action of hu-
man placenta which survived transplantation in the anterior
chamber of the female rabbit's eye. The secreted hormone
affected the animal's ovary and could be detected in the
urine.

The most striking new fact clearly demonstrated in respect
of the urinary excretion of prolan is that an enormous excre-
tion is observed about the 50-60 day following the last men-
strual period (Browne and Venning, 1936; Evans, Kohls,
and Wonder, 1937). Figure 18 is reproduced from the article
of Browne and Venning. The highest figures reported by
these authors are 100,000-300,000 rat-units per liter of urine
in comparison with a later fall to about 3,000 rat-units per

^ E.g., see Astwood and Creep (1938).

■5 See chap, v and Table VI of the earlier volume. Guercio (1936) believed that
prolan can be detected in the saliva of pregnant women; however, this was denied
by Weisman and Yerbury (1936).

[125]

320000

:] 260000-

^2000001-

^ 140000
^ 80000
20000 f-

■A

— C

—

••■•HJri>

->^^'-..,.,.^

—

20 40

60 80
DAYS

100

120 140

-^ 9000
^ 6000 [
^ 3000 '

§^9000
v^ 6000 -
^ 3000 -

5 6000

^ 3000F ""-.

5 6000
5 3000

—

.'■

1 *

•

i '

"s.

■-'

'"•■

130 150 170 190 ZIO 230 Z50 270 290
DAYS

Fig. 1 8. — The excretion of gonadotropic substance(s) in the urine during preg-
nancy. Days are counted from the first day of the last menstrual period. The
termination of pregnancy is indicated by arrows. (From Browne and Venning,
Lancet, 231, 1 507-11 [1936].)

THE GONADOTROPIC HORMONES

liter, a concentration which persists after 120 daysJ The
rapid rise is prevented by fetal death or if the fetus is dying.
Less accurate studies have been reported by Bourg and Le-
grand (1935), Ehrhardt (1936), and Spoto (1936). Bourg
and Legrand also investigated the concentration of prolan in
the serum and placenta. Their results justify the belief that
the peak of urinary excretion coincides with high concentra-
tions of prolan in the serum and placenta. (Ehrhardt like-
wise concluded that the concentration of prolan in the urine
and serum is about the same.) The concentration of prolan
in the amniotic fluid was found to be 7-33 per cent of that in
serum. 5

Smith and Smith (1935) have again pointed out that high
concentrations of prolan in the serum are associated with
toxemias of pregnancy, including eclampsia. However, Bourg
and Legrand (1935) as well as Ehrhardt concluded that, al-
though this is true of what are termed toxemias, an ab-
normally high prolan titer may not be found in the serum in
eclampsia.

Some aspects of the fate of prolan after its administration
to normal men or animals have been investigated. Fried-
man and Weinstein (1937) found that no more than 20 per
cent of a dose of prolan injected intramuscularly into men
could be recovered in the urine. After large doses by mouth
(8,000-42,500 rat-units), none was detected in the urine.
Stamler (1937) made other observations in the dog and the
gelding. New experiments in rabbits were reported by Lip-

^ Evans, Kohls, and Wonder observed maximum excretions of 75,000-1,040,000
rat-units in 24 hours compared with 2,600-15,000 rat-units at other times.

5 The convenient and accurate methods of diagnosing pregnancy are those de-
pending upon ovarian changes in immature rodents or ovulation in adult isolated
rabbits. Intracutaneous tests in the patients themselves are of no value (Schneider
and Cohen, 1937). Although chromatosome-dispersing ("melanophore-expanding")
hormone is found more frequently in the urine of pregnant women, its presence is
not reliable as indication of pregnancy (Mandelstamm, 1935; Jores, 1936; Bruck-
mann, 1937; Raza and Spurrell, 1937). Dychno (1936) considered such a test
reliable.

For descriptions of a method based upon a color-reaction in urine see Visscher
and Bowman (1934) and Friedrich (1936).

[ 127]

THE PITUITARY BODY

schiitz, Fuente-xAlba, and Vivaldi (1935). Tissue fixation or
destruction of the hormone was indicated by the fact that
10 hours after intravenous injection, 30 per cent of the prolan
had disappeared from the blood of nephrectomized rabbits;
80 per cent was lost in normal rabbits. Nizza and Berutti
(1936) compared the changes in one intact ovary with the
other which was transplanted into a second rabbit 30-120
minutes after the injection of urine of pregnancy. The differ-
ences appeared to be quantitative.

The gonadotropic ejects of prolan in fishes, amphibia, and
reptiles. — Some of the effects of prolan in cold-blooded ani-
mals have been described already. *" Schreiber (1935) reported
that the administration of prolan to immature eels can cause
changes characteristic of testicular maturation, including the
differentiation of spermatogonia into normal spermatozoa.
According to Morosowa (1936), perch (November to March;
weight 250-750 gm.) receiving prolan, although kept in
water at 6-9° C, produce ripe eggs and spermatozoa, from
which fertilized eggs can be secured. Shapiro (1936) demon-
strated that in the toad, Xenopus laevis, the injection of pro-
lan evoked amplexus in animals which otherwise were in a
state of complete sexual inactivity. Ovulation, oviposition,
and fertilization occurred. The offspring were raised to the
tadpole stage. Turner's experiments (1935) were performed
with the lizard, Eumeces laticeps. During the season of in-
volution of the gonads, the injection of prolan (20 rat-units
twice daily for 20 days) caused hypertrophy of the testes and
the epididymides with the production of mature sperma-
tozoa. Such treatment caused enlargment of the oviducts
but had no effect on the ovaries. When the animals were ac-
tive sexually, the response was much smaller.

The effects of prolan in warm-blooded animals.'^ i. Male

^ See chap, iii and the Index.

' Prolan is without demonstrated action on the gonads of birds (see pp. 52, 58).
Schunterman (1935) declared that an intravenous injection of an extract of digitahs
evoked emesis less frequently in pigeons which had received 1 units of prolan intra-
muscularly ID minutes before.

[ 128 1

THE GONADOTROPIC HORMONES

mammals. — In normal male mammals, the typical effects of
prolan — best observed in immature specimens — are on the
interstitial cells of the testis (cells of Leydig). These secrete
"male hormone," which is probably testosterone, at a more
rapid rate so that the secondary sexual organs, such as the
epididymides, seminal vesicles, and prostate, undergo ab-
normal hypertrophy and, histologically, may resemble the
organs of adult animals. Such changes, of course, are absent,
if the prolan-sensitive cells have been removed by castra-
tion. In immature mammals prolan does not initiate sperma-
togenesis. In adult animals, however, prolan, if administered
immediately after operation, will maintain spermatogenesis
after hypophysectomy (Smith and Leonard). This probably
is due to the fact that the secretion of androgenic hormone
by the interstitial cells continues as a result of the injec-
tion of prolan. It is well known that androgens by them-
selves may have this effect (see chap. iii). This fact probably
accounts for the spermatogenesis which may be initiated in
the ground squirrel {Citellus tridecemlineatus) by the injection
of prolan at times of seasonal involution of the gonads (Baker
and Johnson, 1936; Wells and Moore, 1936).

Other reports not reviewed previously are those of van Os
(1936) and Kuschinsky and Tang (1936). Van Os could not
bring about spermatogenesis in the testes of rats in which
testicular degeneration had followed vitamin-A deficiency or
cryptorchidism, Kuschinsky and Tang stated that the typi-
cal effects of prolan (seminal-vesticle hypertrophy, no con-
sistent effect on testicular weight) could be observed in rats
receiving prolan when only 6-13 days old.

1. Female mammals. — In female mammals the most strik-
ing effect of prolan is on the cells of the corpus luteum or
on the cells of the theca interna — parent cells of corpora
lutea. It may appear that follicle growth is stimulated, and
some authors believe that prolan is composed of an "A"
component, stimulating the follicle, and a "B" component,
causing luteinization. Good evidence that both components

[129I

THE PITUITARY BODY

exist has never been offered. It is more simple and more
accurate to consider that prolan is primarily a luteinizing
gonadotropic hormone. Its presumed follicle-stimulating ef-
fects are seen in animals with intact hypophyses which con-
tribute the important, and perhaps the only, share in bring-
ing about follicle-stimulating effects. Anterior pituitary se-
cretion is of great importance in permitting the recognition
of the luteinizing effects of prolan. In hypophysectomized
female rats, prolan may cause hypertrophy of the cells of
the thecae and interstitium, with which may be associated a
persistent oestrus; it does not bring about follicular growth.

Kuschinsky and Tang (1935) described luteinization of
the ovaries of rats receiving large doses (25 rat-units daily)
during the second week of life. A deciduoma reaction of
the uterus could not be produced. Hohlweg (1936) com-
mented on the large doses of prolan required to produce
luteinization or corpora lutea in very young or abnormally
small immature rats. Probably the important factor is the
inability of the pituitary to secrete satisfactory amounts of
follicle-stimulating hormone at this age. Ljachowezki and
Chwatow (1937) believed that the administration of prolan
in small doses (2-5 mouse-units daily) permitted successful
transplantation of the ovary or testis, if injections were be-
gun immediately after transplantation and continued for 10-
12 days. They stated that such transplants could function
(apparently judged by the morphology of the transplant) for
more than 2 months in animals (mice, rats, guinea pigs, and
cats) with their own gonads intact.

According to Desaive (1935), although repeated injections
of prolan (25 rat-units daily) increase markedly the rate of
development of primordial follicles, they produce an even
greater rate of follicular atresia, which was considered to be
the important effect in the rabbit. Moricard (1935) Injected
prolan for 2-5 months into rabbits. After about 3 weeks
enormous numbers of corpora lutea might be found; later
the predominant effect was a pronounced development of

[130]

THE GONADOTROPIC HORMONES

interstitial tissue which gradually receded as "antihormone"
was produced. The experiments of Bachman (1936) indi-
cated that prolan might produce hypertrophy of the inter-
stitial stroma or non-functional corpora lutea, if injected into
young rabbits. Padootcheva and her colleagues (1935) be-
lieved that prolan is of practical value in rearing rabbits.
Pregnancy was successfully initiated by causing ovulation by
the injection of prolan after a suspension of spermatozoa had
been injected into the uterus. The vaginal instillation of
spermatazoa also was successful. The authors stated that on
a rabbit farm pregnancy occurred in 74 per cent of animals
receiving an ovulating dose of prolan, whereas the propor-
tion was only 30 per cent without such treatment. The in-
jection of prolan by various routes brings about ovulation in
sheep without signs of oestrus, according to Zawadowsky and
others (1935). They recommended the administration of
100-500 mouse-units and found that corpora lutea due to
this treatment did not interfere with expected oestrous
cycles.^

Comparisons of the dose of prolan necessary to cause
ovulation in pregnant and non-pregnant rabbits have been
made by Rowlands (1935) and are discussed on pages 69-70,^
Prolan has some replacement value in pregnant rabbits which
have undergone hypophysectomy, as was shown by Robson
(1937). The same author found that, although hypophysec-
tomy of the rabbit is followed by a rapid loss of ovarian
sensitivity toward gonadotropic hormone, the injection of
prolan will postpone the appearance of this refractory condi-
tion for nearly two weeks. In hypophysectomized rabbits

* Markee and Hinsey (1936) injected urine of pregnancy into rabbits, so that the
course of ovulation could be carefully stud'ed by observing the ovary through an
abdominal window or in the anterior chamber of the eye after transplantation.

Holtz and Wollpert (1937) used prolan to induce the formation of luteal tissue
in the ovaries of guinea pigs and cats. They were interested in the uterine response
to epinephrine under these conditions.

' Weinstein and Makepeace (1937) estimated that the dose of prolan causing
ovulation in oestrous rabbits must be doubled or trebled in pseudopregnant rabbits.

[131]

THE PITUITARY BODY

also, the administration of prolan will maintain the corpora
lutea of pseudopregnancy for more than a week. These ef-
fects of prolan apparently are due to its luteinizing proper-
ties; it replaces the pituitary luteinizing hormone which
normally is so important for corpus luteum function and the
maintenance of pregnancy. On the other hand, von Arvay
(1937), who was able to prevent normal parturition and
cause the prolonged retention of the dead fetuses by injecting
prolan into pregnant rabbits, contended that these changes
were not due to the persistent action of corpus luteum secre-
tion.''*

Reynolds' observations on the inhibitory action of prolan
on the motility of the uterus of the unanesthetized rabbit
were confirmed by Sager and Leonard (1936), who observed
a similar effect following the injection of extract of urine of
patients with testicular tumor or of others following gonadec-
tomy or the menopause. The inhibitory effect could be pre-
vented by the injection of oestrin."

There are other miscellaneous observations which are diffi-
cult to classify. Vercesi and Guercio (1935) stated that the
growth in vitro of ovarian fragments from rabbits is poor
even in the presence of prolan; however, the administration
of prolan for several days before ovarian removal greatly
facilitates the growth of fibroblasts, which the authors con-
sidered is an important part of the response in vivo. Accord-
ing to Kiyohara and Isawa (1936), the oxygen-consumption
of the isolated ovary of the guinea pig (300 gm.) is nearly
doubled 10-15 hours after the injection of 7-8 cc. of urine of
pregnancy. Some effect could be observed 2-3 hours after
injection or as long as 10 days later. There were no similar
changes in the metabolism of liver and kidney.

Hamblen in association with Ross (1937) reviewed the

'" See also Spreng (1937) who investigated the action of a single intravenous dose
of prolan on the duration of pseudopregnancy in the rat and the rabbit.

" Pierson (1936) produced cancer-like adenomata of the uterus in 2 of 16 rabbits
by injecting a concentrated extract of pregnancy-urine on alternate days. However,
it is not certain that her extract was free of oestrin.

[ 132]

THE GONADOTROPIC HORMONES

effects of prolan in a large number of patients. In a smaller
series of 7 patients, in whom ovarian specimens were avail-
able in 3 instances and endometrial samples were available
in all, they found no evidence of ovulation and corpus luteum
formation as a result of the injection of prolan. The authors
injected total doses of 6,000-24,000 rat-units (400-8,000 rat-
units daily). Among other recent descriptions of the clinical
effects of prolan in women are those of Anselmino and Hoff-
mann (1935), Moricard (1936), and Trettenero (1936). The
effects of prolan (2,000-22,000 rat-units in 4-6 days) are
difficult to evaluate in the report of Anselmino and Hoff-
mann, because the patients all suffered from carcinoma of
the uterus. Apparently the important changes were atresia
of the follicles and luteinization of the thecae. Moricard
transplanted the ovary into the vulva. The injection of an
extract of pregnancy-urine was followed by hypertrophy of
the transplant, from which oestrin-containing fluid could be
aspirated. Trettenero believed that his extract of pregnancy-
urine produced ovarian changes — chiefly persistence or new
formation of luteal tissue in the ovaries — which modified the
menstrual rhythm.

Modifications of the action of prolan may occur as a result
of the injection of an oestrogen. The augmentation of the size
of the corpora lutea, if an oestrogen also is administered, is
probably due to the added eft'ect of luteinizing hormone lib-
erated from the injected animal's anterior pituitary (Wolfe,
1936; see chap. iii). It could be inferred from other data that
progesterone might lessen the action of prolan. Recently,
Jacobsen (1936) found that the injection of progestin (0.03-
0.04 rabbit-unit daily), if made before and during the ad-
ministration of prolan, markedly interfered with the forma-
tion of corpora lutea in immature mice.

In confirmation of previous work, Connon (1937) reported
that large doses of prolan (80-125 rat-units daily for 2~S
days) inhibit lactation in rats, as shown by the failure of
the young to grow and by the histological appearance of the

[^33]

THE PITUITARY BODY

breasts. The author injected the hormone intraperitoneally
from the day of delivery. The treatment caused considerable
ovarian hypertrophy owing, apparently, to new formation of
lutein tissue. Howard (1936) as well as Jadassohn, Uehlinger,
and Ziircher (1937) observed that the injection of prolan-
containing extracts caused enlargement and elongation of
the nipples in rats and guinea pigs. The effects, which can
also be produced by an oestrogen, were more marked in fe-
male animals. The prolonged injection of Howard's acid ex-
tract of the blood of pregnant women caused growth and
differentiation of the mammary glands which often secreted
milk (after injection for 90 days). The injection of the ex-
tract for 6.5-9 iiioriths was accompanied by regression of the
secretory phenomena and the development of adenomata in
the breasts. Howard stated that all these changes were ab-
sent in gonadectomized rats.

The effects of pro I mj in relation to glands of internal secretion
other than the gonads, i. The thyroid. — Thyroidectomy does
not alter the response of the rabbit's ovary to prolan (Pit-
zorno and Serra, 1936: 20 rat-units on alternate days for
10 days). The same is true of the hormone's gonadotropic
effect in male or female rats (Leonard, 1936; Leonard and
Hansen, 1936).

1. The adrenals. — Several recent authors agree in their
description of the effects of prolan on the adrenal glands in
such mammals as the guinea pig, rabbit, rat, and mouse
(Inohara, Savona, 1935; De Boissezon, 1936). The hyper-
trophy which occurs is limited to the cortex and has been
compared with that of pregnancy. The chief alteration is
in the zona fasciculata, the cells of which enlarge and con-
tain more lipoid than usual. The zona glomerulosa may be
narrowed.'^ According to Pitzorno and Serra (see above),

"Takewaki (1935) stated that the prolonged injection of prolan or pregnancy-
urine had little effect on the adrenal of the female mouse, whereas in males it caused
a disappearance of the zona reticularis with the formation of a membrane in its
place.

Bau (1936) declared that pregnancy-urine, extract of corpora lutea, pars neuralis

[134]

THE GONADOTROPIC HORMONES

the cortical hypertrophy due to prolan in the rabbit is pre-
vented by thyroidectomy.

De Fremery (1934) stated that the weight of the male
rat's adrenal before puberty is correlated with body-weight,
whereas after puberty adrenal weight does not increase as
rapidly as that of the rest of the body. (In adult female
animals, adrenal weight is proportional to body-weight.) The
injection of doses of prolan causing an enormous hypertrophy
of the seminal vesicles did not cause any fall in the weight
of the adrenals in immature male rats; as in normal imma-
ture males, there was found still to be a correlation between
the weight of the body and of the adrenal glands.

3. The thymus. — Klein (1935-36) investigated the action
of prolan on the thymus of guinea pigs. Atrophic changes
were noted in both sexes. In females, however, the number
of Hassal's corpuscles appeared to be increased and was ac-
companied by the appearance of cells described by Fulci as
characteristic of the thymus of pregnant guinea pigs. Prolan
did not produce such changes in male animals.

4. The epiphysis. — There is not acceptable evidence that
pineal extract antagonizes the gonadotropic action of prolan.
Vinals (1935) even believed that a suspension of beef pineal
synergizes with prolan in some of its ovarian effects (see also
the reports of Engel, 1936; Engel and Buno, 1936; Wade,
1937; and others).

The metabolic efects of prolan. — Prolan (20 rat-units daily
for 7 days) does not alter the oxygen-consumption of albino
female rats (Danforth, Greene, and Ivy, 1937). Although
the administration of desiccated thyroid appeared to produce
less of a calorigenic effect after the injection of oestrogens,
this was not shown to be true after the injection of prolan.

Osada (1935) believed that an increased deposition of

extract, etc., but not prolan, cause a development of the zona reticularis in the
adult male mouse. In normal adult mice this zone is readily identified in females
but not in males.

[135]

THE PITUITARY BODY

glycogen in the liver was the result of the injection of prolan
into normal or gonadectomized rabbits of both sexes.

Creatine-creatinine metabolism in relation to age, sex, and
the effect of prolan was studied in a small number of rabbits
and dogs by Biihler (1935). He concluded that gonadectomy
of adult animals is followed after 2-3 months by an increased
urinary excretion of both creatine and creatinine. Later only
the excretion of creatinine remained elevated. (Gonadectomy
in immature animals did not result in such changes.) The
administration of prolan was found not to affect creatine-
creatinine excretion in immature dogs. In the sexually ma-
ture dog it caused a disappearance of creatine from the
urine. Although prolan did not affect the urinary excretion
of creatine in adult normal rabbits, it caused an increased
excretion after castration. This effect could not be observed
in castrated dogs. The dose of prolan used by the author in
dogs or rabbits was 120 rat-units administered twice. Nit-
zescu and Gontzea (1937) studied creatine-creatinine metab-
olism in an achondroplastic, infantile dwarf. The injection of
200-300 rat-units of prolan intramuscularly brought about
a reduction in the excretion of creatine but scarcely affected
that of creatinine. Also there appeared to be an increased
creatine-tolerance. The same phenomena were more pro-
nounced following the administration of male hormone (4
capon-units of "Erugon").

The effects of prolan on the metabolism of only one lipoid,
cholesterol,'-^ have been investigated recently. Szpidbaum
(1935) found that the blood-cholesterol rose (e.g., 40-50 per
cent or more) after the injection of prolan into patients re-
covering from typhoid fever. He believed that the hormone
caused a mobilization of cholesterol reserves with consequent
benefit to patients because of an increased non-specific im-
munity. Szpidbaum injected total doses of 1,500-3,000 rat-
units as 500 rat-units daily or on alternate days. Other ob-
servations have all been made in rabbits (Cioglia, 1935-36;

'J Presumably all the authors determined the total cholesterol.

[ 136 ]

THE GONADOTROPIC HORMONES

Teilum, 1936; and Tramontana, 1936). There was observed
consistently a hypercholesterolemia following the injection
of prolan. Cioglia concluded that hypercholesterolemia of
early pregnancy is due to prolan, whereas the reduced or ab-
normally low concentration of the lipoid in later pregnancy
depends upon the effect of an oestrogen.

Two reports deal with the action of prolan on the con-
centration of inorganic substances in the blood. According
to Klodt (1937), the subcutaneous administration of prolan
to rabbits (500 rat-units daily for 6 days) brings about a
transient rise in the concentration of Na associated with a
fall of K and inorganic P. Less water and Na are excreted
by the kidneys. In the other report Dell'Acqua (1935) con-
firmed Cannavo's statement that prolan causes a rise in the
concentration of Mg in the blood. The average increase was
38 per cent (20-78 per cent; 6 experiments in 2 cats).

Marchesi (1935) reported that female rats on a diet free
from vitamin E, and otherwise sterile, could become preg-
nant (by normal males) following the administration of pro-
lan. The young died shortly after birth, because of the ab-
sence of lactation. A glycerol extract of the placenta was
even more effective than prolan. Van Os (1936) studied the
effect of prolan on the degenerated testis of the rat on a
vitamin-A-free diet. The interstitial cells were stimulated,
but there was not resumption of spermatogenesis.

The growth of neopIas?ns hi relation to pro/a?7. — Prolan ap-
pears not to have important inhibitory effects on the growth
of neoplasms. Magath and Smoilowskaia (1935) concluded
that the injection of 50-100 rat-units daily for as long as a
month might cause a maximum inhibition of 50 per cent in
the growth of a neoplasm. These investigators used mice
and rats (transplanted mammary adenocarcinoma and Jen-
sen sarcoma) . Other reports of Bischoff" and Maxwell, Druck-
rey, Engel, and Katz are discussed in chapters ii and iii.

Miscellaneous observations. — Prolan does not affect the
coagulation-time of the blood in man (125-250 rat-units

[137]

THE PITUITARY BODY

daily for 9-20 days; Chew and others, 1935). Nicolle (1936)
concluded that the hormone causes a reticulocytosis in the
rabbit, whereas oestrone has the opposite effect. In the rab-
bit, also, Wilson (1937) observed a marked leukocytosis in
normal female rabbits 5-8 hours after injection. Repeated
injections did not produce this effect. Wilson was not con-
vinced that this was a specific effect.

Prolan appears not to be of value in the treatment of acne
vulgaris (total dose about 5,700 rat-units over 8-1 1 weeks;
Williams and Nomland, 1937). Moffat (1937) believed that
small doses of prolan may cure "menstrual migraine"; how-
ever, he gave no evidence that such treatment is of specific
importance. According to Steinbach and Klein (1937), ex-
perimental tuberculosis caused by a standardized dose of
bovine bacilli in guinea pigs takes a much less severe course,
if extract containing prolan or pregnant-mare serum be in-
jected repeatedly. A similar effect could not be observed
following the administration of anterior pituitary extract.

The contractile activity of the isolated ureter of the pig
is not affected by the addition of 500 rat-units of prolan to
150 cc. of bath fluid (Schmitz, 1937).

The experimental augmentation or inhibition of the gonado-
tropic effects of prolan, i. Augmentation. — It is well known
that gonadotropic extracts of the pituitary (or probably de-
rived from the pituitary as in the urine of spayed women) may
enormously enhance the gonadotropic action of prolan, as
indicated by hypertrophy of the ovary of the immature ro-
dent. Probably the follicle-stimulating component of such
extracts is reponsible for this synergism. The luteinizing ef-
fects of prolan can be manifested to a maximum extent, if
the ovaries are properly prepared by widespread growth of
follicles. Non-specific augmentation, as with ZnS04, usually
cannot be demonstrated if prolan instead of anterior pituitary
extract is used as the gonadotropic agent. '^

'-I For an apparent exception see Emery (1937).

[138]

THE GONADOTROPIC HORMONES

2. Inhibition. — The administration of certain anterior
pituitary extracts may inhibit the gonad-stimulating effect
of prolan. This phenomenon is best observed after the intra-
peritoneal administration of the anterior pituitary extract.
The mechanism of this inhibitory action is not known; the
obvious possibility that a local action on the ovary is im-
portant has not been investigated.

The doctrine of antihormones as related to prolan.^^ — The
degree of purity of the best preparations of prolan is not
known. Like similarly impure anterior pituitary extracts,
preparations of prolan, if repeatedly administered for weeks
or longer, produce progressively reduced gonadotropic effects
until the organ affected — whether ovary or testis — is refrac-
tory to further treatment. "Antihormone" or a substance
inhibiting the action of the extract in fresh, non-injected
animals can be detected in the serum at this time. Its site
of formation may be the reticulo-endothelial system.''' Are
these phenomena important physiologically? Probably not.
The chorionic epithelium of the placenta of women secretes
enormous quantities of prolan into the blood throughout
pregnancy, although the peak of formation suddenly appears
at about the end of the second lunar month. There is no evi-
dence of any formation of antihormone by the tissues of
pregnant women. It appears that the numerous investiga-
tions of the formation and characteristics of prolan-anti-
hormone represent, at most, contributions to a new field of
immunology.

Eichbaum and Kindermann (1935) and Kindermann and
Eichbaum (1936) have published several communications on

■5 Other experiments in which prolan was used are discussed in chap, iii (pp.
iioff.).

'^Experiments of Gordon, Kleinberg, and Charipper (1937) in splenectomized
rats to some of which trypan blue was also administered to "block" the reticulo-
endothelial system. The refractory (non-responsive) condition of the ovary ap-
peared much later in splenectomized rats also receiving trypan blue. Ten rat-units
of prolan were injected daily. When refractoriness of the ovary finally appeared, it
was attributed to the production of antithormone by redeveloped reticulo-endo-
thelial tissue.

[ 139]

THE PITUITARY BODY

the immune aspects of antihormone due to prolan prepared
from urine of pregnancy. They found that the apparent con-
centration of antihormone present in the serum of rabbits
could not be correlated with precipitin or complement-devia-
tion reactions. Such immune reactions appeared to depend
upon (i) an antibody specific for human protein and (2) an
antibody specific for an antigen associated with prolan but
occurring in human urine irrespective of the presence or ab-
sence of prolan. The results of Bachman (1935), although
less complete, are in agreement with those of Kindermann
and Eichbaum. Twombly (1936) favored the view that anti-
hormone toward prolan is similar to an antibody formed in
response to a foreign protein. The precipitin-reaction (rab-
bits were given an extract of pregnancy-urine) was parallel
to the antihormone content of sera. Prolan inactivated be-
cause of heat or age was about as efficient in evoking anti-
hormone formation as were potent preparations. The serum
of patients receiving prolan (100 rat-units daily) for 2-6
weeks or for more than a year contained no antihormone —
indicating that the protein, being homologous, evoked no
antibody reaction. In confirmation of Twombly, De Fremery
and Scheygrond (1937) reported that an extract of male
urine, if injected into rabbits, caused the production of sub-
stances preventing the gonadotropic effects of prolan. It
seemed unlikely that the small amount of gonadotropic ac-
tivity in the '"antigen" could be responsible for the effect.
The urine contained non-specific substances with the anti-
genic properties of prolan.'^

Harington and Rowlands (1937) investigated the chemical
nature of gonadotropic antihormone in the serum of the goat
or the rabbit which had received repeated injections of pro-
lan or extract of pregnant-mare serum. The antihormone
of prolan was recovered quantitatively in the globulin frac-
tion of serum and was distributed between the pseudoglobulin

" See also Laroche and Simmonet (1936J who injected "Antelobine" into patients
and subsequently tested their serum for antihormone.

[ 140]

THE GONADOTROPIC HORMONES

and euglobulin fractions. The antihormone inhibiting the
action of the extract of pregnant-mare serum could not be
completely recovered; most of it appeared also to be asso-
ciated with the globulin fraction of serum. Zondek and Sul-
man (1937) have published several reports on biochemical
reactions between prolan and its antihormone. They con-
cluded that the antihormone is similar to an antibody. The
reaction between prolan and its antibody is reversible.'^ The
authors were unable to detect antihormone in tissues (liver,
spleen, muscle) or in the urine of animals whose serum con-
tained the substance. Biochemical differences between prolan
and its antihormone were also described."'

The assay of prolan.^" — The remarks which were made in
chapter iii in reference to the assay of pituitary gonado-
tropic hormone apply with equal force to prolan. As soon as
suitable standards have been assayed by different technics
and the results evaluated, it will be possible to recommend
preferred assay technics. Among reports published recently
are those of Davy (1935), Korenchevsky, Dennison, and
Simpson (1935), Owen (1936), Morosowa (1936), and Kelly
and Woods (1937). Nelson and Overholser (1935), basing
their results on various criteria — i.e., opening of vaginal ori-
fice, oestrus, ovulation, follicular stimulation, luteinization —
estimated the relationship between the mouse-unit and the
rat-unit for several gonadotropic hormones to be as given in
Table 3. Their belief in the remarkable lack of potency of
prolan in the mouse as compared with the rat is in agreement
with most of the older reports.

Levin and Tyndale (1937) found that the increase of uter-

'* In one report the authors state that the antihormone destroys prolan.

" Zondek and Sulman also studied biological effects of the antihormone of
prolan. Antihormone produced no effect after administration by way of the gastro-
intestinal tract. After subcutaneous injection, antihormone could be retained in the
body for several days. Also it could inhibit the effect of prolan, if injected 24 hours
after the hormone was administered. They regarded it as being both species and
organ specific (it did not antagonize the gonadotropic action of extract of blood of
pregnant women or of extract of the human anterior pituitary).

^° See also chap. iii.

[141]

THE PITUITARY BODY

ine weight in the immature rat, although suitable for the
biological estimation of pituitary follicle-stimulating hor-
mone, cannot be used for the accurate assay of prolan or the
active principle of pregnant-mare serum.

The chemistry of prolan. — Prolan has not been prepared as
a pure substance. There is not good additional evidence that
it is composed of more than one gonadotropic principle, al-
though Brindeau, Hinglais, and Hinglais (1936) contend that
it is a mixture of 3 principles. Reports of the hormone's prep-
aration by modifications of the tannic acid, tungstic acid, or
benzoic acid methods as applied to urine have been made
by Hellbaum, Fevold, and Hisaw (1935), Freud and Hechter
(1936), and Ito, Hajazu, and Ueno (1936). xAlso, Fevold and

TABLE 3

Gonadotropic Extract of

Relative Dose for One Unit in

Mouse

Rat

Pregnancy-urine

Sheep pituitary

Pregnant-mare serum

5
I
I

Hisaw (1936) described a method based on the extraction of
the hormone from urine by means of 10 per cent cresol. The
effect of hydrogen-ion concentration,^' various organic re-
agents, etc., on the hormone has been studied by Bischoff
and Long (1936).

GONADOTROPIC HORMONES ASSOCIATED WITH
NEOPLASMS IN MAN

The neoplasms with which the excretion of large quantities
of what is probably prolan are most definitely associated
are hydatidiform mole and chorionepithelioma. Malignant
testicular neoplasms likewise may produce large quantities
of prolan-like hormone which, however, may differ from pro-

^' See also Elden and Fellows (1935).

[142]

THE GONADOTROPIC HORMONES

Ian in important aspects of its action (see the earlier volume).
Bliimel (1935) emphasized the diagnostic significance of the
presence of considerable quantities of gonadotropic hormone
in the urine. However, cerebral disease with increased intra-
cranial tension as well as the disappearance of internal secre-
tory activity by the gonads, as after the menopause, must
be ruled out, because these conditions may give rise to the
excretion of gonadotropic hormone in quantities greater than
normal. Search should then be made for hydatidiform mole,
chorionepithelioma, or teratoma. The last-named tumors
may, of course, also occur in males. Provided the neoplasm
secretes gonadotropic hormone, determinations of the latter
during treatment have obvious prognostic significance.

Testicular tumors in relation to hormone-excretion have
been recently discussed by Freed and Coppack (1935), Zon-
dek (1937), and Hinman and Powell (1938). Fifty-eight pa-
tients with testicular neoplasms were investigated by Hinman
and Powell. The greatest amount of hormone was excreted
by patients with teratoid chorionepithelioma of the testis
(20,000 to 3,000,000 mouse-units per liter of urine). Large
amounts might be secreted by teratoid adenocarcinomata,
by "differentiated" (partly carcinomatous) teratoid neo-
plasms or by primitive monocellular carcinomata. Only
small amounts of hormone were excreted by the large number
of patients with differentiated monocellular carcinoma of the
testis. No hormone could be found in the urine of patients
with dysgerminoma (Zondek) or '"adult" tumors classified as
adult teratoma or adult seminoma (Hinman and Powell).
Benign hypertrophy and carcinoma of the prostate or hyper-
nephroma do not secrete gonadotropic hormone, as indicated
by its absence in the urine of patients (Owen and Cutler,
1936)."

So-called prolan A or B may be found in women with
genital carcinoma other than the tumors already discussed.
It has not been shown that such hormone is not secreted by

"See also Aron (1935) and Baudler (1936).

[143]

THE PITUITARY BODY

the pars glandularis. Baudler (1935-36) in recent reports as-
sociates such findings with destructive malignant tumors
such as carcinoma of the cervix, vulva, or ovary. Sometimes
the same is true of extragenital malignant tumors of men or
women. It must be remembered that the tumor itself or
radiation therapy of such tumors might interfere with the
secretion of male or female hormone by the gonads, so that
the increased excretion of gonadotropic hormone could re-
semble that following gonadectomy.

Lewis and Geschickter (1936) investigated the concentra-
tion of gonadotropic hormone in various tumors. Some of the
results, expressed as rat-units per kilogram tumor, were as
follows: breast tumors — carcinoma (5 negative), 6,000-
7,000 rat-units, fibromyxoma, 60,000 rat-units, fibroadenoma,
2,500 rat-units; uterine myomata (2 negative), 4,500-11,000
rat-units; irradiated sclerosing osteogenic sarcoma, 4,500 rat-
units.

THE GONADOTROPIC HORMONE OF PREGNANT-MARE SERUM^^

In several respects, the gonadotropic hormone of the serum
of the pregnant mare is strikingly different from prolan.
Considerable quantities are present in the serum only during
a limited part of the gestation period. It is not excreted in
significant amounts in the urine even at times when its con-
centration is highest in the serum. It can produce marked
stimulation of the gonads of birds, whereas prolan is without
action in this class of animals. As might be inferred from its
failure to appear in the urine, it is slowly metabolized, so
that the administration of a single dose, during a period of
several days, may be as effective as repeated doses. It ap-
parently can replace the gonadotropic hormones no longer
secreted because of hypophysectomy, at times when prolan
is patently inadequate. It produces unquestionable follicle-
stimulating effects, whereas prolan does not.

^^ See the Index for references to other reports.

[ 144]

THE GONADOTROPIC HORMONES

Methods of securing purified hormone have been described
lately by Evans and others (1936), Gustus, Meyer, and
Woods (1936), and Cartland and Nelson (1937). Gustus,
Meyer, and Woods adsorbed the hormone on a suspension of
A1(0H)3 from which elution was accomplished by means of
dilute NH4OH. Cartland and Nelson not only described in
detail a method of making very potent extracts but also
studied some of the hormone's properties. It was found to be
soluble in serum containing 50 per cent acetone or 60 per cent
ethanol. When the percentage of acetone or alcohol was
raised to 70 per cent (pH 6) the greater part of the gonado-
tropic substance was precipitated. Further manipulation
permitted the isolation of preparations of a potency of 0.05
mg. for each rat-unit. (In terms of ovarian effect, their rat-
unit was 2-10 times as potent as that used by others.) The
hormone could be inactivated by HCHO (4 per cent, pH 8.0,
3 hours) or heat at 70° C. or above. Inactivation by heat was
studied at three hydrogen-ion concentrations: pH 6.0, 7.0,
and 8.0. Destruction, especially at 70° C, was greatest at pH
6.0 and least at pH 8.0. Enzymic destruction took place in
the presence of trypsin (also reported by others), but not in
the presence of emulsin or invertin. The high concentration
of hydrogen ions necessary for investigating the effect of pep-
sin produced inactivation in the absence of the enzyme.

The investigation of Evans and his colleagues is of inter-
est because of their finding that suitable concentrations of
(NHJ2SO4 can be used to fractionate pregnant-mare serum
into two components, one chiefly stimulating follicle-growth
and the other causing a "hypertrophy of the theca interna
and interstitial tissue" without follicle growth or the forma-
tion of lutein tissue. The second fraction restored the func-
tion of the interstitial cells of hypophysectomized rats. The
follicle-stimulating fraction apparently was not free from the
second principle; its action in male rats after hypophysec-
tomy was not described. Hellbaum (1937) declared that fol-
licle-stimulating, luteinizing, and augmenting substances can

[ 145 ]

THE PITUITARY BODY

be separated by suitable methods; however, his views have
been given only in the form of an abstract. Although Cole
earlier believed that more than one gonadotropic principle is
present in pregnant-mare serum (e.g., Saunders and Cole,
1935), he later reported (1936) that he was unable to confirm
this belief. Also, Cartland and Nelson at no time secured
evidence of the presence of more than a single principle. For
purposes of discussion it will be assumed that there is but one
gonadotropic principle, although new work may support the
belief that a mixture of principles really is secreted.

The slow metabolism of the hormone and the failure of the
kidneys to secrete appreciable amounts have already been
mentioned. In this connection the experiments of Catchpole,
Cole, and Pearson (1935) are of interest. The authors found
that about 50 per cent of the hormone disappeared from the
rabbit's blood 26 hours after intravenous injection (see Fig.
19). In the gelding the same proportion disappeared in 6
days. The hormone probably was destroyed, inasmuch as
none could be found in the urine or feces or in tissues such as
the uterus, lungs, kidneys, spleen, or liver. The rate of de-
struction was not affected by gonadectomy.

Extract of the serum of pregnant mares stimulates the
gonads of male or female fowls. ■'^ In the immature cockerel
the homone causes testicular hypertrophy (without preco-
cious spermatogenesis) and a marked growth of the comb.^-^
In immature females there is only moderate hypertrophy of
the ovary without ovulation but with marked growth of the
oviduct; the head furnishings are female in type.

Cole (1936) as well as Hamburger (1936) investigated the
action of the hormone in both sexes of several species of mam-

^'i Recent reports are those of Asmundson and Wolfe (1935), Hamburger (1936),
Uhl, Engelbreth-Holm, and Rothe-Meyer (1937), and Zavadowsky and others
(1937)-

25 The cockerels used bv Zavadowsky and his colleagues were 50 days old. In-
jections of 50-200 mouse-units of the hormone for 20-40 days produced tremendous
comb growth, testicular hypertrophy, and spermatogenesis. Regression and even
degenerative changes appeared after long-continued administration of the hormone.

[146]

THE GONADOTROPIC HORMONES

mals.^^ Saunders and Cole (1936) showed that only the ovar-
ian interstitial tissue is stimulated in rats 10-15 days old,
whereas follicular stimulation was marked in animals 18 days

i/tf

o fiadd/^ S/- Mod
0 fioiiii J/- coj(ra(g(f
+ /Poii/^ SS ■ //Jiaci
A fioiiU 6/- //Jtoci
* li>f/o cor)ce/7iroi/o/?

7£ 96

Tz/ne //7 />oi/rs

Fig. 19. — The rate of disappearance of the gonadotropic hormone of pregnant-
mare serum following the intravenous injection of 3,000 rat-units into rabbits.
(From Catchpole, Cole, and Pearson, Amer. J. Physiol., 112, 21-26 [1935].)

old, and ovulation and corpus luteum formation appeared
with increasing frequency in still older rats (19-25 days old.)^^

^^ Wells (1937) describes the action of the hormone in a hermaphrodite ground
squirrel.

Engel (1936) and Engel and Buno {1936) believed that certain pineal extracts
antagonize the gonadotropic action of the hormone.

^' None of the rats was hypophysectomized. However, others, including Ham-
burger, have observed the formation of lutein tissue in hypophysectomized rats re-
ceiving an extract of pregnant-mare serum.

[147]

THE PITUITARY BODY

Cole was able to produce ovulation in the rat, ewe, cow, and
sow. Both Cole and Hamburger agree that the seminiferous
tubules and interstitial cells are affected in male rats; how-
ever, the greater effect is on the interstitial cells. The hyper-
trophy of the testis in relation to that of accessory sexual or-
gans is greater after pregnant-mare serum than after prolan;
however, anterior pituitary extract excels both in this respect
(Leonard and Hansen, 1936). The same authors found that
the action of pregnant-mare serum is not altered after
thyroidectomy.

Cole (1937) reported that the injection of the hormone into
adult female rats at a suitable time (12 rat-units during
metoestrus) was followed by pregnancies resulting in an in-
creased percentage of large litters. Matings occurred in about
half of a series of immature rats receiving daily injections
when 26-31 days old. At necropsy about the 10-12 day of
pregnancy, more than 20 implanted fetuses could be counted
in 38 per cent of the immature rats. There were 17 young in
the largest litter born alive. The percentage of fertile matings
in immature or adult rats was reduced by large doses of the
hormone.

SUMMARY

Large quantities of gonadotropic hormone may be liber-
ated into the blood stream during pregnancy in man and
other primates and in the mare. Presumably, such hormone
is important in insuring the maintenance of pregnancy which,
especially at first, requires adequate amounts of the internal
secretion of the corpus luteum of the ovary. The corpus
luteum in turn cannot flourish unless it is furnished with
"luteinizing" gonadotropic hormone either by the anterior
pituitary or by some other organ. In some animals, for at
least part of the period of gestation, the anterior pituitary ap-
pears to supply most of the gonadotropic hormone required.
In man, however, the chorionic epithelium of the placenta
furnishes enormous quantities of luteinizing hormone (pro-

[148I

THE GONADOTROPIC HORMONES

Ian), especially toward the end of the second lunar month,
and thus possibly replaces the anterior pituitary. When ges-
tation is completed or fails because of fetal death, this hor-
mone is no longer secreted, either because the placenta, to-
gether with the other products of gestation, leaves the body
or because the placenta degenerates and is resorbed or re-
moved.

Conditions in the pregnant mare appear to be different, al-
though the function of the gonadotropic hormone probably
is similar. The period of secretion is more sharply limited
(especially between the 40-80 days of gestation). The endo-
metrium as well as the chorionic epithelium secretes a hor-
mone which is far more complete in its gonadotropic effects
than is prolan. Whereas prolan is chiefly a hormone facilita-
ting the growth and function of lutein tissue in the ovary or
of the interstitial cells in the testis, the gonadotropic princi-
ple(s) of pregnant-mare serum resembles anterior pituitary
gonadotropic principles in respect of the adequacy and com-
pleteness of its effects. The chorionic-endometrial hormone
of the pregnant mare can maintain the gonads of hypophy-
sectomized male or female animals and therefore affects the
follicles, corpora lutea, and interstitial tissue of the ovary or
the interstitial cells and germinal epithelium of the testis.
Likewise this hormone stimulates the gonads of birds, where-
as prolan does not. Some believe that the hormone is a mix-
ture of gonadotropic principles. However, more evidence is
needed before this belief can be accepted. On the other hand,
prolan appears to be a single gonadotropic substance.

In this chapter and in others which have preceded it, the
recent investigations of the effects of these hormones charac-
teristic of pregnancy are discussed. Neither hormone has
been isolated as a pure substance. If either is injected re-
peatedly, the gonadotropic effects disappear, and an as-
sociated production of "antihormone," which can be found
in the globulin fraction of serum, takes place. The hormone
of pregnant-mare serum appears to have much the greater

[ 149]

THE PITUITARY BODY

promise as a therapeutic agent, both because its gonadotropic
effects are nearly complete and because it is remarkably
slowly metabolized, apparently not being excreted but only
undergoing a slow destruction.

Gonadotropic hormone can be found in certain neoplasms
in man such as hydatidiform mole, chorionepithelioma, cer-
tain malignant tumors of the testis (especially teratoid neo-
plasms),^^ and in some extragenital tumors (e.g., sarcoma of
breast or bone). Urinary excretion of hormone may be marked
in patients with hydatidiform mole, chorionepithelioma, or
testicular tumor; its course in relation to treatment may fur-
nish information of great value with respect to prognosis.
The excreted gonadotropic hormones may be different — that
of chorionepithelioma or hydatidiform mole resembles the
prolan of normal pregnancy, whereas those associated with
testicular neoplasms may have different or additional bio-
logical effects.

It has not been shown that the moderate quantities of
gonadotropic hormone excreted by women with other types
of carcinoma of the genital tract do not arise in the anterior
pituitary.

^^ The absence of gonadotropic hormone in the urine does not indicate that a
testicular tumor is not mahgnant.

[50

CHAPTER V

THE PARS GLANDULARIS OF THE PITUITARY
BODY IN RELATION TO THE DEVELOPMENT
OF THE BREASTS AND THE SECRE-
TION OF MILK^

THE relationship between lactation and the secretory
activity of the pars glandularis is complex and only
incompletely understood.'' It is agreed that the lacto-
genic hormone initiates and maintains lactation. However,
its presence in adequate concentration in the blood is a neces-
sary but not a sufficient condition of lactation. Moreover,
preceding lactation there must be proper development of the
mammary glands. The extent to which this prelactation
growth depends either directly on an internal secretion of the
pars glandularis or indirectly on gonadotropic hormones
which increase gonadal function is still a problem undergoing
active investigation.

Lactation cannot continue in the absence of the pituitary
body. The correctness of this statement which has been gen-
erally held for some years was recently again confirmed in the
guinea pig (Gomez and Turner, 1936; Macchiarulo, 1936) and
in the dog (Houssay, 1935). The other aspect of this dis-
covery is represented by the following question: After hy-
pophysectomy in a lactating animal, can lactation be main-
tained by the lactogenic hormone alone, or are several an-
terior pituitary hormones required? In the pigeon, according
to Schooley, Riddle, and Bates (1937), proliferation of the
crop-glands and the formation of crop-milk, which are
changes homologous to breast development and lactation in

' The pars neuralis, pars intermedia, and pars tuberalis have not been shown to
be of significance. '*•

' See also reviews of other work in chaps, iii and iv.

THE PITUITARY BODY

mammals, can be produced by the injection of lactogenic hor-
mone into hypophysectomized birds. The authors mention
that the response to this hormone in hypophysectomized rab-
bits is a small fraction (about one-eighth) of that in normal
rabbits. Other authors agree that the lactogenic hormone, by
itself, can neither initiate nor maintain lactation in hypophy-
sectomized mammals, although the breasts may appear to
be fully prepared for stimulation or continuance of stimula-
tion. It appears that the initiation or continuance of lacta-
tion requires at least two hormones of the pars glandularis —
the lactogenic hormone and the hormone stimulating the
adrenal cortex ("corticotropic" hormone). Some authors
would further lengthen the list, especially with respect to a
separate action of the anterior pituitary on carbohydrate
metabolism. The importance of all these factors will be con-
sidered after the conditions necessary for breast development
prior to lactation have been discussed.

THE INFLUENCE OF THE ANTERIOR PITUITARY ON THE DEVEL-
OPMENT OF THE BREASTS PRIOR TO LACTATION

Before lactation can occur, there must be suitable develop-
ment of the breasts. Such development cannot occur in
hypophysectomized animals, probably because of two fac-
tors: (i) any favorable influence of the gonad will be pre-
vented by the lack of gonadotropic hormone, and (2) the an-
terior pituitary appears to secrete a hormone essential for
mammary development, even when the latter follows the ad-
ministration of an oestrogen.

The development of the mammary gland in relation to oestro-
gens? — In a mammal like the rabbit the repeated injection of
an oestrogen such as oestrone may cause a marked develop-
ment of the mammary tree, especially of the ducts. The

3 Debre, Marie, and Bernard (1935) described marked development of the
breasts in a girl eight years of age without any other signs of puberty. The develop-
ment of the vulva and bones corresponded to the child's age. There had been no
uterine bleeding.

[152]

PARS GLANDULARIS AND LACTATION

growth of alveoli appears to depend to an important extent
on the action of progesterone, although this may not be true
of other mammals, e.g., the guinea pig. Gardner, Gomez, and
Turner (1935) produced mammary development in normal
male rabbits or in normal or spayed (multiparous) female
rabbits by injecting 20-25 rat-units of oestrone daily for
about 3 weeks. If lactogenic hormone was injected within not
more than 3 days after oestrone treatment was stopped, lac-
tation promptly appeared. The observations of others who
used rabbits do not require a detailed description.'' Similar
experiments have been performed in castrated male rabbits.
In the normal monkey (xAllen, Gardner, and Hill, 1935) and
in the goat (De Fremery, 1936) the administration of an oes-
trogen will likewise suitably prepare the mammary gland so
that lactogenic hormone is then effective. Gardner (1935)
produced general development of the duct system, as well as
some localized growth of alveoli in male mice with ovarian
grafts in the testis. In the depancreatized bitch treated with
insulin, lactogenic hormone produces lactation, provided that
mammary development corresponds to that of pregnancy or
pseudopregnancy (Nelson, Himwich, and Fazekas, 1936).
Houssay (1935) used only an oestrogen to bring about mam-
mary development in normal or gonadectomized dogs of both
sexes ("folliculin" as 1,000-10,000 international units daily
for 49-90 days). The intraperitoneal administration of what
was probably a crude extract of beef anterior lobe then
caused lactation. ^

Certain experiments in the mouse, rat, and guinea pig are
of particular interest because they indicate that mammary
development following the administration of an oestrogen
cannot take place in the absence of the pituitary body.^

•< Anselmino, Herold, and Hoffmann (1935), Macdonald (1936), Margulis (1936),
Fallot (1936), and Gillard (1937).

5 The effects were present after removal of the lumbar sympathetic chains.

^Houssay stated that the pituitary is not necessary in the dog. Nelson (1935^
reported that oestrone produced about the same degree of mammary development in
male guinea pigs, whether or not the pituitary had been removed. Also, Asdell and

[153]

THE PITUITARY BODY

Gomez, Turner, Gardner, and Hill (1937) observed no de-
velopment of the rudimentary mammary glands in com-
pletely hypophysectomized male mice receiving injections of
various oestrogens (50-500 international units weekly). If,
however, a very minute fragment of the pars glandularis re-
mained, the injection of oestrogen brought about mammary
growth and development. Likewise in male or female rats
oestradiol benzoate will cause no growth of the breasts after
hypophysectomy, although this action is not prevented by
gonadectomy (Reece, Turner, and Hill, 1936). Atrophy of
the mammary glands due to the removal of the pituitary
from the rat cannot be halted by oestrone; however, inani-
tion seems to be an important factor (Astwood, Geschickter,
and Rausch, 1937). Other experiments by Gomez and Tur-
ner (1936), who used guinea pigs, also lead to the conclusion
that growth and development of the mammary ducts and
parenchyma following the injection of moderate to enormous
doses of oestrone or oestradiol benzoate (e.g., 25-1,000 inter-
national units daily) cannot take place after hypophysectomy
has been performed.' If, however, hypophysectomized male
guinea pigs receive implants of the pituitary of male rats in
which breast development has been induced by injections of
oestrone, growth of the nipples and breasts including the de-
velopment of alveoli occurs, whereas implants from rats to
which no oestrone has been given do not affect the recipient
guinea pig's rudimentary nipples and breasts (Gomez, Tur-
ner, and Reece, 1937). x^ccording to Robson (1936), little or
no development of the mammary glands occurs in rabbits
hypophysectomized about the 22-24 ^iay of pregnancy de-

Seidenstein (1935) found that oestrone in combination with progestin caused about
equally good development of the mammary glands in spayed rabbits with an intact
pituitary or after partial or complete hypophysectomy. Do these findings indicate
that the animals used were not completely hypophysectomized? According to
Gomez and others (1937), remnants of the anterior pituitary, too small to main-
tain the gonads or the adrenals, permit the response of the mammary gland of the
mouse to an oestrogen.

' The growth of the nipple due to administered oestrogen is not affected by
hypophysectomy (Gomez and Turner, 1936).

[154]

PARS GLANDULARIS AND LACTATION

spite the injection of progestin or progesterone to term.
Gomez and Turner (1938) suggest that a pituitary "mam-
mogenic" hormone is secreted in response to an oestrogen or
to an oestrogen and progesterone and that this hormone, per-
haps made up of two components, brings about the growth of
the mammary ducts and the development of the lobules and
their alveoli. The authors injected simple preparations of the
anterior pituitary of pregnant or non-pregnant heifers into
a small number of rats and rabbits which had been spayed
when immature. The administration of anterior pituitary
from non-pregnant heifers — although lactogenic hormone was
present in the injected anterior pituitary — did not affect the
mammary gland. On the other hand, if anterior pituitary of
pregnant heifers was injected for several weeks, mammary
development corresponding to advanced pseudopregnancy
or pregnancy could be produced both in rabbits and rats.

These results indicate that the growth and development
of the breasts are as dependent upon the pars glandularis as
lactation itself. A complex interplay of the hormones of the
anterior pituitary and the ovary may take place normally.
Gonadotropic hormone secreted by the anterior pituitary
maintains ovarian function, whence arises the secretion of
oestrogen and progesterone. In non-pregnant animals oestro-
gen chiefly causes the formation and liberation of a substance
from the anterior pituitary, so that partial growth and de-
velopment of the breasts occur. In pregnant animals the
production of "mammogenic" hormone(s) is increased further
not only by the increased quantities of oestrogen produced in
the ovaries and placenta but also by the added stimulation
afforded by the prolonged secretion of corpus luteum hor-
mone. As a result, full development of the breasts prepara-
tory to lactation occurs. The lactogenic hormone of the
anterior pituitary then initiates the secretion of milk.

Progesterone as a factor in the development of the mammary
glands. — Progesterone, the secretion of the corpus luteum, is

THE PITUITARY BODY

believed to vary in significance as a cause of breast develop-
ment. Certainly, it is much less important than oestrogen
and is thought to act only after some growth, especially of
the ducts, has already occurred, following the secretion or
administration of oestrogen. Most authors have concluded
that the secretion of the corpus luteum is of definite im-
portance in bringing about alveolar development in the rab-
bit's breast, provided that growth of the ducts has been
stimulated by oestrogenic hormone.^ Lactogenic hormone
then readily produces or "releases" the secretion of milk. On
the other hand, in the guinea pig and rat, progesterone ap-
pears to be of little significance in supplementing the effects of
oestrogens on mammary growth and development (Gardner
and others, 1935; Repetti, 1936; Astwood and others, 1937;
and Nelson, 1937).^

The effect of androgens on the development of the mammary
glands. — As in female rats, the post-pubertal development of
the breasts in male animals is prevented by gonadectomy.
Testosterone propionate, although without oestrogenic ef-
fects, will cause mammary development in spayed rats (Mc-
Euen, Selye, and Collip, 1936). The authors injected 3 mg.
of testosterone propionate as the total dose over 1 1 days.
Astwood, Geschickter, and Rausch (1937) concluded that tes-
tosterone can bring about, in young male rats, mammary de-
velopment corresponding to that in adult males. Large doses
of the hormone, although causing cyst formation and an in-
crease in the fibrous tissue, produced no development of the
mammary tree such as followed the administration of oes-
trone. Apparently the effects of testosterone on the breast,
like those of an oestrogen, are secondary to the secretion of
an anterior pituitary hormone; hypophysectomy prevents
such effects (McEuen, Selye, and Collip, 1937).

^ Gardner, Gomez, and Turner (1935) ; Anselmino, Herold, and Hoffmann (1935) ;
Macdonald, Pallet (1936); Gillard (1937).

' Such observations should be made in spayed animals, inasmuch as the oestrogen
may bring about the new formation of lutein tissue by increasing the rate of libera-
tion of luteinizing hormone from the anterior pituitary.

[156I

Fig. 20. — Photomicrographs of biopsy specimens of breast from a single cas-
trated male rabbit. (From Anselmino, Herold, and Hoffmann, Zbl. Gyniikol.,
S9» 963-69 [1935] ) .;?, After castration. B, After treatment for 25 days with oestro-
gen. Development of the ducts has taken place. C, After further treatment for 6
days with corpus luteum hormone. There is marked development of the alveoli.
D, After the administration of anterior pituitary extract (lactogenic hormone) for
5 days. Lactation is under way.

THE PITUITARY BODY

The effects of various hormones on the morphology of the
breast are well illustrated by figures reproduced from a re-
port by Anselmino, Herold, and Hoffmann (1935). All the
samples of breast tissue were removed from the same cas-
trated male rabbit after castration (Fig, 10, A) and after
treatment for nearly 4 weeks with oestrin (Fig. 20, 5), fol-
lowed by the daily injection of progesterone for 6 days (Fig.
20, C). Finally, extract containing anterior pituitary lacto-
genic hormone was administered for 5 days; lactation then
appeared (Fig. 20, D).

THE LACTOGENIC HORMONE^"

Provided that there is adequate development of the
breasts, the secretion of milk in normal mammals probably
takes place because of the release and continued secretion
of the lactogenic hormone of the anterior pituitary. How-
ever, this statement is not meant to exclude the participation
of other hormones, including, particularly, the adrenal corti-
cal hormone. After hypophysectomy, with which is associ-
ated a marked reduction of the activity of the rest of the
endocrine system, lactogenic hormone alone will not initiate
or support lactation, although the breasts may be suitably
developed or secreting milk at the time of operation.

It is now proposed to discuss factors which influence, both
positively and negatively, the action or the conditions neces-
sary for the action of the lactogenic hormone.

The effect of suckling on the secretion of lactogenic hormone. —
Selye, CoUip, and Thomson had earlier demonstrated that
the stimulus of suckling, without the escape of milk, main-
tains the secretion of lactogenic hormone, as shown by lacta-
tion in breasts from which the nipples had been excised."
Ingelbrecht's experiments (1935) indicate that the reflex

■" Synonymous terms are galactin, mammotropic hormone, and prolactin.

" In the guinea pig, unlike the rat, ligation of the galactophores is rapidly fol-
lowed by failure of lactation in the corresponding breast, although suckling and
lactation continue in the other breast with a normal nipple (Hesselberg and Loeb,

1937)-

PARS GLANDULARIS AND LACTATION

stimulation of the release of lactogenic hormone from the
pars glandularis is prevented by section of the spinal cord.
The author severed the spinal cord between the last thoracic
and first lumbar segments in lactating rats and covered the
6 upper nipples, which were still sensitive, with tape. Despite
vigorous suckling of the insensitive nipples, the young died
within 48 hours. However, if only two sensitive nipples were
left exposed or if a hemisection of the spinal cord was per-
formed, lactation continued in the breasts of the anesthetized
and paralyzed abdomen. Reece and Turner (1936) investi-
gated the effect of suckling and removal of the secreted milk
on the amount of lactogenic hormone in the pituitary of
lactating rats. In terms of pigeon-units, the results obtained
in one set of observations are given in Table 4. Thus, it ap-

TABLE 4

Units per Gland

I. Normal suckling 7.7

1. Accumulation of milk without suckling tor 15 hours. 9.2

3. No suckling for 12 hours followed by suckling tor

3 hours 31

4. Suckling (as in 3) but without removal ot milk due

to ligation of main galactophores 5.2

pears that suckling causes a marked release of stored lacto-
genic hormone and that the removal of accumulated milk
may be an additional factor.

Lactogenic hormone as a factor in promoting the secretion of
milk in hypophysectomized a?iimals. — It is well known that
lactation promptly ceases after the pituitary body has been
removed from lactating animals. For the restoration of lac-
tation in such animals the lactogenic hormone is necessary
but not sufficient. Several authors have pointed out that
crude anterior pituitary extracts will again initiate lacta-
tion in hypophysectomized mammals, whereas refined lacto-
genic extracts will not (Gomez and Turner, 1936; Nelson and
Gaunt, 1936).

[159]

THE PITUITARY BODY

It is probable that the successful initiation of lactation by-
means of the crude anterior pituitary extracts depends upon
the presence of adrenal cortical stimulating hormone (as well
as, perhaps, that affecting carbohydrate metabolism) in such
extracts.'^ According to Gaunt and Tobin (1936), the adrenal
glands contain no substance with lactogenic effects. How-
ever, after bilateral adrenalectomy has been performed in
lactating rats, the secretion of milk ceases but can be re-
stored by the administration of about twice the dose of
adrenal cortical extract necessary to prevent death. Smaller
doses can be used in conjunction with salt therapy, and
sometimes salt therapy alone is sufficient. After hypophysec-
tomy in lactating guinea pigs, lactation ceases but can be
initiated again by the administration of refined lactogenic
extract and adrenal cortical hormone (Gomez and Turner,
1936; Nelson and Gaunt, 1936.)''^ However, this treatment
permits lactation for only a few days and does not prevent
the involution of the breasts. Either extract by itself is of no
value. Gomez and Turner (1937) later reported on the use
of adrenal cortical stimulating hormone, obtained from the
anterior pituitary, in place of adrenal cortical extract. By
injecting an extract containing this hormone as well as lac-
togenic extract and glucose, they could maintain lactation
in hypophysectomized guinea pigs for as long as 8-15 days.

The effects of ''sex hormones'' on lactation, i. Oestrogens. —
Numerous earlier reports indicated that the secretion of
lactogenic hormone as indicated by lactation is inhibited by
the internal secretions of the gonads. For example, ovariec-
tomy may be followed promptly by lactation. On the other

'^Thyrotropic hormone may be of importance but certainly is not essential,
inasmuch as lactation takes place in thyroidectomized mammals (see pp. 165-66).

Schooley, Riddle, and Bates (1937) found that the response of the crop-glands
of one pigeon following the injection of lactogenic hormone was not prevented by
adrenalectomy four days before.

'•5 Gomez and Turner (1936-37) beheved that it is important also to administer
glucose, which they injected in amounts as high as 100 mg. per ico gm. of body-
weight daily.

f 160 1

PARS GLANDULARIS AND LACTATION

hand, lactation may occur in spite of the continued injection
of an oestrogen into mammals like the rat and rabbit.

A distinction should be made between the formation and
storage of lactogenic hormone and its release in adequate
amounts into the circulating blood. Recent experiments fur-
nish us with some information on the effects of oestrogens on
the storage of lactogenic hormone. Reece and Turner (1937)
reported that the total amount (and often the concentration)
of lactogenic hormone in the rat's anterior pituitary is in-
creased following the injection of oestrone or oestradiol
benzoate. The pituitary of the ovariectomized rat contained
less lactogenic hormone in a lower concentration. Margulis
(1936) concluded that the injection of "folliculin" into cas-
trated rabbits is accompanied by an increase in the content
of lactogenic hormone in the pituitary. However, Margulis
used only a few animals.""

The inhibitory effect of oestrogens on lactation has been
studied by other authors. Folley and White (1937) injected
into male or female pigeons 5 mg. of oestradiol benzoate, fol-
lowed a few days later by a dose of lactogenic hormone suffi-
cient to cause a marked hypertrophy of the crop-glands. In
birds also receiving oestradiol benzoate the hypertrophy of the
crop-glands was only about one-half (males) to three-fourths
(females) that in control birds. The injection of large doses
of oestrogens may inhibit normal lactation in rats, guinea
pigs, and rabbits (Folley and Kon, 1938; Mugnai, 1937;
Smith and Smith, 1933; Custo, 1937). Folley and Kon ob-

'•* In Wiegand's experiments (1937) ovarian secretion "as stimulated in rats,
initially immature, by the injection of 100 rat-units of prolan daily for 15-20 days.
The amount of lactogenic hormone in the pituitary was much greater than in con-
trol animals receiving no prolan. If, however, the injections were stopped and the
ovaries were removed, lactation appeared after about 36 hours. At that time there
had occurred a marked fall in the lactogenic action of the pituitary in agreement
with the view that stored hormone had been discharged. Such an effect of gonad-
ectomy was not observed in normal rats.

In other reports (1937) Wiegand attributed the marked increase in the amount of
lactogenic hormone in the pituitary immediately following delivery to an increased
formation of the hormone caused by the loss of the inhibitory effect of oestrone be-
lieved to be present during pregnancy in the rat.

f 161 1

THE PITUITARY BODY

served a definite but much less marked inhibition, if the
ovaries were removed immediately following parturition in
rats. Nelson (1937) observed lactation in guinea pigs (nor-
mal or gonadectomized of both sexes), when the injection of
oestrone, which had caused a complete development of the
breasts, was stopped. Also he reported that lactation after
oestrone continued in hypophysectomized guinea pigs, if
crude pituitary extract was injected; if injections of oestrone
were again administered, the lactogenic action of the crude
pituitary extract was inhibited. According to Richter (1936),
spaying is not followed by any improvement in the quantity
or fat-content of the milk in lactating cows; also the duration
of lactation is not affected. However, the injection of an
oestrogen like oestradiol benzoate is followed by a reduction
in the quantity of milk produced by cows (Folley, 1936;
Waterman, Freud, and Vos-De Jongh, 1936). Folley studied
the effects of oestrogen on some of the constituents of milk
and serum. The percentage of fat and non-fatty solids of
milk was increased, whereas the nitrogen-partition was not
affected, indicating that the milk was not colostrum-like.
In the serum the treatment appeared to cause some increase
in the concentration of inorganic P and, transiently, of phos-
phatase; also there was observed a temporary fall in the con-
centration of Ca.

Other investigators have studied the practical importance
of oestrogens as means of suppressing lactation after abortion
or stillbirth (Snoeck, 1935; Hoffmann, Mayor, van Tongeren,
1936; Mugnai, 1937). Such treatment is of value only when
enormous doses are injected. Snoeck injected 100,000 inter-
national units of oestrone (?) within three days. Mayor as
well as Mugnai concluded that the injection of 250,000 units
(mouse-units [Mayor], international units [Mugnai]) of oest-
radiol benzoate can completely suppress lactation follow-
ing delivery. Breast tension may be lessened by smaller
doses. Mugnai recommended the use of oestrogen to inhibit

[162]

PARS GLANDULARIS AND LACTATION

the discharge from fistulas of the breast following incision
for abscess.

2. Progesterone. — Folley and Kon (1937-38) particularly
doubt that the inhibition of lactation during pregnancy is
caused by the secretion of progesterone. However, they ad-
mit that the inhibiting effect of oestrogen on lactation may
be reinforced by progesterone, which by itself is without such
action. In their experiments with lactating rats, they in-
jected I mg. of progesterone daily to the mothers from the
fifth day after parturition. There was no detectable effect
on the weight-curve of the nursing young. Anselmino, Her-
old, Hoffmann, and Pencharz (1936) also used rats but con-
cluded that progesterone can cause marked inhibition of lac-
tation. The authors injected 200 rat-units of prolan daily
for 14-18 days to bring about breast development in imma-
ture rats. The animals were then spayed, following which
(36-48 hours) lactation appeared. Almost complete inhibi-
tion of lactation then followed the injection of two doses of
0.5 unit each of progesterone, whereas the administration of
4,000 units of oestrogen was without effect. '^

3. Androgens. — Suitable doses of testosterone propionate
apparently can completely inhibit lactation in intact lactat-
ing mice or rats, whereas androsterone has practically no
effect (Robson, 1937; Folley and Kon, 1938). Robson in-
jected 0.1 mg. of testosterone propionate in oil daily to lac-
tating mice; nearly all the young died in less than three
weeks. Similar injections of 0.2 to 0.4 mg. of androsterone
were without action. Lactation (but not suckling or ma-
ternal care) rapidly disappeared, if 0.05 mg. of testosterone
propionate suspended in 0.05 cc. of 10 per cent alcohol were
injected every 2 hours. Control experiments indicated that
the solvent did not contribute to the effect. The observations

'5 Folley and Kon (1938) found that the inhibitory action of oestrogen on lac-
tation is less readily observed in spayed animals. The possible luteinization of the
ovaries owing to the liberation of luteinizing hormone from the pituitary following
the injection of a large dose of an oestrogen seems to have been left out of considera-
tion.

[163]

THE PITUITARY BODY

of Folley and Kon were made in lactating rats. Lactation
was markedly inhibited by the injection of 0.4 mg. of testos-
terone propionate per 100 gm. body-weight; on the other
hand, three-fourths of this dose of androsterone had no effect.
The authors suggest the generalization that substances which
cause growth and development of the breasts also inhibit
lactation.

OTHER BIOLOGICAL INTERRELATIONSHIPS
OF THE LACTOGENIC HORMONE

New observations on the distribution of the hormone. — The
concentration of lactogenic hormone in the pars glandularis
of the sperm whale is less than 1.5 per cent of that in the
anterior pituitary of the ox (Geiling, 1935). Leblond and
Noble (1937) attempted to determine the amount of lac-
togenic hormone in the pituitary of animals of several classes.
Their assays were performed in pigeons, into which they
made injections intradermally over a crop-gland. They
doubted the specificity of some responses because, although
undulated thickenings were produced, the cells of the crop-
gland contained few or no fat-granules (Scharlach R). The
clearest responses were obtained by the injection of the pitui-
tary of mammals (mice, rats, rabbits) or of birds (fowls,
pigeons). Glands from various fishes were implanted, some-
times as many as 100 in a single assay. Attempts also were
made to detect and determine the amount of hormone in
the pituitary of an amphibian {Rana pipiens) and a reptile
{Kinosternon odoratum) .

The secretion of milk in response to the injection of extract
containing the lactogenic hormone. — Grant (1936-37) has in-
vestigated the action of lactogenic extract on the regressing
mammary glands of the guinea pig. Large doses of the hor-
mone caused the transient reappearance of a small amount
of mammary secretion which, however, contained little or
no lactose (0.04-0. 24 per cent). The volume of secretion was
increased tremendously if preliminary treatment with oestra-

[164]

PARS GLANDULARIS AND LACTATION

diol (0.5 mg. daily for 7 days) followed by progesterone (0.4
mg. daily for 4 days) was given. '^ De Fremery (1936) con-
cluded that lactogenic extract can initiate the secretion of
milk in the goat, irrespective of the season or the phase of the
oestrous cycle. Other studies in lactating cows have been
made by Waterman, Freud, and Vos-De Jongh (1936) and
by Asimov and Krouze (1937). Only two cows were used
by Waterman and others whose experiments indicated that
lactation is favorably influenced by the hormone. xAsimov
and Krouze concluded that milk production is increased ap-
proximately 20-40 per cent by the injection of a crude an-
terior pituitary extract every 10 days. Five hundred and ten
lactating cows which received injections were compared with
90 control animals. The effect of the extract was much
greater in the first half of the normal period of lactation.
Except for a temporary rise of 0.1-0.8 per cent in the con-
centration of fat, the milk was found to resemble normal
milk. (The pH and the concentration of lactose and chloride
were also studied.)

Among observations in primates are those of Geschickter
and Lewis (1936), who studied the action of lactogenic ex-
tract in women who had received injections of oestrin for a
month previously. The administration of a total dose of
600-1,120 bird-units of lactogenic hormone during a week
was followed by the elaboration of a secretion which per-
sisted only a few days, despite further injections or mechani-
cal stimulation. Histological examination of breast tissue in-
dicated that true lactation had not appeared. The authors
believed that such combined treatment might cause changes
resembling cystic disease of the breast.

The thyroid gland in relation to lactation. '^"^ — Lactation and,

'^ The injection of 80 units of pregnant-mare serum daily for 3 days prior to the
injection of lactogenic extract appeared not to be of value.

■' Riddle and others (1936-37) pointed out that lactogenic extracts may have a
marked calorigenic action in pigeons. This effect, like similar effects of thyroid ex-
tract or thyrotropic hormone, can be observed at 30° C. At 20° C. the change
may be slight, and at 15° C. it may be in the opposite direction. The calorigenic

[165]

THE PITUITARY BODY

therefore, the action of the lactogenic hormone do not de-
pend on the normal secretion of thyroid hormone to any im-
portant extent. Schooley, Riddle, and Bates (1937) were
able to produce a typical crop-gland response to lactogenic
hormone in a thyroidectomized pigeon. In mammals like the
dog, guinea pig, and rat, lactation following parturition or
the withdrawal of oestrin or the injection of anterior pitui-
tary extract is not prevented by thyroidectomy (Houssay,
1935; Nelson and Tobin, 1937). Likewise the development
of the breasts during pregnancy is not significantly inhibited
by thyroidectomy in the rat (Nelson and Tobin, 1937). Un-
like adrenal cortical extract, thyroid extract or thyroxine ad-
ministered coincidently with lactogenic extract will not ini-
tiate lactation in suitable hypophysectomized animals (Go-
mez and Turner, 1937; Nelson and Tobin, 1937).

De Fremery (1936) reported that doses of thyroxine suffi-
cient to cause a severe hyperthyroidism (15 mg. daily) in
goats brought about a reduction in the volume of milk se-
creted daily. No change in the composition of the milk was
noted. After the administration of thyroxine was stopped, the
output was not restored to its original level. Van Tongeren
(1936) could demonstrate no action of thyroxine in lactating
women. Probably the doses he used were too small.

Miscellaneous observations. — Additional evidence in favor
of the view that broody behavior of fowls depends upon the
lactogenic hormone has been gathered by Burrows and
Byerly (1936). The authors compared the proliferative
changes in the crop-glands of pigeons by implanting one pi-
tuitary (e.g., from a broody hen) over one crop-gland and the
other (e.g., from a laying hen) over the other crop-gland.

action of lactogenic extract is not prevented by thyroidectomy. Riddle, Dotti, and
Smith suggest that a moderate increase (about 20 per cent) in the blood-sugar con-
centration as well as a calorigenic effect are caused by an action of lactogenic
hormone on adrenal cortical tissue.

The concentration of sugar in the blood of the normal rabbit or of the normal
or depancreatized monkey is not affected by the injection of lactogenic extract
(Nelson, Turner, and Overholser, 1935).

f 166I

PARS GLANDULARIS AND LACTATION

The pituitary gland of broody hens produced much more
hypertrophy of the crop-gland than that of laying hens or of
cocks. Other comparisons between the pituitaries of hens of
broody or non-broody genetic constitution indicated again
that broodiness is associated with the larger amount of lacto-
genic hormone in the pituitary.

Leblond and Nelson (1937) concluded that the maternal
instinct in lactating mice and rats does not depend upon the
secretion of lactogenic hormone because the instinct persists
after hypophysectomy.

De Fremery (1936) was able to terminate pregnancy, either
as fetal death or abortion, by the injection of lactogenic ex-
tract into pregnant goats, guinea pigs, rabbits, or rats. He
stated that the effect was not due to gonadotropic or thyro-
tropic hormone.

According to Salle and Schechmeister (1936), embryonic
crop-gland cultured in vitro is not affected by lactogenic ex-
tract. The growth of the Simpson mammary carcinoma in
mice is not altered after the injection of 60 bird-units of lac-
togenic hormone (Bischoff and Maxwell, 1936).

The metabolism of the lactogenic hormone. — Wiegand (1937)
found that little change in the amount of lactogenic hormone
is found in the pituitary body of the rat during pregnancy.
Immediately after parturition the amount present is doubled
or trebled; however, the quantity of the stored hormone falls
as it is liberated into the blood stream and lactation appears.
Perhaps a similar change occurs in women. At any rate,
several authors have demonstrated lactogenic hormone in the
urine of lactating women. Like Wiegand, these authors relied
on the hypertrophy of the pigeon's crop-gland to detect the
hormone.'^ Lactation in new-born children — the secretion of
"witches' milk" — is attributed by Lyons (1937) to the action

'* Lyons and Page (1935), Hoffmann (1936), and Tesauro (1936). Lyons and
Page estimated that the daily excretion of hormone in the urine of women 4-13
days after parturition was at least equivalent to what can be extracted from one
pars glandularis of the ox. Liard's experiments (1937) appear not to be adequately
controlled.

[167]

THE PITUITARY BODY

first of oestrin and then of lactogenic hormone. He was able
to detect lactogenic hormone (0.03-0.5 unit'^ per cc.) in the
urine of new-born babies. Two units'^ per cc. of urine were
excreted by a lactating baby boy.

Reece and his associates investigated the concentration
and total amount of lactogenic hormone, as assayed in
pigeons, in the pituitary of rats with various vitamin defi-
ciencies. There appeared to be a reduction in the total
amount of hormone, if the diet was deficient in vitamins A,
B (as B complex), and D; however, the concentration of the
hormone was increased in vitamin-B deficiency, whereas if
vitamin A, or especially vitamin D, was lacking, the con-
centration was diminished. No change in the total amount
or concentration of the hormone accompanies vitamin-E de-
ficiency.^"

According to Lewis and Geschickter (1936), cyst fluid of
cystic disease of the breast, although sometimes without ac-
tion, contains on the average about 500 bird-units of lacto-
genic hormone per liter. Colostrum as well as the tissue of
the udders of lactating cows contain lactogenic hormpne
(Geschickter and Lewis, 1936).

The lactogenic extract used by GiufFrida (1937) was ad-
ministered repeatedly to pigeons. The maximvim hyper-
trophy of the crop-glands was observed after seven daily in-
jections. The effects disappeared despite injections for a
longer period. Refractoriness toward the extract appeared
earlier if larger doses were used. Young (1937) prepared an
extract with lactogenic and diabetogenic effects but without
significant action on either the thyroid or the gonads. x'\l-
though this extract was injected daily — in some instances
for as long as 9 weeks — into rabbits, dogs, or monkeys, the
sera of these animals not only contained no lactogenic "an-

" Intradermal "micro-units" in the pigeon.

'" Marchesi (1935) administered gonadotropic extract, so that pregnancy and
parturition took place in animals presumably receiving no vitamin E. Lacta-
tion either did not appear or was hopelessly inadequate.

f 168 1

PARS GLANDULARIS AND LACTATION

tihormone" but even seemed to augment the action of the
hormone.

The assay of lactogenic hormone. — The only satisfactory-
methods of assaying the lactogenic hormone are based upon
the response of the crop-glands of pigeons — a test introduced
by Riddle and his colleagues. After the injection of extract
containing lactogenic hormone, the crop-glands undergo
hypertrophy which may be limited to only one of the two
glands, provided that not too large a dose is injected into
the skin overlying the gland. Pigeons of the same stock vary
greatly, of course, in sensitivity. Some varieties of pigeons
are more suitable than others; Bates and Riddle (1935) found
that a tenfold variation in sensitivity may be encountered in
different races of pigeons (see also Evans, 1 937) . Wolff ( 1 937)
concluded that the response of young birds is more regular
than that of adults. Birds of either sex can be used.

The effect of a dose of lactogenic hormone depends upon
the route of absorption. The greatest response follows the
intracutaneous administration of extract over a crop-gland.
The dose causing a given response is about i per cent of that
necessary, if injection is subcutaneous, intramuscular, or
intraperitoneal (Lyons and Page, 1935; Bates and Riddle,
1936; and Chasin, 1936). According to Bates and Riddle
(1936), the relative efficacy of injected hormone is approxi-
mately the following: intracutaneous, 1,000; subcutaneous,
10; intramuscular, 2; intraperitoneal, 1.3; and intravenous,
0.9.

Varous authors^' have devised methods of assay and have
often determined the relationship between dose and response,
which usually is given in terms of crop-gland weight, some-
times in relation to body-weight. Potency also may be esti-
mated from the percentage of birds in which a minimum
response is produced. Probably few investigators will oppose
the view that a standard preparation, perhaps crystalline

" Bates, Riddle, and Lahr (1936), Dyer (1936), McShan and Turner (1936),
Lyons (1937), Rowlands (1937).

[169]

THE PITUITARY BODY

hormone, must be introduced. An example of the relation-
ship between dose and response is the graph of Rowlands re-
produced in Figure 21. Rowlands' extract, which contained
neither gonadotropic nor thyrotropic hormones, was in-
jected subcutaneously once daily for 6 days when the maxi-
mum effect was observed. The crop-glands were removed on
the seventh day, fixed in Bouin's fluid, and weighed after
they had been carried to 70 per cent alcohol. Weights of

= 0 12345678

AMOUNT OF EXTRACT (MGM.) GIVEN DAILY

Fig. 21. — The relationship between the dose of anterior pituitary extract (con-
taining lactogenic hormone) and the growth of the crop-gland of the pigeon. (From
Rowlands, Quart. J. Pharm. Pharmacol, lo, 216-21 [1937].)

crop-glands are expressed as percentages of body-weight. In
birds receiving no injections the crop-glands constitute about
0.3 per cent of the body-weight. Rowlands recommended
that the glands of injected birds should fall within a weight-
range represented by 0.8-2.0 per cent of the body-weight.

Leblond and Allen (1937) stated that the action of lacto-
genic hormone could be detected as soon as 10 hours after
injection, if 0.5 mg. of colchicine also was administered.
After the injection of either the hormone or colchicine, about
2 per cent of the cells of the crop-glands were in mitosis; how-
ever, if both were injected, "arrested" mitoses were present

[170]

PARS GLANDULARIS AND LACTATION

in about 20 per cent of the cells. According to Valle (1937),
smears of the cells of crop-gland secretion can be obtained
by means of a fistula. Especially 48-72 hours after the injec-
tion of lactogenic extract, the cells are found to contain
orange-colored droplets of various sizes after fixation in
formalin and staining by sudan III and methylene blue."

The chemistry of the lactogenic hormone. — White, Catch-
pole, and Long (1937) recently described a method of isolat-
ing a crystalline lactogenic principle which presumably is the
pure hormone. By the two-day intracutaneous test of Lyons
and Page a "unit" was found to be 0.05-0.1 7; by a systemic
test, also in pigeons, o.i mg. was designated a unit. The
method used was briefly as follows: 100 mg. of purified ex-
tract was dissolved in 2 cc. of 13 per cent acetic acid to which
was added 2 cc. of 13 per cent pyridine. The cloudy mixture
was set aside and later centrifugated. The precipitate was
subjected to the same treatment — the whole process being
repeated ten times. Crystalline hormone was finally ob-
tained either by allowing the acetic acid-pyridine mixture to
stand in the refrigerator or by the careful addition of i per
cent NH4OH to the mixture followed by centrifugation and
refrigeration of the turbid mother-liquor. The crystalline
material yielded on analysis 51. 11 per cent of C, 6.76 per
cent of H, 14.38 per cent of N, and 1.77 per cent of S. It
appeared to be protein or protein-like. The following reac-
tions were positive: xanthoproteic, biuret, labile S, Millon,
and Hopkins-Cole.

Other reports are of interest so far as the preliminary puri-
fication of the hormone is concerned.^-' The most varied
media have been used for initial extraction: 60-70 per cent
alcohol at "pH" 9-10 (this was used by Bates and Riddle

"Leblond and Nelson (1937) and Leblond and Noble {1937), who injected ma-
terial intracutaneously, concluded that non-specific proliferation of the crop-glands
can be produced (e.g., by liver). In proliferation not due to lactogenic hormone, fat-
granules are not found in the growing epithelium.

^3 Bates and Riddle (1935), Bergman and Turner (1937), Evans (i937)> Lyons
(1937), and McShan and French (1937).

[171]

THE PITUITARY BODY

and is recommended by Bergman and Turner), dilute acetic
acid or acidified acetone (Lyons, and McShan and French),
0.05 N NaOH (Evans). The further details of preparation
can be found in the reports of the various authors.

McShan and French confirmed the statement of Bates and
Riddle that purified extracts withstand boiling in a solution
of pH 8. If the substance is a protein, this is a remarkable
property. So far, this experiment has not been performed
with crystalline hormone. In a solution at a lower or a higher
pH, the hormone is inactivated at a temperature of 100° C.

SUMMARY

The manner in which the anterior pituitary controls the
development of the breasts and the secretion of milk is more
complex than was suspected a few years ago. The important
and probably essential glands of internal secretion are the
pars glandularis of the pituitary body, the ovaries,^^ and the
cortex of the adrenal glands.

For the growth and development of the breasts, an oestro-
gen analogous to what is obtained from ovarian tissue must
be secreted or injected. In some mammals like the guinea
pig this appears to be the only ovarian secretion required
for prelactation development. In other mammals like the
rabbit it is believed that corpus luteum hormone (proges-
terone) is also required later. However, development of the
breasts due to an oestrogen is prevented by hypophysectomy.
Also, there is other evidence that an anterior pituitary secre-
tion, which brings about development of the mammary
glands, is formed and liberated into the blood stream in re-
sponse to ovarian (or placental) secretion or to the injection
of an oestrogen. A working hypothesis regarding the growth
and development of the breasts is as follows: gonadotropic
hormones from the anterior pituitary are essential for the

^"t For the purposes of this summary, breast development and lactation in male
animals will not be specifically considered. It may be mentioned that the develop-
ment of the rudimentary breasts of male animals appears to depend upon the testes
and the anterior pituitary.

[172]

PARS GLANDULARIS AND LACTATION

normal secretory activity of the ovaries; ovarian secretions
(or placental secretions, or both in pregnant animals) bring
about the elaboration of a new anterior pituitary secretion
which causes growth and development of the mammary
glands.

Provided that prelactation development has occurred in
the breasts, another anterior pituitary hormone — the lacto-
genic hormone — brings about lactation. However, this hor-
mone alone cannot initiate lactation in hypophysectomized
animals. Perhaps because of its effects on salt metabolism,
adrenal cortical hormone must also be available to the
organism. In hypophysectomized animals lactation from
adequately developed breasts can be initiated by the injec-
tion of lactogenic hormone in combination with adrenal cor-
tical hormone from the adrenals or adrenal cortical stimu-
lating hormone from the pituitary. It is probable that the
maintenance of lactation depends upon additional hormones,
including those responsible for the continued development
of the breasts.

The greater part of the attention of investigators has been
focused on the lactogenic hormone. This substance appar-
ently has been isolated as a crystalline substance, which is
either a protein or is closely related to proteins. It is con-
veniently assayed by its stimulating effect on the growth of
the crop-glands in the pigeon. In the rat, at least, its libera-
tion from the pars glandularis largely depends upon centripe-
tal nervous impulses due to suckling. The amount of hor-
mone secreted during lactation may exceed the needs of the
mammary glands, so that the unused portion is excreted in
the urine. Other data concerning the physiology of the lac-
togenic hormone are discussed not only in this chapter but
also in the two which precede it.

173

CHAPTER VI

THE THYROTROPIC HORMONE

ONE of the impressive effects of hypophysectomy in
mammals is a marked fall in the rate at which heat
is produced. This change is due principally to in-
adequate function of the thyroid gland and can be correlated
with morphological changes in the thyroid — i.e., undis-
charged colloid accumulates in vesicles lined by flat, "in-
active," epithelial cells. A specific substance called the thy-
rotropic hormone is secreted only by the anterior pituitary;^
it is responsible for the maintenance of normal thyroid func-
tion and may be important in disorders attributed to deficient
or excessive thyroid secretion. In classes of animals other
than mammals different changes, likewise dependent on the
virtual absence of thyroid secretion, follow the removal of
the pars glandularis. A well-known example is the absence
of metamorphosis after the removal of the gland from anuran
larvae.

The thyrotropic hormone has not been isolated as a pure
substance. Nearly all the recent progress is concerned with
its biological action.

The biology of thyrotropic hormone in fishes^ amphibia^ and
reptiles. — Young and Bellerby (1935) were not successful in
attempts to produce metamorphosis in lampreys {Lampetra
planeri) by the injection of an extract of the anterior pitui-
tary of the ox.

The pioneer work of Adler, Smith, and Allen clearly dem-
onstrated that metamorphosis in anuran amphibia is pre-

' Sturm and Schoning (1935) believed that extracts of the ovary or the medulla
of the adrenal gland may act like true thyrotropic hormone. Repetition of their
work with ovarian tissue yielded no confirmation (Ballif and Gherscovici, 1936;
McGinty and McCullough, 1936; and Emerson, 1937).

[174]

THE THYROTROPIC HORMONE

vented by the removal of the anterior lobe or the buccal
anlage of the pituitary, because what is now termed thyro-
tropic hormone is no longer available. Without thyrotropic
hormone from the anterior pituitary, thyroid function is so
deficient that metamorphosis is prevented. The experiments
of Voitkevic (1937), who used larvae of Rana esculenta and
R. temporaria^ confirm observations — i.e., such as the greater
thyrotropic efi?"ect of implants of basophilic chromophils in
comparison with oxyphilic chromophils — which have already
been discussed in my monograph of 1936. The author's ob-
servation that implants of beef anterior pituitary containing
oxyphils as the principal chromophil antagonize spontaneous
metamorphosis or metamorphosis caused by anterior pituitary
basophils or thyroid extract has not been independently con-
firmed. Etkin's study (1935), in which larvae of /?. sylvatica
were used, led to the following conclusions: (i) The pars
buccalis is self-differentiating (i.e., differentiation occurs after
its transplantation to a new site), (2) thyrotropic hormone is
secreted in an amount proportional to the amount of actively
secreting pituitary tissue, and (3) the liberation of the hor-
mone appears not to depend on nerves. Metamorphosis oc-
curred at about the normal age and stage of growth in em-
bryos which had been hypophysectomized and given re-
placement therapy in the form of a transplant of the re-
moved pituitary which was placed in the eyecup or under
the adhesive disk. If similar embryos received three trans-
plants of the pars buccalis under the adhesive disks after
hypophysectomy, precocious metamorphosis (at 8 instead of
the normal 18 days) followed; also, the length of the larvae
was less than that of normal larvae at the time of the cor-
responding change (29 instead of 44 mm.). According to
Atwell (1935), the differentiation and subsequent secretory
activity of the anterior pituitary in larvae of R. sylvatica or
R. pipiens can take place without contact with nervous tissue
or foregut. (Atwell could not be sure that this statement
holds for the pars intermedia; also, he stated that Etkin's

[175]

THE PITUITARY BODY

transplants were not free from nervous tissue.) Similar ex-
periments in Amblystoma punctatum were unsuccessful.^

Atwell (1937) found that compensatory hypertrophy of
thyroid fragments in larvae of R. pipie?js is prevented by
hypophysectomy. This finding is in accord with other work
in amphibia and mammals.

x^nother group of authors has published observations
largely confirming and extending previously reported experi-
ments in urodele amphibia. Uhlenhuth and his collabora-
tors^ again described the stimulating effect of anterior pitui-
tary extract on the thyroid as indicated by morphological
changes in the latter, by increased oxygen-consumption or
by precocious metamorphosis. Most of their observations
were made in Amblystoma tigrinum. The photomicrographs
of Figure 11 are reproduced from those published by Adams
and Martindale (1936). The injection of an alkaline extract
of the pars glandularis of the ox ("Phyone") produced a
marked stimulation of thyroid function in hypophysecto-
mized newts {Triturus viridescens). Maximum changes were
produced after daily injections had been given for about three
weeks. The thyroid underwent regression to its former con-
dition, characteristic of hypophysectomy, only weeks after
injections were stopped.

Hypophysectomy prevents molting in adult urodele am-
phibia and, in this respect, resembles thyroidectomy. The
cornified cells of the epidermis are retained as successive
layers. These effects of extirpation of the pituitary do not
occur in larval urodeles or in neotenous forms, except per-
haps in Necturus maculosus (Osborn, 1936). Adams and Gray
(1936) were able to cause molting of the layers of cornified
epidermis of hypophysectomized newts {T. viridescens) by
the administration of anterior pituitary extract, thyroxine, or

2 Blount's results in Amblystoma indicated that the pars neuralis is required for
the differentiation of the pars glandularis. In his animals there also were a pro-
nounced intensification of pigmentation and distortions of growth.

3 Uhlenhuth and Schwartzbach (1935); Uhlenhuth, Schwartzbach, and Thomp-
son (1935); and Schwartzbach and Uhlenhuth (1936).

[176]

Fig. 22. — The effects of hypophysectomy and of the injection of anterior pitui-
tary extract after hypophysectomy on the thyroid gland of the newt, Trituriis viri-
descens. (From Adams and Martindale, Anat. Rec, 65, 319-31 [1936].)

i,£, Photomicrographs of thyroid of normal newt at low and high magnifications.
2, 6, Photomicrographs of thyroid of newt 5 weeks after hypophysectomy. j,
Photomicrograph of thyroid of newt receiving anterior pituitary extract for 10 days.
Treatment was begun 5 weeks after hypophysectomy. ^, Treatment begun as in j",
but continued for 20 days. Photomicrographs /-^ were made at the same low mag-
nification, photomicrographs 5-6 at the same high magnification.

THE PITUITARY BODY

iodine, or by grafts of the thyroid. Anterior pituitary extract
was effective because it contained thyrotropic hormone. The
mechanism by which iodine facihtates molting in such ani-
mals is not clear; the element produced no morphological
change in the thyroid gland.

After hypophysectomy, repeated molting occurs in snakes
{Tham?20phis sirtalisy T. radix) (Schaefer) — the reverse of the
effect induced in urodele amphibia. Hellbaum (1936) recent-
ly described the effects of hypophysectomy as well as those
following the injection of anterior pituitary extract into such
snakes. The cytological changes in the anterior pituitary of
thyroidectomized snakes {T. radix) were investigated by
Siler (1936).

Recent observations in birds. — After the complete removal
of the pituitary from Brown Leghorn cocks, the feathers
finally resemble those of thyroidectomized cocks — loss of
black pigment of feathers of part of the neck, of the breast,
and of the legs. Hill and Parkes (1935), who made this ob-
servation, were able to restore the pigment to normal by ad-
ministering thyroxine to a hypophysectomized cock.

The biology of the thyrotropic hormone in mammals. —
Numerous experimental observations with a great variety of
objectives have been made in mammals. Much of the work
only adds adornment to knowledge previously available; in
addition, however, new facts have been gathered. The clas-
sification of extensions of our knowledge as well as additions
to it will now be attempted.

The efects oj thyroidectomy on the anterior pituitary. — Hy-
pertrophy of the pars glandularis, which is often more marked
in male than in female animals, usually follows thyroidec-
tomy. It is generally agreed that an important histological
change in the anterior pituitary is a marked reduction in the
proportion of oxyphils. Also there is an increase in the per-
centage of cells with an afiinity for basic dyes; such' cells,
often first undergoing hypertrophy, may become vacuolated
or appear to be filled with hyaline material and usually are

[i/^l

THE THYROTROPIC HORMONE

identified as "thyroidectomy-cells." Their origin is still a
matter of disagreement. Some authors believe that they arise
at least partly from basophils and either are identical with
"castration-cells" or are completely different/ Their rela-
tionship to the hypertrophied reserve cells which other au-
thors have so frequently noted in the anterior pituitary of
animals with thyroid deficiency probably also is close. ^

Lebedewa (1936) believed that the pituitary of young
thyroidectomized rats contains less thyrotropic hormone than
normal. However, her conclusion is not based on enough ex-
periments to warrant its acceptance. According to Zeckwer
(1936), although the concentration of thyrotropic hormone
in the pituitary of thyroidectomized rats is greater than nor-
mal in terms of body-weight, the amount present is less than
normal in terms of age.*" Chen and van Dyke (1936) investi-
gated the anterior pituitary of normal and thyroidectomized
rabbits. In littermate normal animals there was no sexual
difference in thyrotropic potency. Three months or more
after thyroidectomy an increase in the total amount of hor-
mone in the hypertrophied anterior pituitary of female rab-
bits was noted. Although hypertrophy of the gland was
greater in male rabbits, a similar change in potency could not
be found. In both sexes the hypertrophied anterior pituitary
associated with thyroid deficiency contained more water
than the normal gland (total solids 19.1-19.4 per cent com-
pared with the normal of 22.2-23.7 per cent).

The ejects of hypophysectomy on thyroid Junction. — There
is little to add to the previous account. Normal thyroid
function and all that this implies is markedly but not com-
pletely deficient after hypophysectomy. Low-grade thyroid

^ See chap, i, p. 11.

5 Altschule and Cooper (1937) recently reported on the changes in the human
pituitary associated with operative or spontaneous hypothyroidism. They con-
cluded that the number of basophils, often markedly vacuolated, may be 2-4 times
as great as normal. Like other authors they believed that hypothyroidism may be
due to a primary disturbance of either the pars glandularis or the thyroid.

^ See also Zeckwer and others (1935).

[179]

THE PITUITARY BODY

activity is indicated morphologically by the atrophy of the
epithelium of the thyroid follicles and the distention of the
latter with dense, non-vacuolated colloid. Such changes were
again reported by Rowlands (1935), who hypophysectomized
fowls and mammals of several species (ferret, guinea pig,
and hedgehog). It is of interest that weight-atrophy does not
follow hypophysectomy in the guinea pig. The morphologi-
cal signs of inactivity of the thyroid could be observed in the
various animals 1-2 weeks after hypophysectomy."

Other aspects of the biology of thyrotropic hormone. — The
most significant action of thyrotropic hormone is to facilitate
or promote the discharge of thyroid hormone from the thy-
roid gland. The colloid becomes vacuolated; the thyroid vesi-
cles diminish in size; the epithelial cells become hypertro-
phied. Its further effect is to promote hyperplasia of the
epithelium, so that doses much larger than those causing the
discharge of stored hormone may bring about marked hyper-
trophy of the thyroid. There still is disagreement as to the
unity or duality of the anterior pituitary hormone(s) causing
these two principal effects.

Several new reports concerning the amount of hormone
in the pituitary body of various mammals have been pub-
lished. Miiller, Eitel, and Loeser (1935) declared that the
human gland contains 5-30 "guinea pig units." Undoubtedly
there was great variation in the degree of postmortem autoly-
sis in their material. The variations in potency were great
and appeared not be be related to age or sex; high values
were obtained if death was due to tuberculosis or other infec-
tions. According to Saxton and Uoeb (1937), the amount of
thyrotropic hormone in the human pars glandularis is quite
constant irrespective of age or other factors such as preg-
nancy and lactation. Rowlands (1936) used a reliable uni-

' Reiss and Fischer-Popper (1936) injected 0.1-0.5 r"g- of thyroxine daily into
rats. They concluded that after hypophysectomy the sensitivity of such animals
was greatly increased (loss of body-weight, increased rate of urinary excretion of N,
increased basal metabolic rate), because compensating "antithyroid" effects of the
pituitary, mediated through the adrenal glands, were absent.

[ 180 1

THE THYROTROPIC HORMONE

form method of assay (hypertrophy of the guinea pig thyroid
according to Rowlands and Parkes). Two methods of initial
extraction of the same acetone-desiccated powders were
employed with the results shown in Table 5. From this data
it appears that the best practical sources of thyrotropic hor-
mone are the pituitaries of cattle and pigs.^

TABLE 5

Powdered Pituitary of

Units per Gram of Desiccated

Powder after Initial

Extraction with

* Anterior lobe only. Apparently the other figures refer to whole
pituitary.

The efects of the injection of pituitary extracts containing
thyrotropic hormone, i. Morphological changes in the thyroid
gland. — The response of the thyroid of different animals to
thyrotropic hormone probably varies widely. A good ex-
ample is the great susceptibility of the guinea pig's gland in
comparison with the insensitivity of the rat's thyroid. With
doses near the threshold, all parts of the gland are not equally
sensitive; in the thyroid of the guinea pig the first and more
pronounced changes due to thyrotropic hormone are observed
in the central part of the thyroid lobes. Compensatory hy-
pertrophy of the thyroid following partial extirpation de-
pends upon the secretion of thyrotropic hormone by the an-
terior pituitary. Albani's recent report (1936) indicated that
in young dogs this may be a very slow process, different from

* The anterior pituitary of the ox contains a higher concentration of thyrotropic
hormone than that of the guinea pig (Emerson, 1937); however, the rat's gland con-
tains 7-9 times as much as that of the ox (McQueen- Williams, 1935).

[181I

THE PITUITARY BODY

the rapid, dramatic changes which can be induced by an-
terior pituitary extract; however, this is hardly proof, as the
author suggests, that the mechanisms involved are differ-
ent. Extracts containing thyrotropic hormone probably facil-
itate the survival and growth of transplants as has again
been reported by Eitel (1936). According to Koch, Schreiber,
and Schreiber (1937), the peripheral growth of a transplant
of the thyroid in the guinea pig is facilitated, if thyroid and
pituitary tissue are transplanted together.

For some years it has been known that the rate of mitotic
division of thyroid epithelium may be greatly increased in a
mammal like the guinea pig, if anterior pituitary extract
(thyrotropic hormone) be injected. An enormous change was
reported by Kippen and Loeb (1935), who injected anterior
pituitary extract into immature guinea pigs and removed the
thyroid gland 48 hours later. In comparison with the normal
thyroid in which was found an average of about 150 mitotic
figures, the thyroid of injected animals contained as many as
190,000 mitotic figures. The effects observed by Bastenie
and Zylberszac (1937) were clear cut but much less pro-
nounced. These authors also injected colchicine (about 0.8
mg. per kg. body-weight) to bring out clearly the action of
thyrotropic hormone on mitotic division. "^ Guinea pigs
weighing 220-250 gm. were used. In thyroid tissue from con-
trol animals 6.3 mitotic figures per 100 follicles were found.
The number increased to 16.8 after the injection of thyro-
tropic hormone. However, if both thyrotropic hormone and
colchicine were injected, 1 19 mitotic figures — in the prophase
for the most part — were found in 100 follicles.

Halpern (1935) investigated the action of anterior pitui-
tary extract or KI on the appearance of the mitochondria
and Golgi apparatus of epithelium of the thyroid of rats
2.5-3 months old.

' Bastenie and Zylberszac mention two interpretations of the manner in which
colchicine acts: it may bring about an increased rate of karyokinesis (Dustin) or it
may arrest karyokinesis before the process is completed (Allen and others).

[ 182]

THE THYROTROPIC HORMONE

2. Physiological^ pharmacological^ and biochemical aspects of
the action of thyrotropic hormone. — The administration of suffi-
ciently large doses of anterior pituitary extract rich in thyro-
tropic hormone into a susceptible animal like the guinea pig
may produce a "syndrome" strikingly resembling Graves's
disease in man. These changes, of course, are prevented by
thyroidectomy. Friedgood's article (1934) contains a discus-
sion of the manner in which symptoms in guinea pigs may
develop in relation to the administration of extract toward
which refractoriness finally appears. The basal metabolic
rate rises at first but later returns to normal, whence re-
crudescences of an elevated rate may appear. The rate is not
necessarily high, although a well-pronounced thyroid hyper-
plasia may persist. Exophthalmos likewise is not necessarily
associated with an increased rate of basal metabolism and
may still be present after a long series of injections. Patho-
logical changes in organs like the heart, kidneys, and liver
are not like those of Graves's disease in man (Heinemann,
1937); however, this is not surprising. A number of authors
have offered evidence indicating that an increased concen-
tration of thyroid hormone is present in the blood after the
gland has been stimulated by thyrotropic hormone. Zunz.
and La Barre (1935) found that the concentration of thyroid
hormone in the serum of dogs is increased 2-4 times only 30
minutes after the injection of 60-80 guinea pig units of
thyrotropic hormone. (Thyroid hormone was estimated by
the method of von Euler and Holmquist.)

Several authors have paid particular attention to the in-
direct effect of thyrotropic hormone on the oxygen-consump-
tion of man and animals under basal conditions after the ad-
ministration of thyrotropic hormone.'" Observations in man

"According to O'Donovan and Collip (1937), pituitary extract may contain a
substance causing an elevation of the basal metabolic rate persisting only a few
hours after injection. The authors concluded that this substance is not thyrotropic
hormone but probably is related to or identical with the melanosome-dispersing
hormone of the pars intermedia and that it accelerates the rate of oxidation of fat.

Kuschinsky (1935) reported that if rats were kept at 4° C, their pituitaries con-

[18^1

THE PITUITARY BODY

have been reported by Lederer (1935), Sylla (1935), Thomp-
son and others (1936), and Scowen (1937). Thompson and
his colleagues found that extracts containing thyrotropic hor-
mone were without action, if thyroid tissue capable of func-
tion was lacking, as in certain patients with marked myxe-
dema. The basal metabolic rate could be raised to normal
(mild or moderate hypothyroidism) or elevated (non-toxic
goiter), sometimes strikingly (exophthalmic goiter). Ap-
parently becavise of the development of "antihormone," the
change induced was only temporary and could not be elicited
by a second course of injections. Sylla listed three therapeutic
uses to which he put an extract containing thyrotropic hor-
mone: (i) to cause complete recovery from pituitary cachex-
ia, (2) to cause a loss of weight in obesity of certain types,
and (3) to inhibit diuresis in a single patient with diabetes
insipidus, as effectively as after the injection of extract of
the posterior lobe. Lederer as well as Scowen has described
the beneficial effects of the treatment of hypothyroidism due
to pituitary insufficiency by the injection of extracts con-
taining thyrotropic hormone. Measurements of the basal
metabolic rate furnished objective proof of the favorable
action of the hormone. Scowen found that much larger doses
of thyrotropic hormone did not affect the basal metabolism
of patients with classical myxedema, whereas the administra-
tion of thyroxine Na caused a prompt response. Presumably

tained about the same amount of thyrotropic hormone in association with histologic
signs of diminished (at first) or increased (later) thyroid function. However, thyro-
tropic hormone might almost disappear from the pituitary of animals with inactive
thyroids because of an environmental temperature of 38°-40° C.

See also the reference to the observation of Riddle and others (pp. 165-66).
Riddle, Smith, and Moran (1935) found that the basal metabolic rate of pigeons is
reduced as a result of hypophysectomy { — 33 per cent at 30° C. or —17 per cent at
20° C). If 10-23 per cent of the gland remained, there was a definite, but
less pronounced, fall.

The hypophysectomized rat adapts itself slightly but very poorly to a cold en-
vironment (Wolf and Creep, 1937). Its body temperature is abnormally low (e.g.,
34°-35?5 C. after 29 days in an environment at 2°-4?5 C). In the thyroids of such
animals is found some colloid absorption at the periphery; the central part of the
gland is atrophic.

1184]

THE THYROTROPIC HORMONE

such patients suffer from a purely "thyrogenic" hypothy-
roidism.

Mahaux (1937) found that the elevation of the basal meta-
bolic rate of guinea pigs, an effect ordinarily appearing about
48 hours after the injection of a large dose of thyrotropic
hormone, was absent if i mg, of thyroxine had been adminis-
tered. (The calorigenic action of thyroxine was allowed to
decay before thyrotropic hormone was administered.) Like-
wise using guinea pigs, Gessler (1936) reported that oestradiol
or its benzoate (5.0 mg.) caused a fall in the basal metabolic
rate of ^-'^J, per cent. The oestrogen also appeared to lessen
the calorigenic action of thyroid extract. Sherwood and
Bowers (1936) stated that the injection of oestrone or oestrin
may lower the basal metabolic rate of rats as much as 28-54
per cent. Also, the return of the rate to normal, after a
marked elevation had been caused by thyroid extract, was
accelerated by the injection of oestrin, Oestrogens appear to
antagonize the action of thyroid hormone, not that of thyro-
tropic hormone as Gessler (1937) suggested. In the dog, ac-
cording to Zajic (1935), the increased metabolic rate follow-
ing the injection of thyrotropic hormone is not accompanied
by any change in the respiratory quotient."

Extracts containing thyrotropic hormone readily cause
exophthalmos in thyroidectomized guinea pigs (Smelser,
1936; Paulson, 1937); therefore, this change cannot be caused
by an increased secretion of thyroid hormone. Smelser even
found that exophthalmos is more readily produced in thy-
roidectomized guinea pigs. He studied anatomically the con-
tents of the orbit in normal animals and those with experi-
mental exophthalmos. The increase in the bulk of the retro-
bulbar tissues amounted to as much as 40 per cent, because
of hypertrophy of the fatty connective tissue, the dorsal
lacrimal gland, the extraocular muscles, etc. As in certain
instances of exophthalmos associated with a low basal meta-
bolic rate in man, a fluid containing lipoid droplets and gran-

" See also O'Donovan (1937) and Sinha (1937).

[185]

THE PITUITARY BODY

Liles as well as lymphocytes was found to infiltrate the orbital
tissues. Paulson particularly described degenerative changes
in the lacrimal glands sometimes associated with similar al-
terations in the extraocular muscles and, occasionally, in
the orbicularis oculi. Altered activity of the sympathetic
nervous system appears not to be a factor (Smelser).

Eitel's observations (1936) are in accord with other views
that the action of thyrotropic hormone does not depend on
peripheral nerves innervating the thyroid. On the other
hand, Uhlenhuth (1937) believed that the effectiveness of
thyrotropic hormone in salamanders or guinea pigs is in-
creased if epinephrine or pilocarpine is also injected; however,
he was not certain that this phenomenon was due to action
on peripheral fibers of the autonomic nervous system. The
experiments of Scharrer and Gaupp (1935) led them to con-
clude that thyrotropic hormone is not secreted by dien-
cephalic "glands" (neurons of the supraoptic and paraven-
tricular nuclei). As a result of hypophysectomy, toads do
not molt. This defect is due to a deficiency of thyrotropic
hormone and is not corrected by the administration of as
many as three diencephalic "glands" rich in colloid.

One aspect of the possible interrelationship of the gonads
and thyrotropic hormone has already been discussed in the
section dealing with the action of thyrotropic hormone on the
gaseous metabolism (p. 185). Certain other aspects of
this interrelationship remain for consideration.'^ Voss (1935)
was able to produce oviposition in the axolotl as many as
three times a year by the injection each time of 1 20 guinea pig
units of thyrotropic extract.'^ In confirmation of Riddle and
Krizenecky, Marza and Blinov (1936) found that the thyroid
of the pigeon appears histologically to be more active at
times of sexual activity and ovulation. According to Chouke,
Friedman, and Loeb (1935), mitotic activity in the guinea

" See chap, iii, pp. 94-95.

'■i Adams and Hilsman had shown that pituitary transplants cause oviposition.

[186I

THE THYROTROPIC HORMONE

pig's thyroid is highest during the ovarian luteal stage and
lowest during the follicular stage. Female thyroids appeared
to be more active than those of male animals. Likewise,
Franck (1937) declared that the injection of oestrone (250-
2,500 international units) into guinea pigs is followed by his-
tological signs of thyroid inactivity. The young male albino
rat was the experimental animal chosen by Amilibia, Men-
dizabal, and Botella-Llusia (1936). They believed that the
daily injection of 200 mouse-units of oestrin ("Progynon")
for 5 days causes the histologic changes commonly described
as characteristic of increased thyroid activity and that this
is due to an effect on the anterior pituitary. Also, they stated
that a stage of thyroid inactivity followed that of activity.'''
According to Cramer and Horning (1938), the injection of
extracts containing thyrotropic hormone prevents the follow-
ing effects of the prolonged administration of oestrin to
mice: (i) the spontaneous development of mammary carci-
noma in a special strain of mice with a high, spontaneous in-
cidence, (2) the development of the mammary gland in male
mice, and (3) alterations of the anterior pituitary, likewise
caused by oestrin, such as marked congestion and disappear-
ance of the oxyphils.

Gehme (1936) concluded that one adrenal cortical extract
("Cortidyn"), but not a second called "Pancortex," prevents
the elevation of basal metabolism due to thyrotropic hor-
mone. However, the histological signs of thyroid stimulation
appeared as usual. The effect observed appeared not to be
due either to ascorbic acid or to tyrosine.

An increased rate at which isolated strips of the auricle
beat can be observed, if guinea pigs receive injections either
of thyroxine or of thyrotropic hormone (Ferrannini, 1936).
From observations of the heart rate in rabbits, Rihl, Oest-
reicher, and Reiss (1936) concluded that the effects of thy-
roxine are strikingly different from those of thyroid hormone

''• The similar injection of progesterone as i Clauberg-unit daily was found to
have no effect.

[187I

THE PITUITARY BODY

secreted in response to the injection of thyrotropic hormone.
After the injection of the latter, the heart rate begins to rise
within an hour and is 30-50 per cent more rapid after 7-9
hours. On the other hand, even after 4 mg. of thyroxine the
heart rate is not significantly changed within a day. The
authors' other comparisons of the effects of repeated doses
appear to be less significant. Page and Sweet (1937) pro-
duced hypertension in dogs by means of Goldblatt's clamp.
After hypophysectomy the blood pressure fell but could be
raised moderately by the daily administration of 0.8 gm. of
desiccated thyroid. The authors suggest that the lack of
thyrotropic hormone following the removal of the hypophy-
sis may account partly for the fall in blood pressure in dogs
with experimental hypertension.

Anderson and Alt (1937) found that the addition of thyro-
tropic hormone to slices of isolated canine thyroid increased
the oxygen-consumption of the tissue 17-120 per cent per
hour during the first 3 hours; a similar change could not be
produced if isolated slices of liver or kidney were used. These
observations confirm the earlier report of Eitel, Krebs, and
Loeser.

Either thyrotropic hormone or thyroid extract brings about
a reduction in the concentration of hepatic glycogen. This
effect appears not to be modified by the administration of KI
(Holden and Thurston, 1935). Another action on carbo-
hydrate metabolism attributed to the thyrotropic hormone is
an increased rate of liberation of insulin in dogs, whether or
not the vagi have been cut (Zunz and La Barre, 1935). Con-
firmatory experiments were performed in non-anesthetized
dogs by Kotchneff and London (1937), who concluded that
the concentration of insulin in the blood may be quadrupled
30 minutes after the injection of extract containing 20-60
units of thyrotropic hormone. There appeared to be no effect
on the rate of liberation of epinephrine. After the repeated
injection of thyrotropic hormone into guinea pigs, the heart
undergoes considerable hypertrophy (about 60 per cent in

[ 188I

THE THYROTROPIC HORMONE

excess of its initial weight); coincidently, the concentration of
glycogen is reduced to about one-fourth its former value
(Lederer, 1935). Both of these effects can be observed after
the basal metabolic rate has returned to normal but are less
pronounced as the rate falls below normal with continued in-
jection of the extract and the probable formation of "anti-
hormone."

The metabolism of proteins or of substances related to pro-
teins is referred to in a few reports.'^ Schonholzer (1937) fed
casein to rats and relied upon the Unna-Pappenheim histo-
logical technic for recognizing protein in the liver. The in-
jection of 100-300 units of thyrotropic extract for 1-7 days
was followed by markedly diminished numbers or almost a
complete absence of the Eiweissschollen (but see also the re-
port of Liang and Wu [1937], who considered that a special
hormone is responsible for such effects). According to Biihler
(1935), thyrotropic hormone, by its action on the thyroid, in-
creases the rate of excretion of creatine and creatinine in the
dog but not in the rabbit. Maloberti (1936) believed that an
increase in the concentration of glutathione in the blood and
certain tissues of the guinea pig parallels the symptoms of
hyperthyroidism provoked by the injection of thyrotropic
hormone. Maloberti's results often were variable and would
be more convincing if he had secured more supporting data.

Pugsley (1935) reported that thyrotropic hormone causes
a fall of approximately 35-50 per cent in the concentration of
serum-cholesterol in both rats and dogs. Injections were
made intraperitioneally, sometimes twice daily for as long as
8-10 days. Only total cholesterol was determined. The effect
could not be produced in one dog after thyroparathyroidec-
tomy. Rothschild and Staub (1935) were not able to detect
any effect of thyrotropic hormone on the lipoids of the blood
of rabbits.

The relationship of the anterior pituitary, the thyrotropic

'5 For reports dealing with the specific dynamic response in patients, see Sylla
(1935) and Mahaux (1936).

[189]

THE PITUITARY BODY

hormone, and the thyroid gland to the metabolism of water
is discussed in chapter x.

In the immature guinea pig the administration of a large
dose of vitamin A (i,8oo units daily for lo days) prevents the
action of 6 guinea pig units of thyrotropic hormone (Fellinger
and Hochstadt, 1936).'^ Elmer, Giedosz, and Scheps (1935)
concluded that both vitamin A and ascorbic acid inhibit the
action of thyrotropic hormone in the guinea pig but are much
less effective than iodide. Vitamin D appeared to be without
action/'^

According to Eitel and Lexer (1936), the healing of bone
fractures in rabbits is facilitated by the administration of
thyrotropic hormone or thyroid extract.'^ Likewise the heal-
ing of wounds in guinea pigs takes place at a faster rate, if
thyrotropic hormone be administered (Eitel and Riecker,
1936). Arsenic (as 0.003-0.3 mg. AS2O3 per kg. rat for 20
days) or CO (as repeated exposure of guinea pigs to an atmos-
phere containing 0.5 per cent CO) was believed to bring about
a reduction in the amount of thyrotropic hormone (Kam-
pelmann, and Kampelmann and Schulze, 1937).

The metabolism of thyrotropic hormone. — Fellinger (1936)
and Bodart and Fellinger (1936) have undertaken the assay
of thyrotropic hormone in the blood of patients. Before the
material was injected, an attempt was made to remove thy-
roid hormone which would be a source of interference with
the assays, as they were performed in guinea pigs. The au-
thors concluded that a positive histological response of the
guinea pig's thyroid can be secured from the thyrotropic hor-

''' 1 he authors do not mention whether or not the presence of iodine in the
vita:nin-A preparation was excluded.

" Demole and Ippen (1935) stated that ascorbic acid can prevent death after a
fatal dose of thyroxine.

The experiments of Loeser and Trikojus (1937) indicated that thyrotropic
hormone does not alter to any important extent the concentration of ascorbic
acid in the liver and the adrenals. The authors found that adrenal hypertrophy
followed the long continued administration of thyrotropic hormone. This effect
was not prevented by the administration of ascorbic acid.

'* See also chap. ii.

[ 190]

THE THYROTROPIC HORMONE

mone in 5-8 cc. of blood. Generally the blood of patients
with hyperthyroidism contained less hormone than normal;
the findings were similar in patients thought to be suffering
from hypothyroidism due to hypofunction of the anterior
pituitary. On the other hand, the concentration of thyro-
tropic hormone in the blood of patients with hypothyroidism
of purely thyroid origin or in that of patients with a pituitary
tumor associated with an elevated basal metabolic rate was
higher than normal. In investigating the thyrotropic hor-
mone of serum, Hertz and Oastler (1936) relied upon an ex-
ceedingly specific test — i.e., the induction of histological
signs of thyroid activity in hypophysectomized rats. Thyro-
tropic hormone was detected in the serum of 9 patients with
myxedema, whereas none could be found in the serum of 5
normal individuals or of 7 patients with hyperthyroidism.
Serum in doses of 1-2 cc. twice daily was administered intra-
muscularly for 5 days.

There is still controversy concerning the excretion of
thyrotropic hormone in the urine. Antognetti and Geriola
(1936) could secure no convincing evidence that thyrotropic
hormone can be extracted from the urine of normal persons
or of patients with Graves's disease or myxedema, whether
spontaneous or resulting from thyroidectomy. In the work of
Hertz and Oastler referred to in the preceding paragraph the
detection of thyrotropic hormone in urine was also under-
taken. The authors usually injected 5 cc. of urine twice daily
for 5 days by an intramuscular route into hypophysec-
tomized male rats. Thyrotropic hormone could be detected
in the urine of patients with myxedema, whereas none could
be found in the urine of patients with hyperthyroidism or in
that of normal persons. Nitescu and Timu§ (1938) agree
that the hormone cannot be found in normal urine or in urine
of patients with Graves's disease; however, they did detect
thyrotropic hormone in the urine of an acromegalic with
symptoms of hyperthyroidism. Grumbrecht (1935) believed
that the urine of women past the menopause contains thyro-

[191]

THE PITUITARY BODY

tropic hormone; he performed assays in the rabbit by in-
jecting the extract of urine intravenously.

Goiter was produced by Remington (1937) in rats by feed-
ing a diet containing too little iodine. The effects of thyro-
tropic hormone were no less difficult to elicit in such rats than
in normal rats. On the other hand, thyroids of rats, goitrous
for unknown reasons, were found by Anderson and Collip to
be abnormally sensitive to the thyrotropic action of anterior
pituitary extract.

The effects of iodides will be considered in this section.
Friedgood (1936) reported that the administration of sodium
iodide caused a remission of the symptoms of hyperthyroidism
in guinea pigs receiving anterior pituitary extract. He con-
cluded that the remission resembled that produced in human
beings with exophthalmic goiter or with the hyperthyroidism
of early acromegaly. Weil and Bernheim (1936) made auto-
transplants of the thyroid after total thyroidectomy in the
guinea pig. The effect of 70-400 units of thyrotropic hor-
mone, indicated by histological signs of stimulation of the
thyroid, could be antagonized by the administration of KI;
however, a much greater antagonistic action was produced
by thyroxine and, to a less extent, by diiodotyrosine. The re-
sults of Anderson and Evans (1937) were different from those
of the authors just cited. Anderson and Evans concluded that
the coincident administration of KI does not interfere with
the production of thyroid hyperplasia by thyrotropic hor-
mone but that the iodide prevents the liberation of thyroid
hormone into the blood, so that a calorigenic effect does not
appear. This conclusion was based on experiments in normal
guinea pigs and hypophysectomized rats.'^

Extracts containing thyrotropic hormone in relation to anti-
hormone effects. — Some authors believe that a small amount
of antithyrotropic substance is present in normal serum

■' See also Franck's interpretation (1937) of histological changes in the pituitary
after the injection of anterior pituitary extract with or without Lugol's solution or
diiodotryosine.

[192]

THE THYROTROPIC HORMONE

(Herold, 1934; Scowen and Spence, 1936); however, this ap-
pears doubtful and was not confirmed by Rowlands and
Parkes (1936). Various investigators^" have experienced no
difficulty in confirming earlier experiments on the production
of thyrotropic antihormone; even with the best extracts
available, repeated injections soon appear to lose their
thyroid-stimulating properties, as is shown by the absence of
anatomical signs of thyroid stimulation and of physiological
changes, such as an increased basal metabolic rate due to the
increased liberation of thyroid hormone. The serum of blood
removed at this time prevents the thyrotropic action of an-
terior pituitary extract. Sometimes the antihormone effect
appears to be specific for the animal species furnishing the
pituitary tissue from which the extract was made (Eichbaum
and Kindermann, 1936; Gudet, 1937); in other experiments,
as in those of Thompson (1937), there seems to be no species
specificity, and the serum alone seems to cause atrophic
changes in the thyroid which resemble the condition follow-
ing hypophysectomy. An intermediate phenomenon was de-
scribed by Gudet, who concluded that species specificity is
present after a short course of injections but not after a long
course. A later report by Eichbaum and others (1937) sug-
gested that two types of antibody are formed — one character-
istic of the proteins of the species, the other characteristic of
thyrotropic hormone.

Loeser (1936) has confirmed earlier experiments indicating
that hypophysectomy does not interfere with the formation
of thyrotropic antihormone. He continues to affirm (Eitel
and Loeser, 1935; and Loeser, 1936) that the presence of the
thyroid gland greatly facilitates the formation of antihor-
mone; but this is improbable and could not be confirmed
either by Gudet (1936) or by Chou (1937).

Gkkels' experiments (1937) likewise indicate that tissues

^° Extracts with thyrotropic effects were used in a number of the experiments
discussed in chap. iii.

[ 193 ]

THE PITUITARY BODY

other than the thyroid are sources of antihormone and that
the neutrahzation of thyrotropic hormone does not occur in
the thyroid. After anterior pituitary extract had been in-
jected into rabbits for i months and the thyroid was then re-
fractory toward further treatment, the gland was removed
and, presumably still living, was perfused by the Carrel-
Lindbergh technic with normal serum containing anterior
pituitary extract. Thyroid-stimulating effects could be ob-
served within 24 hours. In other experiments the author was
surprised by the fact that a large volume of rabbit serum con-
taining antihormone only partially neutralized the thyro-
tropic action of anterior pituitary extract with which it was
mixed. The mixture was perfused through the isolated thy-
roid of the normal rabbit.

Werner's experiments (1936) strongly support the view
that thyrotropic antihormone is an artifact characteristic of
relatively crude anterior pituitary extracts. Equivalent doses
(in terms of weight of crude gland) of extract of the beef
anterior pituitary were injected into guinea pigs and led to
the following conclusions: (i) whether or not antihormone is
produced depends on the type of extract not on its potency,
(2) it may be possible to produce antihormone by doses of ex-
tract without thyroid-stimulating effects, (3) the thyroids of
animals completely refractory to one extract may be readily
stimulated by the other — yet both were obtained from ox
pituitary — and (4) an extract may cause the formation of no
antihormone in the majority of animals even after injection
for nearly 3 months. As a basis for these conclusions the
author relied upon the basal metabolic rate and the histology
and total iodine-content of the thyroid.

The assay of thyrotropic hormone. — Among mammals no
animal is as convenient for the assay of thyrotropic hormone
as the immature guinea pig. The histological signs of thyroid
stimulation — vacuolization of the colloid, hypertrophy, and
later, hyperplasia (increased mitotic division) of the epithe-

[ 194]

THE THYROTROPIC HORMONE

Hal cells — were first investigated by Aron and Loeb^' and
have been extensively used as a means of assay. According
to Wilcke (1935), fixation is of great importance, if an at-
tempt is made to grade the histologic effects by the plan of
Heyl and Laqueur; Wilcke recommended 10 per cent forma-
lin as a fixative. The production of thyroid hypertrophy as a
means of assay (Rowlands and Parkes) is more objective but
requires much larger doses of hormone. There is no confirma-
tory evidence to support the contention of Heyl and Laqueur
that a different principle is responsible for hypertrophy.

Smelser (1937) recommended the use of day-old White Leg-
horn chicks. His practice was to divide the total dose into
five daily injections and to perform the necropsy 24 hours
after the last injection, when the thyroid lobes were dissected
out under a binocular microscope. The method was found to
be more sensitive than a similar technic applied in guinea pigs.

Other methods which may be sensitive are either incon-
venient or are difficult to evaluate. For example, the decrease
in the total amount of iodine in the thyroid of chicks or
guinea pigs as a result of thyroid stimulation is a method sug-
gested by Cuyler, Stimmel, and McCuUagh (1936) and Stim-
mel, McCullagh, and Picha (1936). Atwell (1935) recom-
mended the hypophysectomized tadpole as a very sensitive
biological indicator; the prominent change which occurs if
thyrotropic (or thyroid) extract is administered is meta-
morphosis. Collip and his collaborators have frequently de-
tected the presence of thyrotropic hormone by its calorigenic
action in hypophysectomized rats.

The chemistry of thyrotropic hormone. — Thyrotropic hor-
mone is available only as an impure extract. It is a heat-
sensitive substance which, like other anterior pituitary hor-
mones, appears to belong to the group of proteins. Readers
interested in a new report on the preparation of extract are
referred to the article of Lambie and Trikojus (1937). There

''The following are late reports by these authors: Kippen and Loeb (1935)
and Aron (1936).

[195]

THE PITUITARY BODY

are no new experimental data enabling us to decide whether
or not thyroid stimulation in amphibian larvae is due to a
principle different from that stimulating the mammalian
thyroid.

SUMMARY

The recent investigations of the various aspects of the
biology of the thyrotropic hormone have yielded a disap-
pointingly small crop of new facts. Much of the effort has
been expended in consolidating or extending slightly knowl-
edge which was already available.

Probably there is general agreement on the principal func-
tions of the thyrotropic hormone. Its importance is great in
nearly all classes of vertebrates — i.e., to insure normal thy-
roid function, especially the discharge of thyroid secretion.
Unless thyroid hormone is actually liberated from the gland,
various striking effects occur in cold-blooded animals — i.e.,
the metamorphosis of tadpoles cannot take place; in both
urodele and anuran amphibia molting or the desquamation
of cornified epidermis is absent; on the other hand, in reptiles
molting may either be accelerated or take place less fre-
quently. In both classes of animals, as in mammals, the rate
of heat-production is abnormally slow and cannot be adapted
readily to the demands of the environment. Atrophy of the
thyroid gland may or may not rapidly appear after hypophy-
sectomy. The invariable effect of the operation is to pro-
duce all the histological signs of inactivity of the thyroid,
such as the accumulation of densely staining colloid in vesi-
cles lined by flat epithelium, together with physiological evi-
dences of thyroid deficiency, such as a low rate of metabolism.

Changes in the opposite direction are readily produced by
the injection of extracts of the anterior pituitary. The colloid
becomes vacuolated and may almost disappear. The epithe-
lium, now active, is cuboidal or columnar and begins to pro-
liferate. Animals of various classes exhibit changes de-
pendent upon thyroid secretion. Metamorphosis can be pro-

[196]

THE THYROTROPIC HORMONE

duced in hypophysectomized anuran larvae. x'\dult amphibia,
subjected to the same operation, shed the accumulated layers
of cornified epidermis. Heat-production is raised to normal
or can be elevated above normal.

These facts have led to efforts to attribute deficiency or
hyperfunction of the thyroid in man to a deficient or ab-
normally rapid rate of secretion of thyrotropic hormone.
Such an explanation, it appears, may be of value in unravel-
ing the genesis of certain types of hyperthyroidism in man.
The hyperthyroidism associated with acromegaly probably
is the result of the secretion of excessive amounts of thyro-
tropic hormone. On the other hand, thyroid deficiency in
man less often seems to depend upon a disturbance of the
anterior pituitary.

The effects of anterior pituitary extracts containing thyro-
tropic hormone have been studied extensively in mammals.
Occasionally all the histological signs of thyroid stimulation
are present without the expected general physiological
changes, such as an elevated basal metabolic rate. Usually,
however, the phenomena are associated. Under suitable con-
ditions thyroid hormone is found to be liberated within a few
hours or less following the injection of thyrotropic extract and
acts more rapidly than its essential fraction, thyroxine, x-^n-
tagonistic substances such as oestrogens, thyroxine, iodides,
etc., appear to act in a variety of ways. Sometimes the action
is peripheral to the thyroid; at other times the thyroid itself
or the interaction between thyrotropic hormone and the
thyroid appears to be affected.

Thyrotropic extracts contain both the hormone and other
substances. If such extracts are repeatedly injected, "anti-
hormone" may be produced. This phenomenon has not been
shown to be of physiological importance.

Exophthalmos can be produced by the injection of anterior
pituitary extract into normal or thyroidectomized animals.
It is not known whether or not thyrotropic hormone is re-
sponsible for its appearance.

i 197]

CHAPTER VII

THE INTERRELATIONSHIP BETWEEN THE PARS
GLANDULARIS AND THE ADRENAL GLANDS;
THE INFLUENCE OF THE PARS GLANDULARIS
ON THE METABOLISM OF CARBOHYDRATES,
LIPOIDS, PROTEINS, AND MINERALS (WITH RE-
MARKS ON THE PITUITARY-PARATHYROID IN-
TERRELATIONSHIP)

NUMEROUS interrelationships between the anterior
pituitary and the adrenal glands have been sug-
gested or investigated in almost every field of in-
terest to the endocrinologist. Much of this work is discussed
elsewhere and, for complete references, the reader is referred
to the Index. The review in this section will be principally
confined to a discussion of the part taken by the anterior
pituitary in preserving the function of the adrenal cortex as
demonstrated by the morphology of that structure. The
important interrelationships affecting the metabolism of car-
bohydrates and fats are taken up in the sections dealing with
the metabolism of these foodstuffs.

It is well known that the cortex of the adrenal glands
undergoes a pronounced atrophy after hypophysectomy,
whereas the medulla is affected scarcely at all. Likewise ex-
tracts of the anterior pituitary affect the cortex chiefly, if not
entirely. Therefore, almost all the discussion will refer to the
adrenal cortex.

New observations oyi the effects of hypophysectomy or of an-
terior pituitary extract^ on the morphology of the adrenal glands.
— Adrenal cortical stimulating hormone is probably as wide-

' No short, unobjectionable term to describe the hypothetical adrenal cortical
stimulating hormone has been devised. Such terms as "adrenotropic" and "corti-
cotropic" are undesirable from an etymological standpoint.

I 198]

PARS GLANDULARIS AND ADRENAL GLANDS

ly distributed as other hormones of the anterior pituitary.
Leonard (1937) concluded that it is present in the pituitary
of the fowl. ^According to the assays of McQueen-Williams
(1935) in rats, the anterior pituitary of the ox contains a
higher concentration of adrenal cortical stimulating hormone
than that of the rat. The author's preliminary experiments
indicated that the removal of both adrenal glands is followed
by an increase in the amount of the hormone in the pitui-
tary.

Extracts of the anterior pituitary readily cause enlarge-
ment of the adrenal glands of normal or hypophysectomized
animals chiefly by bringing about hypertrophy of the cortex.
The effects of extracts in normal animals are, of course,
difficult to evaluate accurately because the pituitary is in-
tact. Among such observations are those of Bierring (1935),
Friedgood (1936), and Latyszewski (1937) who used rats,
guinea pigs, and rabbits. Bierring, who injected crude an-
terior pituitary extract into rats — sometimes for months —
considered that the important effect is on the zona glomer-
ulosa but that the three cortical zones were more clearly
demarcated in the treated animals. Some of Moon's observa-
tions (1937) also were made in normal rats. He reported that
cells of the glomerular and fasciculate zones underwent both
hypertrophy and hyperplasia after the injection of extract.
In the guinea pig, according to Friedgood, the left adrenal
undergoes more hypertrophy than the right. Latyszewski
did not feel convinced that the changes he observed in the
guinea pig and rabbit after the injection of extract were
specific or easily reproducible. The principal effects he de-
scribed were in the zona fasciculata and consisted of the loss
of lipoids and cellular hypertrophy affecting both the proto-
plasm and the nuclei.

The effects of extracts in hypophysectomized animals are
more easily analyzed, because normally secreted cortical-
stimulating hormone is not an unknown and therefore con-

[ 199]

THE PITUITARY BODY

fusing factor.^ Davidson (1937) produced a marked hyper-
trophy of the adrenal glands in hypophysectomized rats by
injecting anterior pituitary extract. He concluded that the
cortical enlargement was due to cellular hypertrophy, not
hyperplasia. The histological appearance of the cortical
lipoids has received the special attention of Reiss and others
(1936) and of Moon (1937). In normal rats there exists a
narrow band of tissue between the zone fasciculata and the
zona glomerulosa, which histologically appears to contain
little or no lipoid. Deposition of lipoids in the cells of this
band is one of the earliest signs of a cortical-stimulating effect
(Moon). After hypophysectomy the outer part of the zona
fasciculata'' rapidly loses its lipoids, which are specifically
restored by the injection of pituitary extract containing
adrenal cortical stimulating hormone (Reiss and others;
Moon).

The development of the "X-zone" of the mouse adrenal,
located as a central fringe of the cortex, appears to depend
on sex, inasmuch as it is found in immature or young female
mice, whereas it fails to develop in male mice unless castra-
tion is performed. Deanesly (1938) suggested that the de-
velopment of the X-zone probably depends upon a secretion
of the anterior pituitary. She found that the castration of
mice with hereditary dwarfism and with partial pituitary de-
ficiency is not followed by the development of an X-zone.

^ Cutuly (1936) studied quantitatively the morphology of the adrenal glands of
rats 30 days after hypophysectomy. At death, the male rats weighed an average of
166 gm., the female rats, 139 gm. Atrophy appeared to be due solely to cortical
shrinkage and was relatively greater in female rats. His results were as follows (the
figures refer to the mean of the calculated weights in milligrams):

Part

Sex

Normal rats

Operated controls

Hypophysectomized rats .

* Differences in weight not statistically significant.

3 Moon's Fig. 3 indicates that this does not represent a widening of the lipoid-
free band of normal animals.

[ 200 ]

PARS GLANDULARIS AND ADRENAL GLANDS

Lacassagne and Raynaud (1937) stated that, although oes-
trone or oestradiol do not disturb the development of the
X-zone, these oestrogens do cause regressive changes in the
adrenals, e.g., loss of lipoids. The regressive changes were
attributed to an interference with pituitary secretion.

Several reports on the morphology of the adrenal cortex
in relation to the pars glandularis also mention the medulla.
In Cutuly's quantitative morphological study (1936) of the
adrenals of normal and hypophysectomized rats of both
sexes the mean weight of the medulla of operated rats was
less than that of control animals. However, the difference
was not statistically significant. Davidson (1937) stated
that after the injection of adrenal cortical stimulating ex-
tract into hypophysectomized rats the medulla appeared
more normal. Specifically, he mentioned the absence of vac-
uoles, which sometimes appeared in the adrenal medulla of
operated, non-treated rats. Normal rats received daily in-
jections of a crude anterior pituitary extract for as long as
9 months in the experiments of Bierring (1935). He reported
that the medulla appeared hyperplastic and that enlarged
chromaffin cells were crowded with granules. The changes
observed by this author are the reverse of those attributed by
Anselmino and Hoffmann to medulla-stimulating ("adreno-
tropic") hormone. The observations do not offer convincing
evidence that the pars glandularis has an important influence
on the morphology of the adrenal medulla.

Physiological and pharmacological correlations. — Grollman
and Firor (1935) used several methods to produce chronic
adrenal insufficiency in rats, cats, and dogs. They concluded
that if no attempt was made to treat the cortical deficiency
for a considerable time, adrenal cortical extract could not
cause a resumption of growth, a reappearance of normal sex-
ual performance, or the maintenance of a normal body-tem-
perature. The lack of benefit of adrenal cortical hormone
under such conditions was attributed to irreparable damage
of the pars glandularis; for anterior pituitary extract repaired

[201 ]

THE PITUITARY BODY

the defects. Early treatment by cortical hormone prevented
pituitary damage, i.e., the defects of growth, gonadal func-
tion, and metabolism did not appear. In the experiments of
Gaunt, Remington, and Schweizer the metabolism of water
after the intraperitoneal injection of isotonic glucose solution
was investigated. xAt least in respect of the ease with which
"water intoxication" was produced or ameliorated or pre-
vented by cortical extract, it appeared that hypophysecto-
mized rats suffered from a deficiency of adrenal cortical hor-
mone.

All recent work indicates that thyroidectomy interferes
neither with the release of adrenal cortical stimulating hor-
mone from the pituitary nor with the peripheral action of the
hormone. Cortical-stimulating hormone produces about the
same adrenal hypertrophy and increased accumulation of
osmiophilic material in the cortical cells of tadpoles, whether
or not the thyroid is present (Atwell, 1937). Thyroidectomy
appears not to affect the adrenal-stimulating effects of an-
terior pituitary extract in guinea pigs (Jores and Boecker,
1937).'^ Compensatory hypertrophy of an adrenal gland after
the removal of its mate depends upon the liberation of
adrenal cortical stimulating hormone from the pituitary;
however, thyroidectomy does not interfere with this phe-
nomenon in the male rat (Winter and Emery, i936).5

^ These authors found that adrenal hypertrophy following the administration of
thyroxine was associated with a loss of lipoids from the cortex. This effect, of course,
is the reverse of that considered to be typical of adrenal cortical stimulating hor-
mone.

5 These authors found that gonadectomy does not interfere with compensatory
adrenal hypertrophy in rats of either sex. If both adrenals are intact, castration is
followed by adrenal hypertrophy, spaying by adrenal atrophy.

Elmer, Giedosz, and Scheps (1937) concluded that thyrotropic hormone
played the important part in the adrenal hypertrophy which follows the administra-
tion of acid extract of the anterior pituitary, because the effect was prevented by the
administration of iodide. Friedgood (1936) also administered iodides and alkaline
anterior pituitary extract to guinea pigs and found that adrenal hypertrophy
and splenomegaly were less pronounced or even absent. However, Friedgood did
not feel that the h pothe-is that thyrotropic hormone is responsible for the cortical-
stimulating effects of pituitary extract is warranted.

[ 202 ]

PARS GLANDULARIS AND ADRENAL GLANDS

Perla (1935-36) and Perla and Rosen (1935) have re-
ported new experiments indicating that the increased toxicity
of histamine in hypophysectomized rats is due to a deficiency
of adrenal cortical hormone resulting from the absence of
cortical-stimulating hormone. According to Selye and Collip
(1936), large doses of oestrone or the administration of for-
maldehyde bring about hypertrophy of the adrenal cortex of
the rat. These changes appear to be due to the increased
liberation of adrenal cortical stimulating hormone, because
they cannot be produced in hypophysectomized rats.

Some aspects of the metabolism oj adrenal cortical stimulating
hormone. — Several authors have shown that the pars glandu-
laris must be intact if compensatory hypertrophy of an
adrenal is to take place after the other has been removed.
Reiss, Balint, and Aronson (1936) found that compensatory
hypertrophy amounts to about 95 per cent if partial hypo-
physectomy has been performed, whereas in normal animals
the compensatory hypertrophy is only 20 per cent. Ap-
parently operative trauma is followed by changes facilitating
the formation or liberation of adrenal cortical stimulating
hormone. The adrenal cortices of the female rat are con-
siderably larger than those of the male. This suggests that
the female pituitary liberates more cortical-stimulating hor-
mone than the male. This hypothesis was tested by Wyman
and tum Suden (1937) by determining the survival of homo-
transplants. Regeneration of such transplants occurred in
71 per cent of female recipients but in only 20 per cent of
male recipients. The sex of the donor appeared not to affect
the results. These authors also showed (1937) that the suc-
cessful transplantation of the adrenal requires pituitary se-
cretion. The adrenal of the hypophysectomized rat can be
successfully transplanted into a normal rat. Regeneration of
a transplant is particularly favored by adrenal insufficiency
(Wyman and tum Suden, Ingle and Higgins), probably be-
cause the rate of formation and liberation of cortical-stimu-

203

THE PITUITARY BODY

lating hormone is accelerated.^ On the other hand, the rate
of secretion of cortical-stimulating hormone is so diminished
as a result of the administration of adrenal cortical extract
that cortical atrophy appears but can be prevented, if cor-
tical-stimulating extract be simultaneously administered
(Ingle and Kendall, 1937).

In human beings with increased intracranial tension, usu-
ally the result of primary cerebral tumors, Kraus (1937) ob-
served a hyperplasia of the pars glandularis associated with
a similar change in the cortex of the adrenal glands, including
an increased accumulation of lipoids.^ Kraus believed that
the cortical hyperplasia was due to an increased secretion of
adrenal cortical stimulating hormone by the anterior pitui-
tary and described the phenomena as "corticotropic hyper-
pituitarism." He pointed out that cortical atrophy occurs in
the pituitary cachexia of Simmonds. The reports of Giordano
and Zeglio (1936) were available only in the form of ab-
stracts. These authors reported that adrenal cortical stimu-
lating hormone, recognized by its effect on the adrenal of the
guinea pig, can be extracted from the urine of patients with
hypertension. They believed that effects of urinary extracts
on the adrenal medulla could be detected but were less im-
portant.

The chemistry and assay of adrenal cortical stimulating hor-
mone.— Little is known concerning the chemistry of cortical-
stimulating hormone. Although incidental observations on
the extraction and some properties of potent extracts are
mentioned in several reports, it appears that little is to be
gained from a review at this time. One method of extraction
which should be cited is that of Moon (1937), who reported
that by Lyons' method of preparing lactogenic extract the
material which is insoluble at pH 6.5 is rich in cortical-stim-
ulating hormone. Extract rich in lactogenic hormone is, by
this method of extraction, least soluble at pH ^.1^.

* See also McQueen- Williams (1935).

? The weight of the adrenal glands was 30-40 per cent greater than normal.

[204I

PARS GLANDULARIS AND ADRENAL GLANDS

The methods which have been used for the assay of adrenal
cortical stimulating extract have received no careful quanti-
tative study. LInquestionably, hypophysectomized animals
should be used, if there is to be the least possible doubt as
to the specificity of the effects. Reiss and others (1936),
Collip (1937), and Moon (1937) have all used hypophysec-
tomized rats for assay and usually have relied upon both the
gross change — hypertrophy — and microscopic evidences of
repair — especially the reappearance of lipoids distributed
generally. Methods based upon the use of normal mice or
rats have been described by Jores and Beck (1936) and by
Moon (1937).

THE METABOLISM OF CARBOHYDRATES IN RELATION
TO THE PARS GLANDULARIS

Great interest in the importance of the pituitary body in
carbohydrate metabolism was aroused by Houssay and
Biasotti, who discovered that the course of diabetes following
pancreatectomy in the dog is greatly ameliorated by re-
moval of the hypophysis. Without doubt the extirpation of
the pars glandularis is responsible for this change. The prob-
lem, in general terms, is: How and to what extent is the
metabolism of carbohydrates regulated by the pars glandu-
laris? Numerous aspects of this problem have been studied,
especially since 1934. However, it will be seen that our
knowledge of the mechanisms in operation is still regrettably
limited.

The metabolism of carbohydrates after h\poph\sectomv. —
Previous work had demonstrated several important changes
consequent to hypophysectomy — i.e., the blood sugar of fast-
ing animals falls to abnormally low levels; the sensitivity
toward insulin is greatly increased; the regulation both of the
absorption of glucose and of the formation and degradation
of glycogen is disturbed.

If animals are fed adequate amounts of carbohydrate, the
concentration of sugar in the blood is not strikingly different

[205]

THE PITUITARY BODY

in hypophysectomized animals from that in normal animals.
Shortly after food is withheld, however, a marked hypo-
glycemia appears in successfully operated animals. For ex-
ample, Russell (1936) found that the concentration of sugar
in the blood of young male rats, 3-4 weeks after hypophysec-
tomy, was reduced approximately 50 per cent after a fast of 8
hours, whereas the reduction occurring in normal rats was
only 20 per cent. If the fast was continued for 10 hours longer
(total 18 hours) a greater change then occurred in normal

0 NORMAL

1 HYPOPHYSECTOMIZED

■ 1 1 1 ' I M '

!0 I 30 I -^0 I so I 60

J_l

»0 I 90 I 100 I IIP I 120 I 130 I HO | 150

BLOOO SUGAR MG. PER lOOCC.OF BLOOD

Fig. 23. — The concentrations of sugar in the blood of normal and hypophysecto-
mized monkeys in relation to their frequency. The monkeys were first starved i6-
18 hours. (From Smith, Dotti, Tyndale, and Engle, Proc. Soc. Exp. Biol. Med., 34,

247-49 [1936].)

rats (total reduction, 32 per cent) than in hypophysecto-
mized animals (total reduction, 54 per cent). The results of
the withdrawal of food are similar in the rabbit (Cope, 1937)
and monkey (Smith and others, 1936). Figure 23 illustrates
the distribution of concentrations of sugar in the blood of
normal and hypophysectomized monkeys, as determined by
Smith, Dotti, Tyndale, and Engle after the animals had been
fasted for 16-18 hours. The concentration of sugar in the
blood of partially hypophysectomized monkeys was found
to lie (87 + 2.7^ mg. per cent) between that of normal
monkeys (iio + 2.0^ mg. per cent) and that of hypophysec-

' Standard error of the mean.

206

PARS GLANDULARIS AND METABOLISM

tomized monkeys (59 + 3.1^ mg. per cent).' The reasons
for the precipitate diminution of the sugar of the blood of
hypophysectomized animals as a result of fasting will be dis-
cussed later.

The rate at which glucose is absorbed from the digestive
tract by hypophysectomized animals is abnormally slow, as
was first demonstrated by Phillips and Robb in rats. Ben-
nett (1936), Fisher and Pencharz (1936), Russell (1937), and
Russell and Bennett (1937) all used rats and agree with the
conclusion of Phillips and Robb. According to Bennett, the
amount of glucose absorbed in an arbitrary period is about
2^ per cent less in hypophysectomized than in normal rats.
Russell and Cori (1937) reported that the tolerance for intra-
venously injected glucose is reduced in hypophysectomized
rats to the same extent that oxygen-consumption suffers a
reduction.'" The renal threshold of glucose was found to be
abnormally high in operated rats. Russell and Bennett
found that as early as 24 hours after hypophysectomy,"
fasting is followed by an abnormally rapid decrease in the
concentration of glucose in the blood and of glycogen in the
liver and striated muscle. If such animals are then fed, the
return of these carbohydrates to normal levels is abnormally
slow, principally because the reserves are abnormally low
and because the absorption of glucose is abnormally slow.

'Scott (1937) investigated the concentration of lactic acid in the blood of
normal and hypophysectomized monkeys and obtained high values, which she
attributed to muscular activity which was beyond her control. Blood obtained from
the heart of normal monkeys contained 104 ± 6.5 mg. per cent of lactic acid, whereas
similar blood of hypophysectomized monkeys contained 37 + 4.5 mg. per cent.

See the article of Marenzi (1936) for an account of the changes in, and the
effects of pituitary (extracts) on, the following constituents of striated muscle of the
toad after hypophysectomy: glycogen, inorganic P, phosphocreatine, glutathione,
and lactic acid.

'" There are few new data on changes in glucose-tolerance as a result of hy-
pophysectomy. For example, Slome (1936) found that glucose- tolerance is increased
after hypophysectomv in the toad, Xenopus laevis. There are other references in the
text.

" Inanition or brain injury or the absence of the pars neuralis was not responsible
for the change.

[207]

THE PITUITARY BODY

After hypophysectomy, rats continue to oxidize glucose
readily. In fact, when such animals depend upon their own
reserves of foodstuffs, as in fasting, they depend to an un-
usual extent on carbohydrate-oxidation for their energy re-
quirements (Fisher and Pencharz, 1936). Fisher and Pen-
charz also found that if hypophysectomized rats are fed glu-
cose, they oxidize more carbohydrate to supply energy than
do normal rats, despite the fact that the rate of oxygen-
consumption and of absorption of glucose is lower after
hypophysectomy.'^ A high-fat diet prior to glucose feeding
appeared to lessen the oxidation of glucose only slightly.
Greeley (1935) attempted to determine the rate of utilization
of glucose by hypophysectomized rabbits at the time of maxi-
mum need during fasting. He considered that such a need
occurred 5-8 hours after a drop in blood sugar appeared
(11-32 hours of fast) in fasting hypophysectomized rabbits.
He concluded that at least 0.50-0.67 gm. of glucose per kg.
body-weight per hour is required by an intravenous route,
if the blood sugar is to be maintained near (usually below)
the normallevel. Russell (1937) investigated the action of thy-
roxine on the metabolism of glucose by hypophysectomized
rats. From comparisons with operated animals receiving glu-
cose alone, she concluded that thyroxine causes an increase
in the rate of absorption of glucose and in the rate of oxida-
tion of glucose, roughly proportional to the increase in oxygen
consumption caused by the hormone.

According to Weichselbaum, Heinbecker, and Somogyi
(1937), tolerance toward glucose is improved in hypophysec-
tomized dogs by a high-carbohydrate diet compared with a
high-fat diet. The diets did not uniformly cause this sort of
a difference in normal dogs. These authors also found
(Somogyi, Weichselbaum, and Heinbecker, 1937) that hyper-
glycemia following hypoglycemia due to the administration

'- During the first 4 hours after the feeding of glucose, normal rats might oxidize
I44 mg. of the sugar per 100 gm. body-weight in comparison with 190 mg. per
100 gm. bodv-weight in hypophysectomized rats.

[208I

PARS GLANDULARIS AND METABOLISM

of either glucose or insulin appeared both in normal and
in hypophysectomized dogs.

Abnormalities in the deposition and degradation of glyco-
gen in hypophysectomized animals have already been re-
ferred to briefly. Bennett (1936) as well as Russell (1936)
determined the concentration of sugar in the blood and of
glycogen in the liver and striated muscle of normal and hy-
pophysectomized rats under various conditions. After a fast
of 8 hours, the operated rats metabolized much more of the
glycogen of the liver (95 per cent compared with 27 per cent
in normal rats) and of striated muscle (24 per cent compared
with 8 per cent). If the fast was prolonged to 18 hours, both
normal and operated animals had consumed most of the
hepatic glycogen, whereas a further loss of muscle glycogen
occurred only in hypophysectomized rats. These observa-
tions were made by Russell, who also reported that the chief
abnormality found in hypophysectomized rats fed 2 gm.
of starch within 8 hours after a fast of 18 hours was a low
concentration of glycogen in the liver. Likewise, after the
feeding of glucose, partly because of slow absorption, hy-
pophysectomized rats restore the glycogen of the liver and
striated muscle only slightly (Bennett). Bennett's results
are summarized in Table 6. His calculations of the propor-
tion of absorbed glucose converted into glycogen indicated
that the percentage so converted is much higher in normal
animals — especially in respect of hepatic glycogen. Cope
( 1 937) has reported further experiments in rabbits from which
he concluded that hypophysectomy interferes with the endog-
enous formation of carbohydrate and that when hepatic
glycogen is exhausted, the concentration of sugar in the blood
rapidly falls to levels associated with the onset of convulsions
so that the animal, in this respect, behaves like a hepatecto-
mized animal. In the hypophysectomized animal the hepatic
glycogen appears to be only of exogenous origin. According
to Soskin and others (1935), the hypophysectomized dog,

[209]

THE PITUITARY BODY

unlike the normal, cannot form carbohydrate from fat/^
Ketonuria does not appear readily in hypophysectomized-
depancreatized dogs even in the presence of hyperglycemia
and glycosuria. The authors concluded that glucose can be
endogenously derived only from carbohydrate and protein
after hypophysectomy. Crandall and Cherry (1937) likewise

TABLE 6

Carbohydrate Metabolism in Normal and in

HVPOPHYSECTOMIZED RaTS*

Glucose
Absorbed

Glucose
IN Blood

Glycogen in

All Rats Fasted for 24 Hours

Liver

Striated
Muscle

Mg.per 100
Gm. Body-
Weight in
2 Hours

Mg. Per

Cent

Mg. Per
Cent

Normal

140
I 1 I

1,348
194

50a
322

Hypophysectomized

After administration of 2.5 cc. 35 per cent
glucose to normal

After similar treatment of hypophysecto-
mized

412

247

673
378

* From Bennett, Proc. Soc. Exp. Biol. Med., 34, 277-79 (1936).

performed experiments with dogs and believed that their re-
sults indicated that the formation of glucose from one amino-
acid, glycine, is not prevented by hypophysectomy. The
technic of their experiments is described in the section
dealing with the effects of insulin.'^

The recent experimental work so far reviewed, as well as

'i However, even in normal dogs, it is not generally believed that proof of the
formation of carbohydrate from fat, other than glycerol, is available.

'■•According to Schott, Samuels, and Ball (1937), the Walker tumor No. 256
in male rats contains significantly more glyocgen (but grows more slowly) in hy-
pophysectomized than in normal rats. The amount of glycogen in the tumor of rats
was: (i) 4 hours after feeding: normal, 0.026 per cent; hypophysectomized, 0.046
per cent, and (2) on high caloric diet: normal, 0.058 per cent; hypophysectomized,
0.186 per cent.

[210]

PARS GLANDULARIS AND METABOLISM

previous work, indicates that hypophysectomy leads to the
following changes in the metabolism of carbohydrates.'^

1. The rate of absorption of glucose is abnormally slow.

2. Fasting leads to an abnormally rapid utilization of glycogen both of
the liver and of striated muscle. The more labile hepatic glycogen is more
strikingly depleted. In the opinion of Fisher, Russell, and Cori (1937), a
secretion of the pars glandularis regulates the (formation and) utilization
of glycogen in fasting animals and spares carbohydrates so that fat and
protein are utilized to a greater extent as sources of energy. This regula-
tory influence is lost after removal of the gland, so that carbohydrate
oxidation continues at an abnormally rapid rate until even the concentra-
tion of sugar in the blood falls to low levels.

3. A further metabolic abnormality probably is an interference with
gluconeogenesis from non-carbohydrate sources. It appears that the
glycerol of fats cannot be used to form carbohydrate in hypophysectomized
animals. The degree of disturbance of gluconeogenesis from proteins is
not known with any accuracy. Apparently glycine can be utilized. Also,
Fisher, Russell, and Cori found that the excretion of nitrogen in the urine
is not affected by hypophysectomy. However, the G/N ratio of hy-
pophysectomized dogs receiving phlorhizin is lower than normal and the
quantity of N excreted is less (Houssay and others), which suggest a
lowered rate of formation of glucose from protein.

4. All the foregoing changes help to explain the slow rate at which carbo-
hydrate reserves are replenished when food is again furnished to fasting
hypophysectomized animals. Absorption is slow; the reserves are low or,
in the case of the liver, may be virtually exhausted; the animal continues
to depend to an abnormal extent on carbohydrate-oxidation as a source of
energy; and, finally, carbohydrate from non-carbohydrate sources can be
secured only to a limited extent.

The effects of epinephrine in hypophysectomized animals. —
So far as carbohydrate metabolism in normal animals is con-
cerned, epinephrine appears to produce the following changes:

I. A hyperglycemia appears and persists. The increased concentration
of blood sugar is partly due to increased hepatic glycogenolysis and part-
ly due to diminished utilization of sugar by the tissues.

a. Simultaneously epinephrine promotes the formation of glycogen in
the liver from lactic acid, the formation of which depends upon the deg-
radation of muscle glycogen. In the formation of lactic acid from mus-
cle glycogen, hexosemonophosphate must be formed; phosphate is there-
fore mobilized, and the concentration of inorganic P in the blood falls.

■5 The most numerous experiments have been performed with rats in which, as
Fisher, Russell, and Cori emphasize, experimental procedures such as fasting may
produce changes different from those observed in larger animals.

[211]

THE PITUITARY BODY

Therefore, the injection of epinephrine produces a hyper-
glycemia, a fall in the hepatic glycogen (which is restored
later), a fall in the glycogen but an increase in the hexose-
phosphate of striated muscle, a fall in the concentration
of inorganic P in the blood, and a change in the reverse direc-
tion of lactic acid. It is proposed to examine, in the light of
new work, how these effects are modified by hypophysec-
tomy.

Years ago Aschner learned that the subcutaneous injec-
tion of epinephrine produces glycosuria in hypophysectomized

TABLE 7

Change as Mg. Per Cent in

Sugar of blood after subcutaneous injection

Sugar of blood after intravenous injection

Hexosephosphate* of muscle after subcutaneous in-
jection

Hexosephosphate* of muscle after intravenous in-
jection

Glycogen of muscle after subcutaneous injection

Glycogen of muscle after intravenous injection

* The figures refer to the concentration of hexose.

dogs much less readily than in normal animals. This obser-
vation applies with equal force to the behavior of the sugar
in the blood and has been extended to other mammals. De-
ficient absorption as an important factor in explaining the
small response was not considered experimentally until Rus-
sell and Cori (1937) undertook their work in rats. These
authors observed changes after the injection of epinephrine
into anesthetized rats as shown in Table 7. This brief sum-
mary of the results indicates that the delayed absorption of
epinephrine from the subcutaneous tissues is of great impor-
tance in accounting for the apparent insensitivity of hy-

[212]

PARS GLANDULARIS AND METABOLISM

pophysectomized animals toward changes in carbohydrate
metabolism caused by epinephrine.'^

In all other work epinephrine was administered subcuta-
neously. Obviously, then, if observations were made in well-
fed animals, differences in the reponse of normal and hy-
pophysectomized animals cannot be attributed to a funda-
mental change in the action of epinephrine, unless the factor
of deficient absorption has been ruled out. Cope (1937) and
Cope and Thompson (1937) used rabbits. They believed that
storage of hepatic glycogen does not follow the subcutaneous
injection of epinephrine, but they did find in a different series
of animals that the hormone causes an increase in the con-
centration of lactic acid in the blood comparable to that
produced before hypophysectomy. (It appeared that less
glycogen was formed by the liver from intravenously injected
lactate as a result of hypophysectomy.) The lactic acid of
the blood of hypophysectomized rats, which were fasted but
received no epinephrine, began to rise when the concentration
of sugar in the blood fell below 40 mg. per cent. Cope and
Thompson believed that hypophysectomy does not affect the
mobilization of the glycogen of muscle. Chaikoff and others
(i 935) used dogs for their experiments. They injected epineph-
rine subcutaneously and concluded that the response of
hypophysectomized animals — in respect of increase in the
concentration of sugar and lactic acid in the blood and of de-
crease in inorganic P — is indefinitely smaller than that of

'^ Heinbecker and Weichselbaum (1937) found that the intraperitoneal injection
of epinephrine provokes hyperglycemia with equal effectiveness in normal and hy-
pophysectomized dogs, provided that the nutritional condition is good.

CoUip, Thomson, and Toby (1936) injected epinephrine subcutaneously and
concluded that, as a result of hypophysectomy, hyperglycemia and reduction of
muscle glycogen are prevented but that restoration of the effects appears if anterior
pituitary extract be injected. The authors used rats. Bachman and Toby (1936)
reported that hypophysectomy interferes with the mobilization of glycogen in muscle
caused by the injection of epinephrine into rabbits. These authors injected the hor-
mone subcutaneously but sometimes observed a satisfactory hyperglycemic re-
sponse, if the liver contained an adequate amount of glycogen.

[^-13]

THE PITUITARY BODY

normal animals or of animals subjected to all the operative
procedures except hypophysectomy.'"

The effects of insulin in hypophysectomized animals. — It has
long been known that, as a result of the extirpation of the
pituitary body, sensitivity toward insulin is greatly in-
creased. The change is due to the removal of the pars glandu-
laris and not to removal of the pars neuralis (see the recent
articles of Pencharz, Cori, and Russell, 1936; and of Karlik,
1936). However, Chaikoff, Reichert, Larson, and Mathes
(1935) showed that retraction of the right temporal lobe of
the dog (after craniotomy and incision of the dura mater)
alone was sufficient frequently to increase insulin-sensitivity
even 3 months after operation. There occurred in some ani-
mals as much fall in the concentration of sugar and inorganic
P in the blood as in hypophysectomized animals. In the in-
sulin-sensitive animals, in which operation had been carried
only to the stage of temporal-lobe retraction, the pituitary
appeared normal; however, the authors suggest that an un-
recognized injury of the region about the pituitary had oc-
curred. The quantitative studies of Heinbecker, Somogyi,
and Weichselbaum (1937) indicated that in the dog insulin-
sensitivity is approximately doubled 4 weeks after hypophy-
sectomy and, after a year, is quadrupled.

From the discussion of the metabolism of carbohydrates
in hypophysectomized animals it is clear that such animals
tend rapidly to use up all available carbohydrate reserves
when fasting is imposed, whereas in normal animals some
carbohydrate is spared and more fat and protein are oxidized.
These facts alone would justify the expectation that the
blood sugar would fall to lower levels and that shock would
be more easily induced in hypophysectomized animals re-
ceiving insulin. Kater (1936) reported new experiments on
the insulin-sensitivity of hypophysectomized rats. Whereas

'' According to Di Benedetto and Di Benedetto (1935), hyperglycemia caused by
ether is less in hypophysectomized dogs than in control aimals. However, this
would be expected if carbohydrate reserves were low as a result of hypophysectomy.
Hyperglycemia caused by morphine (30 mg. per kg.) appeared not to be affected.

[214]

PARS GLANDULARIS AND METABOLISM

after the injection of 1-5 (?) units of insulin into normal fast-
ing rats, there appeared to be no other change except a fall
in the concentration of sugar in the blood from 90 mg. per
cent to 60-70 mg, per cent, the injection of 0.05 unit into
fasting hypophysectomized rats depressed the level of the
blood sugar to 30-40 mg. per cent, with which were asso-
ciated myasthenia, rapid, shallow respiration, and coma often
with convulsions. The injection of i cc. of 20 per cent glucose
15 minutes after the administration of insulin maintained the
level of the blood sugar above normal; the rats appeared
normal and did not lapse into coma — yet they usually died
within about 5 hours. Smith and others (1936) tested the
insulin-sensitivity of normal, partially hypophysectomized,
and completely hypophysectomized monkeys which first
underwent a fast of 16 hours. Thirty minutes after the in-
jection of 0.06 unit of insulin per kilogram body-weight, the
following changes were observed in the concentration of
sugar in the blood of the heart (the figures refer to milligrams
per cent; the pre-injection concentration is given first): nor-
mal, 115 then 99; partially hypophysectomized, 78 then 66;
completely hypophysectomized, 57 then 37. According to
Crandall and Cherry (1937), who performed their experi-
ments in dogs, either hypophysectomy or denervation of the
adrenals — i.e., excision of one adrenal and splanchnotomy on
the other side — prevents an increased liberation of glucose
from the liver after the injection of insulin. The authors
secured blood from the hepatic and portal veins and arterial
blood without recourse to anesthesia.

The effect of diet on the response of normal and hypophy-
sectomized dogs to insulin was studied by Heinbecker,
Somogyi, and Weichselbaum (1937). In operated, but not
in normal, dogs the response to insulin was uniformly better
if the animals were fed a high-carbohydrate, low-fat diet in
comparison with a diet low in carbohydrate and high in fat.
On the other hand, Himsworth and Scott found that normal
rabbits, on a diet low in carbohydrate, exhibited a disturbed

[215]

THE PITUITARY BODY

sugar-tolerance and a diminished sensitivity toward insulin.
Diet was without effect in hypophysectomized rabbits which,
irrespective of food high or low in carbohydrate, were found
to possess a high sugar-tolerance and an increased insulin-
sensitivity. However, anterior pituitary extract altered the
response of hypophysectomized rabbits to a high-carbohy-
drate diet, so that it resembled that of normal animals on a
low-carbohydrate diet. Cope (1937) was interested in the
effect of hypophysectomy on the rabbit's ability to store
glycogen in the liver. There seemed to be no interference
with this process after the intravenous injection of glucose
into fasting animals. However, unlike normal animals re-
ceiving no food for 48 hours, hypophysectomized rabbits
stored no glycogen in the liver after the injection either of
insulin or of epinephrine. After the intravenous injection of
lactate, less glycogen was stored by hypophysectomized rab-
bits than by normal rabbits.

The interrelationship of the pars glandularis and pancreas
as revealed by extirpation experiments.'''^ — It is well known
that Houssay and Biasotti first demonstrated that the course
of diabetes mellitus due to pancreatectomy is greatly amelio-
rated by the removal of the pars glandularis. This observa-
tion has been confirmed by a number of investigators who
have added new data on the manner in which hypophy-

'* According to Krichesky (1936), the volume of islet tissue in the pancreas of the
rat increases after hypophysectomy. The increase in the volume of islet tissue per-
haps was less (in terms of body-weight), if hypophysectomized rats were given in-
jections of anterior pituitary extract. Hypophysectomy was performed 30-60
days before observations were made.

Fichera and Aldoni (1937) studied the pituitary body of depancreatized cats.
The pituitary was hypertrophied (20.80 mg. per kg. body-weight compared
with 9.69 mg. per kg. body-weight in normal cats). Histological changes were
beheved to be a marked reduction or even a disappearance of oxyphils and a pro-
nounced increase of the percentage of reserve cells.

The observations of Jacobs and Colwell (1936) are believed to have a bearing on
the subject matter of this chapter. These authors infused glucose solution intra-
venously into non-anesthetized dogs until death occurred as a result of a non-keto-
genic acidosis. There was congestion of all the tissues; however, specific, marked
hemorrhage and evidences of destruction occurred in the pars glandularis and
pancreas.

[216]

PARS GLANDULARIS AND METABOLISM

sectomy modifies pancreatic diabetes. So far as the toad is
concerned, Slome (1936) confirmed in another species,
Xenopus laevis^ observations of Houssay and Biasotti who
used Bufo arenarum. If hypophysectomy be performed first
and the pancreas be removed later, the concentration of
sugar in the blood of Xeyiopus does not rise above about
40 mg. per cent about 12 hours after the second operation,
whereas after pancreatectomy alone it reaches a level of
about 230 mg. per cent under similar conditions.''^

All the other observations were made for the purpose of
studying diflferent aspects of metabolism in hypophysecto-
mized-depancreatized dogs ("Houssay dogs").^" The metab-
olism of isolated tissues of hypophysectomized-depancrea-
tized dogs was studied by Shorr, Richardson, and Sweet
(1936) and by Fazekas, Campbell, and Himwich (1937). Ac-
cording to Shorr and his colleagues, the metabolism of excised
skeletal muscle of doubly operated dogs is like that of normal
dogs rather than that of depancreatized dogs, e.g., in capac-
ity to utilize added lactate. On the other hand, Fazekas,
Campbell, and Himwich concluded that the metabolism of
isolated renal tissue of hypophysectomized-depancreatized
dogs resembles that of depancreatized dogs, because oxida-
tion of lactate but not of glucose takes place.

The experiments of Chambers, Sweet, and Chandler (1937)
led them to conclude that relatively little carbohydrate can
be oxidized by hypophysectomized-depancreatized dogs. If
such dogs were on a diet of meat and carbohydrate, the post-
absorptive respiratory quotient was only 0,76. The injection
of 50 gm. of glucose daily might or might not elevate the
respiratory quotient (+0.05); however 20-80 per cent of the
glucose administered appeared in the urine. Carbohydrate-

" Slome found that the level of the blood sugar of fasting normal toads was 35
mg. per cent in animals on a black background, and 26 mg. per cent in animals on a
white background.

^° Kepinov (1936) reported that the blood of depancreatized dogs contains a sub-
stance producing hyperglycemia but that this substance cannot be detected in the
blood if hypophysectomy has also been performed.

[217]

THE PITUITARY BODY

balance studies indicated that doubly operated dogs might
oxidize as much as i6 gm, of glucose per day. Despite the
absence of insulin, hypophysectomized-depancreatized dogs
can deposit glycogen in the liver — even in excess of 2 per
cent (Chaikoff, Gibbs, Holtom, and Reichert, 1936). These
authors also concluded that insulin is essential for the sur-
vival of the doubly operated dog but that survival is long
if the animal is in an excellent nutritional condition at the
time of operation. Chaikoff and his colleagues observed in
hypophysectomized-depancreatized dogs all the changes
characteristic of pancreatic diabetes, including ketonuria.
However, Soskin and others (1935) denied that ketonuria
can be detected in such animals.

Interrelationships of the pars glandularis and other glands
of internal secretion in affecting carbohydrate metabolism.^^
I . The adrenals. — Problems which have interested investiga-
tors in this complex field are illustrated by experiments which
Houssay and Biasotti undertook in the toad, Bufo arenarum.
They relied on quantitative determinations of the blood
sugar to measure changes in carbohydrate metabolism. Some
fall in the concentration of sugar in the blood appeared after
the destruction of all adrenal tissue. Diabetes caused by
pancreatectomy was less pronounced, in terms of the level
of blood sugar, if either hypophysectomy or adrenalectomy
also was performed. In either case, the administration of an-
terior pituitary but not of adrenal cortical extract caused a
further elevation of the level of the blood sugar. The findings
were similar if all three structures were removed. The au-
thors suggest the possibility that adrenalectomy may favor-
ably influence the course of diabetes because it lessens the

" It appears that for purposes of discussion there is still too little experimental
basis for understanding the manner in which the central nervous system — especially
the hypothalamus — affects carbohydrate metabolism, as this is related to the func-
tional activity of the anterior pituitary, the adrenal medulla, and the pancreas.
References to recent work in this field are the following: Davis, Cleveland, and
Ingram (1935); Dawson and Milne (1935); Houssay (1935); Cleveland and Davis
(1936); Ingram and Barris (1936); Lucke (1937).

[218]

PARS GLANDULARIS AND METABOLISM

secretion of the anterior pituitary hormone affecting carbo-
hydrate metabolism.

It is still the belief of Lucke (Lucke, 1936; Lucke and
Kroger, 1936) that the diabetogenic effects of anterior pitui-
tary extract are due ultimately to an action on the adrenal
glands — presumably because unusual amounts of epinephrine
are liberated. This view appears to be untenable, because
extract of the pars glandularis causes typical diabetogenic
effects, including, of course, an elevation of the blood sugar
after removal of all adrenal medullary tissue or bilateral
splanchnotomy (Houssay and Leloir, 1935). However, Hous-
say and Leloir do agree that an immediate temporary rise
in the concentration of sugar in the blood due to the injec-
tion of anterior pituitary extract requires the presence of
adrenal tissue,"

Confusion is the chief result of considering reports on the
effects of adrenal cortical extract or of extracts of the anterior
pituitary with cortical-stimulating effects. Anselmino, Hoff-
mann, and Rhoden (1936) concluded that adrenal cortical
extract prevented the loss of hepatic glycogen which other-
wise occurred after the injection of an anterior pituitary ex-
tract into rats. Corey's experiments (1937), likewise in rats,
were performed under different conditions. Adrenal cortical
extract caused hyperglycemia in non-fasted hypophysecto-
mized rats and in normal and hypophysectomized rats fasted
for 48 hours. ^^ In the latter group there was no apparent
effect on the glycogen of the liver or muscle; however, the
concentrations of glycogen before injection are not given

" Kepinov (1936) concluded that the hberation of epinephrine from the adrenal
in response to the injection of insulin is not disturbed by hypophysectomy in the
dog. The liberated epinephrine, however, affected the level of blood sugar much less.
The same author (1937) also believed that anterior pituitary extract or extract of
liver or muscle restores epinephrine glycogenolysis in the liver of the frog after a long
perfusion. An obvious objection to this conclusion is the author's failure to estimate
the lactic acid, glucose, or glycogen in his extracts, although extracts of liver or
muscle of hypophysectomized animals were said not to contain the necessary sub-
stance.

^3 The extracts did not alter the blood pressure of cats anesthetized by "Amytal."

[219I

THE PITUITARY BODY

but presumably were low. The observations of Bennett
(1937) are difficult to evaluate. An extract of the anterior
pituitary causing stimulation of the adrenal cortex was found
to prevent a fall in the concentration of glycogen of muscle
of hypophysectomized rats, whereas it did not affect hepatic
glycogen or blood sugar. However, the effect was not attrib-
uted to adrenal cortical stimulating hormone. Treatment for
longer periods (10-24 days) did cause an elevation both of the
level of glucose in the blood and of the concentration of
hepatic glycogen. The effects of repeated injections of the
extract on the glucose of the blood and on the glycogen of
the liver did not appear in "demedullated," hypophysecto-
mized rats; but the author attributed this finding to cortical
deficiency rather than to loss of medullary tissue.

Both the pituitary body and the adrenal glands have been
removed from rats by Corey and Britton (1937) and by
Samuels, Schott, and Ball (1937). Corey and Britton did not
fast their rats and found that doubly operated animals, in
comparison with hypophysectomized animals, were unable
to maintain the levels of blood sugar (64 mg. per cent com-
pared with 121 mg. per cent), muscle glycogen (0.24 per cent
compared with 0.43 per cent), or hepatic glycogen (0.23 per
cent compared with 0.94 per cent). According to Samuels
and his colleagues, the double operation did not affect glu-
cose tolerance (in comparison with the effect of hypophy-
sectomy alone) but, not remarkably, did hasten death when
fasting was instituted. Neither group of authors was in a
position to state the relative importance of the cortex and
medulla.

Long and Lukens^^ have published further work on the
amelioration of pancreatic diabetes by adrenalectomy both in
cats and in dogs. The effects resemble those of hypophysec-
tomy in depancreatized animals to such an extent that it is
possible to raise the question of whether or not marked lower-

^■t Long (1935), Long and Lukens (1936), Long (1937), and Long, Lukens, and
Dohan (1937).

[ 220 ]

PARS GLANDULARIS AND METABOLISM

ing of adrenal function as a result of hypophysectomy ac-
counts for the amelioration due to the latter operation. (An-
other possibility suggested by Long and Lukens is that
adrenalectomy suppresses the secretion of diabetogenic hor-
mone by the pars glandularis.) Insufficiency of epinephrine
appeared not to be responsible for the prolonged survival of
depancreatized-adrenalectomized cats. On the other hand,
adequate doses of adrenal cortical extract or of Kendall's
crystalline compound B prevent or restore, at least in rats,
the marked loss of the glycogen of liver or muscle and the
fall in the level of the blood glucose of fasting hypophysec-
tomized animals (Long and Katzin, 1938).

It is, of course, important that there be agreement as to
the action or lack of action of anterior pituitary extract after
complete adrenalectomy. Houssay and Leloir (1935) con-
cluded that extract can cause a definite increase in the con-
centration of sugar in the blood of bilaterally adrenalecto-
mized dogs. On the other hand, the more extensive experi-
ments of Long and his associates in the cat and rat indicate
that, in the absence of adrenal cortical tissue, glycosuria or
an increase of glycosuria does not follow the injection of a
potent extract. ^"^

2. The ejfects of oestrogens. — Evidence that the injection of
large doses of oestrogen prolongs the survival period and
ameliorates the symptoms of pancreatic diabetes in the dog
and monkey was offered several years ago. Recently, Nelson
and Overholser (1936) published further details of their ex-
periments in monkeys and concluded that secretion of the
diabetogenic hormone by the pituitary is depressed, with
consequent improvement of the symptoms appearing after
pancreatectomy, if oestrogen in doses such as 300 rat-units of
oestrone be injected daily. Unfortunately, their observations
could not be confirmed by Collip, Selye, and Neufeld (1937),
who concluded that as much as i mg. of oestrin (oestrone?)

^5 See also Anselmino and Hoffmann (1936) and Russell (1936).

[221 ]

THE PITUITARY BODY

daily affected neither the hyperglycemia nor the glycosuria
due to pancreatectomy. Depancreatized monkeys survived
even several months without insulin and irrespective of oes-
trin treatment. The depancreatized monkey resembled the
dog or cat after removal of the pancreas and adrenals or
of the pancreas and hypophysis.

The effects of extracts of the pars glandularis on the metabo-
lism of carbohydrates. — Young's experiments in dogs (1937)

0 5 10 15 20 25 30 35 40
Days oFter pituitary injections wci-e begun

Fig. 24. — Diagram illustrating the production of a condition resembling dia-
betes mellitus by repeated injections of anterior pituitary into a dog. The numerals
between arrows refer to the grams of fresh anterior pituitary of the ox used to pre-
pare the extract injected daily until the next larger amount was used. Injections
were stopped on the twenty-sixth day. (From Young, Lancet, 233, 372-74 [1937].)

indicate that anterior pituitary extract can be truly diabeto-
genic. Figures 24 and 25 are reproduced from his report.
xAfter repeated injections of anterior pituitary extract were
stopped, a permanent diabetes mellitus appeared in 2 dogs.
However, the animals remained vigorous without the admin-
istration of insulin, and in one there was no loss of weight.
If insulin was injected to prevent almost entirely the excre-
tion of glucose, it appeared that more was required (4.4 units

[ 222 ]

PARS GLANDULARIS AND METABOLISM

per kg. body-weight per day) than in the depancreatized
dog. However, Young emphasizes that this is only his
impression, xAmong other general observations are those of
Etcheverry (1937) and Foglia and others (1937), Etcheverry
concluded that bilateral supra-diaphragmatic vagotomy with
or without removal of the abdominal sympathetics does not
modify the course of diabetes caused either by pancreatec-

!.,§ 2000

1$ 1000 - Urine vol.

275 280 285 290 295 300 305 310
Days oFter pituitary injections were begun.

Fig. 25. — Continuation of Figure 24 after a long interval not shown in the dia-
grams. The daily injection of 60 units of insulin was begun at the first arrow and
stopped at the second arrow. Death occurred on day 309. (From Young, Lancet,
233, 372-74 [1937]-)

tomy or by the injection of anterior pituitary extract, Foglia
and others injected crude anterior pituitary extract into dogs
with diabetes following pancreatectomy. The extract short-
ened survival time, increased the formation of acetone bodies
and the deposition of lipoids in the liver, and antagonized
the action of insulin.

The effects of anterior pituitary extract in experiments of
short duration were observed in normal and hypophysecto-

[223]

THE PITUITARY BODY

mized rats by Fisher, Russell, and Cori (1936) and Russell
(1936). To some groups of animals glucose was fed after
fasting; the percentage which underwent oxidation was re-
duced. The respiratory quotient of fasted, hypophysecto-
mized rats receiving injections tended to be lower, i.e., some
carbohydrate was spared as is the case when a normal animal
fasts. Also, less muscle glycogen disappeared. Russell con-
cluded that the normal rat can deposit much more carbohy-
drate than the hypophysectomized animal, if anterior pitui-
tary extract be injected after a fast but before the administra-
tion of glucose. These observations were extended by Meyer,
Wade, and Cori (1937) who used normal rats. The animals
were fasted 24 hours, after which they received anterior pi-
tuitary extract intraperitoneally. A short time later glucose
was fed. The extract produced two principal effects: (i) the
amount of carbohydrate oxidized was markedly reduced (fol-
lowing the injection of active extract, the respiratory quo-
tient was 0.77, whereas after inactivated extract it was 0,88),
and (2) the carbohydrate spared appeared to be distributed
among the liver, striated muscle, and blood and tissue fluids.
More than two-thirds was stored in the liver and striated
muscle. Bennett (1937) found that, for a short time only, a
crude anterior pituitary extract will restore the muscle glyco-
gen to a normal level in hypophysectomized rats. He could
not demonstrate "antihormone" in the blood of animals
which received much less benefit from repeated injections.
An increase in the deposition of glycogen in the liver and
probably in striated muscle was demonstrated by Young
(1937), who injected anterior pituitary extract into fasting
mice and rabbits. He suggests that gluconeogenesis from fat
(glycerol?) may be an important part of the effect (rather
than a depression of carbohydrate oxidation) or that another
principle is responsible for glycogen deposition.

''Pancreatropic'' effects of extracts of the pars glandularis. —
Several years ago Anselmino and Hofl'mann published their
first reports on the "pancreatropic" hormone of the pars

[224]

PARS GLANDULARIS AND METABOLISM

glandularis. Extracts of the anterior pituitary were found
to cause hypertrophy and hyperemia of the islet tissue of the
pancreas of the rat. New formation of islet tissue was also
reported. Changes in the level of the blood sugar or hepatic
glycogen were found to conform to the interpretation that
the extract also promoted the secretion of insulin.

So far as the histological change is concerned, confirma-
tory reports have been published by the authors themselves,
by Picinelli (1936), Chrzanowski and Grzycki (1937), and
Roussy and Mosinger (1937). Roussy and Mosinger believed
that the effect is associated with suitable contact with neuro-
ganglionic tissue {neu7'ocrifjie pancreatique). On the other
hand, despite efforts to duplicate exactly the experiments of
Anselmino and Hoffmann, neither Elmer, Giedosz, and
Scheps (1937) nor Santo (1938) could offer confirmatory ob-
servations. The obvious importance of an effort to evaluate
"pancreatropic" effects quantitatively has been neglected by
all authors except Richardson and Young (1937). These au-
thors demonstrated that a saline extract of fresh anterior
pituitary of the ox can cause, after daily injection for 2-3
weeks, an increase in the absolute amount of islet tissue as
well as a doubling of the ratio of islet tissue to acinar tissue.
However, in another strain of rats, receiving no treatment,
the ratio was found to be just as high.

There appeared to be little or no effect of the extract of
Richardson and Young on the blood-sugar level of their rats.
Elmer and his colleagues (1937) likewise could demonstrate
no effect with extracts made according to the directions of
Anselmino and Hoffmann. Positive results were obtained by
Zunz and La Barre (1935). Pancreatropic extract furnished
by Anselmino and Hoffmann was injected intravenously into
dogs with the pancreatic vein anastomosed with a jugular
vein of a second animal which, preferably, was prevented
from liberating epinephrine. The injection of the extract
caused a lowering of the level of the blood sugar in the second

[225]

THE PITUITARY BODY

animal. No noteworthy effect on the thyroid or adrenals
(epinephrine-liberation) could be detected.

Anselmino and Hoffmann (1936) injected pancreatropic ex-
tract into anesthetized dogs and concluded that the drop in
blood sugar produced was increased if the adrenals were re-
moved. These authors also detected the principle in serum
and in urine of normal and diabetic individuals and of preg-
nant women (see also Picinelli, 1936).

The effects of hypophysectomy and of the injection of
alkaline anterior pituitary extract (ox) were investigated in
adult male newts {Triturus viridescens) by Adams and Ward
(1936) and appear to be different from those in mammals.
For example, the liver was found to weigh more in hy-
pophysectomized newts than in normal animals. xAfter hy-
pophysectomy the liver by histological examination appeared
to contain more fat. The authors also investigated the
weight, number of islets, and cytology of the islets of the
pancreas as well as the concentration of glycogen in the liver
by a method of doubtful quantitative value. Although the
pancreas was smaller after hypophysectomy, yet it was found
to contain an increased number of islets. The reader is re-
ferred to their report for a detailed description of their re-
sults.

Observations on the effects of serum ^ cerebrospinal fluids or
urine on the metabolism of carbohydrates. — The observations
to which reference is made in the heading of this paragraph
are commonly interpreted by the authors as evidence that
anterior pituitary hormones affecting carbohydrate metabo-
lism have been identified. This view, of course, may be en-
tirely incorrect. Harrow and others (1936) extracted from
the urine of normal young men a substance which causes a
marked hyperglycemia in rabbits. Elmer, Giedosz, and
Scheps (1937) reported that the serum of a patient with
acromegaly produced a similar effect after injection into
the rabbit. ^According to De Wesselow and Griffiths (1936),
if the serum of aged individuals with glycosuria be injected

[226]

PARS GLANDULARIS AND METABOLISM

subcutaneously into rabbits, there is definitely less hypo-
glycemia produced by a subsequent dose of insulin. This
finding suggested that diabetes in the aged may be the result
of a relative excess of diabetogenic hormone in the body
fluids, because the serum of normal individuals or of young
people with diabetes produced almost no antagonism of in-
sulin.^''

Anselmino and Hoffmann (1936), Anselmino and Rhoden
(1936), and Anselmino (1937) detected "carbohydrate-
metabolism hormone" of the anterior pituitary by the de-
crease of hepatic glycogen following administration to rats.
In terms of such an effect, the substance has been detected
in the serum and urine of young persons with severe diabetes
and in the serum of normal individuals or dogs after the ad-
ministration of 125-150 gm. of glucose by mouth. The latter
change is said not to occur if fat also is fed or if large doses
of insulin are given. ^' Anselmino and Hoffmann have not
defined in terms of accurate experiments how "carbohydrate-
metabolism hormone" is related to the diabetogenic hormone
of the majority of authors (see also the report of Anselmino
and Hoffmann as published in 1935). Future work must de-
cide whether or not "carbohydrate-metabolism hormone"
really exists. This is doubted by Singer and Taubenhaus
(1937). Diabetes mellitus in relation to "carbohydrate-
metabolism" and "fat-metabolism" hormones is discussed by
Anselmino and Hoffmann (1935-36) and Effkemann (1936).

In general, diabetogenic extracts of the anterior pituitary
do not readily produce changes which can be attributed to
antihormone-formation. Although the effects of an extract

^^ Hahndel (1935) stated that the cerebrospinal fluid of normal men, if
injected intravenously into rabbits, does not affect the level of the blood sugar.
However, if insulin be injected first, the cerebrospinal fluid then causes hyper-
glycemia which the author attributes to contra-insulin hormone liberated into
the cerebrospinal fluid.

^^ The serum of cattle suffering from "paresis puerperalis" — vegetative endo-
carditis with an associated disturbance of mineral metabolism — is reported to pro-
duce a decrease of the concentration of liver glycogen in rats without affecting the
blood-sugar level (Seekles, 1937).

[227]

THE PITUITARY BODY

may appear to diminish progressively, the serum of such
animals is reported not to antagonize the hormone's effects
in fresh animals (particularly see Young, 1937).

THE METABOLISM OF LIPOIDS IN RELATION TO

THE PITUITARY BODY

According to Lee and Ayres (1936), hypophysectomized
rats lose less "fat," i.e., substances extracted by ether, than
normal rats when both groups are fed identical amounts of
the same diet. The results of Reiss, Epstein, and Gothe
(1937) were variable. A few weeks after hypophysectomy
the total fat of the body appeared to have fallen to about
40 per cent of the normal value, to which it returned several
weeks later (8 weeks after operation). On the basis of other
experiments the authors suggest that adrenal cortical stimu-
lating hormone is of great importance in facilitating the dep-
osition of fat and that this action ultimately depends upon
the liberation of adrenal cortical hormone. The administra-
tion to man or the dog either of adrenal cortical extract or of
pituitary extract causing cortical stimulation was followed
by a fall of 25 per cent or less in the concentration of fat in
the blood because, according to the authors' interpretation,
more fat is deposited in the tissues. In the dog, Chaikoff
and his colleagues (1936) found that long after hypophysec-
tomy all the lipoids^^ of the blood may be present in normal
concentrations; in about one-third of the animals, however,
the lipoids of the blood were present in higher concentrations
than were ever encountered in normal animals.

A number of reports are concerned with the behavior of
the fat of the liver in relation to the anterior pituitary. In
the terminology of Benoit (1937) the "hepatotropic func-
tion" of the pituitary is increased in the duck after thyroid-

^* Oestreicher (1936) reported that the oxygen-consumption of isolated fatty
tissue of the rat (white subcutaneous fat or testicular fat body) is increased by the
addition of "thyrotropic hormone" or "fat-metabolism hormone."

^' Total fatty acids, phosphatide, and free and ester cholesterol.

1228 1

PARS GLANDULARIS AND METABOLISM

ectomy; in other words, the removal of the thyroid is fol-
lowed by enlargement of the liver. The experimentally en-
larged liver contains about twice as high a concentration of
lipoids (10.4 per cent) as the normal liver (5.1 per cent), but
if, in addition to thyroidectomy, anterior pituitary extract
be injected into the duck, there is further hypertrophy and
the concentration of lipoid rises to 38.6 per cent (Benoit,
1936). The observations of Best and Campbell (1936) were
made in rats. Large doses of anterior pituitary extract were
followed by the deposition of large amounts of fat (total fatty
acids together with unsaponifiable material) in the liver. As-
sociated changes in fasting rats were a decrease in the fat of
other parts of the body and an increased excretion of acetone
bodies. The accumulation of fat in the liver as a result of the
injection of anterior pituitary extract is prevented by adren-
alectomy but not by demedullation of the adrenals (Fry,
1937). Likewise, MacKay and Barnes (1937) showed that
adrenalectomy prevents the deposition of fat in the liver,
caused either by anterior pituitary extract or by fasting.

Pancreatectomy is ordinarily followed by an accumulation
of lipoids in the liver of animals such as the dog. This change
is not prevented if hypophysectomy also is performed (Chai-
koff and others, 1936).

The relation of what Anselmino and Hoffmann term the
"fat-metabolism hormone" to the accumulation of lipoids in
the liver is not clear. Pituitary extract may cause, under
proper experimental conditions, an accumulation of acetone
bodies in the blood and an increased excretion of the bodies
in the urine. An extract with such effects is what Anselmino
and Hoffmann have called the "fat-metabolism hormone."
Its other effects come up for discussion shortly. Although
Anselmino, Hoffmann, and Rhoden (1936) state that extract
with the previously described properties is identical with the
active substance present in the extracts of Best and Camp-
bell and causes an increase of about 50 per cent in the con-
centration of ether-soluble substances in the liver dried at

[229I

THE PITUITARY BODY

60° C, their earlier report (Anselmino, Effkemann, and Hoff-
mann, 1935) emphasized that (i) the consistent effect of the
extract is an unsaturation of fatty acids of the Hver and (2)
the concentration of total fatty acids in the liver falls or
rises depending upon the presence of high or low initial
levels. •'°

It must be remembered that, if the concentration of ace-
tone bodies in the blood increases or if the urinary excretion
of these bodies becomes markedly elevated after the injec-
tion of anterior pituitary extract, these facts do not justify
naming the causative substance "fat-metabolism hormone."
The experimental data indicate that its action depends upon
the presence of intact adrenal tissue. Dingemanse (1936) is
not convinced that a ketogenic hormone exists and found (i)
that only an occasional extract raises the level of acetone
bodies in the blood of the rat (but not the rabbit), (2) its
detection is difficult because of the effect of fasting, time of
day, etc., and (3) the ratio of (3 hydroxybutyric acid to
acetoacetic acid and acetone is the same, whether keto-
genesis is caused by fasting or by extract.

Mirsky (1936) takes the position that inasmuch as keto-
genesis cannot occur in the absence of the liver, a ketogenic
effect depends upon the utilization of non-carbohydrate foods
in the absence of ample carbohydrate available for oxidation
by the cells of the liver. He prevented the ketogenic action
of anterior pituitary extract in rabbits fasted for 24 hours by
the injection of insulin (1.3-3 units per kg. body-weight)
or ergotamine tartrate (2 mg. per kg. body-weight). Both of
these substances were considered to prevent glycogenolysis,
thus acting as ketolytic agents. Anselmino and Hoffmann
(1936) concluded that insulin inhibits the liberation of a
ketogenic hormone occurring otherwise as a result of feeding
butter. The authors used dogs.

3° The same authors (1935) stated that "carbohydrate-metabolism hormone"
causes an effect the opposite of (i) and also brings about a fall in the concentration
of total fatty acids.

[ 230 ]

PARS GLANDULARIS AND METABOLISM

There appears to be little doubt that the ketogenic effect
of anterior pituitary extract, as determined by ketonuria in
the rat, is prevented by the removal of the adrenal glands
(Fry, 1937; Houssay and Rietti, 1937; MacKay and Barnes,
1937). The acetoacetic acid of blood was determined by
Houssay and Rietti, whereas the other investigators esti-
mated the acetone bodies of urine. Cortical tissue alone
seemed to be necessary for a ketogenic action, inasmuch as
the latter is not affected by demedullation (Fry). Houssay
and Rietti stated that the administration of adrenal cortical
extract restores the ketogenic action of anterior pituitary
extract in adrenalectomized rats, whereas this is not accom-
plished by means of salt therapy.^'

According to Fry (1937), the ketogenic effects of anterior
pituitary extract can be observed in the rat even 7 weeks
after thyroidectomy. However, Best and Campbell (1936),
who performed their experiments in rabbits, found that as
hypothyroidism became more pronounced (e.g., 4-6 weeks
postoperatively) no ketogenic effect could be produced un-
less thyroid extract was administered.

Anselmino and Hoffmann (1936) discuss the extraction of
ketogenic principle from the anterior pituitary and from
blood and urine. Its detection in the blood and urine of dia-
betic individuals has been reported (Anselmino and Hoff-

3' Mirsky (1938) suggested that adrenalectomy in the rat does not affect keto-
genesis caused by anterior pituitary extract as measured by the acetone bodies of
the blood, but that the operation does raise the threshold of renal excretion of ace-
tone bodies. Thus, authors investigating only ketonuria would erroneously con-
clude that the operation prevented the ketogenic action of extract. However, Hous-
say and Rietti studied the acetoacetic acid of blood and found that adrenalectomy
largely prevented (or even reversed) the ketogenic effect of extract 6-14 days after
operation. Earlier than 6 days after adrenalectomy, when Mirsky made his ob-
servations (48 hours after operation), Houssay and Rietti found that the ketogenic
action of extract was unimpaired. If the method of estimating acetoacetic acid used
by Houssay and Rietti be considered accurate, their extract produced an adequate
ketosis, inasmuch as acetoacetic acid probably represents less than 20 per cent
of the total acetone bodies.

Anselmino, Hoffmann, and Rhoden (1936) concluded that adrenal cortical ex-
tract fully antagonizes the ketogenic action of anterior pituitary extract.

[231 ]

THE PITUITARY BODY

mann, 1936; Taubenhaus, 1936).-'^ If a ketogenic pituitary
extract be injected repeatedly, the animal becomes refractory
to this effect (Bennett, 1937).

Teilum (1937) attributes to the pituitary the hyper-
cholesterolemia which he observed invariably in gonadec-
tomized persons or patients with hypogonadism. He offers
no satisfactory evidence for this interpretation. If we accept
the data of Cioglia and Tore (1936), gonadectomy is followed
by hypocholesterolemia (rabbit). These authors observed
hypercholesterolemia after the administration of prolan or
pituitary gonadotropic hormone.

THE METABOLISM OF PROTEIN AND SOME NON-PROTEIN

NITROGENOUS COMPOUNDS IN RELATION TO

THE ANTERIOR PITUITARY

The metabolism of protein in relation to the pituitary body. —
In addition to references in other chapters, there remain a
few general reports on the metabolism of protein. Gaebler
and Price (1937) studied the action of single large doses of
anterior pituitary extract (with growth-promoting proper-
ties) on the metabolism of protein in dogs. The authors
found that a fall in the rate of excretion of N, S, and phos-
phate was associated with a rise in weight. At the same time
the ratio of N to S increased and more N was retained. All
these changes are similar to those occurring when synthesis
of protein is in progress and suggest that the extract had, in
fact, brought about an increased rate of protein synthesis. •'•'

^' The obesity of a patient with Cushing's syndrome was considered by Freyberg
and Newburgh (1936) not to be caused by any unusual metabolic derangement,
because loss of weight due to undernutrition took place exactly as in normal
persons.

33 See also the report of Paschkis and Schwoner (1937), who investigated the
action of commercial anterior pituitary extracts on the level of the amino acids in
the blood of patients who had been given gelatine by mouth.

Binet, Kepinov, and Weller (1935) published determinations of reduced and total
glutathione in the liver, thyroid, and testis of normal and hypophysectomized dogs.
Hypophysial deficiency was found to be accompanied by reductions in the concen-
tration of glutathione in all three tissues; the most marked reduction occurred
in the thyroid, the least in the testis.

[232]

PARS GLANDULARIS AND METABOLISM

Perla and Sandberg (1936) observed that the excretion of
N in the urine is increased by 100 per cent during the first
few weeks after hypophysectomy and remains elevated for
weeks later. The observations of Yokoyama (1935) indicated
that, several weeks after hypophysectomy, the dog excretes
considerably less total N, uric acid, and urea. Slighter but
similar changes in the behavior of allantoin, ammonia, and
creatinine were also reported.

The metabolism of creatine and creatinine in relation to the
anterior pituitary. — The excretion of nitrogen and creatinine
are about the same in normal and hypophysectomized rats,
provided that the diet contains sufficient protein. However,
if the diet is free from nitrogen, less of both constituents is
excreted by hypophysectomized animals. Braier and Morea
(1935) interpret these findings as further evidence that endog-
enous protein metabolism is reduced as a result of hypophy-
sectomy.

The concentration of creatine in the hamstring muscle of
the toad {Xenopus laevis) falls about 15 per cent 18-22 weeks
after the removal of the pars glandularis or the whole pi-
tuitary. The opposite effect is produced by the injection of
anterior pituitary extract — the concentration of creatine may
increase about 30 per cent "^i^-^^ weeks after injections are
started in normal toads. These observations were reported
by Shapiro and Zwarenstein (1936), who believed that the
effect is mediated through another gland. '^ Nitzescu and
Gontzea (1937) concluded that the anterior pituitary extract
"xAntuitrin G," although without effect in normal indi-
viduals, increases the creatinuria of patients classified as suf-
fering from infantilism, dwarfism, and dystrophia adiposo-
genitalis. The extract also lessened the tolerance for creatine

3^ The secretions of the gonads are of great importance in the metabolism of
creatine; e.g., Kun and Peczenik (1936) recently concluded that, at least in the rat,
creatinuria appears if there is testicular deficiency and disappears after the injection
of male hormone, whereas spayed females excrete no creatine in the urine unless an
oestrogen be injected. The male and female hormones, therefore, appeared to
affect creatine-metabolism in opposite directions.

[233I

THE PITUITARY BODY

and antagonized the effect of male hormone ("Erugon") on
creatine-excretion.

According to Perla and Sandberg (1936) creatinuria tran-
siently appears in male but not in female rats after hypophy-
sectomy.

THE ANTERIOR PITUITARY AND THE METABOLISM
OF MINERALS; THE PITUITARY-PARA-
THYROID INTERRELATIONSHIP

The pituitary body and the metabolism of minerals {^except
calcium). — Gerschman and Marenzi (1935) reported that the
injection of large doses of alkaline anterior pituitary extract
into hypophysectomized dogs was followed by a diminished
concentration of Na and CI in the blood, whereas the con-
centration of "CO2," glucose, Ca, Mg, and inorganic P was
elevated following this treatment. Friedgood and McLean
(1937), however, could not observe any change in the con-
centration of serum phosphate of guinea pigs receiving daily
injections of alkaline anterior pituitary extract for more than
a week. Perla and Sandberg (1936) found that hypophysec-
tomy accelerates the loss of P in the feces (but not in the
urine) of rats. Later, a study of the effects of partial or com-
plete hypophysectomy on the metabolism of water, Na, K,
CI, and S was made in rats by Sandberg, Perla, and Holly
(1937). The reader is referred to their article for a description
of their findings. That the concentration of Mg in blood is
greatly affected by anterior pituitary secretion is the belief of
Cannavo and Beninato (1935), who extended the work of
their laboratory in this aspect of mineral metabolism. The
pituitary of rabbits was irradiated by X-rays so that the pars
glandularis was severely injured and a cachexia followed by
death in 2-3 weeks appeared. The serum-concentration of
neither Ca nor inorganic P was clearly affected. About 10
days after irradiation the level of Mg was reduced from the
normal level (3.25-4.04 mg. per cent) to a new, lower level
(1.83-2.54 mg. per cent). The authors believed that the ex-

[ \U ]

PARS GLANDULx^RIS AND METABOLISM

cretion of Mg both in the urine and in the feces was reduced
in irradiated animals.

/According to the interpretation of Brull (1937) the pitui-
tary body is important in the maintenance of the level of in-
organic P in the blood, because after hypophysectomy the
renal threshold for PO4 rises. In the dog anesthetized by
chloralose, the excretion of PO4 almost disappears but can be
reinstated by the injection of parathyroid hormone, which is
believed to act directly on the kidneys. If hypophysectomy
is then performed, urine is excreted at an increased rate, but
PO4 almost disappears from the urine, although its concen-
tration in the blood rises from a level of 8.4 mg. per cent to a
level of 10. o mg. per cent.

The pituitary body and the metabolism of calcium. The in-
terrelationship of the pars glandularis and the parathyroid
glands?'" — Some further evidence that parathyroid function
is affected by the anterior pituitary has been published.
Gerschman and Marenzi (1935) concluded that large doses of
alkaline anterior pituitary extract can cause a small elevation
(i .9 mg. per cent) of the level of Ca in the blood of dogs and
that such an effect still can be produced after hypophysec-
tomy or thyroidectomy but not after thyroparathyroidec-
tomy. However, the authors' data do not include the level of
Ca after thyroparathyroidectomy but before injection; after
injection the concentration of Ca was 5.02 mg. per cent. The
reports of Speransky-Stepanova (1936) (Speranskaia-Stepa-
nowa) were based upon observations in two hypophysecto-
mized dogs. The level of Ca in the serum was not affected by
hypophysectomy but promptly fell after subsequent thyro-
parathyroidectomy which, of course, caused tetany.''^ Both
in rats (Friedgood, 1936) and in guinea pigs (Friedgood and

•is Freyberg and Grant (1936) studied the metabolism of Ca and P in a patient
described as suffering from pituitary basophilism. The changes, contrary to what
might be expected, were found not to resemble those of hyperparathyroidism (see
also the review of Rivoire, 1935).

^^ Tetany was not accompanied by an inhibition of diuresis as in dogs with an
intact pituitary.

[235]

THE PITUITARY BODY

McLean, 1937) alkaline anterior pituitary extract can cause
an elevation of 0.9-2,0 mg. per cent in the concentration of
Ca in the serum.

An increased excretion of Ca in the urine following hy-
pophysectomy has been observed in the rat by Perla and
Sandberg (1936). The change in absolute terms was slight
but represented an increase of several hundred per cent.
Perla and Sandberg found that the principal loss of Ca oc-
curred by way of the digestive tract and that fecal loss was
increased after hypophysectomy, Teel and Cushing had
found that the urinary loss of Ca by the dog is increased after
the injection of anterior pituitary extract.

Anselmino, Hoffmann, and Herold, who first described his-
tological signs of a parathyrotropic effect of anterior pituitary
extract have investigated the action of an aqueous extract of
acetone-desiccated anterior pituitary powder (ox) in various
animals (Anselmino, Herold, and Hoffmann, 1936). They
stated that macroscopic enlargement could be produced in
the rat and rabbit but not in the cat, dog, or guinea pig. In
all the species, histological changes appeared — principally
hyperplasia of cells resembling the chief cells of the normal
parathyroid.

MISCELLANEOUS OBSERVATIONS

Perla (1936) investigated the relationship between the
spleen and the anterior pituitary and concluded that the
gland is required for the normal maintenance of the spleen."
However, it is not possible to state that the anterior pituitary
secretes a separate spleen-stimulating principle. Hypophy-
sectomy in rats is followed by splenic atrophy, which regres-
ses considerably if an emulsion of pituitary be injected. Re-
generation of a remnant of the spleen after partial splen-
ectomy likewise is prevented by hypophysectomy but takes
place as a result of administration of pituitary emulsion. The
injection of an emulsion of anterior pituitary of the ox into

3' See also Friedgood (1936J and earlier reports on the effect of hypophysectomy.

[236I

PARS GLANDULARIS AND METABOLISM

normal rats — or of an alkaline extract of fresh or desiccated
gland — can cause a marked hypertrophy of the spleen due
chiefly to hyperplasia and hypertrophy of the reticulo-endo-
thelial cells of the red pulp. In addition, there is some growth
of follicles, but the KupfFer cells are not affected. Hyper-
plasia of the reticular cells of the bone marrow likewise oc-
curs. Wetzler-Ligeti and Wiesner (1937) measured the effect
of anterior pituitary extract on the reticulo-endothelial sys-
tem by the rate at which Congo red was removed from the
blood after the dye had been injected intravenously. They
concluded that anterior pituitary extracts can either favor or
interfere with the removal of Congo red from the circulating
blood (positive and negative "restropic" effects).

The relation of the pituitary to erythrocyte- (and leu-
cocyte-) formation was investigated by Kapran (1935) and
Flaks, Himmel, and Zlotnik (1937). Kapran reported on the
changes following hypophysectomy in the dog — i.e., di-
minished number of erythrocytes, elevated color-index, in-
terference with reticulocyte formation, slight leucopenia, and
eosinophilia even to 20 per cent; but that these changes were
specifically due to hypophysectomy was not shown. On the
other hand, McFarlane and McPhail (1937) were unable to
detect any change in erythrocyte count or content of hemo-
globin in guinea pigs because of the removal of the pituitary.
According to Flaks and his colleagues, a thermostable sub-
stance can be extracted from the anterior pituitary which di-
rectly stimulates the red bone marrow even after adminis-
tration by mouth. Reticulocytosis and later polycythemia
can be observed in rats receiving the extract.

Keller and D'Amour (1936) occasionally found hemorrhage
into and ulceration of the gastrointestinal tract of dogs in
which hypophysectomy had been undertaken. However,
they were not certain that these pathological changes were
not caused by injury of the central nervous system. Belief
in the efficacy of heterotransplants of the anterior pituitary
was expressed by Kylin (1937), who concluded that they were

[237I

THE PITUITARY BODY

of great value in the treatment of Simmonds' disease; he also
described the successful transplantation of calf pituitary into
the peritoneal cavity of the rabbit.

According to Gagyi (1936), who performed titrations with
2,6 dichlorophenolindophenol, the pars neuralis (contrary to
Giroud and Leblond) contains about three times as much
ascorbic acid as the pars buccalis in terms of concentration
(pars neuralis 7.2 and the pars glandularis-pars intermedia
2.3 mg. per gm). Also he stated that the gland of immature
animals, especially females more than males, contains a
higher concentration of the vitamin than the gland of adults.
The observations were made in guinea pigs. Two other re-
ports refer to constituents of the pituitary. Regnier (1936)
found that sulfonal (diethylsulfonmethane) was deposited in
the pars glandularis to a greater extent than in any other
tissue after the drug had been administered by mouth to a
horse (40 gm. to a horse weighing 450 kg.). The tissues con-
taining the highest concentrations of this hypnotic, expressed
as milligrams per 100 gm., were: pars glandularis, 750;
adrenals, 426; pars posterior, 200; blood, 29.4. The brain con-
tained 7.8 mg. per 100 gm. It is extremely unlikely that the
presence of bromine in the pituitary body has any signifi-
cance. Dixon's recent report (1935) indicated that the pitui-
tary of the normal pig contains about 0.27 mg. of Br per 100
gm. of fresh tissue. As in other organs the ratio of Br to CI
roughly corresponded to what was probably the ratio of these
elements in the diet. According to Moruzzi and Guareschi
(1936), the fresh pituitary of the ox and of man contains re-
spectively about I or about 0.6 mg. of Br per 100 gm.

SUMMARY

The morphological and functional maintenance of the cor-
tex of the adrenal glands depends upon secretion (s) of the
pars glandularis. (The medulla of the adrenal gland may
have important indirect interrelationships with the anterior
pituitary ; its direct dependence on the anterior pituitary prob-

[238]

PARS GLANDULARIS AND METABOLISM

ably is slight and unimportant.) Without pituitary secre-
tion either from the intact gland or from administered ex-
tract, the adrenal cortex rapidly diminishes in size and per-
forms its usual functions only imperfectly. The principal
morphological evidences of atrophy are in the outer part of
the thickest layer of the cortex, the zona fasciculata, al-
though the zona glomerulosa also is affected. There is a
striking loss of lipoids. The administration of a suitable an-
terior pituitary extract not only restores the lipoids lost but
may increase their concentration in association with hyper-
trophy and hyperplasia of cortical cells. In this way an ex-
tract may cause cortical enlargement in hypophysectomized
rats, so that the adrenal glands are larger than any ever en-
countered in normal rats receiving no treatment.

The X-zone of the innermost part of the cortex of young
female mice or of castrated males seems also to depend upon
an anterior pituitary hormone for its development (Deanes-

ly).

The physiological interrelationships of the adrenal cortex
and the anterior pituitary are important and numerous; un-
fortunately, however, they have been explored only imper-
fectly. Compensatory adrenal hypertrophy requires adrenal
cortical stimulating hormone. This hormone probably is se-
creted at an increased rate if there is cortical deficiency,
whereas a change in the opposite direction takes place if
abnormally large amounts of adrenal cortical hormone(s) are
present in the body-fluids. Some of the most important cor-
relations appear to affect the metabolism of carbohydrates
and fats and are mentioned in later discussion.

The pars glandularis appears to be the principal division
of the pituitary body important in the metabolism of car-
bohydrates. The substance or substances responsible for par-
ticipation in this important phase of metabolism has been
detected in anterior pituitary extracts which, for the most
part, are quite crude. The isolation of these substances must

[ 239 ]

THE PITUITARY BODY

be carried much farther before definite statements can be
made concerning either their number or their other biological
effects (e.g., on the mammary glands or adrenal cortices).
However, a number of other methods has been employed to
learn how regulation by the anterior pituitary is effected.
Carbohydrate metabolism has been studied after hypophy-
sectomy; in such studies, epinephrine or insulin also has been
used. The remarkable amelioration of diabetes which follows
the removal of the hypophysis from depancreatized animals
has received further attention. The most important inter-
relationships with other glands of internal secretion are those
with the pancreas and adrenal glands.

The anterior pituitary appears to be necessary for the ab-
sorption of glucose at a normal rate from the digestive tract;
however, there is no evidence that a specific hormone, such as
that affecting the metabolism of carbohydrate after absorp-
tion, alters the process of absorption. The "diabetogenic"
hormone of the anterior pituitary probably prevents the
prodigal waste of important, but sometimes small, carbo-
hydrate reserves which, for example, are maintained in spite
of fasting. An animal isolated from all sources of the hor-
mone (as after hypophysectomy) and dependent upon its
own reserves of food, dangerously uses up all available carbo-
hydrate. It is able readily to mobilize the glycogen of both
the liver and striated muscle and to oxidize glucose. Perhaps
another important metabolic function of anterior pituitary
secretion is to facilitate the new formation of carbohydrate
from both fat (glycerol) and protein.

The diabetogenic hormone can be viewed as an antagonist
of insulin, the internal secretion of the pancreas. There is evi-
dence that this antagonism is indirect and depends upon the
support of adequate adrenal function. However, there is not
complete agreement that bilateral adrenalectomy prevents
the disturbing effects of anterior pituitary extract on carbo-
hydrate metabolism — e.g., hyperglycemia in the dog. On the
other hand, the glycosuria which follows the injection of an-

[240]

PARS GLANDULARIS AND METABOLISM

terior pituitary extract into cats or rats is not observed after
complete adrenalectomy. Insulin-sensitivity is increased by
hypophysectomy, because an important physiological antag-
onist of insulin — diabetogenic hormone — is no longer avail-
able, and carbohydrate reserves both disappear at an ab-
normally rapid rate and probably are restored from other en-
dogenous sources only with great difficulty. After pan-
createctomy, secretion(s) of the anterior pituitary is not an-
tagonized (however indirectly) by insulin and may be re-
garded as an important contributor to changes which threat-
en life — e.g., the accumulation of acetone bodies. Anterior
pituitary secretion can also be pictured as interfering with
the oxidation of glucose which otherwise is facilitated by
insulin. If, however, both glands are removed, the important
means of regulating carbohydrate metabolism are lost. A
unique derangement of metabolism appears and, depending
upon conditions such as nutritional state before operation,
fasting, diet, etc., the animal resembles sometimes the dia-
betic animal — e.g., with hyperglycemia and glycosuria — and
sometimes the animal with hypophysial deficiency — e.g.,
with hypoglycemia.

Although the effects of subcutaneously injected epineph-
rine are less pronounced after hypophysectomy, it is prob-
able that delay in absorption accounts for most of this
change, provided that reserves of carbohydrate are adequate.
Any diminished effect of epinephrine is observed in respect of
all the expected changes — elevation of the level of sugar and
lactic acid in the blood, depression of the level of inorganic P,
lowering of the concentration of glycogen in muscle, etc.

New observations support the belief that anterior pituitary
extract can cause hypertrophy of the islet tissue of the pan-
creas. The physiological significance of this effect has not
been adequately explored.

Any attempt briefly to summarize our knowledge of the
relation of the anterior pituitary to carbohydrate metabolism
is necessarily confusing, because we know only some phases

[ 241 ]

THE PITUITARY BODY

of processes of unknown complexity. However, the potential
value of what can be learned is immense in its implications
not only to physiology but also to clinical medicine.

The metabolism of fat, depending upon conditions, is
probably closely interrelated with that of carbohydrates.
Since little is known concerning the nature of the substance(s)
aifecting the metabolism of carbohydrates and fats which
can be extracted from or are secreted by the pars glandularis,
it is by no means clear whether or not one or more substances
is responsible for the effects, or, indeed, whether the effects
are due to a hormone to which another name has already been
given. Perhaps an anterior pituitary hormone which de-
presses the rate of catabolism of carbohydrate (and increases
the rate of protein anabolism) indirectly necessitates the
mobilization and oxidation of an increased proportion of fat,
so that ketogenesis is facilitated. The outstanding facts con-
cerning the effects of pituitary extract on the metabolism of
fat appear to be (i) large doses of anterior pituitary extract
bring about a deposition of fat in the liver which, in fasted
animals at least, is enriched at the expense of other tissues
and (2) anterior pituitary extract produces ketosis which
probably is associated with the changes described under (i).
(It is generally believed that acetone bodies are formed in
the liver.) It is of great interest that both of these changes
are said to be prevented by adrenalectomy, apparently be-
cause of the removal of the cortex. This, in turn, suggests
that an adrenal cortical stimulating substance is the pituitary
secretion affecting the metabolism of fats.

There still is not a sufficiently large body of data to enable
one to discuss with any assurance the manner in which the
metabolism of proteins is influenced by secretion(s) of the
pars glandularis. It appears that hypophysial deficiency
probably is accompanied by increased catabolism of proteins
of endogenous origin and imperfect utilization of proteins of

[242]

PARS GLANDULARIS AND METABOLISM

exogenous origin, whereas anterior pituitary extract favors
protein synthesis.

Additional reports on the interrelationship of the anterior
pituitary and the metabolism of minerals have been made.
However, there frequently is a lack of agreement. Possible
effects of extracts on the metabolism of water are usually
neglected. There is evidence that the activity of the para-
thyroid glands is regulated to some extent by the pars glandu-
laris. This control appears to be slight and is much less ef-
fective than that exercised over the adrenals, gonads, or
thyroid.

CHAPTER VIII

THE PITUITARY BODY IN RELATION TO THE

REGULATION OF THE DISTRIBUTION OF

PIGMENT IN CHROMATOPHORES

CELLS containing granules of pigment of various
colors may be found in the skin and other tissues
of cold-blooded animals. These cells often are of
great importance in the adaptation of color to background
or in effecting color changes for other purposes — e.g., that
associated with the breeding season. The change of color is
effected by the movement of the granules of pigment,
chromatosomes, in cells which are called chromatophores.
These cells commonly are named in accordance with the
color of the pigment they contain. Melanophores are so
named because they contain melanin-granules for which the
term melanosomes will be used. Likewise erythrosomes refer
to the granules of red pigment in erythrophores, etc.

The pituitary body is of importance in this aspect of bi-
ology because extracts of the pars intermedia (or of the pars
glandularis) may bring about a striking dispersion of chroma-
tosomes, especially melanosomes or erythrosomes. The re-
moval of most of the pituitary may be followed by the oppo-
site effect, e.g., a marked concentration of the melanosomes
may follow hypophysectomy in the frog. In addition. Hog-
ben and his collaborators have inferred that a hormone of the
pars tuberalis is important in certain amphibia in bringing
about adaptation to light backgrounds.

The degree to which the position of pigment-granules in
chromatophores is regulated by the pituitary body varies
greatly in different classes of animals, such as fishes, am-
phibia, and reptiles. The importance of the gland generally

[244]

CHROMATOSOME-DISPERSING HORMONE

is more easily demonstrated in certain amphibia than in
animals of other classes.'

The importayice of the pituitary body in regulating chromato-
some dispersion in fishes. — In fishes hypophysectomy often
is followed by a marked concentration of the melanosomes
(the "melanophore contraction" of some authors). However,
the change appears more sluggishly than in amphibia. Most
of the successful experiments have been performed in various
elasmobranchs. Lundstrom and Bard had shown that the
removal of the neuro-intermediate lobe from the dogfish,
Mustelis canis^ is followed by a marked pallor of the skin
due to the concentration of the melanosomes in the central
part of the melanophores. As a phase of his investigation of
the physiology of the chromatophores of various animals,
Hogben (1936) studied the effects of hypophysectomy in
several elasmobranchs. Figure 26 is reproduced from Hog-
ben's article and illustrates the cutaneous pallor of Rhina
squatina following hypophysectomy. The adaptation of
fishes such as dogfishes {Scy Ilium catulus^ S. canicula)^ the
angel shark {Rhina squatina), and rays {Raia maculata, R.
brachiura) to a black background is abolished by hypophy-
sectomy. However, in some species the operation may not
be followed by as striking a macroscopic effect as is illus-

■ Abramovitz (1936-37) has published several reports extending the observa-
tions of Megasur and of Carlson on the hormone in the eye-stalks of Crustacea. This
hormone appears to be responsible for melanosome dispersion in Crustacea such as
Callinectes, Libinia, Palaemoyietes, and Uca. Extirpation of the eye-stalks of the
crab, Uca, is followed by paleness of the integument (Megasur); if an extract of
eye-stalks be injected into such pale crabs, dispersion of the melanosomes occurs
and the animal becomes dark (Carlson). Abramovitz found that an extract of the
eye-stalks of Palaemonetes vulgaris produces effects similar to those of the chromato-
some-dispersing hormone of the pituitary. This was shown by the dispersion of
the pigment in the melanophores following injection of the extract into Hght-adapt-
ed or hypophysectomized fishes {Anieiurus nebulosus, Mustelis), frogs [Rana
pipiens), or reptiles {Anolis carolinensis). The erythrophores and melanophores of
the dace (Chrosomus erythrogaster) were similarly affected.

The substance responsible for these effects was found to be remarkably stable.
It could survive boiling in water or in aqueous solutions of i per cent HCl or KOH.
It appeared to be soluble in water and in methanol or ethanol — although the extent
to which this is true was not accurately described.

[245]

THE PITUITARY BODY

trated in Figure 26, As in the dogfish, the loss of the neuro-
intermediate lobe is responsible for the failure of the melano-
somes to disperse when the background is black. Hogben is
of the opinion that adaptation of elasmobranchs to light
backgrounds, due to a concentration of the melanosomes, de-

, ^-i

Right

Fig. 26. — The effect of hypophysectomy on the appearance of the adult angel-
shark, Rhina squatina. Left: normal; right: hypophysectomized lo days before.
Both kept continuously in black tank. (From Hogben, Proc. Roy. Soc, B, 120,
142-58 [1936].)

pends upon a secretion from a part of the pars buccalis
homologous with the mammalian pars tuberalis. However,
adaptation to light backgrounds may be slight, e.g., in Raia
clavata. Hogben's results support the general belief that the
pars intermedia of the pituitary body of animals in which it
can be identified morphologically elaborates the secretion

[ ^-46 ]

CHROMATOSOME-DISPERSING HORMONE

causing dispersion of the melanosomes.' In fishes, as in am-
phibia, optic stimuli chiefly determine whether or not the
secretion will be released.

Likewise in elasmobranch fishes, other authors have dem-
onstrated that hypophysectomy is followed by a cutaneous
pallor which persists irrespective of the background. Barry
(1937) described a dogfish {Scylliorhinus canicula)^ the cuta-
neous melanophores of which resembled those of a hypophy-
sectomized fish in respect of the unchanging concentra-
tion of the melanosomes and their rapid dispersion after the
injection of a pituitary extract. However, his description of
the histological appearance of the pituitary body and its re-
lated structures is of little assistance in explaining the phe-
nomenon. The removal of the pituitary from Torpedo
marmorata causes a light coloration of the skin as a result of
melanosome concentration (Veil and May, 1937). Vilter
(1937) attributed the "melanophore contraction" which ap-
pears as a result of hypophysectomy in two rays, Trigon
pastinaca and Raia undulata^ to a pronounced tonus of the
sympathetic nervous system because ergotamine, which may
cause paralysis of sympathetic terminal fibers, brought about
a marked dispersion of the melanosomes in either normal or
hypophysectomized fishes of these species.^

In teleost fishes the role of the pars intermedia in effecting
color changes by means of the melanosome-dispersing hor-
mone is less important and often is difficult to evaluate. Veil
recently stated (1937) that the removal of the gland from the
catfish {Ameiurus) is followed by blanching of the skin, which
can again be made dark by the administration of fish pitui-
tary or an extract of the mammalian posterior lobe. x'\ccord-
ing to Parker (1935), chromatosome dispersion in Ameiurus

^ Neither the oxytocic nor the vasopressor hormone of the pars neuralis is re-
sponsible for melanosome dispersion.

^ For years, epinephrine has been regarded as a substance causing melanosome
concentration. So far as fishes are concerned, it appears that the importance of a
sympathetic innervation of the melanophores is greater in teleosts than in elasmo-
branchs.

[ 247 ]

THE PITUITARY BODY

is effected both by nervous impulses and by the hormone;
however, he regarded the latter as the less important. Parker
believed that melanosome concentration is chiefly under the
control of the (sympathetic) nervous system in both teleosts
and elasmobranchs, whereas in elasmobranchs the dispersion
of pigment-granules is due to a hormone of the pituitary. In
another teleost, Fundulus heteroclitus, both the light and dark
phases of pigment distribution appeared to be regulated by
nerves (Parker). However, Kleinholz (1935) showed first
that the pituitary of Fundulus contains melanosome-dis-
persing hormone as demonstrated by experiments in catfish,
frogs, and lizards, and second, that denervated melanophores
of Fundulus responded in a typical fashion (melanosome dis-
persion) to extracts of the pituitary oi Fundulus^ of the frog,
or of the mammal."^ Such an effect was never observed in
melanophores with a normal innervation. Abramovitz (1937)
concluded that the melanosome-dispersing hormone of the
pituitary probably is of real significance in the physiology
of the melanophores in Fundulus^ despite the fact that adap-
tation to light and dark backgrounds ordinarily is not af-
fected by hypophysectomy. Abramovitz found that the op-
eration prevented the complete dispersion of the melano-
somes of denervated melanophores, when the fish were placed
on a black background.

In other teleost fishes such as Phoxinus laevis the distribu-
tion of pigment in erythrophores is principally affected by
the chromatosome-dispersing hormone of the pars inter-
media. Fleischmann and Kann (1937) injected posterior-
lobe extract into several species of marine fishes {Coris julis,
Crenilabrus pavo^ Serranus scriba^ and Tripterygium nasus)
and found that the changes in coloration strongly resembled
those appearing in fishes in full "wedding dress." They were
unable to detect an effect on the melanophores. Erythro-

" The melanosomes of isolated scales oi Fundulus generally become concentrated,
if the scales are placed in a solution of posterior-lobe extract. Such an observation is
of little assistance for purposes of interpretation.

[248]

CHROMATOSOME-DISPERSING HORMONE

some dispersion in the erythrophores of intact fish or of
isolated scales has again been used in recent experiments for
purposes of assay.

The regulation of chromatosome dispersion in amphibia.^ — ■
Especially in anuran amphibia past work has shown that
adaptation of the skin's color to dark or black backgrounds
chiefly depends upon an internal secretion of the pars inter-
media. After the removal of the pars intermedia (or the
neuro-intermediate lobe), marked aggregation of the melano-
somes takes place, so that animals like the frog remain pale
indefinitely, irrespective of the background. Atwell and
Holley (1936) found that the pars intermedia may be re-
moved from tadpoles, and yet sufficient tissue of the pars
glandularis is spared, so that in such silvery tadpoles com-
plete or partial metamorphosis occurs and normal develop-
ment of the thyroid, gonads, and adrenals takes place. The
authors suggested that the pars intermedia of tadpoles of
Rana syhatica can undergo development without contact
with nervous tissue.

New studies by Hogben and Slome (1936) support their
conclusion that both the white- and black- background re-
sponses of the toad, Xenopus laevis, depend upon hormones.
Their study was limited to the dermal melanophores and
indicated that dispersion of the melanosomes is caused by a
hormone of the pars intermedia, whereas concentration of
the melanosomes is dependent upon an intact pars tuberalis.
Their results are summarized in Table 8. Presumably the
low sensitivity of the melanophores toward the melanosome-
dispersing hormone in animals without a pars intermedia (and
pars neuralis) is due to the pars tuberalis, the effects of the
secretion of which are no longer antagonized by the normal
secretion of the pars intermedia. On the other hand, the
great sensitivity of the melanophores of toads after the re-

s The chromatosome-dispersing hormone can cause dispersion of the pigment-
granules in the melanophores of certain reptiles such as lizards (e.g., Anolis caroli-
nensis [Kleinholz, 1935]).

[249]

THE PITUITARY BODY

moval of all parts of the pituitary body is the result of the
removal of the antagonistic influence of the pars tuberalis.^
According to Jores and Caesar (1935), pigment of the
retina of the frog's eye assumes the dark position at a more
rapid rate, if the eye be treated by a solution of the "melano-
phore hormone" in the dark. Similar treatment of the eye
in the light only rarely is followed by an effect. Hypophysec-
tomy, however, does not alter the movement of retinal pig-

TABLE 8

The Effects of Extirpation of Various Divisions of the Pituitary

Body on the Condition and Response of the Dermal Melano-

PHORES IN Xenopus laevis*

MELANOPHORE-lNDExf ON

Sensitivity

TOWARD

Condition of Toad

White
Background

Black

Background

Melanosome-
dispersing
Hormone

Normal

After removal of the pars glandularis

only

After removal of the pars glandularis

and the pars tuberalis

1-4
14
50
I .0
1.8

4-5
4 5
50
I .0
1.8

+ +

After removal of the pars intermedia
and the pars neuralis

+
+ + +

After removal of all parts of the pitui-
tary body

* From Hogben and Slome, Proc. Roy. Soc, London, B, 120, 158-73 (1936).

t The higher the melanophore-index, the greater the degree of dispersion of the melanosomes, i.e.,
the greater the "expansion" of melanophores.

ment in response to light or darkness in either frogs (Jores
and Caesar, 1935; Matuo, 1935) or toads (Okamato, 1937).
Dubois-Poulsen (1937) also agreed that chromatosome-dis-
persing hormone facilitates the wandering of retinal pigment
into the position characteristic of darkness." The author
used frogs {Rana temporarid) and concluded that epinephrine
less effectively produces a change in the opposite direction.

* The authors also investigated the manner in which optic stimuli affect the
background response. They concluded that the behavior of the melanophores of
toads on white or black backgrounds depends upon retinal localization.

^ See also Matuo (1935).

[250]

CHROMATOSOME-DISPERSING HORMONE

New observations on the pharmacology of melanophores or of
the melanosome-dispersing hormone. — Shen (1937) has studied
the effects of a number of drugs on the behavior of the gran-
ules of pigment in the melanophores of the skin of frogs.
Substances like F 933 and F 883^ bring about marked dis-
persion of the melanosomes, provided that the pituitary is
intact. After hypophysectomy, "expansion" of the melano-
phores does not appear. The conditions under which chlo-
ralosane, nicotine, or yohimbine cause melanosome disper-
sion are similar. Therefore, all these substances appear to
act either by increasing the rate of secretion of the hormone
or by markedly potentiating its peripheral effects or by both
mechanisms. Shen found that melanosome concentration is
reversed by F 933, if it is due to epinephrine but not if it fol-
lows stimulation of "pigmento-motor" nerves. Hence, in
respect of a congregating effect on the melanosomes, he de-
scribes F 933 as a substance which is adrenolytic but not
sympatholytic. The injection of either atropine sulphate or
ergotamine tartrate into normal frogs adapted to a dark
background is followed by paling;' in hypophysectomized
frogs, however, either drug causes some melanosome disper-
sion. The author's experiments yield no specific information
on the possible importance of effects on the secretion or
peripheral action of a hormone of the pars tuberalis in rela-
tion to melanosome concentration. Hypophysectomy does
not affect the dispersion of the melanosomes which is the re-
sult of the administration of amyl nitrite, chloroform, ether,
or strychnine.

According to Jores (1935), the injection of extract contain-
ing melanophore hormone into rabbits by either an intra-
ventricular or an intravenous route is followed by a fall in

*F933: piperidino-methyl-3-benzodioxane; F 883: diethylamino-methyl-3-ben-
zodioxane.

'The injection of ergometrine," Ephetonin" (synthetic ephedrine), or lobeline is
followed by a similar effect.

[251]

THE PITUITARY BODY

body-temperature (o?7-o?8 C.) and arise in the concentra-
tion of sugar in the blood. Atropinization or treatment by
"Somnifen" lessened or abolished the apparent depressing
effect on temperature. Both Jores (1936) and Parhon and
Cahane (1936) reported that the repeated administration of
epinephrine to rats is followed by an increase in the amount
of melanosome-dispersing hormone in the pituitary body."
Jores attributed this change to a corresponding hypertrophy
of the pars intermedia. In the mouse, on the other hand, a
single large dose either of epinephrine or of "Cortidyn" (an
extract of the adrenal cortex) caused an immediate reduc-
tion of the amount of melanosome-dispersing hormone in the
pituitary. Jores also found that similar treatment of the
rabbit or of man brought about an acute fall in the concen-
tration of melanophore hormone in the blood. ("Cortidyn"
alone or in combination with epinephrine had the same action
in rats as epinephrine.)

Melanosome-dispersing hormone in relation to the metabolis?n
of water. — The belief of some observers, such as Sulzberger,
that the chromatosome-dispersing hormone (or some other
new principle) of the pars intermedia is an agent capable of
inhibiting diuresis cannot be accepted. Bottger (1936) even
called this substance "adiuretin," but his evidence that it
differed from the vasopressor principle of the pars neuralis
consisted of comparisons of vasopressor and antidiuretic ef-
fects of extracts. Later (1937), he agreed that chromatosome-
dispersing hormone is diuresis-inhibiting in proportion to its
contamination by the vasopressor principle. Dischreit (1935)
was unable to produce diuresis inhibition by "Intermedin"
free from vasopressor hormone, although he used much
larger doses, in terms of melanosome-dispersing hormone,
than did Sulzberger. Eraser (1937) also was convinced that

" Parhon and Cahane believed that testicular or corpus luteum hormone po-
tentiates the action of melanosome-dispersing hormone, whereas thyroid hormone
or oestrin is without such action.

[252]

CHROMATOSOME-DISPERSING HORMONE

the vasopressor principle is responsible for any antidiuretic
effects of chromatosome-dispersing hormone."

The metabolism of chromatosome-dispersing hormone. —
Chromatosome-dispersing hormone can be detected in the
urine of normal men and women. It appears with increased
frequency in the urine of pregnant women; this fact, how-
ever, does not make tests for its presence of much value in
diagnosing pregnancy (see p. 127, n. 5).

Lewis, Lee, and Astwood (1937) have extended the obser-
vations of others on the distribution of chromatosome-dis-
persing hormone in the pituitary body and adjacent struc-
tures of cattle. The unit used by them was the minimum
amount of material causing an erythrosome dispersion in all
fish {Phoxinus laevis) receiving that dose.'^ The error of
assay apparently was high. Their estimate of the concentra-
tion of the hormone in various parts of the gland was as fol-
lows (all figures refer to units per gram fresh tissue) : pus-
like material in cleft consisting chiefly of desquamated cells
of the pars intermedia, 270,000; pars intermedia, 255,000;
colloid in cleft, 123,000; pars neuralis, 33,000; pars glandu-
laris, 20,000-31,000; inferior part of stalk, 3,500; superior
part of stalk, 300; tuber cinereum, 30; region about third
ventricle, 12; cerebrospinal fluid, o. The authors concluded
that typical basophils could not be responsible for the secre-
tion of the hormone by the pars intermedia, inasmuch as
these were absent from that division of the gland. Their re-
sults are in agreement with the best data which had been
gathered previously: in the pituitary of the ox, the chroma-
tosome-dispersing hormone is secreted by the pars inter-
media. Posterior-lobe extract contains the hormone because

" Jones and Steggerda (1935) could detect no change in the rate of loss of weight
of frogs in water in relation to color adaptation to light, dark, or neutral back-
grounds. In fact, hypophysectomized frogs lost weight at a similar rate.

" Bottger (1937) assayed chromatosome-dispersing hormone by using the isolated
fin of male specimens of Phoxinus laevis. He observed microscopically the number
of erythrophores affected as well as the degree of dispersion of the erythrosomes.
Maximum effects occurred in 30-45 minutes. The error of determination was be-
lieved to be ±20 per cent.

[ ^:}> ]

THE PITUITARY BODY

it is commonly made from tissue containing the pars inter-
media and because the hormone readily diffuses into it and
into other parts of the pituitary body. It is interesting that
Lewis and his colleagues could furnish no support for the
view, which has been popular with some European authors,
that chromatosome-dispersing hormone may be secreted by
way of the stalk into the cerebrospinal fluid.

The chromatosome-dispersing hormone is secreted by cells
of the pars buccalis. In animals in which the pars intermedia
can be identified morphologically there can be little doubt
that that division of the pars buccalis secretes the hormone.
In animals like the whale in which no pars intermedia can
be found, the hormone can be extracted from the pars glandu-
laris (Geiling, 1935). Fisher (1937) reported that in the pos-
terior lobe of the pituitary of cats in which marked atrophy
of the pars neuralis had been produced experimentally, there
appeared to be no reduction in the amount of chromatosome-
dispersing hormone as determined by the response of the
melanophores of frogs or the erythrophores of the red-bellied
dace {Chrosomus erythrogaster)^^ The atrophied pars neuralis
contained no oxytocic or vasopressor (and diuresis-inhibiting)
hormone. The results of Geiling and Lewis (1935) also in-
dicated that the pars intermedia is the site of formation of
the chromatosome-dispersing hormone. The authors under-
took to make tissue cultures of the pars glandularis, the pars
intermedia, or the pars neuralis of the mouse and rat. The
pituitary of the mouse was preferred as a source of the tissues
because the various divisions could be separated more com-
pletely. After culture for 50 days, the pars intermedia con-
tained chromatosome-dispersing hormone but no vasopressor
hormone, indicating that the latter is not secreted by the
pars intermedia. Both hormones could be detected in cul-
tures of the pars neuralis not entirely free from pars inter-

'■5 Fisher was not satisfied that accurate results could be obtained by the use of
this fish,

[ ^-54 ]

CHROMATOSOME-DISPERSING HORMONE

media. Cultures of the pars glandularis contained neither
chromatosome-dispersing hormone nor vasopressor hormone.

Jores (1935) was convinced that melanophore hormone ac-
cumulates in the pituitary of mice kept in darkness (1.45
units), whereas the amount falls rapidly when animals are
exposed to light (0.27 unit). Responsibility for this change
appeared to rest chiefly with light of shorter wave-lengths
(blue), although exposure of mice to yellow and red light was
followed by a slower and less pronounced reduction.

According to Rodewald (1935), if frogs are kept in dark-
ness, their blood contains a substance "binding" chromato-
some-dispersing hormone. The author believed that this sub-
stance is closely associated with the erythrocytes. It was
not found in the blood of light or dark frogs exposed to light.
Rodewald believed that two mechanisms operate to prevent
any action of chromatosome-dispersing hormone in frogs
kept in darkness: (i) no hormone is formed by the pituitary
body,'-* and (2) a substance inactivating the hormone is lib-
erated into the blood. Jores and Hoeltje (1936) believed that
they confirmed the observation of Rodewald. Their results
varied greatly and the differences found appear to be small.
However, the authors reported that the blood of mammals
(the rabbit and man) kept in darkness does not contain the
inactivating substance but, on the other hand, seems to con-
tain a higher concentration of the hormone itself. Later,
Rodewald (1936) reported that the serum of patients with
cancer contains a substance binding (or inactivating) melano-
phore hormone. Such a result was obtained by the use of the
serum of 105 of 109 patients investigated (96 per cent). The
reaction of the serum was positive in 2 of 50 pregnant women
(4 per cent) but was negative in patients with carcinoma of
the skin.

New observations on the chemistry of the chromatosome-dispers-
ing hormone. — ^Among principles which can be extracted from

'•• A change in the opposite direction was recorded by Jores, who used mice.

[ 255 ]

THE PITUITARY BODY

the pituitary body, none withstands chemical manipulation
better than the chromatosome-dispersing hormone. The hor-
mone is soluble in dilute aqueous solutions of acid or alkali
and in certain organic solvents such as methanol and ethanol.
Like the hormones of the pars neuralis, it is not destroyed by
boiling in acidified water. However, it is remarkable that
the hormone not only survives treatment by, or boiling in,
fairly strong alkaline solutions, e.g., N/io, but also that its
effects appear to be much more pronounced after this treat-
ment, as was first shown by Hogben and Gordon. Bottger
(1937) believed that after alkali has acted upon the hormone,
the latter is metabolized more slowly, as shown by changes
in the intensity and duration of its effects. According to
Stehle (1936), the hormone is altered qualitatively, i.e., the
initial effect is less intense but the duration of action is much
longer. The degree of potentiation of the action of the hor-
mone as a result of treatment by alkali has not been exactly
defined. Stehle is of the opinion that it is much greater than
Jores' estimate of 200-300 per cent. According to Abramo-
vitz (1937), the chromatosome-dispersing effect of the pitui-
tary o{ Fundulus is increased about twenty-five fold by boil-
ing in N/io NaOH.

It is probable that the same hormone causes dispersion of
both melanosomes and erythrosomes. This view has recently
been supported by Bottger (1937). New methods of purifying
chromatosome-dispersing hormone have been described by
Stehle (1936) and Bottger (1937). Stehle's product was about
twenty-five times as active as International Standard Powder
(posterior-lobe).

SUMMARY

The pituitary body or homologues of its divisions may be
of great importance in the regulation of the distribution of
pigment-granules in chromatophores of cold-blooded animals.
Almost all the detailed studies are concerned with melano-
phores (fishes, amphibia, reptiles) and erythrophores (fishes).

[256I

CHROMATOSOME-DISPERSING HORMONE

Chromatosome dispersion is caused by a secretion of the
pars intermedia or of the pars glandularis in animals other-
wise lacking the anatomical equivalent of the pars inter-
media.'^ The experiments of Hogben and Slome suggest that
a secretion of the pars tuberalis causes the opposite effect —
a concentration of the chromatosomes.

The significance of the chromatosome-dispersing hormone
in vertebrates with functional chromatophores varies greatly.
In some fishes, e.g., dogfishes, the hormone may be the prin-
cipal means of chromatosome dispersion and, hence, of adap-
tation to dark backgrounds. In others, such as the catfish,
nerves also play a part in melanosome dispersion. Finally,
in a teleost fish like Fundulns^ the hormone is present in the
fish's pituitary but plays a negligible part in the regulation
of chromatosome distribution, which is largely under the con-
trol of nerves. In the fish Phoxinus laevis the erythrophores
and xanthophores are more specifically affected by the
chromatosome-dispersing hormone than the melanophores.
In amphibia like the frog the hormone appears to be the
principal means of effecting dispersion of melanosomes. The
action of the hormone in some reptiles — e.g., the lizard,
Anolis carolinensis — may be similar, but its importance in
normal animals has not been precisely investigated. Disper-
sion of either melanosomes or erythrosomes appears to be
due to the same hormone.

The chromatosome-dispersing hormone can be extracted
from the mammalian pars intermedia or pars glandularis. A
substance with similar properties has been recovered from
the blood and urine of mammals. If the substance has a
function of importance to mammals, this has not been con-
vincingly demonstrated. There probably is no foundation for
the belief that melanosome-dispersing hormone can inhibit
diuresis.

'sThe eye-stalks of Crustacea appear to be homologous with the pars intermedia
in this respect.

257

CHAPTER IX

NEW OBSERVATIONS ON THE CHEMISTRY

AND PHARMACOLOGY OF EXTRACTS

OF THE PARS NEURALIS

THE purpose of this chapter is to review recent in-
vestigations of the chemistry and pharmacology of
extracts of the pars neuraHs. There is no satisfactory
additional evidence that more than two hormones — the oxy-
tocic hormone and the vasopressor or diuresis-inhibiting hor-
mone— are secreted by the pars neuralis. The advances
which have been made in elucidating the cellular origin of the
hormones are described in chapter i. The physiological im-
portance of these hormones is discussed in chapter x.

The chemistry of the active principles. — The isolation of
either the oxytocic or the vasopressor principle as a pure,
crystalline substance is a goal yet to be attained. Stehle and
Eraser (1935) have described new methods for separating
and concentrating both hormones. However, these methods
are too complicated for detailed review here. The authors
found that, after the removal of most of the impurities, both
of the hormones are soluble in 96 per cent methanol. Subse-
quent separation and concentration of the hormones was ef-
fected by the addition of ethyl acetate to solutions of both
or one hormone in methanol (96 per cent) or ethanol {ca. 98
per cent). The pressor hormone was concentrated to about
100 times the value of International Standard Powder, the
oxytocic hormone to about 125 times that value. Therefore,
the potency of the preparations of Stehle and Eraser was
about the same as that of the extracts of Kamm and his
colleagues (1928). Tests for various amino-acids in the puri-
fied extracts were reported. The depressor substances in the
posterior lobe were studied by Larson (1936), who attributed

[ 258 ]

EXTRACTS OF THE PARS NEURALTS

most of the depressor action to histamine. This organic base,
of course, was isolated from the posterior lobe years age.'

Gulland and others (1935) have particularly studied the
oxytocic principle. They were unsuccessful in attempts to
employ adsorbents to effect a high degree of purification.
Electrodialysis also was found not to be of value. At pH
6.0-6.5 °^ ^^^^ ^^^ hormone migrated toward the cathode;
at a higher pH (8 or greater) the hormone remained in the
central cell. No ultraviolet absorption spectrum characteris-
tic of the hormone could be detected.

Gulland and Randall, Freudenberg, Weiss, and Biller, and
Sealock and Du Vigneaud all published in the same year
(1935) evidence that posterior-lobe hormone(s) contain an
oxidation-reduction system probably dependent upon a di-
sulphide linkage. According to Gulland and Randall, the
E'o of the oxytocic principle is —0.025 volts at pH 6. They
found the activity of the principle to be 100 per cent in the
oxidized state and 50 per cent in the reduced state and of-
fered an interpretation of this finding. Also, they suggested
that there may be a second oxidation-reduction system in
the molecule of the oxytocic hormone. Sealock and Du
Vigneaud concluded that an -SH group, real or potential
(-S-S-group), must be present in active extracts of either
oxytocic or vasopressor hormone. Activity was preserved
after reduction by cysteine or after reoxidation following such
reduction but not after benzylation or methylation of the re-
duced compounds. The activity of the oxidized forms was
not affected by treatment with methyl iodide or benzyl
chloride. The activity of the oxytocic and vasopressor prin-
ciples seems to be less dependent on the state of their oxida-
tion-reduction systems than is the case with insulin.

The assay of the active principles of the pars neuralis. — In
addition to the procedures reviewed previously, a few new
methods have been employed for the assay of the hormones.

' It is not clear whether the chenical studies of Downes and Richards (1935) are
of any significance,

[^59]

THE PITUITARY BODY

Sealock and Du Vigneaud (1935) assayed the oxytocic prin-
ciple by means of its depressor action on the blood pressure of
fowls. As the authors point out, troublesome difficulties due
to the action of foreign substances (such as those used for
chemical manipulation of the hormone) may appear if the
isolated guinea pig uterus be employed, whereas these sub-
stances may be without effect on the fowl's blood pressure.
In addition, several authors have introduced refined methods
of determining oxytocic effects both in vitro and in vivo.

For the assay of the vasopressor principle, Simon (1937)
recommends that the effect on the blood pressure of the de-
capitated rat be determined. By this method as little as
0.0025-0.005 unit (0.00125-0.0025 mg. equivalent of Inter-
national Standard Powder) can be detected. Small doses of
histamine were found to be without action. The most sensi-
tive test for vasopressor (diuresis-inhibiting) hormone is
based upon the inhibition of water diuresis in the non-
anesthetized dog. If the extract be given intravenously, as
little as 0.0001-0.0003 unit may cause a recognizable effect.

The pharmacology of the oxytocic principle.^ — Newton
(1934, 1937) found that the cervix of the uterus of the preg-
nant goat or of the rat and guinea pig in pregnancy or in
other stages of sexual activity is very insensitive toward the
oxytocic principle in comparison with the uterine cornua.
According to the findings of Li (1935), the isolated fallopian
tube of the monkey is much more sensitive toward posterior-
lobe extract during the secretory (corpus luteum) or men-
strual phases of the uterus than during the proliferative (fol-
licular) phase. Also, spontaneous activity of the fallopian
tube tended to be lower during the growth of the ovarian
follicle.

^ The intact, but not the isolated, uterus of the cat, dog, or rabbit relaxes and
becomes quiescent in response to the administration of vasopressor hormone. This
effect is most readily observed in animals which have received oestrogen previously
and is said not to appear if the uterus is pregnant (cat and dog). Robson and
Schild (1937) believed that the effect should not be attributed to the vascular action
of the hormone (see also Azuma and Kumagai, 1935; Robson, 1936; and Morgan,
1937, as well as earlier reports previously reviewed.)

f 260I

EXTRACTS OF THE PARS NEURALIS

Nearly all the other observations on the pharmacology of
the oxytocic principle were made to ascertain the uterine re-
sponse after the secretion or injection of oestrogen or pro-
gesterone or both. For example, under the influence of oes-
trogen the uterus of some species of animals may exhibit a
heightened sensitivity toward the oxytocic principle. Abor-
tion, as shown by Parkes in the pregnant mouse, may occur
after the administration of oestrogen followed by oxytocic
principle, although either substance by itself does not inter-
rupt pregnancy. To some authors (e.g., Druckrey and Bach-
mann, 1937) it has seemed that these and related observa-
tions satisfactorily explain the initiation of parturition and
perhaps its continuation. However, the experimental basis
for such a belief is far from satisfactory.^ The later experi-
ments of Marrian and Newton (1935) and of Robson (1935)
in pregnant mice fully confirm Parkes's findings. The in-
creased sensitivity to oxytocic principle after the administra-
tion of oestrogen can also be observed in the isolated uterus.-*
From experiments in other animals^ such as the rabbit and
man there is also evidence that both spontaneous activity of
the uterus and its sensitivity toward the oxytocic principle
are increased when follicular hormone (oestradiol) is pre-
dominantly affecting the uterus. The specificity of this in-
creased sensitivity has not been proved. For example, ergot-
amine, like posterior-lobe extract, has been found to elicit
uterine contraction more readily during ovarian follicular
growth.

Undoubtedly, the uterus of the rabbit is less sensitive
toward the oxytocic principle during pseudopregnancy or

•i The reader is particularly referred to the articles of Marrian and Newton (1935),
D'Amour and Dumont (1937), and Robson (1937).

■"The isolated pregnant uterus of the mouse or rabbit is more sensitive toward
the oxytocic principle after ovariectomy but not if the uterine contents also have
been removed (Robson, 1936).

5 Robson and Henderson (1936) reported that the oxytocin-sensitivity of the
uterus of the hypophysectomized dog is, if anything, reduced after the administra-
tion of oestrin.

[261I

THE PITUITARY BODY

during much of pregnancy — an effect which is usually attrib-
uted to the internal secretion of the corpus luteum, proges-
terone. The effect can be produced in rabbits, spayed im-
mediately after mating, by the injection of 4-5 mg. of natural
or synthetic progesterone distributed over 5 days (Make-
peace, Corner, and Allen, 1936). No corresponding decrease
in the sensitivity of the urinary bladder or colon was ob-
served by Podleschka and Dworzak (1936), who used pos-
terior-lobe extract; their results, therefore, have no apparent
significance. Robson (1935-36) found that it was difficult
to demonstrate any change in the activity of oxytocic hor-
mone on the uterus of pregnant or pseudopregnant rabbits
as a result of the administration of oestrogen.

It is probable that the decreased oxytocin-sensitivity of
the pregnant or pseudopregnant rabbit's uterus has no gen-
eral significance. When the uterus of other animals is under
the influence of the corpus luteum, there may be no evidence
of diminished uterine sensitivity. This is true of the cat (van
Dyke and Li, 1938), guinea pig (Bell and Robson, 1936),
mouse and rat (Brooksby, 1937). From observations previ-
ously reviewed, as well as from new experiments, it may be
concluded that the human uterus likewise is not less sensi-
tive toward the oxytocic principle during the luteal phase of
ovarian secretion. Although Kraul (1935) and Podleschka
(1935) believed that the oxytocin-sensitivity of the uterus is
reduced in the latter part of the menstrual cycle, their find-
ings were not confirmed by the experiments of Kurzrok and
others (1937), Miller, Cockrill, and Kurzrok (1937), and
Robertson (1937).

Androsterone appears not to affect the sensitivity of the
rabbit's uterus toward posterior-lobe extract (van Bokkum,

1936).

The pharmacology of the vasopressor hormone apart from its
metabolic effects.- — Following the intravenous injection of pos-
terior-lobe extract or of an extract containing principally the
vasopressor principle, a contraction of capillaries and arteri-

[262]

EXTRACTS OF THE PARS NEURALIS

oles takes place as shown most simply by a rise in the blood
pressure. The degree and the duration of the contraction
depend to a considerable extent on the dose administered.
Moreover, the vascular spasm produced may affect the coro-
nary vessels, especially the left coronary artery,^ so that
tachycardia, disturbances of conduction, and cardiac dilata-
tion appear. As a result, the blood pressure may fall initially
but rises later as the coronary circulation is adequately re-
established and an increased or normal volume of blood is
pumped against the increased peripheral resistance. This
effect on the heart may or may not be observed, if small
doses of vasopressor principle are used. If posterior-lobe ex-
tract is injected, it may be absent or less evident, perhaps
because the oxytocic principle antagonizes the action of
vasopressor principle on the coronary arteries.

According to Watrin and Frangois (1937), repeated sub-
cutaneous injections of posterior-lobe extract may be followed
by cardiac hypertrophy in the guinea pig. The doses used
(4-10 units on alternate days for 49-90 days) were large
enough to cause convulsions occasionally. The maximum
change observed was represented by a cardiac weight of 2.75
gm. (The weight of the heart of control animals was about
1.6 gm.) Enlargement of the heart was found to be due
to hypertrophy, not hyperplasia, of the muscle fibers. The
toxicity of vasopressor principle is known to be increased
after the administration of thyroid extract, chiefly because
of a change in cardiac response. Gruber, Moon, and Sufrin
(1935) reinvestigated this problem by studying the electro-
cardiographic abnormalities in non-anesthetized rabbits. The
histology of the hearts was also described.

Byrom (1937) injected enormous doses of vasopressor
principle (5-40 units once or twice daily for 2 days or longer)
subcutaneously into rats. Apparently marked arterial spasm
locally gave rise to such pathological changes as infarction
and necrosis in the kidneys, liver, etc. Like other authors,

^ See the recent articles by Frommel and Zimmet (1937).

[ 263 ]

THE PITUITARY BODY

Byrom was impressed by the analogy between the effects of
the vasopressor principle and the symptoms and pathology
of eclampsia. Later (1938), he observed that the prior in-
jection of oestrogen sensitized the rat toward the vasopressor
principle, so far as the production of eclampsia-like changes
in the kidneys are concerned. The author believed that this
later finding strengthens the view that the vasopressor hor-
mone is etiologically important in eclampsia.

Several authors have published new reports on the action
of posterior-lobe extract or of purified vasopressor principle
on the medulla^ If 5-10 units be injected intracisternally
into the dog, a pressor effect immediately appears, probably
because of stimulation of bulbar centers such as the vaso-
motor center. In comparison with intravenous injection, (i)
the pressor effect is less pronounced but persists longer in
terms of the rise in blood pressure and (2) a preliminary fall
(coronary constriction) is not observed. It is probable that
the effects cannot be attributed to the absorption of the hor-
mone into the blood stream.

In the experiments of Daly, Mark, and Petrovskaia (1937)
posterior pituitary extracts were added to the blood used
to perfuse the lungs of dogs. A suitable period later it was
found that there was a reversal of the usual action of epineph-
rine on the bronchi — i.e., broncho-constriction instead of
broncho-dilatation was produced. This effect was prevented
by ergotoxine. The extracts, of which "Pitocin" appeared
the least active and "Pituitrin" the most active, also poten-
tiated the action of epinephrine on the vascular system of the
lungs.

Among new observations on the effects of posterior-lobe
extracts on the eye are those of Holtz and Jancke (1936).
Only the vasopressor principle was found to cause definite
changes. For example, the instillation or subconjunctival in-
jection of a large dose of the hormone (10 units) caused a

7 Van Bogaert, Sacchi (1935); Deleonardi, Seligsohn (1936).

[264]

EXTRACTS OF THE PARS NEURALIS

fall in intraocular pressure and a miosis which was present
after the administration of 2 drops of i per cent atropine
sulphate. The fall in intraocular pressure apparently was
due to vasoconstriction.

Reports on the action of posterior-lobe extract or of vaso-
pressor principle on the movements of the gastrointestinal
tract appear to require only brief mention.^ Posterior-lobe
vasopressor extract appears to be of considerable clinical
value in stimulating peristalsis of the lower part of the small
intestine and of the colon.

It seems unlikely that the enormous doses of vasopressor
principle — e.g., 200 units subcutaneously in rabbits — used by
Dodds and his colleagues to produce gastric lesions such as
hemorrhage and ulceration are of any etiological significance
in the formation of such lesions under other circumstances.'
Large doses of posterior-lobe extract did not cause gastric
lesions in the guinea pig (McFarlane and McPhail, 1937).
Various studies of Dionessov (1936), Ejdinova (1936), Lan-
geron, Paget, and Danes (1936), Merkulow (1936), and Cut-
ting and others (1937) on the secretion of saliva, gastric juice,
succus entericus, and pancreatic juice indicate that the effect
of vasopressor principle is largely or entirely due to its vaso-
constrictor action on the blood vessels supplying the glandu-
lar secreting cells.

The effects of posterior-lobe extracts on the metabolism of
water and minerals. — The important changes in the metabo-
lism of water and minerals following the injection of an ex-
tract of the posterior lobe are usually attributed to the vaso-
pressor principle. In anesthetized or, under certain condi-
tions, in non-anesthetized animals, the principal effect is an
increased rate of urinary secretion which recently has been
attributed to a change in the metabolism of salt, for which
water is required for renal excretion. In non-anesthetized

' De Biasio (1935), Guthrie and Bargen (1936), Melville, Necheles, and others
(1936), and Frazier (1937). See also Schofield and Blount (1937).

' See also Laporta, Pepe, and Marinelli (1936).

[265]

THE PITUITARY BODY

mammals water diuresis is markedly and specifically in-
hibited by the vasopressor principle; simultaneously certain
salts, particularly NaCl, are excreted at an increased rate.
Diuresis inhibition usually is attributed to an increased re-
absorption of water by the tubular epithelium of the kid-
neys (loop of Henle?). In addition, however. Eraser (1937)
has found that the oxytocic principle appears to cause an
increased secretion of urine in both "hydrated" and "nonhy-
drated" rats without clearly affecting the chloride in the urine.
Eraser could not demonstrate any diuretic effect of oxytocic
principle in the non-anesthetized dog with a fistula of the
bladder. (Whether or not water was administered is not
stated.)

The observations of Unna and Walterskirchen (1935-36)
were made in non-anesthetized dogs with a permanent fistula
of the bladder. Of particular interest is their report on
Leerdiurese. The animals'" were fasted 16-20 hours but were
allowed water until 2 hours before the experiment. The in-
jection of as little as 0.01 unit of posterior-lobe extract sub-
cutaneously or o.oooi unit intravenously could cause a defi-
nite increase in the excretion of CI. If a diuresis appeared, it
was thought to be caused by the CI excreted. Both the CI
excretion and the diuresis were higher if the diet was high
in CI; likewise they were low in animals on a low CI diet.
Also Melville (1936) was of the opinion that a "salt-mobiliz-
ing" action is responsible for any diuretic action of vaso-
pressor hormone. In anesthetized or non-anesthetized dogs,
the diuretic effect of extract could be increased by the ad-
ministration by mouth or by intravenous infusion under
anesthesia of solutions of NaCl, KCl, or KNO3 but not
Na.SO,."

Eurther investigations of the mechanism of the diuresis-

'" Dogs weighing 6-12 kg.

" See also Frey (1937) for a discussion of factors influencing the diuretic action
of posterior-lobe extract. PVey believed that increased glomerular filtration accounts
for the change. It is not possible to state that this view is correct.

[266I

EXTRACTS OF THE PARS NEURALIS

inhibiting effect of vasopressor principle (either as purified
principle or as a simple extract of the pars neuralis) have
been reported in the past few years by Samaan (1935),
Handovsky and Samaan (1936), and Walker, Schmidt, El-
som, and Johnston (1937). Samaan confirmed previous ob-
servations on the lack of effect of renal denervation on di-
uresis inhibition due to the hormone. He found that pos-
terior-lobe extract could cause very constant effects under
standardized conditions. The extract caused no effect on
the secretion of urine in dogs receiving repeated large doses
of a solution of urea. The other authors reported on the be-
havior of the renal blood flow in non-anesthetized dogs and
rabbits and in anesthetized dogs as revealed by the thermo-
stromuhr. It appears that Handovksy and Samaan injected
extract intravenously and found that the renal blood flow
might or might not diminish during diuresis inhibition be-
cause of the extract. Walker and his colleagues used only
non-anesthetized dogs and rabbits into which they injected
extract subcutaneously. No change in renal blood flow oc-
curred in association with the inhibition of diuresis.

If a large enough dose of vasopressor principle is injected
subcutaneously into the non-anesthetized animal, hydremia
is observed as in the experiments of Yanagi (1936). The
author also found that the concentration of K in plasma is
increased'^ and suggested that vasopressor extract brings
about a transfer of water and K from the interior of cells
to the extracellular fluid. '-^ Anemia due to the injection of
large doses of posterior-lobe extract was first reported by
Dodds and his colleagues who used rabbits. It can also be
produced in normal or hypophysectomized guinea pigs (Mc-

"2 According to Blazso (1936), this change is observed in anesthetized animals,
whereas the opposite change — i.e., decreased concentration of K in serum — takes
place in the absence of anesthesia.

'^ The skin, which is important as a depot for chlorine, is believed by Toxopeus
(1935) t^o deposit less of the element after the administration of NaCl if posterior-
lobe extract also is injected. In addition, the author studied the chlorine of muscle
without much success.

[267]

THE PITUITARY BODY

Farlane and McPhail, 1937). Oilman and Goodman (1935,
1937) attributed the effect to marked water retention, so
that dilution of the blood renders the environment of the
erythrocytes so unfavorable that a hemolytic anemia is pro-
duced. Using rats, Arnold and Marx (1937) observed hemo-
globinuria which they also believed to be due to intravascular
hemolysis. Arnold and Marx administered subcutaneously
15 units of posterior-lobe extract for each 100 gm. of body-
weight.

In patients with edema chiefly caused by renal disease con-
siderable excess water can be removed during the diuresis
which follows diuresis inhibition induced by vasopressor prin-
ciple (McQuarrie, Thompson, and Ziegler, 1936). "Pitres-
sin" was repeatedly injected, until the retention of water
was represented by an increase of 3-4 per cent in weight.
Administration of the hormone was then stopped abruptly.
During the subsequent diuresis, edema fluid often was re-
moved, especially if the diet was low in NaCl. The balance
of NaCl was negative during both phases of renal secretion,
whereas that of K, Ca, P, and N appeared not to be efi^ected.'^

It will be recalled that, if frogs are kept in water, the in-
jection of posterior-lobe extract promotes the transfer of
water through the skin (and perhaps its retention), so that
the body-weight increases. In confirmation of earlier work,
Oldham (1936) found that the oxytocic principle is 2.5-5.0
times as efl^ective as the vasopressor hormone in causing this
efi^ect. The chromatosome-dispersing hormone probably is
not a factor (Jones and Steggerda, 1935; Oldham, 1936).
There is no agreement as to the action of posterior-lobe ex-
tract on the kidneys of the frog. Rey (1935) concluded that
diuresis inhibition can be produced in either dry or wet frogs
by a large dose of extract (about i unit injected into the

'■* See also the preliminary report of Smith and MacKay (1936), who studied the
action of posterior-lobe extract on the intake and urinary excretion of NaCl in a
normal man and in a patient with diabetes insipidus. Beltrametti (1935) believed
that oestrogens or androgens favor the secretion of vasopressor hormone and thus
are useful in the treatment of diabetes insipidus.

[268]

EXTRACTS OF THE PARS NEURALIS

lymph sac). On the other hand, Granaat and Hillesum (1937)
reported that doses of "Pitressin" which cause retention of
water absorbed through the skin were without appreciable
effect on the secretion of urine. If posterior-lobe extract pro-
duces anuria in frogs, it probably arrests the circulation of
blood in the glomeruli ( Adolph, 1936).

The effects oj posterior-lobe extracts on the metabolism oj car-
bohydrates.— It is not yet known to what substance the prin-
cipal effects of posterior-lobe extract on carbohydrate
metabolism should be attributed. In the rabbit, at least, ex-
tracts rich in the vasopressor principle usually appear to be
the most powerful both in causing an elevation of the level
of the blood sugar and in antagonizing the hypoglycemic
action of insulin or the hyperglycemic action of epinephrine.'^
In this last case the vasopressor hormone perhaps facilitates
liberation of insulin; however, there may be a simpler ex-
planation such as an effect on the absorption of epinephrine.
According to Ellsworth (1935-36), who confirmed the re-
sults of others in rabbits, it is the oxytocic fraction and not
the vasopressor fraction which is responsible both for the
production of hyperglycemia and for the antagonism of insulin
in the dog. Moreover, Ellsworth found that the effect of the
purified oxytocic extract in the dog was produced by much
smaller doses (in terms of units) than are necessary to cause
corresponding changes in the rabbit, which apparently is
sensitive only to the vasopressor principle. Further studies
are greatly needed to decide conclusively whether or not the
action on carbohydrate metabolism is caused by some sub-
stance not identifiable otherwise.

Experimental work in animals indicates that hypergly-
cemia or insulin antagonism caused by posterior-lobe extract
is the result of an action on the liver from which an increased
quantity of glucose is liberated into the hepatic veins and
thence into the general circulation because of glycogenolysis

's See the recent article of Gurd (1934).

[269]

THE PITUITARY BODY

(see reports such as those of Clark, 1928, and of Hogler and
Zell, 1935). However, it is the opinion of Cohen and Lib-
man (1937), who performed their experiments in healthy
men, that posterior-lobe extract lessens the utilization of
glucose by the tissues and thus antagonizes the action of
insulin. This belief arises from the following observations
and reasoning: in comparison with the results of injecting
only glucose, the injection of both glucose and posterior-lobe
extract is followed by a longer and more pronounced rise in
the level of the sugar of the blood; at the height of the effect
the arteriovenous difference in the concentration of sugar
in the blood is reduced; the arteriovenous difference in the
level of the blood sugar is an index of the activity of insulin,
which should be secreted at an increased rate in response to
the hyperglycemia.

According to Ferrannini (1937), poisoning by phlorhizin
in the rabbit affects only slightly the diuresis-inhibiting ac-
tion of posterior-lobe extract. The latter in turn appears not
to influence the glycosuria.'^

Other effects of posterior-lobe extracts on metabolism. — Biihler
(1935) reported that oxytocic extract can cause creatinuria
in dogs or rabbits to disappear. In the toad, Xenopus laevisy
neither the injection of posterior-lobe extract nor the re-
moval of the pars neuralis seems to affect the creatine of
muscle (Shapiro and Zwarenstein, 1937).

Blotner (1935) concluded that posterior-lobe extracts,
after administration intranasally, prevent the rise — or even
cause a fall — in the concentration of cholesterol in the plasma
of patients with obesity or diabetes insipidus to whom 500 cc.
of "20 per cent" cream had been given.

Some recent observations on the metabolism of the principles
of the pars neuralis. — As is the case with anterior pituitary
gonadotropic extracts, certain salts of metals delay absorp-
tion and thus prolong the action of the hormone(s). Dodds

'^ The effect of posterior-lobe extract on the glucose, CI, and protein of the
blood of normal and diabetic persons was investigated by Dell'Acqua (1935).

f270l

EXTRACTS OF THE PARS NEURALTS

and others (1937) demonstrated this phenomenon by observ-
ing the diuresis-inhibiting action of posterior-lobe extract
with and without the addition of acetates of Zn, Ni, or Cd to
the extract.

Jones and Schlapp (1936) found that both principles are
metabolized alike after their intravenous injection in a large
dose (about 20 units per kilogram body-weight) into decapi-
tated cats. Within 20 minutes most of the hormones (85
per cent) had disappeared from the blood; there was none
present after 2 hours. About 30 per cent of the extract in
terms of vasopressor hormone could be recovered from the
urine. The work of Heller (1937) indicated that, after the
intravenous injection of posterior-lobe extract into the rabbit
(and rat), the vasopressor hormone, measured by its diuresis-
inhibiting effect, is excreted in the urine up to about 30
minutes after injection. Apparently, the amount excreted is
not proportional to the dose but is limited because of un-
known factors. Consequently, the higher the injected dose,
the lower is the proportion of hormone recovered in the
urine. Heller has found that blood adsorbs the hormone and
has concluded that the kidney liberates the adsorbed hor-
mone which is excreted at its point of action, the renal
tubules.'^

Certain tissues, especially the liver, can rapidly adsorb
vasopressor hormone. According to Heller and Urban (1935),
the adsorbing substance is heat labile and can be removed by
animal charcoal. The hormone can be released from the ad-
sorbent by boiling in saline solution. In addition, blood or
liver contains an enzyme-like substance which destroys the
hormone. Destruction by such a mechanism is rapidly ac-
complished by human blood, but not by cerebrospinal fluid.
About 0.025-0.05 unit per cc. of blood is thus inactivated
after 1.5-2 hours (see also Jones and Schlapp, 1936; and
Heller, 1937).

'7 See also pp. 265-66, 278-79.

[271 ]

THE PITUITARY BODY

SUMMARY

Only two active principles have been identified as char-
acteristic secretions of the pars neuralis: the oxytocic prin-
ciple and the vasopressor or diuresis-inhibiting principle. It
is not certain whether there is a third principle affecting car-
bohydrate metabolism. The oxytocic and vasopressor prin-
ciples have been markedly concentrated and nearly com-
pletely separated from each other but are not yet available
as pure substances. In both, an oxidation-reduction system
dependent upon the disulphide linkage appears to be present;
however, the state of this system seems to be much less im-
portant in determining activity than is true of insulin.

The physiological importance of these hormones is dis-
cussed in chapter x.

The oxytocic principle is usually more effective when the
uterus is under the influence of oestrogen. In the rabbit the
activity of the principle is markedly reduced if the condition
of the uterus corresponds to that of pregnancy (except near
term) and pseudopregnancy. However, this relationship is
not found in other animals, including, probably, man. The
important vascular effects of oxytocic principle appear to
be (i) a depressor effect in birds and (2) possibly a relaxing
effect on the coronary arteries. Recently it has been reported
that the principle can promote diuresis in the rat.

The vasopressor principle is most important, not for its
pressor action, but because it brings about water retention
by facilitating the tubular reabsorption of water in the kid-
neys. It is difficult to describe the significance of its action
on mineral metabolism. The hormone usually increases the
rate of excretion of sodium chloride especially. Some evi-
dence suggests that actions on tissues other than the kidneys
are important; however, the findings so far are inconclusive.
Larger doses of the vasopressor hormone are required to
elicit a pressor effect, which initially may be masked by a
fall in blood pressure caused by coronary constriction, which

[272I

EXTRACTS OF THE PARS NEURALIS

in turn may markedly reduce the efficiency of the heart.
Stimulation of peristaltic movements of the lower intestine
and colon is produced by the vasopressor hormone. Also, the
vasopressor hormone may cause an inhibition of movements
and a relaxation of the uterus in situ. Very large doses of
vasopressor hormone may cause anemia or lesions of the
gastrointestinal tract. These effects probably are not of phys-
iological interest. In the case of anemia, the change perhaps
is due to facilitation of hemolysis by water retention. Le-
sions, especially of the stomach, probably are the result of a
prolonged spasm of the organ's arterial supply.

Posterior-lobe extract may affect carbohydrate metabolism
by (i) producing a moderate hyperglycemia, (2) antagoniz-
ing the hypoglycemic action of insulin, and (3) antagonizing
the hyperglycemic action of epinephrine. The explanation of
these phenomena cannot be satisfactorily given after a con-
sideration of the data which have been published.

It is not yet possible to ascribe consistent effects on the
metabolism of lipoids or proteins to extracts of the pars
neuralis.

273

CHAPTER X

THE PARS NEURALIS AS A GLAND OF
INTERNAL SECRETION

THE belief that the pars neuralis is an important
gland of internal secretion has been greatly strength-
ened by recent experimental work on the physiologi-
cal importance of the diuresis-inhibiting (or vasopressor)
principle, confirming the earlier views of Starling and Verney,
to mention only two of many investigators. Some of the re-
ported experiments also indicate that secretion(s) of the pars
glandularis is responsible or necessary for the marked poly-
uria and polydipsia accompanying the suppression of pars
neuralis secretion. On the other hand, the importance of a
secretion of the oxytocic principle has not yet been demon-
strated and no data of great significance have been added to
those previously reviewed. To a less extent this is also true
of the possibly important vascular effects of the vasopressor
principle.

Recent attempts to detect the active principles of the pars
neuralis in cerebrospinal fluid or blood. New studies of the
principles in the pituitary body. — Attempts to detect the ac-
tive principles of the pars neuralis in cerebrospinal fluid have
not met with convincing success. In a recent report Deleo-
nardi (1936) concluded that oxytocic, pressor, and diuresis-
inhibiting effects can be produced both by the cisternal fluid
of the dog and rabbit and by the ventricular fluid (second and
third ventricles) of the human cadaver but only exception-
ally by human lumbar fluid. His observations on the oxytocic
and pressor effects were not adequately controlled, because
he failed to take into account the oxytocic efl'ect of calcium
ions in cerebrospinal fluid (he mentions that he employed a
Tyrode's solution low in calcium for the uterine bath) and

[274]

PARS NEURALIS AND INTERNAL SECRETION

because he did not recognize the possibiHty that cerebrospi-
nal fluid may contain a pressor substance which is not identi-
cal with that of the pars neuralis (Page, 1935 and later).
(The pressor substance described by Page is without effect
after the complete destruction of the central nervous sys-
tem.) Therefore, there remains from Deleonardi's observa-
tions the suggestion that cerebrospinal fluid may produce in
rats, in a dose of i cc. per hundred gm., a slight diuresis-
inhibiting effect similar to that following minute doses of
pars neuralis extract. Levitt's observations (1936) must be
added to those of others who, contrary to Anselmino and
Hoffmann, have been unable to detect the diuresis-inhibiting
(vasopressor) hormone in the blood of patients with hyper-
tension or eclampsia. Simon (1937), using Marx's method,
was unable to extract detectable quantities of vasopressor
hormone from 100-200 cc. of human or canine blood (see
also Neubach, 1937). The oxytocic effects of blood-extracts
(women in second stage of labor, the pregnant cow, the rab-
bit before and after injection of pars neuralis extract) have
been further investigated by Bell and Robson (1935). They
concluded that the oxytocic effects of such extracts, if pres-
ent, probably were neither caused by the oxytocic prin-
ciple of the pars neuralis nor related to parturition.

Fisher and Ingram (1936) have shown that the atrophic
pars neuralis of cats with diabetes insipidus due to a suffi-
ciently extensive lesion of the supraoptico-hypophysial sys-
tem contains only one-tenth or less of the normal total
amount of the principal hormones of the pars neuralis. The
concentration of active principles in the pars neuralis cannot
be calculated from their data. The results of Fisher and
Ingram are given in Table 9.

Jores (1935) reported that, if guinea pigs are kept in dark-
ness for about 6 hours, the concentration of oxytocic and
vasopressor principles in their pituitary bodies increases
markedly. This observation was not confirmed by Simon
(1936), who used guinea pigs, rabbits, and rats for his ex-

[275]

THE PITUITARY BODY

periments. Simon also found that the amount of hormones
in the gland is not disturbed by the injection of posterior-
lobe extract, thyroid extract, thyrotropic hormone extract,
or insulin. Likewise, the amount of the vasopressor princi-
ple in the male guinea pig's pituitary is not altered following
the injection of large doses of oestradiol benzoate or thyrox-
ine (Schockaert and Lejeune, 1935). Determinations of the
amount of oxytocic principle in the pituitary of adult and
fetal sheep and pigs were made by Bell and Robson (1937).
In terms of international units the pituitary of the adult sow
contained 2-4.5 times as much oxytocic principle as that of

TABLE 9

Total Units in Pituitary of

Pressor Activity

Diuresis-inhibiting
Activity

Oxytocic Activity

Normal cats

5-4 -7-5 (3)*
0.25-0.39 (4)

4.0 (I)
0.23-0.29 (2)

2-2 -3-5 (3)

0.18-0.25 (4)

Cats with diabetes in-
sipidus

* The number of cats is indicated by the numerals in parentheses.

the adult ewe (14-32 international units compared with 7).
The maximum amount of the principle in the gland of new-
born animals ranged from 3-7 per cent of the figure for
adults. The pituitary of young fetuses often contained much
less.

Bickenbach (1936) could find no difference in the diuresis-
inhibiting (and chloride-secreting) effects of the pituitaries of
2 patients with eclampsia compared with the effects of 2
normal human pituitaries.

The vasopressor principle. "^ A. As a regulator of water metab-
olism in the body. — Ranson and his co-workers have called
attention to the work of von Hann (191 8) who investigated
the pathology of diabetes insipidus in several human cases

' Nearly all the evidence indicates that the diuresis inhibiting effects of pars
neuralis extracts are due to the vasopressor principle.

[276]

PARS NEURALIS AND INTERNAL SECRETION

and compared his results with the findings of others. Von
Hann conckided that diabetes insipidus in man can occur
only if (i) the pars neuralis is destroyed or severely damaged,
(2) the pars glandularis is functionally active, and (3) there
is no serious disorder of the heart and kidneys. Richter
(1934) also maintained that diabetes insipidus in rats is read-
ily produced, if all the posterior lobe but only part of the
anterior lobe is removed. The majority of the recent reports
support the von Hann-Richter hypothesis that typical dia-
betes insipidus requires the abolition of pars neuralis secre-
tion but the persistence of pars glandularis secretion.

According to this hypothesis the development of diabetes
insipidus may proceed in the following way. Either by dis-
ease or by experiment the internal secretion(s) of the pars
neuralis no longer escapes into the blood or body-fluids. This
may be accomplished by interruption of the secretory fibers
from hypothalamic nuclei to the pars neuralis as by injury
to the nuclei or to the supraoptico-hypophysial tract in the
tuber cinereum or stalk, or by removal or destruction of the
pars neuralis itself. Abnormal depletion (polyuria) of the
body water then occurs, because the vasopressor hormone,
which by its effect on the loop of Henle normally insures an
adequate reabsorption of water during the secretion of urine,
no longer finds its way into the blood. Compensation is then
effected by the drinking of large amounts of water (poly-
dipsia). Why, then, is a normally secreting pars glandularis
also necessary for the maintenance of diabetes insipidus .''
Presumably a normal rate of formation of glomerular filtrate
in the kidneys depends upon normal metabolic activity,
which in turn depends to an important extent on the glands
of internal secretion, particularly the thyroid. If the anterior
pituitary, without whose secretion the principal other endo-
crine glands become inactive, is also removed, metabolic ac-
tivity is reduced and probably abnormal. Consequently, a
marked reduction in the volume and rate of formation of
glomerular filtrate takes place, so that the lack of an adequate

[277]

THE PITUITARY BODY

reabsorption of water is masked and no clear-cut polyuria and
polydipsia occur. A view favored by many is that the thyro-
tropic hormone, by its indirect effect on the thyroid, is chiefly
responsible for the maintenance of a normal rate of glomer-
ular filtration.- In the pages which follow the evidence in
favor of the hypothesis just outlined as well as some observa-
tions to the contrary will be reviewed. Some of the best ob-
servations have been reported only recently and are impressive
because of the care with which they have usually been made.
I . The secretion of the vasopressor principle as a means of
preventing dangerous loss of body water. — Oilman and Good-
man (1936-37) performed a series of interesting experiments
in rats. They found that, if water and food were withdrawn
from normal rats, the rate of secretion of the urine, of course,
fell, depending upon the period of thirst. At the same time
diuresis-inhibiting effects, analogous to those produced by
pars neuralis extracts, could be secured by injecting suitably
prepared urine. The amount of diuresis-inhibiting principle
present increased as the period of water withdrawal was pro-
longed, so that the equivalent of as much as 5 units of hor-
mone was excreted by 20 rats during a period of 72 hours
without water. ^ No detectable amounts of the principle
could be discovered in the urine of rats drinking water ad
libitum. If rats were hypophysectomized and then subjected
to water-withdrawal, they secreted three times as much urine
as normal rats treated similarly; no diuresis-inhibiting hor-
mone could be found in their urine. Control experiments in-
dicated that the procedure used was suitable for identifying
diuresis-inhibiting (vasopressor) hormone. Moreover, the
diuresis-inhibiting substance in the urine of rats receiving

^ Another possibility, in favor of which there is little evidence, is that a secretion
of the pars glandularis has diuretic effects not mediated through another gland of
internal secretion. White and Heinbecker suggested that a secretion of the thyroid
sensitizes the animal toward an anterior pituitary diuretic factor.

3 Diuresis caused by the administration of a solution of NaCl to rats from which
water was withheld likewise was characterized by the rapid appearance of diuresis-
inhibiting principle in the urine.

[ 278 ]

PARS NEURALIS AND INTERNAL SECRETION

no water was destroyed in strong solutions of acid or alls:ali,
as is that in an extract of the pars neuralis. The conclusions
of Oilman and Goodman from these experiments seem logical.
The amount of vasopressor or diuresis-inhibiting principle se-
creted by the pars neuralis fluctuates with the body's need
for water conservation. Normally, the amount secreted is
so small that none can be detected in the glomerular filtrate.
If there is a shortage of water, its retention in the body is
largely due to a reduction in the volume of urine secreted.
And the emergency secretion of an increased amount of
diuresis-inhibiting hormone by the pars neuralis is perhaps
the important means of accomplishing this by increasing the
reabsorption of water in the renal tubules. The unusual
amount of hormone secreted filters in part through the glo-
meruli and can then be detected in the urine.

2. The importance of hypothalamic nuclei^ especially the
supraoptic nuclei^ for maintaining the secretion of the vasopres-
sor principle. — In several recent reports of experiments in cats
and monkeys, Fisher, Ingram, and Ranson^ have shown that
the supraoptic nuclei of the hypothalamus may be essential
not only to liberate suitable amounts of vasopressor hormone
— to prevent undue loss of water by way of the kidneys —
but also to maintain the pars neuralis anatomically. Cats
were used for most of their experiments. Employing the
Horsely-Clarke stereotaxic instrument as a means of placing
lesions in difi-'erent parts of the hypothalamus, they produced
a severe permanent diabetes insipidus in a number of cats.^
Later, sometimes after months of severe diabetes insipidus,
the animals were killed, and the hypothalamus and pituitary

■* Fisher, Ingram, Hare, and Ranson (1935), Fisher, Ingram, and Ranson (1935),
Fisher and Ingram (1936), Ingram and Fisher (1936), Ingram, Fisher, and Ranson
(1936).

s The diabeces insipidus appeared about 8-12 days after a suitable lesion(s) had
been made. Polyuria appeared to precede polydipsia (see also Fisher, Magoun, and
Hetherington, 1938). In addition, a transient polydipsia and polyuria were com-
monly observed immediately after operation. These initial transient changes have
been observed by a number of authors using different animals. Usually they are
attributed to an effect on the nervous system alone.

[279]

THE PITUITARY BODY

body were carefully studied anatomically to determine how
the lesions found could be correlated with animals' symp-
toms. As a result of this study, the authors have reached
the following conclusions:^ (i) diabetes insipidus is due to a
deficiency of pars neuralis secretion, presumably the vaso-
pressor principle; (2) the secretion of the pars neuralis is
not formed and liberated unless at least one supraoptic nu-
cleus is functionally active and connected with the pars
neuralis. The fibers from the supraoptic nuclei to the pars
neuralis appear to be efferent. If the tract(s) is interrupted,
the nerve cells of the nuclei degenerate. The anatomical
changes in the hypothalamic-hypophysial region accompany-
ing diabetes insipidus may be due to {a) a lesion causing
destruction of both supraoptic nuclei, ((^) a lesion interrupt-
ing the tract fibers arising from both nuclei as in the tuber
cinereum or the stalk, or (c) destruction or removal of the
pars neuralis; lesions (a) or (^) are followed by atrophy of
the pars neuralis. (3) The pars tuberalis and probably the
pars intermedia are of no significance in the genesis and main-
tenance of diabetes insipidus; and, finally, (4) the pars
glandularis probably is important or essential, if pronounced
diabetes insipidus occurs.

The relationship of hypothalamic nuclei to the pituitary
as well as the most convenient position in which suprapitui-
tary lesions can be placed to produce diabetes insipidus are
illustrated in Figures 27 (cat) and 4 (monkey). Destructive
lesions of the mammillary bodies or of nuclei other than the
supraoptic nuclei (such as the paraventricular nuclei, the
ventrolateral hypothalamic nuclei, etc.) are not followed by
diabetes insipidus.

Farr, Hare, and Phillips (1937), using cats, have confirmed
the observations of Ranson and his colleagues. In reports
of the anatomical changes in 4 human cases of diabetes in-

^ The conclusions refer to the experiments of Fisher, Ingram, and Ranson. The
authors do not hold that other mechanisms for producing diabetes insipidus — espe-
cially in other animals — do not exist.

(280I

PARS NEURALIS AND INTERNAL SECRETION

sipidus, Biggart (1935-36) also observed changes in the su-
praoptic nuclei and stalk consistent with the views expressed
by Fisher, Ingram, and Ranson. There is little evidence to

Fig. 27. — One position in which bilateral lesions of the hypothalamus can be
placed to produce diabetes insipidus in the cat by interrupting fibers of hypothala-
mic hypophysial tracts. (From Fisher, Ingram, and Ranson, Arch. Neurol. Psy-
chiat., 34, 124-63 [1935]-)

./; pars glandularis; Ent: entopeduncular nucleus; Fil: filiform (paraventricu-
lar) nucleus; /; pars intermedia; L: lesion as stippled area; Mth: mammillothalamic
tract; OT: optic tract; P: pars neuralis; Perivetit: periventricular nucleus; PP:
pes peduncuh; St: stalk; T: pars tuberalis; Tang: caudal part of tangential (supra-
optic) nucleus; VM: ventromedial hypothalamic nucleus.

favor Biggart's opinion that the pars tuberalis is etiologically
important in diabetes insipidus. There is still less justifica-
tion for his belief that diuresis inhibition by the vasopressor
principle depends to an important extent on an action of the
hormone on tuberal nuclei (in Biggart's Case 5 the polyuria

f28il

THE PITUITARY BODY

"was not controlled by injections of pituitrin"). The report
of Adlersberg and Friedmann (1935) deals with changes in
the metabolism of water, under various conditions, in pa-
tients with lesions of the mesencephalon or diencephalon or
both. In some instances the response to posterior-lobe ex-
tract was clearly diminished. Keller, Noble, and Hamilton
(1936) stated that a "complete" separation of the pituitary
from the hypothalamus (including "the greater portion of the
infundibulum") in the dog is not followed by any increased
water or food consumption by the animals. More recently,
Keller and Hamilton (1937) observed complete degeneration
of the nerve fibers in the pars neuralis as a result of lesions
of the tuber cinereum in 7 cats. In 4 of the cats there was no
diabetes insipidus; the authors concluded that degeneration
of the nerves of the pars neuralis — contrary to the views of
Ranson and his colleagues — is not necessarily accompanied
or followed by diabetes insipidus. Other data of less recent
origin, some of which also can be interpreted as opposing the
beliefs of Fisher, Ingram, and Ranson, have been reviewed
already (van Dyke, 1936).

3. To what extent does diabetes insipidus depend upon a func-
tioning pars glandularis? — The hypothesis of von Hann, sup-
ported by the later experimental work of Richter, has already
been discussed (pp. 276-77). It is proposed here to review
briefly a number of recent communications bearing on this
question.

In a few reports diabetes insipidus — or the secretion of an
increased volume of urine — has been observed in completely
hypophysectomized animals (toad: Pasqualini, 1935; rat:'
Dodds, Noble, and Williams, 1937; dog: Page and Sweet,
Reichert and Dandy, 1936). On the other hand, Buratschew-
ski and Rappoport (1936) found that the metabolism of salt
and water in the dog was not disturbed by either hypophy-
sectomy or the removal of the pars neuralis. Such data con-
tradict most of the recent findings of others.

"• See also Sandberg, Perla, and Holly (1937).

[282]

PARS NEURALIS AND INTERNAL SECRETION

The work of Pencharz, Hopper, and Rynearson (1936) in
the rat as well as that of Keller, Noble, and Hamilton (1936)
and of White and Heinbecker (1937) in the dog and that of
Dodds and his colleagues in the cat (1937) indicate that
diabetes insipidus follows the excision of the pars neuralis,
but that it promptly ceases if the pars glandularis is later
removed. Pencharz and others were unable to provoke poly-
dipsia in completely hypophysectomized rats by repeatedly
administering homo-implants (1-3 anterior lobes on alter-
nate days for 3 weeks). However, Keller (1937) observed a
dog whose diabetes insipidus disappeared as a result of
complete hypophysectomy. Inasmuch as the diabetes in-
sipidus reappeared following the administration of anterior-
lobe extract or the feeding of thyroid extract, Keller con-
cluded that the maintenance of polyuria in dogs with an
intact anterior lobe is due to the thyrotropic hormone. White
(1937), like Pencharz and his colleagues, was unable to cause,
by the administration of anterior pituitary extract,^ any con-
vincing change in the amount of urine secreted by rats from
which the pars neuralis or the whole pituitary had been re-
moved a year previously . The administration of thyroid ex-
tract with or without the injection of anterior-lobe extract
likewise was without significant effect.'' Other experiments
of White and Heinbecker (1937) in dogs led to the conclusion
that the pars glandularis secretes a diuretic principle which
is not thyrotopic hormone but, nevertheless, at first is in-
effective in the absence of the thyroid. After the removal
of the thyroid from the dog, the diuretic effect of anterior
pituitary extract gradually reappeared, perhaps, as the au-
thors suggest, owing to regeneration of thyroid tissue or to
some unknown readjustment. Hypophysectomized or nor-
mal dogs were about equally sensitive toward the diuretic

^ White injected an acid extract of beef anterior lobe.

' Farr, Hare, and Phillips (1937) stated that cats with diabetes insipidus caused
by lesions of the supraoptico-hypophysial tract exhibited a pronounced increase in
the polyuria, if a saline suspension of beef anterior lobe had been injected. ■''?vPl'?*^'"

^ ff ^•^ <\M

THE PITUITARY BODY

action of anterior pituitary extract.'" Thyroid extract caused
no change in the metabolism of water either in thyroidecto-
mized or in hypophysectomized-thyroidectomized dogs. As a
result of their experiments in cats and rats, Dodds, Noble,
and Williams (1937) also suggested that the diuretic action
of anterior pituitary secretion after the removal of the pos-
terior lobe is not due to thyrotropic hormone.

Evidence from other types of experiments speaks more in
favor of than against the belief that a secreting thyroid gland
is responsible to an important extent for the polyuria of dia-
betes insipidus. It is necessary also to bear in mind that the
importance of the thyroid gland may vary in different ani-
mals. Mahoney and Sheehan (1935) occluded the pituitary
stalk in dogs by means of a silver clip. The subsequent severe
polyuria and polydipsia could be abolished by thyroidectomy
and later re-established by the feeding of thyroid extract.
The removal of the thyroid in cats with diabetes insipidus
caused by a lesion of the supraoptico-hypophysial system
"may somewhat reduce but does not abolish the polyuria"
(Fisher and Ingram, 1936; Ingram and Fisher, 1937). On
the other hand, the feeding of thyroid to such cats causes a
marked diuresis; after the withdrawal of thyroid-medica-
tion, the polyuria may be as great as before thyroidectomy.
Findley and Heinbecker (1937) completely removed the thy-
roid from a man with syphilis of the central nervous system
and with diabetes insipidus. The important changes observed
subsequent to the operation were some reduction of the poly-
uria when the amount of salt in the diet was high or unre-
stricted and some increase in the diuresis-inhibiting effect
of "Pitressin" (see also Findley, 1937).

4. Miscellaneous observations. — According to Pickford
(1936) as well as others, the action of posterior-lobe extract
after intravenous administration is, within certain limits, in-
versely proportional to the "water load" of the body. This

'" The extract sometimes caused an initial decrease in the rate of formation of
urine. This always occurred in the monkey and might be the only change observed.

I284]

PARS NEURALIS AND INTERNAL SECRETION

conclusion was based upon experiments in dogs with intact
pituitaries. Presumably more vasopressor hormone was se-
creted as the water load diminished.

By means of acute experiments in rabbits which had re-
ceived neither food nor water for 24-48 hours, Janssen (1935)
found that afferent stimuli could cause an increased rate of
secretion of urine in which the concentration of chloride rose.
The fact that this effect occurred after renal denervation led
to the conclusion that it was due to the reflex secretion of a
hormone. Theobald and Verney (1935) measured the action
of afferent stimuli" on the secretion of urine by the denerv-
ated kidney of the dog in which diuresis was provoked by
water. Inhibition of diuresis was readily produced and some-
times persisted for 5-20 minutes after the removal of the
stimulating agent. The authors concluded that the diuresis
inhibition was not caused by epinephrine and suggested that
the hormone responsible for the effect was secreted by the
pars neuralis. This suggestion seems logical and is in agree-
ment with both the earlier work of Verney and his colleagues
and with nearly all recent observations.

Brull (1937) concluded that an unknown pituitary prin-
ciple (not those recognized in the pars neuralis and neither
gonadotropic nor thyrotropic hormone) can lower the thresh-
old of renal excretion of inorganic phosphate, provided that
the parathyroid hormone is also present.

The vasopressor principle. B. As a regulator of the cardio-
vascular system. — Blount (1935) transplanted two pituitary
anlagen (including the future pars neuralis) into individual
urodele larvae, Amblystoma punctatum., and concluded that
the symptoms appearing later were analogous to hyperten-
sion in man. He based this conclusion particularly on the
reduction in the size and number of the peripheral capillaries
associated with "labored attempt(s) at propulsion of cor-
puscles" and an "increased back-flux of diastole." The heart

" E.g., by the insertion of a hypodermic needle in the region of the fourth lumbar
interspace.

[2851

THE PITUITARY BODY

rate was found to be reduced; also, there were enlargement
of the heart and hypertrophy of the ventricular wall. Because
of contraction of the vessels, the spleen was less than half the
normal size. The glomeruli of the kidneys resembled those
of hypertension in man. The profound peripheral vascular
disturbance apparently interfered with the growth of some
of the peripheral structures. Blount also had the impression
that the vascularity of the structures studied was increased
after hypophysectomy.

All the other observations indicating that the cardiovascu-
lar effects of pars neuralis secretion may be physiologically
important have been made in mammals. Chang and his col-
leagues (1937) discovered that stimulation of the central end
of the vagus in the dog whose head is connected with the
body only by blood vessels, causes a rise in blood pressure re-
sembling that following the injection of vasopressor princi-
ple. The effect could be abolished either by hypophysectomy
or by cutting the pituitary stalk. Thus it appears that a re-
flex secretion of vasopressor principle can be demonstrated
in the dog. The vagus nerve is the only part of the afferent
arc known at present; probably the terminal efferent arc is
the supraoptico-hypophysial tract. The experiments of
Schockaert and Lambillon (1935-36), although of more de-
ductive significance, are also of considerable interest. They
showed that the serum of pregnant women seemed to bind
or inactivate, i.e., prevent, the vasopressor effect of a pars
neuralis extract in the decapitated cat. Later they demon-
strated that the intravenous injection of 5 units of a purified
solution of the vasopressor principle ("Tonephin") caused
much more severe symptoms such as precordial and abdomi-
nal pain, vomiting, and involuntary defecation in normal
women than in women in the last third of pregnancy. The
average elevation of the systolic blood pressure in non-preg-
nant women was 43 mm. Hg.'^ In the pregnant women, the

" In spite of the recent statement of Gilman and Goodman (1937) that ". . . . in
unanesthetized dogs and humans, pituitary extract is not pressor," this observation

[286 1

PARS NEURALIS AND INTERNAL SECRETION

injection caused an average elevation of 15 mm. Hg in the
systolic blood pressure; only rarely were symptoms other
than paleness of the face and cyanosis of the lips present.
These observations suggest that the diminished response of
pregnant women to the vasopressor principle is due to a sub-
stance liberated into the blood. Whether or not a disturbance
in its formation may be etiologically important in eclampsia,
as Schockaert and Lambillon suggest, is unknown.

The experiments of Anselmino and Hoffman were the basis
for the attractive hypothesis that the reduced urinary secre-
tion and the hypertensive symptoms of certain diseases such
as eclampsia and essential hypertension are due to a "hyper-
vasopressinemia." However, satisfactory confirmatory data
are almost entirely lacking. Dieckmann and Michel (1937)
as well as others have pointed out that the pregnant woman
in the pre-eclamptic condition is markedly hypersensitive to
the pressor effect of pars neuralis extract; moreover, they
concluded that this abnormal response constitutes a useful di-
agnostic test for pre-eclampsia, but that it is not free from
danger. Byrom (1938) has suggested that abnormally large
amounts of free oestrin may circulate in the blood of patients
with eclampsia and that this oestrin synergizes with vaso-
pressor hormone in causing the important pathological
changes (see pp. 263-64). According to Coester (1935), puri-
fied extracts of urine from normal individuals or from patients
with two varieties of hypertension produced about the same
diuresis-inhibiting and pressor effects. Still other observa-
tions have been made by Jores (1936), who concluded that
abnormal amounts of anterior pituitary hormones stimulat-
ing the adrenals (cortex and medulla) circulate in the blood
in certain hypertensive disorders, such as essential hyper-
tension and pituitary basophilism (Gushing), and that these

and others which have been made before indicate that man, Hke other animals,
exhibits a clear-cut pressor response to intravenous injections of pars neuralis ex-
tracts.

[287]

THE PITUITARY BODY

hormones are causally related to the symptoms.'^ Van
Bogaert (1936) was convinced that neither the pituitary nor
the adrenals is etiologically important in hypertension but
that the pituitary may be important in maintaining the
symptoms.

The relationship between the pituitary and the experi-
mental hypertension due to renal ischemia produced by the
clampof Goldblatt and others has been investigated in the dog
by Page and Sweet (1936-37). In normal animals hypophy-
sectomy caused some reduction of the arterial blood pres-
sure. In dogs in which hypertension (240/160 mm. Hg) had
been produced by means of Goldblatt's clamp, the high level
of arterial pressure was maintained for several months unless
hypophysectomy was performed. Some weeks after hypophy-
sectomy, the blood pressure fell, sometimes nearly to
normal (150/100 mm. Hg), sometimes below normal (90/40
mm. Hg). Subsequent further constriction of the renal arter-
ies again produced a rise in blood pressure which tended to
be transient. The administration of thyroid extract also
might be followed by a moderate increase in arterial pressure
(see Fig. 28). The authors concluded that the effects of
hypophysectomy were indirect and depended probably upon
the removal of the pars glandularis without which the thyroid
and adrenal glands performed their functions imperfectly.
It is regrettable that this interpretation was not strengthened
by observing the effects of extirpation of either the pars
glandularis or the pars neuralis alone, because their observa-
tions do not satisfactorily exclude the possibility that the
pars neuralis plays some part in maintaining the hyperten-
sion. Page (1936) was not able to detect any increased
amount of hypertensive principle in the blood of dogs with
the hypertension of renal ischemia; however, his method of

'•! Positive results were obtained in 20 of 28 patients with essential hypertension
and in 6 with Cushlng's syndrome. The findings were negative in 8 patients with
eclampsia or renal disease of pregnancy.

[288 1

Tlm.Hg
260

240

220

200

180

160

140
120

I*.

I * •• •

•0 -S

• ••

>• .^^« .

1 r . .V

.o |, .. • .*'.

> ^ • •

Days-40 60 80 100|210 230 250 270 290 310 330 350 370 390

6U^J

Thyroid Thcelin

240-i .

12 gr q.d. Iccq.d.

220- •*• • , * •

• • % • - :!i"

• •• a

200- • •,•*"*

. • • • • • •

180- • . .*••»•
•• •

• • •

• •

• •• •

160- '^ • »

• • •

•

140-

i?n 1 1 1 1

1 1 1 1 1 1 1

Days- 410 430 450 470 490 510 530 550 570 590 610 630

F"iG. 28. — The relation of the pituitary body to hypertension caused by renal
ischemia following the application of Goldblatt's clamp to the renal arteries. (From
Page and Sweet, Amer. J. Physiol., 120, 238-45 [1937].)

Ordinate: arterial blood pressure; abscissa: time in days. Without hypophy-
sectomy, the hypertension following the application of the first clamp probably
would have persisted some months. Hypertension subsequently produced by
tightening the right and left clamps was transient. The administration of thyroid
gland in other experiments caused a recurrence of the hypertension.

THE PITUITARY BODY

making extracts (alcoholic extracts of plasma) may not have
been suitable for the pituitary vasopressor principle.

The oxytocic prhiciple. — The additions to our knowledge of
the possible physiological importance of the oxytocic princi-
ple in parturition are, for the most part, only of inferential
value. Newton (1937) found that the isolated cervix uteri
of the rat and guinea pig, in any stage of sexual activity in-
cluding pregnancy, is very insensitive toward the oxytocic
principle (concentration of 40 units per liter of bath-fluid).
Newton considers that this fact strengthens the evidence
favoring the importance of oxytocic-principle secretion in
normal parturition. Possibly important interrelationships
between the secretion of oestrogens or progesterone and the
action of the oxytocic principle are discussed on pages 261-62.
According to Ingram and Fisher (1937), if diabetes insipidus
is produced in pregnant cats by a lesion of the supraoptico-
hypophysial system, the subsequent parturition is incom-
plete and terminates in death. However, others (including
Houssay, 1935, and Robson, 1936-37) have demonstrated
that normal parturition can take place in the cat, dog, mouse,
rabbit, and rat after the removal of the posterior lobe or after
hypophysectomy. This fact must be taken into account if
the initiation or continuation of labor is to be explained as
the result of oestrogen-sensitization of the uterus toward the
oxytocic principle or if the interference with parturition ob-
served by Ingram and Fisher is to be ascribed to a deficiency
in the secretion of the oxytocic principle.

The pars nenralis and menstruatio?2. — Hartman and Firor
(1935) have again suggested that menstruation possibly re-
quires a functioning pars neuralis. However, the evidence
offered does little to commend this hypothesis: of four im-
mature monkeys in which complete hypophysectomy was at-
tempted, the operation was successful in only one; "oestrin-
deprivation" bleeding after 640 rat-units of oestrin was ob-
served in all the animals except the one completely hy-
pophysectomized. In the experiments of Smith, Tyndale, and

[290]

PARS NEURALIS AND INTERNAL SECRETION

Engle (1936), 400-500 rat-units of oestrin were injected daily
for 10 days into young or adult hypophysectomized monkeys.
After injections were stopped, delayed bleeding was observed
in 8 instances. In 2 instances bleeding did not occur. The
authors were loath to attribute the delay in or absence of
bleeding to a specific factor.

SUMMARY

Contrary to the view previously expressed (van Dyke,
1936), there is now good evidence that the pars neuralis is an
important gland of internal secretion. The best data have
been gathered in studies of the metabolism of water. In the
normal mammal, it seems probable that the reclamation of
water filtered through the glomeruli of the kidney when urine
is secreted depends upon the diuresis-inhibiting (vasopressor)
hormone of the pars neuralis. If a dangerous loss of water
from the body is threatened, diuresis-inhibiting hormone is
secreted at an increased rate and by its local action on the
tubular epithelium of the kidneys increases the rate of re-
absorption, and hence the conservation, of water. The nerv-
ous control of the secretion of diuresis-inhibiting hormone
appears to be of the greatest importance and explains how
afferent stimuli can affect (inhibit) the secretion of urine
after renal denervation. In an animal like the cat the paired
supraoptic nuclei of the hypothalamus apparently supply
most of the secretory fibers of the pars neuralis which under-
goes atrophy and secretes little or no hormone if the nuclei
have been destroyed or the fibers have been cut, as after sec-
tion of the stalk. Under such circumstances, the kidneys lose
their ability to concentrate urine, so that water loss, poly-
uria, is abnormally rapid. In compensation the animal drinks
an increased volume of water (polydipsia). The changes,
therefore, are analogous to diabetes insipidus in man.

Furthermore, it appears that the function of another part
of the pituitary, the pars glandularis, is necessary for the

[291 1

THE PITUITARY BODY

complete development of diabetes insipidus. Generally, it
has been found extremely difficult to produce diabetes in-
sipidus after complete hypophysectomy, whereas, if the pars
glandularis is intact, the suppression of posterior-lobe secre-
tion readily produces that condition/'' (Also, if diabetes in-
sipidus has been produced, it can be abolished by removal of
the pars glandularis.) Most observations indicate that the
thyroid gland also must be intact. However, it is not certain
that the diuretic principle of the anterior pituitary is identi-
cal with thyrotropic hormone.

Diuresis-inhibiting hormone facilitates the excretion of cer-
tain cations and anions, especially Na and CI. Future work
will have to decide what is the best interpretation of this
phenomenon in terms of the physiological importance of the
hormone.

Whether or not the vasopressor hormone is physiologically
important because of its cardiovascular effects is not known.
Recently it has been shown that the hormone probably is
liberated by stimulation of the central end of a vagus nerve.
Its possible clinical significance in disorders like hypertension
and, especially, eclampsia, however great it may be, has not
been demonstrated.

In view of the highly specific action of the oxytocic princi-
ple on the uterus, it is to be expected that new observations
on its importance in normal parturition will be gathered.
At present it appears that the hormone, i.e., the pars neu-
ralis, is not necessary for parturition. It is possible that par-
turition in normal animals may be greatly facilitated by its
action, perhaps in synergism with oestrogen.

Although changes in the metabolism of carbohydrates can
be produced by posterior-lobe extracts, it is not possible to
state whether these effects are physiologically important.

'•• It is to be hoped that older observations indicating that diabetes insipidus
can be produced by hypothalamic lesions after complete hypophysectomy will
be either disproved or confirmed, so that they can be evaluated.

[ '^~<r- ]

APPENDIX

THE STRUCTURAL FORMULAS AND PRIN-
CIPAL ACTIONS OF HORMONES OF
NATURAL ORIGIN

Notable advances have been made in isolating and de-
termining the structure of hormones and of substances
necessary for their synthesis or produced in their degrada-
tion. Moreover, a number of synthetic hormones has been
made. The skill of chemists has been most fruitfully applied
in studying substances with a nucleus derived from cyclo-
pentenophenanthrene.

The table and formulas of the x-^ppendix deal only with
hormones or related substances of natural origin and of
known structure. Although the list is believed to be complete
at this time, it undoubtedly will be lengthened as a result of
future research. The substances are listed alphabetically in
the table which includes data believed to be of greatest
interest to readers of this book. The formulas likewise are
arranged alphabetically and follow the table.

[ 293 ]

O 5

« t:

Q -g

UJ "*

6
<
z

c
1

" d
o

SO
6

15
(5

« i >

S 2 P

goo

^ E ««
« f; z

Corpus lu-
teum hor-
mone

s
o

Urine of pregnant
women

Corpora lutea of
sows

Urine of men

Adrenal gland

Urine of men

Urine of pregnant

mares
Urine of pregnant

women

Adrenal gland

Urine of pregnant
mares

<
z

Inactive
Inactive

Androgen

Of adrenal corti-
cal hormone
Androgen

Oestrogen

Inactive

Hormone of adren-
al medulla
Oestrogen

U CQ

« a

Allopregnanediol

Allopregnanolone

Androsterone
Corticosterone

Dehydroisoan-

drosterone
Dihydroequile-

nine
Epi-allopregna-

nol-3-one-20

Epinephrine
Equilenine

d
Z

t ^

-1 SC

OO ON

^94

6
<

S
a

o
o
o

IS
(2

O ro

8 8

o o

oo oo

o o

O Q
O 0

o 6

0 < —

Pi ~

— 0

3 £ ^

a. 3 0

c c c i-'o c c c , c ^

C C C -^ ^ C C C.T1° C-rt rt JS T3

^ 2 ^ « ^ 1 S 1 ^ ^ ^ 1 S i « "5 ^ o S II s 2

<
-J

fi E >^o

IL> u -^ £

OOO OOO - o<w

0 |2

0 S

# o o .Sen

.S3- -.2o ^ ^t^g
5-.S-0 OSS Ji gS.^'

<
o

-t

»-n

f ~

295

STRUCTURAL FORMULAS OF HORMONES

1, Allopnegnanediol HCOH

CH,

2. Allopreqnanolone ' ^

^ ^ CH,c=0

3. Androsterone ^^ 0

HO'

. - CH^OH

4. tortico&terone ^^ i

CH, c=o

HO-

5.Dehydroiso- o

androsterone ^"'

6.DihydPoequilenine °,"

* C n J I

7. Epi-^llopregn^nol- i '
3-one-20 . ^"3_J=°

HO'

9. Equilenine

8. Epinephrine

296

STRUCTURAL FORMULAS OF HORMONES

ll.oc-Oestp^diol ^^ oh

15.0estriol

l2./3-0estra.diol ^^ °"

K.Oestrone ^^ °

CHj

IS.Pregnanediol ^^ ^hoh

16.Proge5terone _ co^h.

t /.Testosterone ,^°"

CH,

l8.Thyroxine

i\/^^^^i

CH(NH,)

COOH

297

BIBLIOGRAPHY

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THE PITUITARY BODY

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375

THE PITUITARY BODY

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i8l]

INDEX

Abortion

caused by combined action of oestro-
gen and oxytocic principle, 261
Acetone bodies; see Metabolism, lipoid

Acne vulgaris

treatment of, by prolan, 138
Acromegaly

changes in bones and, 37

changes in joints and, 37
Addison's disease

anatomy of pituitary in, 23

Adenoma; see Neoplasms
Adrenal cortical hormone
effect of, on adrenals, 204
and anterior pituitary, 201-2
and metabolism, carbohydrate, 219-

21
and metabolism, water, 202
and thyrotropic hormone, 187
Adrenal cortical stimulating hormone,
198 ff.
and adrenal hypertrophy caused by
formaldehyde, 203
oestrone, 203
assay of, 205
chemistry of, 204
distribution of, 199, 204
and growth, 41

and toxicity of histamine, 203
in relation to cortical lipoids, 200,

204-5
metabolism of, 203-4
sexual difference in secretion of, 203
in relation to thyrotropic hormone,
202, n. 5

Adrenal glands

acetone bodies, and anterior pituitary,

231
effect of adrenal cortical hormone on,

204
and anatomy of pituitary, 22-23
deficiency of secretion of, in relation

to anterior pituitary, 201-2
after gonadectomy, 202, n. 5

gonadotropic effect of extracts of, 97-

98 .

and gonadotropic hormone, pituitary,

95-98
relation to hypertension, 287-88
compensatory hypertrophy of, and

anterior pituitary, 202-3
after hypophysectomy, 31, 36, 198-

201
and lactation, 152, 160
lipoids of cortex in relation to adrenal

cortical stimulating hormone,

200, 204-5
in relation to lipoid metabolism of

liver and anterior pituitary, 229-

31
and metabolism, carbohydrate as re-
lated to pituitary, 218-21
and metabolism, lipoid, 228
degenerative changes in, caused by

oestrone, 19
action of prolan on, 135
hypertrophy of, after injection of

thyrotropic hormone, 190
and action of thyroxine, 180, n. 7
transplantation of,
effect of adrenal cortical hormone

on, 203-4
and anterior pituitary, 203-4
X-zone of, and pituitary, 201
Adrenalin; see Epinephrine
Adrenine; see Epinephrine
Adrenotropic hormone; see Adrenal

cortical stimulating hormone
Albumin, egg

augmentation of action of gonado-
tropic hormone by, 118
AUopregnanediol, 294, 296
Allopregnanolone, 294, 296
Amniotic fluid

prolan in, 127
Anatomy of pituitary

and adrenal glands, 22-23
comparative, 2, lo-ii

THE PITUITARY BODY

Anatomy of pituitary — Continued
after artificial culture, 28
correlation with disease, 11, 24-26
after gonadectomy, 17-18

androgens and, 18

androstane diol and, 18

androstene dione and, 18

benzpyrene and, 18

dibenzanthracene and, 18

oestrogens and, 18

progesterone and, 18
gonads, internal secretion of, and,

i5ff.
lactation and, 16-17
microscopic

pars glandularis, 12-15 ^•

pars intermedia, lo-ii

pars neuralis, 11-12
effect of oestrogens on, 18-21
oestrous cycle and, 15-16; see also

sexual cycle and
and pancreas, 23-24
and parathyroid glands, 24
parturition and, 16-17
pathological, 23, 24-26
pregnancy-cells, 26
effect of progesterone on, 21
effect of prolan on, 21
sexual cycle and

in frog, 15

in pigeon, 15
effect of testosterone or its propionate

on, 21
and thymus, 24

and thyroid gland, 21-22, 178-79
after transplantation, 27-28
vitamins and, 26-27

Androgens

effect on anatomy of pituitary after

gonadectomy, 18
and development of breasts, 1 56
castration changes in pituitary cor-
rected by, 91-92
and action of chromatosome-dispers-

ing hormone, 252, n. 10
in relation to gonadotropic hormones,

pituitary, 89-94
effect of, on male gonads, 74
effects on lactation of, 163-64
and activity of oxytocic principle,
262

effects in parabiotic animals, 79
maintenance of spermatogenesis by,
after hypophysectomy, 93-94
Androstane diol

effect on anatomy of pituitary after
gonadectomy, 18
Androstene dione

effect on anatomy of pituitary after
gonadectomy, 18
Androsterone, 294, 296; see also An-
drogens
Aneurin; see Vitamin Bj
Antagonism; see also Antihormone
of gonadotropic hormone, pituitary,
by pituitary extract, 106, 11 5-17
of hormone of pregnant-mare serum
by pituitary extract, 106, 11 5-16
of prolan by pituitary extract, 106,
1 1 5-1 6
Anterior lobe; see Pars glandularis
Anterior pituitary; see Pars glandularis
Antihormone; see also Antagonism
of diabetogenic hormone, 227-28
of gonadotropic hormone, pituitary,
109-15, 117
detection of, 112, n. 71
immune substances and, 111-13
effect on secretion of hormone, 113-

15
source specificity of, 111-12
species specificity of, 1 1 i-i 2
of gonadotropic hormone, pregnant-
mare, 111-15, 141
and growth-promoting extracts, 44-45
of ketogenic principle, 232
of lactogenic hormone, 168-69
of prolan, i 10-15, 139-41
of thyrotropic hormone, 192-94
Ascorbic acid

anatomy of pituitary and, 26
distribution of, in pituitary, 238
and action of thyrotropic hormone,
190
Assay

of adrenal cortical stimulating hor-
mone, 205
of chromatosome-dispersing hormone,

253, n. 12
of gonadotropic hormone, pituitary,
67-70, 107-9

386

INDEX

Assay — Continued

of gonadotropic hormone, pregnant-
mare, 142
of growth-promoting extract, 44-45
of lactogenic hormone, 169-71
of pars neurahs principles, 259-60
of prolan, 69-70, 141-42
of thyrotropic hormone, 194-95
Atropine

effect of, on chromatophores, 251
Augmentation

of action of gonadotropic hormone,
pituitary, 1 16-19
by blood, 118
by casein, 118
by copper salts, 1 18
by egg-albumin, 118
by heme, 1 18
by hemoglobin, 1 18
as result of injections of hormone,

117 _ _
by luteinizing hormone, 117
by merthiolate, 1 18-19
by tannic acid, 1 18
by yeast ash or extract, 1 18
by zinc sulphate, 118
of effects of prolan, 138
of action of vasopressor principle,
270-71
Auxogenic hormone, 106

Basedow's disease; see Graves's disease
Basophilism, pituitary; see Cushing's

syndrome
Benzpyrene
effect on anatomy of pituitary after
gonadectomy, 18
Blood

augmentation of action of gonado-
tropic hormone, by, 118
cells of, in relation to pituitary, 237
action of pars neuralis extracts on,

267-68
sugar of, after hypophysectomy, 205-
7, 209-10
Blood vessels of pituitary, 2-5
Bones

changes in, in acromegaly, 37

effects of anterior pituitary extract

on, 37-38
effects of hypophysectomy on, 38

effect of oestradiol benzoate on, 40
repair of, facilitated by thyrotropic
hormone, 190
Breasts

cystic disease of, and lactogenic hor-
mone, 165, 168
development of
and androgens, 1 56
growth of nipples and pituitary, 154
and oestrogens, 152-55, 157-58
and pars glandularis, 151 ff.
in relation to pregnancy, 155
progesterone and, 155-58
effect of prolan on, 134
Bromine

in pituitary, 238

Broodiness in fowls and lactogenic hor-
mone, 166-67

Cachexia, pituitary; see Simmonds' dis-
ease

Calcium, 102; see also Metabolism,
mineral, and Gonadotropic hor-
mones, pituitary

Cancer; see Neoplasms

Carbohydrate-metabolism hormone, 227

Carcinoma; see Neoplasms

Casein

augmentation of action of gonado-
tropic hormone by, 1 18

Castration; see Gonadectomy

Central nervous system; see also In-
nervation of pituitary. Nervous sys-
tem

after hypophysectomy, 31
Cervix of uterus

action of oxytocic principle on, 260
Cholesterol; see Metabolism, lipoid
Chloralosane

effect of, on chromatophores, 251
Chlorine; see Metabolism, mineral
Chloroform

effect of, on chromatophores, 251
Chorion

as source of gonadotropic hormones,
124-27

Chorionepithelioma; see Gonadotropic
hormones of neoplasms

587

THE PITUITARY BODY

Chromatophores

physiology of, and pituitary, 244 ff.

Cliromatosome-dispersing hormone; see

also Chromatosome distribution

effect of androgens on action of, 252,
n. 10

assay of, 253, n. 12

chemistry of, 255-56

crustacean eye-stalk hormone and,
245, n. I

in relation to culture of isolated pitui-
tary, 254-55

distribution of, 253-55

inactivation of, by serum of patients
with cancer, 255

metabolic effects associated with, 183,
n. 10

metabolism of, 253-55

and metabolism, carbohydrate, pos-
sible interrelationship, 217, n. 19

metabolism, water, and, 252-53

effect of oestrogens on action of, 252,
n. 10

pharmacology of, 251-52

and diagnosis of pregnancy, 127, n. 5

effect of progesterone on action of,
252, n. 10

and position of retinal pigment, 250

thyroid and action of, 252, n. 10

Chromatosome distribution; see also

Chromatosome-dispersing hormone
effect of hypophysectomy on, 244 ff.

in amphibia, 249-50

in fishes, 245-49

in reptiles, 249, n. 5
Colostrum; see Milk
Comparative anatomy of pituitary, 2

Copper salts

augmentation of action of gonado-
tropic hormone by, 118

Corpus luteum hormone; see Progester-
one

Corticosterone, 294, 296; see also
Adrenal cortical hormone. Adrenal
glands

Corticotropic hormone; see Adrenal
cortical stimulating hormone. Ad-
renal glands

Crinogenic hormone, 106

Crop-glands

effect of lactogenic hormone on growth
of, 167, 169-71
Crustacea
eye-stalks of, and chromatosome-
dispersing hormone, 245, n. i

Cushing's syndrome

hypertension of, and adrenal glands,

287-88
metabolism, mineral, associated with,

_235, n- 35
obesity of, 232, n. 32
pathology of pituitary, 24-25

Dehydroisoandrosterone, 294, 296; see
also Androgens

Diabetes insipidus

and pars glandularis, 184, 278 ff.
and pars neuralis, 276 ff.
and pars tuberalis, 281

Diabetes melHtus; see also Insulin,
Metabolism, carbohydrate, Pan-
creas, etc.
and anatomy of pituitary, 25
and diabetogenic hormone, 222-24,
226-27

Dibenzanthracene

effect on anatomy of pituitary after
gonadectomy, 18

Diencephalon
"glands" of, 10
neurons of nuclei of, 9-10

Dihydroequilenine, 294, 296

Diiodotyrosine

antagonism of thyrotropic hormone
by, 192

Eclampsia

and anatomy of pituitary, 25

titer of prolan in, 127

relation of vasopressor principle to,

276, 287
experimental, and vasopressor prin-
ciple, 263-64
Embryology of pituitary, 1-2

Ephedrine

effect of, on chromatophores, 251, n. 9

Epi-allopregnanol-3-one-2o, 294, 296

388

INDEX

Epinephrine, 294, 296
effect of, on chromatophores, 247, n. 3,

and action of diabetogenic hormone,
219-21

effects of, on metaboHsin, carbohy-
drate, after hypophysectomy,
211-I4, 216

and action of thyrotropic hormone
186

Epiphysis

and gonadotropic hormone, pituitary,

98
and growth, 42

and growth of neoplasms, 43-44
in relation to action of prolan, 135
Eqiiilenine, 294, 296
Equilin, 295-96
Ergometrine

effect of, on chromatophores, 251, n. 9
Ergotamine

effect of, on chromatophores, 251
Ether

effect of, on chromatophores, 251
hyperglycemia of, after hypophysec-
tomy, 214, n. 17
Exophthalmic goiter; see Graves's dis-
ease
Exophthalmos

and anterior pituitary extract, 183,

185-86
sympathetic nervous system and, 186
Eye

action of pars neuralis extracts on
intraocular pressure and iris,
264-65

Fallopian tube

action of oxytocic principle on, 260
Fat; see Metabolism, lipoid
Fat-metabolism hormone; see Metabo-
lism, lipoid
F883

effect of, on chromatophores, 251
Fetal growth and pituitary, 36-37

F933

effect of, on chromatophores, 251

Follicle-stimulating hormones; see Go-
nadotropic hormones, pituitary

Formaldehyde

action of, on adrenals and anterior

pituitary, 203

Galactin, 158

Gastrointestinal tract, action of vaso-
pressor principle on, 265
Glutathione

of tissues after hypophysectomy,

232, n. z?,
in muscle in relation to pituitary, 207
and action of thyrotropic hormone,
189
Glycogen

metabolism of, and anterior pituitary
in liver, 209-I4, 216, 218, 219, n. 22,

224,230
in neoplasms, 210, n. 14
in striated muscle, 207, 209-14, 224
Gonadectomy

effect of, on adrenals, 202, n. 5
effect of, on anatomy of pars glandu-
laris, 17-18, 22
correction of changes in pituitary
by androgens, 91-92
by oestrogens, 91-92
by progesterone, 88
Gonadotropic hormone, pregnant-mare,
144-48
antagonism of effects of,

by antihormone, 1 1 i-i 5, 141
by pituitary extract, 106, 11 5-1 6
assay of, 142

biology of, or effects of, on gonads
of birds, 146

of mammals, 73-74, 144-48
chemistry of, 1 45-46
metabolism of, 146
and growth of neoplasms, 43
pregnancy after injection of, 148
principle(s) of, 1 45-46
effect of, after thyroidectomy, I48
Gonadotropic hormones

and growth-promoting hormone, 2?r

34
and growth of neoplasms, 43-44
of neoplasms, 142-44

amount of, in neoplasms, 144
prostatic tumors and, 143
testicular neoplasms and, 143
uterine motihty and, 132

389

THE PITUITARY BODY

Gonadotropic hormones — Continued
pituitary

and adrenal cortical hormone, 201-2

and adrenal glands, 95-98, 201-2

replacement of, by androgens in

hypophysectomized males, 93-

94
in relation to androgens, 89-94
antagonism of

by specific hormone, 106, 11 5-1 7
by antihormone, 109-15, 117
detection of, 112, n. 71
immune substances and, 1 1 1-13
effect on secretion of hormone,

1 13-15
source specificity of, 111-12
species specificity of, 111-12
assay of, 69-70, 107-9
augmentation of effects of, 1 16-19
by blood, 118
by casein, 1 18
by copper salts, 118
by egg-albumin, 118
by heme, 1 18
by hemoglobin, 118
as result of injections of hormone,

117
by luteinizing hormone, 1 17
by merthiolate, 1 18-19
by tannic acid, 1 18
by yeast ash or extract, 118
by zinc sulphate, 1 18
biology of

in amphibia, 49-51
in birds, 52-62
in fishes, 49
in mammals
female, 62-73
male, 67-68, 73-76
in reptiles, 51-52
and calcium, 102
chemistry of, 105-7
in cultures of isolated pituitary, 103
epiphysis and, 98
extraction of, 105-7
follicle-stimulating hormone, 71-
75, 78-79, 84-87, 99, 105-9,
130
response to, after hypophysectomy,

95
specific stimulation of interstitial
cells, 106, 116

lactogenic hormone and, 98-99
light as a means of controlling
secretion of, 58-62
in birds, 58-62
in fishes, 58
in mammals, 60-62
in reptile, 58
luteinizing hormone, 71-75, 78-79,

84-87, 98, 105-7, 1 16-18
male gonads, atrophy of, after

hypophysectomy, 73
metabolism of, 103-5
and growth of neoplasms, 102-3
nervous control of secretion of,

58-62, 99-101
number of, 71-72
in relation to oestrogens, 80-88
and oestrous cycle, 68-69
ovarian deficiency and, 67
ovulation and, 72
parabiosis in relation to, 78-80,

87-88, 90, 1 14-15
pregnancy and, 65, 69-70, 104
in relation to progesterone, 88-89
sexual differences in secretion of,

72, 75-78
and spleen, 105
and thyroid, 60, 94-95
and thyrotropic hormone, 186-87
transplantation of pituitary and,

65-66
and vitamins, 101-2
Cionads

anatomy of pituitary and, 15 ft",
and growth, 39-40

atrophy of, after hypophysectomy, 36
in relation to thyroid, 185-87
Graves's disease; see also Thyroid gland,
Thyrotropic hormone
and anatomy of pituitary, 25-26
experimental, 183-86

Growth; see also Growth-promoting ex-
tract. Growth-promoting hormone
effect of oestradiol benzoate on, 40
effect of oestrone on, 40

Growth-promoting extract; see also
Growth-promoting hormone
and antihormone production, 44-45
assay of, 44-45

effect of, on biochemistry of blood
and tissues, 39

390

INDEX

Growth-promoting extract — Continued
effect of, and carbohydrate metabo-

hsm, 45
effects of, 36-39
and growth of chick embryo, 36
and fetal growth, 36-37
and growth of Lupinus albus seed-
lings, 36
and duration of pregnancy, 36
preparation of, 45-46
properties of, 46
Growth-promoting hormone, 32 ff.; see
also Bones, Growth, Growth-pro-
moting extract, Hypophysectomy,
Joints
and adrenals, 41
and epiphysis, 42
gonadotropic hormones as factor in

effects of, 33-34
and gonads, 39-40
identity of, 32-35
lactogenic hormone as factor in effects

of, 3^-2^5^ 45

neoplastic growth and anterior pitui-
tary, 43-44

and sodium deficiency, 42

and thymus, 41

and thyroid, 40-41

thyrotropic hormone as factor in
effects of, 32-35, 45

transplants of pituitary in sella and,

37
and vitamins, 42
and zinc deficiency, 42-43

Heart

effect of oxytocic principle on, 263
effect of vasopressor principle on, 263
behavior of, after administration of
thyrotropic hormone or thyrox-
ine, 187-89
Heme

augmentation of action of gonado-
tropic hormone by, 1 18
Hemoglobin

augmentation of action of gonadotrop-
ic hormone by, 1 1 8
Hippuline, 295
Histamine

toxicity of, and pituitary, 203
"Houssay dogs," 217

Hydatidiform mole; see Gonadotropic

hormones of neoplasms
Hypertension

adrenals and, 287-88

anatomy of pituitary and, 11, 25

experimental (renal ischemia) and

pituitary, 188, 288-90
and pars neuralis, 287-90
thyroid gland or thyrotropic hormone
and, 188,288-89

Hyperthyroidism

thyrotropic hormone in blood or urine
in, 191

Hypophysectomy

effect of, on adrenals, 31, 36, 198-201
blood sugar after, 205-7, 209-10
bones after, 38
chemical changes in tissues after, 38-

39
effect of, on chromatosome distribu-
tion, 244 ff.
in amphibia, 249-50
in fishes, 245-49
in reptiles, 249, n. 5
cutaneous changes after, 35, 176, 178
effect of, in fowl, 55
gastrointestinal tract after, 237
general effects of, 31
glutathione in tissues after, 232, n. 22
response to gonadotropic hormone,

pituitary, after, 95
atrophy of gonads after, 36, 63-65,

73
growth after, 35-36
lactic acid

of blood, after, 205, n. 9

and action of epinephrine, 211-14
of striated muscle, after, 205, n. 9
metabolism, carbohydrate, after, 205-
16
absorption of carbohydrate, 207
action of anterior pituitary extract,

223-24
blood sugar, 205-7, 209-10
effects of epinephrine, 211-14, 216
ether hyperglycemia, 214, n. 17
and action ot insulin, 208-9, 214-16
and metabolism, fat, 208-10
and metabolism, glycogen
liver, 209-I4, 216
muscle, 207, 209-14

[391]

THE PITUITARY BODY

Hypophysectomy — Continued

metabolism, carbohydrate, after —
Continued

morphine hyperglycemia, 214, n. 17
ketogenesis and, 209-10
and metabolism, lactic acid, 207,

n. 9, 211-14
oxidation of carbohydrate, 208
and metabolism, phosphorus, 207,

n. 9, 211-14
and metabolism, protein, 210-11
sugar tolerance, 207 ff.
and action of thyroxine, 208
metabolism, creatine-creatinine, after,

233-34
metabolism, lipoid, after, 228
metabolism, mineral, after, 234-36
metabolism, protein, after, 38-39, 233
metabolism, water, after, 276 ff.

adrenal cortical hormone and, 202
effect of, on metamorphosis, 174-75
effect of, on molting
in amphibia, 176, 178
in snakes, 178
growth of neoplasms after, 43-44
effect of, on central nervous system, 31
effect of oestrogen after, 81
morphology of ovary after, 63-65
ovogenesis after, 62
anatomy of pancreas after, 216, n. 18
and pancreatectomy, metabolism,
carbohydrate, after, 216-18
carbohydrate oxidation, 217-18
glycogen deposition, 218
ketogenesis and, 218
metabolism, tissue, 217
in parabiotic animals, 79-80
pregnancy and, 65
progesterone and pharmacology of

uterus after, 64
progesterone in pregnant animals

after, 65
effect of, on skin, 35, 176, 178
effect of, on spleen, 35, 236-37
technic of, 31, 73
thyroid after, 36, 176-80, 183, n. 10
uterine bleeding in monkey after, 64,
290—91
Hypophysial deficiency

caused by oestrone, 19-21
Hypophysio-portal system of blood
vessels, 2-4

Hypothalamus; see also Diencephalon
and pars neuraHs secretion, 279 ff.
general relationship to pituitary, 31
Hypothyroidism; see also Thyroidec-
tomy, etc.
thyrotropic hormone in blood or urine

in, 191
treatment of, by thyrotropic hormone,
184-85

Innervation of pituitary, 6-10; see also
Nervous system, control by, of
pituitary secretion
Insulin; see also Diabetes mellitus,
Metabolism, carbohydrate. Pan-
creas, etc.
acetone bodies, and anterior pituitary,

230
effect of, on diabetes mellitus caused
by anterior pituitary extract,
222-23
action of, in relation to pars glandu-
laris, 208-9, 214-16
pars neuralis extracts and action of,
269-70
Intermediate lobe; see Pars intermedia
Intermedin; see Chromatosome-dispers-

ing hormone
Interstitial cells of gonads
effect of prolan on, 129, 131
specific stimulation of, 106, 116

Iodides

prevention of adrenal cortical stimula-
tion by, 202, n. 5

prevention of splenomegaly by, 202,
n. 5

antagonism of thyrotropic hormone
by, 190, 192

Iodine

effect of, on molting in amphibia,

176, 178

Joints

changes in, acromegaly, 37
effects of anterior pituitary extract
on, 37-38

Ketogenesis; see also Metabolism, carbo-
hydrate. Metabolism, lipoid
after hypophysectomy and pan-
createctomy, 218

INDEX

Ketogenic hormone; see Metabolism,

lipoid
Ketone bodies; see Metabolism, lipoid
Kidneys

action of pars neuralis extracts on,
265-69, 276 ff.

Lactation: see also Breasts, develop-
ment of. Lactogenic hormone
and adrenals, 152, 160
and anatomy of pars glandularis,

16-17
effects of androgens on, 163-64
effect of lactogenic hormone on, 159-

60, 164-65
and metabolism, carbohydrate, 152,

160
nervous control of, 158-59
effect of oestrogens on, 160-63
effects of progesterone on, 163
effect of prolan on, 133-34, 161, n. 14
and thyroid, 160, n. 12, 165-66
effect of thyroxine on, 166

Lactic acid
of blood

and action of epinephrine, 211-14
effect of hypophysectomy on, 207,
n. 9
of striated muscle

effect of hypophysectomy on, 207,

n. 9
effect of pituitary on, 207, n. 9

Lactogenic hormone, 151 ff.; see also
Breasts, development of. Lactation
antihormone of, 168-69
assay of, 169-71

and broodiness in fowls, 166-67
chemistry of, 171-72
effect of, on growth of crop-gland,

167, 169-71
cystic disease of breasts and, 165, 168
distribution of, 164
and gonadotropic hormone, pituitary,

98-99
and growth-promoting hormone, 32-

35,45
effect on lactation, 159-60
and maternal behavior, 167
metabolism of, 167-69
and metabolism, carbohydrate, 165,

n. 17

secretion of milk induced by, 164-65
effect on growth of neoplasms, 167
termination of pregnancy by, 167
effect of suckling on secretion of,

158-59
in relation to thyroid gland, 165-66
amount of, in pituitary in vitamin

deficiencies, 168

Lipids; see Metabolism, lipoid

Lipoids of adrenal cortex
behavior of, 200, 202, 204-5

Liver; see also Glycogen, etc.

acetone bodies, and anterior pituitary,

230 _
fat metabolism, and anterior pitui-
tary, 228-31
adrenals and, 229-31
pancreas and, 229
thyroid and, 228-29
Lobeline

effect of, on chromatophores, 251, n. 9
Lungs

action of pars neurahs extracts on
bronchi and vessels of, 264

Luteinizing hormone; see Gonadotropic
hormones, pituitary

Magnesium; see also Metabolism, min-
eral

effect of prolan on metabolism of, 137
Mammogenic hormone, 155
Mammotropic hormone, 158
Maternal behavior

and lactogenic hormone, 167
Medulla of adrenal glands

after hypophysectomy, 200, n. 2, 201

effect of pituitary extract on, 200-201
Medulla oblongata

action of vasopressor principle on, 264
Melanophore hormone; see Chromato-

some-dispersing hormone
Meningeal relations of pituitary, 5
Menstrual migraine, see Migraine, men-
strual
Menstruation; jff a/jo Uterine bleeding

and administration of oestrogens, 83,
290-91

pars neuralis and, 290-91

393

THE PITUITARY BODY

Merthiolate

augmentarion of action of gonado-
tropic hormone by, 1 18-19

Metabolism

of adrenal cortical stimulating hor-
mone, 203-4
of chromatosome-dispersing hormone,

253-55
of gonadotropic hormones, pituitary,

103-5
of lactogenic hormone, 167-69
of pars neuralis principles, 27C-71,

274-76, 286-87
of thyrotropic hormone, 190-92

Metabolism, basal or gaseous

and chromatosome-dispersing hor-
mone, 183, n. 10
effect of prolan on, 135
and thyrotropic hormone, 183-85

Metabolism, carbohydrate

adrenals and pituitary and, 218-21
effect of anterior pituitary extract on,

222-24
effects of extracts of cerebrospinal
fluid, serum, and urine on, 226-27
diabetogenic hormone and, 222-24
glycogen and anterior pituitary
liver, 209-14, 216, 218, 219, n. 22,

224, 230
neoplasms, 210, n. 14
striated muscle, 207, 209-14, 224
effect of growth-promoting extract

and, 45
after hypophysectomy, 205-16
absorption of carbohydrate, 207
action of anterior pituitary extract,

223-24
blood sugar, 205-7, 209-10
effects of epinephrine, 211-14, 216
ether hyperglycemia, 214, n. 17
and action of insulin, 208-9, 214-16
and metabolism, fat, 208-10
and metabolism, glycogen
liver, 209-14, 216
muscle, 207, 209-14
morphine hyperglycemia, 214, n. 17
ketogenesis and, 209-10
and metabolism, lactic acid, 207,

n. 9, 21 1-14
oxidation of carbohydrate, 208

and metabolism, phosphorus, 207,
n. 9, 21 1-14

and metabolism, protein, 210-11

sugar tolerance, 207 ff.

and action of thyroxine, 208
after hypophysectomy and pan-
createctomy, 216-18

carbohydrate oxidation, 217-18

glycogen deposition, 218

ketogenesis and, 218

metabolism, tissue, 217
hypothalamus and, 218, n. 21
and lactation, 152, 160
lactogenic hormone and, 165, n. 17
effect of oestrogens on, 221-22
pancreas after glucose infusion, 216,

n. 18
and stimulation of islet tissue of pan-
creas by pars glandularis, 224-26
pars glandularis after glucose infusion,

216, n. 18
and pars neuraHs extracts, 269-70

insulin and, 269-70
and pituitary, 205 ff.
effect of prolan on, 135-36
and thyrotropic hormone, 188-89

Metabolism, creatine-creatinine
gonads and, 233, n. 34, 234
and pars neuralis extracts, 270
and pituitary, 233-34

after hypophysectomy, 233-34
effect of prolan on, 136
and thyrotropic hormone, 189

Metabolism, fat; see Metabolism, lipoid

Metabolism, lipoid

acetone bodies, and anterior pituitary,
230-32
adrenal glands and, 231
effects of anterior pituitary ex-
tract, 230 ff.
antihormone of, 232
similar effects of extracts of blood
and urine, 231-32
insulin and, 230
relation of liver, 230
thyroid and, 231
in adrenal cortex, 200, 202, 204-5
cholesterol

and anterior pituitary, 228, 232
and prolan, 232

394

INDEX

Metabolism, lipoid — Continued

and chromatosome-dispersing hor-
mone, 183, n. 10
after hypophysectomy, 228
of liver and anterior pituitary, 228-31
adrenals and, 229-31
pancreas and, 229
thyroid and, 228-29
and metabolism, carbohydrate
after hypophysectomy, 208
after hypophysectomy and pan-
createctomy, 218
in relation to metabolism, carbo-
hydrate and pituitary, 209-10,
218
and pars neuralis extracts, 270
phosphatide, and anterior pituitary,

228
and pituitary, 228-32
effect of prolan on, 136-37
and thyrotropic hormone, 1 89
Metabolism, mineral

and gonadotropic hormones, pitui-
tary, 102
effect of oestrogen on, 162
and pars neuralis extracts, or hor-
mone, 265-69, 276 ff., 285
and pituitary, 234-36
effect of prolan on, 137
Metabolism, phosphorus

and carbohydrate in relation to pitui-
tary, 207, n. 9, 21 1-14
Metabolism, protein

after hypophysectomy, 38-39, 233
metabolism, carbohydrate, and pitui-
tary, 210-11
and pars neuralis extracts, 270
and pituitary, 232-33
and thyrotropic hormone, 189
Metabolism, tissue

after hypophysectomy and pancrea-
tectomy, 217
of pituitary, effect of oestrogen on, 88
of pars glandularis in relation to

oestrous cycle, 69
of thyroid, effect of thyrotropic hor-
mone on, 188
Metabolism, water

and adrenal cortical hormone, 202
and chromatosome-dispersing hor-
mone, 252-53

and pars neuralis extracts, or hor-
mone, 265-69, 276-85
effect of prolan on, 137
Metamorphosis

and thyrotropic hormone, 174-76,
195-96
Migraine, menstrual

treatment of by prolan, 138
Milk
composition of, after lactogenic hor-
mone, 164-65
composition of, after oestrogen, 162
lactogenic hormone in, 168
prolan in, 125
Molting

effect of hypophysectomy on
in amphibia, 176, 178
in snakes, 178
effect of iodine on, in amphibia, 176,
178
Morphine, hyperglycemia of, after

hypophysectomy, 214, n. 17
Myxedema; see Hypothyroidism

Neoplasms; see also Gonadotropic hor-
mones of neoplasms
inactivation of chromatosome-dis-
persing hormone by serum of
patients with, 255
glycogen of, after hypophysectomy,

210, n. 14
growth of, in relation to anterior
pituitary, 43-44
and epiphysis, 43-44
and gonadotropic hormones, pitui-
tary, 102-3
and gonadotropic hormone, preg-
nant-mare, 43
and gonads, 43-44
and hypophysectomy, 43-44
and lactogenic hormone, 167
and oestrogen, 44
and prolan, 43, 103, 137
of pituitary, 24-25
Nerves of pituitary; see Innervation of
pituitary

Nervous system

and control of metabolism, carbo-
hydrate, 218, n. 21

regulation of pars neuralis by, 277-82,
286

395

THE PITUITARY BODY

Nervous system, control by, of pitui-
tary secretion; see also Innervation
of pituitary
of gonadotropic hormone, 58-62, 99-

lOI

Nicotine

effect of, on chromatophores, 251

Nipples

growth of, and pituitary, 154

Nitrite, amyl

effect of, on chromatophores, 251

Oestradiol; see also Oestrogens

alpha, 295, 297

beta, 295, 297
Oestradiol benzoate; see also Oestrogens

effect on bones, 40

effect on growth, 40

and growth of neoplasms, 44

Oestriol, 295, 297; see also Oestrogens

Oestrogens

action of, on adrenals and anterior

pituitary, 203
effect on anatomy of pituitary, 18-21

after gonadectomy, 18
and development of breasts, 152-55,

157-58
castration changes in pituitary cor-
rected by, 91-92
and action of chromatosome-dispers-

ing hormone, 252, n. 10
in relation to gonadotropic hormones,

pituitary, 80-88
effect of, after hypophysectomy, 81
effect on lactation, 160-63
and metabolism, carbohydrate, 221-22
effect on composition of milk, 162
effect on minerals of serum, 162
action on uterus and response to

oxytocic principle, 261-62
effect of, on metaboHsm of isolated

pituitary, 88
effects in pregnant animals, 87
alteration of effect of prolan by, 133
effect of, on thyroid, 187
in relation to thyrotropic hormone,

185-87
relation to vasopressor principle and

experimental eclampsia, 264
effects of, on X-zone of adrenals, 201

Oestrone, 295, 297; see also Oestrogens
degenerative changes in adrenals

caused by, 19
effect on growth, 40
action on male after hypophysectomy,

93-94
hypophysial deficiency caused by,
19-21

Oestrous cycle

and anatomy of pars glandularis, 15-
16,26

and secretion of gonadotropic hor-
mone, 68-69

and metabolism of isolated pars
glandularis, 69

Ovaries

deficiency of secretion of, and gonado-
tropic hormone, 67

morphology of, after hypophysec-
tomy, 63-65

Ovogenesis

after hypophysectomy, 62
effect of prolan on, 130

Oxytocic principle; see also Pars neuralis
extracts, Pars neuralis, physiologi-
cal significance of

assay of, 259-60

chemistry of, 258-59

effect of, on heart, 263

metabolism of, 270, 274-76

pharmacology of, 260-62
and abortion, 261
androgen and, 262
response of cervix uteri, 260
response of fallopian tube, 260
oestrogens and, 261-62
parturition and, 261
progesterone and, 261-62

Pancreas; see also Diabetes mellitus.
Insulin, Metabolism, carbohydrate,
etc.
in relation to fat of liver and anterior

pituitary, 229
effect of hypophysectomy on anatomy

of, 216, n. 18, 226
stimulation of islet tissue of, by an-
terior pituitary, 224-26
and anatomy of pituitary, 23-24

39^

INDEX

Pancreatectomy

and hypophysectomy, metabolism,
carbohydrate, after, 216-18
carbohydrate oxidation, 217-18
glycogen deposition, 218
ketogenesis and, 218
metabolism, tissue, 217
Pancreatropic hormone, 224-26
Parabiosis, experimental

in relation to gonadotropic hormones,
pituitary, 78-80, 87-88, 90, 114-

15
Parathyroid glands

and anatomy of pituitary, 24
and pars glandularis, 235-36
Parathyrotropic hormone, 236
Pars anterior; see Pars glandularis
Pars buccalis; see appropriate division
as Pars glandularis. Pars inter-
media, or Pars tuberalis
Pars glandularis; see also all topic head-
ings as Anatomy, etc.
cytogenesis in, 13-15
and diabetes insipidus, 278 ff.
Pars intermedia
anatomy of, lo-ii
and chromatosome dispersion, 244 ff.
embryology of, 249
Pars nervosa; see Pars neuralis
Pars neuralis

anatomy of, 1 1-12
basophils of, 1 1
innervation of, 6-9
Pars neuralis extracts; see also Oxytocic
principle. Pars neuralis, physiologi-
cal significance of, Vasopressor
principle
assay of, 259-60
chemistry of, 258-59
metabolism of, 270-71, 274-76, 286-

87
and metabolism, carbohydrate, 269-

70
and metabolism, cholesterol, 270
and metabolism, creatine-creatinine,

270
and metabolism, mineral, 265-69
and metabolism, protein, 270
and metabolism, water, 265-69, 276-

effect of, on metamorphosis and
growth of tadpoles, i
Pars neuralis, physiological significance
of, 274 ff.; see also Oxytocic prin-
ciple. Pars neuralis extracts. Vaso-
pressor principle, etc.
in cardiovascular regulation, 285-90
and central nervous system, 277-82,

286
diabetes insipidus and, 276 ff.
in relation to hypertension, 287-90
clinical, 287-88
experimental (renal ischemia), 288-

90
in menstruation, 290-91
metabolism of active principles and,

270-71, 274-76, 286-87
in relation to metabolism of water,

276-85
in relation to oxytocic principle, 290
Pars tuberalis
anatomy of, 12

and regulation of chromatosome dis-
persion, 249-50
and diabetes insipidus, 281
Pathology of pituitary, 23-26
Parturition

in relation to oxytocic principle, 261,

290
and anatomy of pars glandularis, 16-
17
Phosphate, inorganic; see also Phos-
phorus, etc.
effect of prolan on metabolism ot, 137
Phosphatide; see Metabolism, lipoid
Phosphocreatine

in muscle in relation to pituitary, 207
Phospholipin; see Metabolism, lipoid
Phosphorus; see Metabolism, mineral.
Metabolism, phosphorus

Pilocarpine

and action of thyrotropic hormone,
186
Pineal body; see Epiphysis
Pituitary basophilism; see Cushing's

syndrome
Placenta; see Chorion, Prolan, metabo-
lism of
Polydipsia; see Diabetes insipidus

397

THE PITUITARY BODY

Polyuria; see Diabetes insipidus

Posterior lobe; see Pars neuralis or Pars
intermedia

Potassium

effect of prolan on metabolism of, 137

Potentiation; see Augmentation

Pregnancy

effect of androgens on duration of,

90-91
in relation to development of breasts,

155

diagnosis of, 127, n. 5

gonadotropic hormones of, I24ff.

and gonadotropic hormones, pitui-
tary, 65, 69-70, 104

after injection of gonadotropic hor-
mone of pregnant mare, 148

duration of, and growth-promoting
extract, 36

hypophysectomy and, 65

termination of, by lactogenic hor-
mone, 167

effects of oestrogens in, 87

progesterone in maintenance of, after
hypophysectomy, 65

effect of prolan during, 69-70, 132

and action of vasopressor principle,
286-87

Pregnancy-cells of pituitary, 26

Pregnanediol, 295, 297

Progesterone, 295, 297

effect on anatomy of pituitary, 21
after gonadectomy, 18

and development of breasts, 155-58

castration changes in pituitary not
corrected by, 88

and action of chromatosome-dispers-
ing hormone, 252, n. 10

in relation to gonadotropic hormones,
pituitary, 88-89

effects on lactation of, 163

and maintenance of pregnancy after
hypophysectomy, 65

inhibition of action of prolan by, 133

effect on pharmacology of uterus af-
ter hypophysectomy, 64

action on uterus and response to
oxytocic principle, 261-62

Prolactin, 158

Prolan

"A" and "B," 129-30

acne vulgaris, treatment of, by, 138

and adrenals, 134-35

in amniotic fluid, 127

effect on anatomy of pituitary, 21

antagonism of effects of

by antihormone, 1 10-15, I39~4i
by pituitary extract, 106, 1 15-16,

139
assay of, 69-70, 141-42
augmentation of effects of, 138
biology of, or effects on gonads in

amphibia, 49-50, 128

birds, 52, 58, 128

fishes, 128

mammals

female, 67, 129-34
male, 73-74, 128-29

reptiles, 51-52, 128
in blood; see metabolism of
effect of, on blood, 137-38
effect on breasts, 134
chemistry of, 142
and cholesterol metabolism, 232
chorion and, 124-27
chnical use of, 132-33
lack of effect in dietary deficiency,

102, n. 60
titer in eclampsia, 127
and epiphysis, 135

effect on ovary after hypophysec-
tomy, 130-32
effect on interstitial tissue

of ovary, 131

of testis, 129
effect on lactation, 133-34, 161, n. 14
luteinizing effects of, 130 ff.
menstrual migraine, treatment of, bv,

138
metaboHsm of, 125-28
effects of, on metabolism

of carbohydrate, 135-36

of cholesterol, 136-37

of creatine and creatinine, 136

gaseous, 135

of magnesium, 137

of phosphorus, 137

of potassium, 137

of sodium, 137

of water, 137

39^

INDEX

Prolan — Continued
in milk, 125
effect of, on growth of neoplasms, 43,

103, 137
effect of, modified by oestrogen, 133
and culture of isolated ovary, 132
ovulation caused by, 69-70, 131
and ovogenesis, 130
in placenta; see metabolism of
and diagnosis of pregnancy, 127, n. 5
effect of, in pregnancy, 69-70, 132
action inhibited by progesterone, 133
in saliva, 125
action of, and spleen, 105
action of, on thymus, 135
thyroid and, 134-35
tuberculosis, experimental, treatment

of, by, 138
effect of, on movements of ureter, 138
in urine; see metabolism of
uterine motility and, 70-71, 132
lack of effect in vitamin A deficiency,

129
and def:ciency of vitamin E, 137

Prostate

tumors of, and gonadotropic hor-
mones, 143

Radon

effects of, on pituitary, 31, 62
Reticulo-endothelial system

in relation to f>ars glandularis, 237
and production of prolan antihor-
mone, 139, n. 16
Retina, pigment of

effect of chromatosome- dispersing
hormone on position of, 250

Saliva

prolan in, 125
Sarcoma; see Neoplasms
Simmonds' disease

and adrenal cortical stimulating hor-
mone, 204
in identical twins, 36
Skin

changes in, after hypophysectomy,

35,176,178
effect of pars neuralis extract on
chloride of, 267, n. 13

Sodium; see also Metabolism, mineral
deficiency of, and gonadotropic hor-
mones, pituitary, 102
deficiency of, and growth, 42
effect of prolan on metabolism of, 137

Spaying; see Gonadectomy

Spleen

and action of gonadotropic hormone,
pituitary, 105
of prolan, 105
effect of hypophysectomy on, 35, 236-

_ 37

iodides and prevention of enlarge-
ment of, by anterior pituitary
extract, 202, n. 5

in relation to pars glandularis, 35,
236-37
Strychnine

effect of, on chromatophores, 251

Suckling

effect of, on secretion of lactogenic
hormone, 158-59

Sugar of blood; see Blood sugar

Sulfonal, in pituitary and tissues, 238

Sulphur; see Metabolism, mineral

Supraoptico-hypophysial tract, 6-8; see
also Pars neuralis, physiological sig-
nificance of

Synergism; see Augmentation

Tannic acid

augmentation of action of gonado-
tropic hormone, by, 1 1 8

Teratoma; see Gonadotropic hormones
of neoplasms

Testis, neoplasms of; see (Jonadotropic
hormones of neoplasms

Testosterone, 295, 297; see also Andro-
gens

Testosterone or testosterone propionate,
effect on anatomy of pituitary of, 21

Thiamin; see Vitamin B,

Thymus

and anatomy of pituitary, 24

and growth, 41

action of prolan on, 135

399

THE PITUITARY BODY

Thyroid gland; see also Graves's disease,
Thyroidectomy, Thyrotropic hor-
mone, Thyroxine

acetone bodies, and anterior pitui-
tary, 231

and adrenal-pituitary interrelation-
ship, 202

and action of chromatosome-dispers-
ing hormone, 252, n. 10

cytological changes in response to
thyrotropic hormone, 182

in relation to diabetes insipidus,
278 ff.

in relation to fat of liver and anterior
pituitary, 228-29

and gonadotropic hormone, pregnant-
mare, 148

and gonadotropic hormones, pitui-
tary, 94-95

in relation to gonads, 60, 186-87

and grov/th, 40-41

and experimental hypertension, 188,
288-89

after hypophysectomy, 36, 176-80,
183, n. 10

and lactation, 160, n. 12, 165-66

effect of oestrogens on, 1 87

anatomy of pituitary and, 21-22

and action of prolan, 134-35

and thyrotropic antihormone, 182,

193
pharmacology of, and vasopressor
principle, 263
Thyroidectomy; see also Thyroid gland.
Thyrotropic hormone
anatomy of pituitary after, 178-79
Thyrotropic hormone, 174-97; ^^^ ^^^^
Graves's disease. Thyroidectomy,
Thyroid gland. Thyroxine
action of, 174 ff.

and adrenal cortical extract, 187
hypertrophy of adrenals after in-
jection of, 190, 202, n. 5
antagonism of, by
antihormone, 192-94
diiodotyrosine, 192
iodides, 190, 192
oestrogens, 185, 187
thyroxine, 185, 192
vitamins, 190
assay of, 194-95

biology of, in

amphibia, 174-78
birds, 178
fishes, 174
mammals, 178-81
reptiles, 178
and bone or wound repair, 190
chemistry of, 195-96
cytology of thyroid after injection of,

182
in relation to diabetes insipidus,

278 ff.
exophthalmos associated with effect

of, 183, 185-86
action of, and glutathione, 1 89
and gonads or gonadotropic hor-
mones, 186-87
and growth-promoting hormone, 32-

35,45
heart after administration of, 187-89
and experimental hypertension, 188,

288-89
treatment of hypothyroidism bv, 184-

85 _ ' '

metabolism of, 190-92

comparison with thyroxine, 187-88
and metaboHsm, carbohydrate, 188-

89
and metabolism, creatine-creatinine,

189
and metaboHsm, gaseous, 183-85
and metabolism, lipoid, 189
and metabolism, protein, 189
and metabolism of isolated thyroid,

188
metamorphosis and, 174-76, 195-96
nervous system and, 186
in relation to oestrogens, 186-87
amount of, in pituitary, 179-81
specificity of, 174

effect of, on thyroid transplants, 182
action of, and

vitamin A, 190

vitamin C, 190

vitamin D, 190

Thyroxine, 295, 297

adrenal hypertrophy caused by, 202,

n. 4
action of, after hypophysectomy, 180,

400

INDEX

Thyroxine — Continued

effect of, on lactation, i66

action of, on metabolism, carbohy-
drate, after hypophysecromy, 208

antagonism of thyrotropic hormone
by, 185, 192

effects of, compared with thyrotropic
hormone, 184, 187-88

Tissue culture
of ovary

effect of prolan on, 132
of pituitary, 28

and chromatosome-dispersing hor-
mone, 254-55
and vasopressor hormone, 254-55
gonadotropic hormone in, 103, n. 61

Tissue metabolism; see Metabolism, tis-
sue

Transplantation

of pars glandularis, 237-38
of pituitary

anatomical changes, 27-28
secretion of gonadotropic hormone
and, 65-66

Tuberculosis

effect of prolan on course of, 138

Tumors; see Gonadotropic hormones of
neoplasms. Neoplasms

Ureter

effect of prolan on movements of, 138
Urine

action of pars neuralis hormones or
extracts on secretion of, 265-69,
276 ff.

Uterine bleeding

in monkey after hypophysectomy, 64,
290-91

Uterus

motility of

anterior pituitary extract and, 70-

71
progesterone and, 64
prolan and, 70-71, 132
hormone of testicular neoplastn
and, 132
and action of oxytocic principle, 260-
62, 290

Vasopressor principle; see also Pars
neuralis extracts, Pars neuralis,
physiological significance of,
assay of, 259-60
chemistry of, 258-69
in relation to culture of isolated pitui-
tary, 254-55
metabolism of, 270-71, 274-76, 286-

87
pharmacology of, 262-65
and eclampsia, 263-64, 287
and eye, 264-65
and gastrointestinal tract, 265
and heart, 263
and lungs, 264
and medulla, 264
oestrogens and, 264
and pregnancy, 286-87
thyroid extract and, 263
Vitamin A
deficiency of

and lactogenic hormone in pitui-
tary, 168
and prolan, 129
and growth, 42
anatomy of pituitary and, 26
and action of thyrotropic hormone,
190
Vitamin B (complex)
deficiency of

and lactogenic hormone in pitui-
tary, 168
Vitamin Bj

anatomy of pituitary and, 26-27
Vitamin C; see Ascorbic acid
Vitamin D
deficiency of

and lactogenic hormone in pitui-
tary, 168
anatomy of pituitary and, 27
and action of thyrotropic hormone,
190

Vitamin E
deficiency of

and lactogenic hormone in pitui-
tary, 168
and prolan, 137
and gonadotropic hormones, pitui-
tary, 101-2
anatomy of pituitary and, 27

[401]

THE PITUITARY BODY

Vitamins

and growth, 42

X-rays

effects of, on pituitary, 31, 62

X-zone of mouse adrenal

and anterior pituitary, 200-201
effect of oestrogens on, 201

Yeast

augmentation of action of gonado-
tropic hormone by ash or extract
of, 1 1 8

Yohimbine

effect of, on chromatophores, 251

Zinc

deficiency of, and growth-promoting
hormone, 42-43

Zinc salts

augmentation of action of gonado-
tropic hormone by, 118

augmentation of action of vasopressor
principle by, 270-71

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