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=The Hormones in Human Reproduction=
=The Hormones in Human Reproduction=
[[File:George Corner.jpg|thumb|link=Embryology History - George Corner|George Corner  (1889 - 1981)]]


{{Corner GW.}} [[Book - The Hormones in Human Reproduction|'''The Hormones in Human Reproduction''']]. (1942) Princeton University Press.<noinclude>[[Category:Template]][[Category:Reference]][[Category:Historic Embryology]][[Category:Endocrine]][[Category:1940's]]</noinclude>
{{Corner GW.}} [[Book - The Hormones in Human Reproduction|'''The Hormones in Human Reproduction''']]. (1942) Princeton University Press.<noinclude>[[Category:Template]][[Category:Reference]][[Category:Historic Embryology]][[Category:Endocrine]][[Category:1940's]]</noinclude>
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To the young physicians and biologists,  
To the young physicians and biologists, Fellows of various foundations and scientific societies, who came from other lands  to study with the author of this book problems common to all humanity Sidney Arthur Asdell, Cambridge, England Seitchi Saiki, Tokyo, Japan Eduardo Burster Montero, Santiago, Chile Friedrich Hoffmann, Dusseldorf, Germany Graham Weddell, London, England Ines Lopez Colombo de Allende, Cordoba, Argentina Luis Vargas Fernandez, Santiago, Chile Washington Buno, Montevideo, Uruguay


Fellows of various foundations and scientific societies,
WE TOOK counsel TOGETHER AND WALKED IN THE WAY OF TRUTH AS FRIENDS  
 
who came from other lands
 
to study with the author of this book
 
problems common to all humanity
 
Sidney Arthur Asdell, Cambridge, England
 
Seitchi Saiki, Tokyo, Japan
 
Eduardo Burster Montero, Santiago, Chile
 
Friedrich Hoffmann, Dusseldorf, Germany
 
Graham Weddell, London, England
 
Ines Lopez Colombo de Allende, Cordoba, Argentina
 
Luis Vargas Fernandez, Santiago, Chile
 
Washington Buno, Montevideo, Uruguay
 
WE TOOK counsel TOGETHER  
 
AND WALKED IN THE WAY OF TRUTH  
 
AS FRIENDS  




Line 81: Line 53:
==Preface==
==Preface==


THIS book represents, with considerable additions, the  
This book represents, with considerable additions, the substance of the [http://lectures.princeton.edu/category/lectures/louis-clark-vanuxem-lectures/ Vanuxem Lectures], given at Princeton University in February 1942. The invitation to be Vanuxem Lecturer carried with it the expressed wish of the Committee that I should discuss the hormones of the reproductive system for the benefit of a general audience, assuming on the part of my hearers no familiarity with biology. This imposed no easy task, for it called upon me to describe some of the most intricate and elaborate mechanisms of the body, to listeners who perhaps had never seen the organs and tissues in which these activities take place. The structure of the living cells and the manner in which they are put together to form the organs are matters not merely so unfamiliar, but actually even so daunting to most people, as to create serious difficulties for the biologist and physician who tries to explain his work. For the first time in my life I could have wished I were an astronomer or physicist, for the heavenly spheres, their orbits and attractions, and even such matters as warps in space and corpuscles of light can be described to a certain extent in terms of the workshop and the household; but how can we explain the marvels of the human egg or the action of an estrogenic hormone without a background of cellular biology.'* My only recourse has been to begin at the very beginning, to devote as many as three chapters to general preparation for actual discussion of the hormones, and at every step to explain and illustrate the underlying anatomy and physiology as clearly as possible. This is, to the best of my knowledge, the first time an American university has devoted one of the great endowed lectureships to the subject of human reproduction. A few years ago it might even have been impossible to break through the old conventions that hampered free public discussion of this subject. We have a tradition that sex and reproduction must be attended by privacy, dignity and romance. It is a good tradition, provided we add a fourth attribute, namely understanding; for otherwise the fundamental life activities concerned in sex may become involved in fears, inhibitions and blind taboos. I emphasize the importance — nay even the necessity — of instruction and understanding in matters of sex, in case there are still among my readers some who are troubled by our free discussion of intimate functions, and especially in case it seems to them that the dignity and the romance of life are threatened by frank acceptance of the animal nature of mankind or by our use of other creatures to explain human affairs. There is of course no denying that man is an animal, and since human physiology cannot always be subjected to direct experiment (particularly in this field of investigation), we must study the lower animals not only for their own intrinsic interest but also in order to understand ourselves. It is equally true that man is more than an animal. The ape, the tiger, and the worm mate and reproduce their kind, and so do human beings, but only man tries to understand what he is doing and why he does it. In such understanding and in right living based upon knowledge lies our best hope of attaining dignity, honor and beauty in the physical life of mankind.
substance of the Vanuxem Lectures, given at Princeton University in February 1942. The invitation to  
be Vanuxem Lecturer carried with it the expressed wish of  
the Committee that I should discuss the hormones of the  
reproductive system for the benefit of a general audience,  
assuming on the part of my hearers no familiarity with  
biology. This imposed no easy task, for it called upon me to  
describe some of the most intricate and elaborate mechanisms  
of the body, to listeners who perhaps had never seen the  
organs and tissues in which these activities take place. The  
structure of the living cells and the manner in which they are  
put together to form the organs are matters not merely so  
unfamiliar, but actually even so daunting to most people, as  
to create serious difficulties for the biologist and physician  
who tries to explain his work. For the first time in my life I  
could have wished I were an astronomer or physicist, for the  
heavenly spheres, their orbits and attractions, and even such  
matters as warps in space and corpuscles of light can be  
described to a certain extent in terms of the workshop and  
the household; but how can we explain the marvels of the  
human egg or the action of an estrogenic hormone without  
a background of cellular biology.'* My only recourse has been  
to begin at the very beginning, to devote as many as three  
chapters to general preparation for actual discussion of the  
hormones, and at every step to explain and illustrate the  
underlying anatomy and physiology as clearly as possible.  
This is, to the best of my knowledge, the first time an  
American university has devoted one of the great endowed  
lectureships to the subject of human reproduction. A few  
years ago it might even have been impossible to break through  
the old conventions that hampered free public discussion of  
this subject. We have a tradition that sex and reproduction  


{ ix }


A book of this kind rests upon the laborious work of many scientific^ investigators. The author, in drawing freely upon the writings of his colleagues, has endeavored to acknowledge their contributions as fully as possible, by mention in the text, footnotes and legends. References however are necessarily limited; readers who wish to consult the original literature will find full bibliographies in Appendix II, note


1. Many fellow workers who have generously permitted the use of illustrations, as indicated in text and legends, deserve especial thanks.


PREFACE


must be attended by privacy, dignity and romance. It is a
The quotation at the head of Chapter I is from Two Lives, by William EUery Leonard, copyright 1922, 1925, by permission of the Viking Press, Inc., New York. The quotation from C. Day Lewis's translation of Virgil's Georgics, in a footnote to Chapter III, is used by permission of Jonathan Cape, Limited, London and Toronto.
good tradition, provided we add a fourth attribute, namely
understanding; for otherwise the fundamental life activities
concerned in sex may become involved in fears, inhibitions
and blind taboos. I emphasize the importance — nay even the
necessity — of instruction and understanding in matters of
sex, in case there are still among my readers some who are
troubled by our free discussion of intimate functions, and
especially in case it seems to them that the dignity and the
romance of life are threatened by frank acceptance of the
animal nature of mankind or by our use of other creatures to
explain human affairs. There is of course no denying that
man is an animal, and since human physiology cannot always
be subjected to direct experiment (particularly in this field
of investigation), we must study the lower animals not only
for their own intrinsic interest but also in order to understand ourselves. It is equally true that man is more than an
animal. The ape, the tiger, and the worm mate and reproduce
their kind, and so do human beings, but only man tries to
understand what he is doing and why he does it. In such
understanding and in right living based upon knowledge lies
our best hope of attaining dignity, honor and beauty in the
physical life of mankind.  


A book of this kind rests upon the laborious work of many
The author's wife, Betsy Copping Corner, and his son, Dr. George W. Corner, Jr., have given unfailing encouragement and have been patient and thoughtful critics. Mr. Arthur G. Rever has been good enough to read the manuscript and has made useful suggestions.
scientific^ investigators. The author, in drawing freely upon
the writings of his colleagues, has endeavored to acknowledge
their contributions as fully as possible, by mention in the
text, footnotes and legends. References however are necessarily limited; readers who wish to consult the original
literature will find full bibliographies in Appendix II, note 1.  


Many fellow workers who have generously permitted the  
The author's researches upon the menstrual cycle of monkeys, cited in this book, were aided by grants to the University of Rochester by the Rockefeller Foundation and the John and Mary R. Markle Foundation.
use of illustrations, as indicated in text and legends, deserve
especial thanks.  


GEORGE W. CORNER


Carnegie Institution of Washington Department of Embryology, Baltimore


PREFACE
==Contents==


The quotation at the head of Chapter I is from Two Lives,
Preface
by William EUery Leonard, copyright 1922, 1925, by permission of the Viking Press, Inc., New York. The quotation
from C. Day Lewis's translation of Virgil's Georgics, in a
footnote to Chapter III, is used by permission of Jonathan
Cape, Limited, London and Toronto.


The author's wife, Betsy Copping Corner, and his son,
List of Plates
Dr. George W. Corner, Jr., have given unfailing encouragement and have been patient and thoughtful critics. Mr.
Arthur G. Rever has been good enough to read the manuscript and has made useful suggestions.


The author's researches upon the menstrual cycle of monkeys, cited in this book, were aided by grants to the University of Rochester by the Rockefeller Foundation and the
List of Text Figures
John and Mary R. Markle Foundation.


GEORGE W. CORNER
[[Book - The Hormones in Human Reproduction (1942) 1|Chapter I. The Place Of The Higher Animals, and of Mankind in Particular, in the General Scheme of Animal]]


Carnegie Institution of Washington
Simple division into parts a frequent mode of reproduction in lower animals; necessity of egg and sperm cells in higher and more complicated creatures ; the participation of two individuals, male and female, essential to the process in all higher animals ; in mammals, including mankind, the fertilized egg sheltered and nourished within the mother's body; correlation of the various organs of the reproductive system to this end by action of chemical substances (hormones) made in the sex glands.
Department of Embryology, Baltimore




[[Book - The Hormones in Human Reproduction (1942) 2|Chapter II. The Human Egg And The Organs That Make And Care For It]]


CONTENTS
The egg a cell growing in a cavity (follicle) in the ovary; its progress, after discharge from the ovary, via the oviduct to the uterus ; its implantation in the uterus, if fertilized by a sperm cell ; division into many cells and development into an embryo ; nourishment from the mother's blood during growth in the uterus, through an organ of attachment, the placenta.


Page
PREFACE ix


LIST OF PLATES xvii
[[Book - The Hormones in Human Reproduction (1942) 3|Chapter III. The Ovary as Timepiece]]


LIST OF TEXT FIGURES Xviii
Development of the eggs of mammals to maturity at regular intervals; occurrence, in most mammals, of a phase of sexual responsiveness (estrus) at the time of ripening of the eggs ; resultant mating, and fertilization of the eggs ; the reproductive cycle constituted by recurrence of these events; peculiar modification of the cycle in the human race, apes and higher monkeys, characterized by monthly disturbance in the uterus resulting in menstruation.


CHAPTER I. THE PLACE OF THE HIGHER ANIMALS,
[[Book - The Hormones in Human Reproduction (1942) 4|Chapter IV. The Hormone of Preparation and Maturity]]
AND OF MANKIND IN PARTICULAR, IN THE GENERAL
SCHEME OF ANIMAL REPRODUCTION 8


Simple division into parts a frequent mode of reproduction in lower animals; necessity of egg and sperm
Production by the ovaries of a remarkable substance, the estrogenic hormone ; its property of causing the other organs of the reproductive tract (oviducts, uterus, vagina, mammary glands) to grow to adult size, and of maintaining them in the adult state.
cells in higher and more complicated creatures ; the participation of two individuals, male and female, essential
to the process in all higher animals ; in mammals, including mankind, the fertilized egg sheltered and nourished
within the mother's body; correlation of the various
organs of the reproductive system to this end by action
of chemical substances (hormones) made in the sex
glands.  


[[Book - The Hormones in Human Reproduction (1942) 5|Chapter V. A Hormone for Gestation]]


Conversion of the ovarian follicle, after discharge of the egg, into a temporary gland of internal secretion, the corpus luteum; production by this gland of a hormone called progesterone, which acts upon the uterus in such a way as to insure attachment and nourishment of the early embryo.


CHAPTER II. THE HUMAN EGG AND THE ORGANS THAT
[[Book - The Hormones in Human Reproduction (1942) 6|Chapter VI. The Menstrual Cycle]]
MAKE AND CARE FOR IT


The egg a cell growing in a cavity (follicle) in the
Menstruation a peculiar phenomenon limited to a few species of higher animals ; its period (in humans) about four weeks, but not perfectly regular. Digression about the cycle in general, showing that it is probably due to interaction between the ovaries and the pituitary gland. Menstruation a periodic breakdown of the uterine lining (endometrium) when the corpus luteum retrogresses. Occurrence, however, of anovulatory cycles, without a corpus luteum, and without "premenstrual" changes. Explanation of the bleeding as due to shutting oflf of the coiled arteries of the endometrium caused by deprivation of estrogenic hormone or of progesterone; bleeding due to progesterone deprivation believed to be a special case of estrin-deprivation bleeding. Theory of the menstrual cycle based on these ideas. The significance of menstruation unknown.
ovary; its progress, after discharge from the ovary, via
the oviduct to the uterus ; its implantation in the uterus,  
if fertilized by a sperm cell ; division into many cells and  
development into an embryo ; nourishment from the mother's blood during growth in the uterus, through an organ
of attachment, the placenta.  


{ adii }
[[Book - The Hormones in Human Reproduction (1942) 7|Chapter VII. Endocrine Arithmetic]]


Calculation of the quantities of the two hormones produced in the ovaries and the rate at which they are secreted; in the case of the corpus luteum, discussion of such questions as the amount of hormone made by a single cell, the amount made by the whole gland in one day, and divers other matters of interest concerning the quantitative aspect of ovarian function.


[[Book - The Hormones in Human Reproduction (1942) 8|Chapter VIII. The Hormones In Pregnancy]]


33
The maintenance of pregnancy a complex affair, dependent partly on the hormones. The placenta as a source of gonadotrophic and estrogenic hormones ; progesterone also apparently made by the human placenta. Lactation induced by a special hormone of the pituitary gland.


[[Book - The Hormones in Human Reproduction (1942) 9|Chapter IX. The Male Hormone]]


The testis constructed of tubules in which the sperm cells are made; the interstitial cells. The seminal ducts, seminal vesicles, and prostate gland under control of the testis through its hormone. Secondary sex characters described and shown to be controlled by the testis. Chemistry and effects of the androgenic hormones.


CONTENTS


CHAPTER III. THE OVARY AS TIMEPIECE
[[Book_-_The_Hormones_in_Human_Reproduction_(1942)_Appendices|Appendices]]


Development of the eggs of mammals to maturity at
==List of Plates==
regular intervals; occurrence, in most mammals, of a
phase of sexual responsiveness (estrus) at the time of
ripening of the eggs ; resultant mating, and fertilization
of the eggs ; the reproductive cycle constituted by recurrence of these events; peculiar modification of the cycle
in the human race, apes and higher monkeys, characterized by monthly disturbance in the uterus resulting in
menstruation.


CHAPTER IV. THE HORMONE OF PREPARATION AND
Plate Facing Page


MATURITY
I. Reproduction by budding, in hydra


Production by the ovaries of a remarkable substance,
II. Sexual reproduction in hydra
the estrogenic hormone ; its property of causing the other
organs of the reproductive tract (oviducts, uterus, vagina,
mammary glands) to grow to adult size, and of maintaining them in the adult state.


CHAPTER V. A HORMONE FOR GESTATION
III. Fertilization and division of the egg of the sea urchin, as seen in sections


Conversion of the ovarian follicle, after discharge of  
IV. Development of the sea urchin's egg, from living specimens
the egg, into a temporary gland of internal secretion, the
corpus luteum; production by this gland of a hormone
called progesterone, which acts upon the uterus in such
a way as to insure attachment and nourishment of the
early embryo.


CHAPTER VI. THE MENSTRUAL CYCLE
V. The human ovaries, oviducts, and uterus


Menstruation a peculiar phenomenon limited to a few
VI. Regner de Graaf's original picture of the graafian follicle, 1672
species of higher animals ; its period (in humans) about
four weeks, but not perfectly regular. Digression about
the cycle in general, showing that it is probably due to


{ anv }
VII. The primate ovary and egg


VIII. GROWTH OF THE FOLLICLE IN THE RAT


IX. THE CORPUS LUTEUM


CONTENTS
X. THE OVIDUCT ( FALLOPIAN TUBe) AND THE TRANSPORT OF THE EGG


interaction between the ovaries and the pituitary gland.  
XI. DIVISION OF THE RABBIt's EGG, FROM LIVING SPECIMENS
Menstruation a periodic breakdown of the uterine lining
(endometrium) when the corpus luteum retrogresses.
Occurrence, however, of anovulatory cycles, without a
corpus luteum, and without "premenstrual" changes. Explanation of the bleeding as due to shutting oflf of the
coiled arteries of the endometrium caused by deprivation
of estrogenic hormone or of progesterone; bleeding due
to progesterone deprivation believed to be a special case
of estrin-deprivation bleeding. Theory of the menstrual
cycle based on these ideas. The significance of menstruation unknown.


CHAPTER VII. ENDOCRINE ARITHMETIC 179
XII. IMPLANTATION OF THE EMBRYO IN THE RHESUS MONKEY AND IN MAN


Calculation of the quantities of the two hormones produced in the ovaries and the rate at which they are secreted; in the case of the corpus luteum, discussion of
XIII. THE VAGINAL CYCLE IN THE RAT
such questions as the amount of hormone made by a
single cell, the amount made by the whole gland in one
day, and divers other matters of interest concerning the
quantitative aspect of ovarian function.  


CHAPTER VIII. THE HORMONES IN PREGNANCY 199
XIV. CASTRATE ATROPHY


The maintenance of pregnancy a complex a£fair, dependent partly on the hormones. The placenta as a source
XV. THE EFFECT OF ESTROGENIC HORMONE ON THE VAGINA
of gonadotrophic and estrogenic hormones ; progesterone
also apparently made by the human placenta. Lactation
induced by a special hormone of the pituitary gland.  


CHAPTER rx. THE MALE HORMONE 217
XVI. THE EFFECT OF ESTROGENIC HORMONE ON THE UTERUS


The testis constructed of tubules in which the sperm
XVII. PROGESTATIONAL PROLIFERATION OF THE UTERUS
cells are made; the interstitial cells. The seminal ducts,


{ aru }
XVIII. THE EFFECT OF PROGESTERONE ON THE UTERUS AND EMBRYOS OF THE RABBIT


XIX. X-RAY PHOTOGRAPH OF THE HUMAN SKULL, SHOWING LOCATION OF THE PITUITARY GLAND


XX. HUMAN INFANT AT BIRTH, WITH PLACENTA


CONTENTS
XXI. THE UTERUS OF THE RHESUS MONKEY AT SUCCESSIVE STAGES OF THE CYCLE


seminal vesicles, and prostate gland under control of the
XXII. The uterus of the rhesus monkey during menstruation
testis through its hormone. Secondary sex characters
described and shown to be controlled by the testis. Chemistry and effects of the androgenic hormones.


APPENDIX. CHEMICAL STRUCTURE OF THE SEX GLAND
XXIII. Structure of the testis
HORMONES 248


INDEX 25?
XXIV. Sperm cell formation ; the cryptorchid testis


==List of Text Figures==


1. Reproduction by lengthwise fission 4


LIST OF PLATES
2. Reproduction by budding 5


Plate Facing Page
3. Reproduction by spore formation 6


I. REPRODUCTION BY BUDDING, IN HYDRA 8
4. Reproduction by transverse fission 6


n. SEXUAL REPRODUCTION IN HYDRA 9
5. Reproduction by eggs and sperm cells, in Hydra 7


III. FERTILIZATION AND DIVISION OF THE EGG OF THE
6. Conjugation of a one-celled animal 13


SEA URCHIN, AS SEEN IN SECTIONS 18
7. Sperm cells of various animals 15


IV. DEVELOPMENT OF THE SEA URCHIn's EGG, FROM
8. The human female reproductive tract 86
LIVING SPECIMENS 19


V. THE HUMAN OVARIES, OVIDUCTS, AND UTERUS S4
9. The corpus luteum 42
VI. REGNER DE GRAAf's ORIGINAL PICTURE OF THE


GRAAFIAN FOLLICLE, 1672 S5
10. Form of the uterus in various animals 49
VII. THE PRIMATE OVARY AND EGG 38
VIII. GROWTH OF THE FOLLICLE IN THE RAT 89
IX. THE CORPUS LUTEUM 44
X. THE OVIDUCT ( FALLOPIAN TUBe) AND THE TRANSPORT OF THE EGG 45
XI. DIVISION OF THE RABBIt's EGG, FROM LIVING SPECIMENS 56
XII. IMPLANTATION OF THE EMBRYO IN THE RHESUS


MONKEY AND IN MAN 57
11. Diagram of the human female reproductive tract 50


XIII. THE VAGINAL CYCLE IN THE RAT 74
12. The lining of the uterus (endometrium) 53


XIV. CASTRATE ATROPHY 76
13. Diagram of a uterine gland 55
XV. THE EFFECT OF ESTROGENIC HORMONE ON THE


VAGINA 84
14. Implantation of the embryo in rabbit and man 58


XVI. THE EFFECT OF ESTROGENIC HORMONE ON THE
15. Diagram of the reproductive cycle of the sow 67


UTERUS 85
16. Diagram of the menstrual cycle and the cycle in general 70


XVII. PROGESTATIONAL PROLIFERATION OF THE UTERUS 108
17. Apparatus for studying the activity of uterine muscle 122


XVIII. THE EFFECT OF PROGESTERONE ON THE UTERUS
18. Effect of progesterone on the rabbit's uterus 125


AND EMBRYOS OF THE RABBIT 109
19. Diagram of the reproductive cycle of mammals 140


XIX. X-RAY PHOTOGRAPH OF THE HUMAN SKULL, SHOWING LOCATION OF THE PITUITARY GLAND 142  
20. Form and location of the pituitary gland 142
XX. HUMAN INFANT AT BIRTH, WITH PLACENTA 143
XXI. THE UTERUS OF THE RHESUS MONKEY AT SUCCESSIVE STAGES OF THE CYCLE 148


{ scvii }
21. Diagram of the hormone-alternation theory of the cycle 143


22. Diagram of the menstrual cycle 147


23. The arteries of the endometrium 150


LIST OF PLATES
24. Diagram, the effect of estrin deprivation 162
Plate Facing Page


XXII. THE UTERUS OF THE RHESUS MONKEY DURING
25. The estrin-deprivation hypothesis 163


MENSTRUATION 149
26. Diagram, effect of progesterone on estrin-depriva tion bleeding 165


XXIII. STRUCTURE OF THE TESTIS 218
27. Hypothetical explanation of the ovulatory cycle 166


XXIV. SPERM CELL FORMATION ; THE CRYPTORCHID TESTIS 219
28. Growth of the human uterus in pregnancy 200


LIST OF TEXT FIGURES
29. Development of the mammary gland 209


Figure Page
50. The human male reproductive tract 219


1. Reproduction by lengthwise fission 4
51. Structure of the testis and epididymis 221


2. Reproduction by budding 5
52. Effect of testis hormone on the cock's comb 2S3


3. Reproduction by spore formation 6


4. Reproduction by transverse fission 6


5. Reproduction by eggs and sperm cells, in Hydra 7
{{Corner1942TOC}}
 
6. Conjugation of a one-celled animal 13
 
7. Sperm cells of various animals 15
 
8. The human female reproductive tract 86
 
9. The corpus luteum 42
 
10. Form of the uterus in various animals 49
 
11. Diagram of the human female reproductive tract 50
 
12. The lining of the uterus (endometrium) 53
 
13. Diagram of a uterine gland 55
 
14. Implantation of the embryo in rabbit and man 58
 
15. Diagram of the reproductive cycle of the sow 67
 
16. Diagram of the menstrual cycle and the cycle in
 
general 70
 
17. Apparatus for studying the activity of uterine muscle 122
 
18. Effect of progesterone on the rabbit's uterus 125
 
19. Diagram of the reproductive cycle of mammals 140
 
20. Form and location of the pituitary gland 142
 
21. Diagram of the hormone-alternation theory of the
 
cycle 143
 
22. Diagram of the menstrual cycle 147
 
23. The arteries of the endometrium 150
 
24. Diagram, the effect of estrin deprivation 162
 
25. The estrin-deprivation hypothesis 163
 
{ ODVili }
 
 
 
LIST OF TEXT FIGURES
 
Figure Page
 
26. Diagram, effect of progesterone on estrin-depriva
tion bleeding 165
 
27. Hypothetical explanation of the ovulatory cycle 166
 
28. Growth of the human uterus in pregnancy 200
 
29. Development of the mammary gland 209
 
50. The human male reproductive tract 219
 
51. Structure of the testis and epididymis 221
 
52. Effect of testis hormone on the cock's comb 2S3
 
 
 
THE PLACE OF THE HIGHER ANIMALS, 4* OF
 
MANKIND IN PARTICULAR, IN THE GENERAL
 
SCHEME OF ANIMAL REPRODUCTION
 
 
 
"of the cell, the wondrous seed
Becoming plant and animal and mind
Unerringly forever after its hind.
In its omnipotence, in flower and weed
And beast and bird and fish, and many a breed
Of man and woman, from all years behind
Building its future"
 
William Ellery Leonard, Two Lives.
 
 
 
CHAPTER I
 
THE PLACE OF THE HIGHER ANIMALS, 4* OF
 
MANKIND IN PARTICULAR, IN THE GENERAL
 
SCHEME OF ANIMAL REPRODUCTION
 
A MONG the life that swarms in our southern waters,
/% there is a charming tiny animal called Cothurnia, the
^ %. buskin animalcule. These creatures cling by thousands to the vegetation on wharf piles in our harbors, and
can be brought into the laboratory on a bit of seaweed in a
drop of water. Because a single Cothurnia is much smaller
than the printed period at the end of this sentence, it must
be watched through the microscope (Fig. 1). It consists of
a graceful transparent cup (formed more like a wineglass
than the classical buskin from which it got its name) which
is attached by its stem to some larger object. Inside the cup
and fixed to its base is a single animal cell, shaped like a
trumpet. While the stem sways gently in the water, the cell
projects from the cup. Into its open gullet particles of food
are swept by a brush of beating lashes or cilia and drift down
into the jelly-like cell substance until they are dissolved and
digested.
 
This simple career of food-gathering is interrupted from
time to time by a few hours devoted to reproduction. Our
pretty little trumpet withdraws itself inside the cup, rounds
up a bit, and slowly separates into two cells by dividing
lengthwise. For a time, both cells resume the task of feeding,
but afterward one of them retires into the cup and begins a
struggle to get away. It pulls so strongly, indeed, upon its
stalk that its shape changes; from a trumpet it becomes a
shoe. The cilia change position so that they can serve for
propulsion in swimming. At last the cell breaks from its
attachment and slips out into the sea, ultimately to settle
 
{ 3 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
 
 
 
Fio. 1. The one-celled animal Cothurnia, reproducing itself by simple
division. The parent animal is seen at a. From 6 to d, successive stages
of division. In e the daughter cell has freed itself and is swimming away,
to settle in a new location. Greatly magnified.
 
 
 
down upon a near-by strand of seaweed, or perhaps (venturing greatly) as far away as the next timber of the wharf.
 
All this makes no difference to the first cell; it undergoes
no pregnancy, feels no pangs while giving birth and takes
no responsibility to nurse, guard, or educate its offspring.
The latter in turn asks nothing at all of its parent, and never
realizes the disadvantages of birth at so low a level of organization, one of which is that the newborn cell faces immediately
and alone all the dangers of its world. The infant mortality
of Cothurnia must be enormous, for there are many enemies
and risks, but what of that.? The parent can easily split off
another cell, and in spite of the wastage it is more economical
(if all you want is a one-celled child) to breed by excess production than by the intricate process through which man
and the higher animals turn out their limited output of
complex and troublesome offspring.
 
Other unicellular animals have developed variations of the
process of reproduction by division. Sometimes they do not
divide into two equal cells, but put out their daughter cells as
mere buds which break off while small and only later reach
 
{4 }
 
 
 
THE GENERAL, SCHEME
 
"adult" size (Fig. 2). Sometimes the parent animal breaks
up by multiple fission into a relatively large number of very
small daughter cells resembling spores (Fig. 3).
 
Reproduction by fission is so easy that in the course of
evolution the animal kingdom held on to it for a long time,
and many animals higher than the unicellular animals made
use of it. Some of the worms, for example, split in two transversely by forming an extra head from some of the segments
near the middle of the body (Fig. 4). This head, with the
rest of the worm that lies behind it, drops off and wriggles
away, while the original worm forms a new tail at its truncated posterior end. Sometimes the worm breaks up into a
whole chain of segments each of which becomes a new worm.
 
Reproduction by budding also continued in higher ani
 
 
 
 
 
 
 
 
 
^Ti^^te^^^j^
 
 
 
'â– ' \
 
Fio. 2. A one-celled animal, AcanthocystiSy reproducing itself by
budding. 3 buds are seen. Greatly magnified. After Schaudinn.
 
 
 
{ 5 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
 
 
 
Fio. 3. A one-celled animal, Trichospherium, reproducing itself by the
formation of spores. In this kind of reproduction the original "parent"
ceases to exist as an individual, being completely dispersed into its
offspring. Greatly magnified. After Schaudinn.
 
 
 
 
Fio. 4. The marine worm Autolytus reproducing itself by transverse
fission. At a, a new head is forming, and the rear part of the worm
will soon drop off to become a separate individual. Magnified. After
Alexander Agassiz.
 
 
 
{ e }
 
 
 
THE GENERAL SCHEME
 
 
 
 
E55 cell
 
 
 
Fio. 5. Diagram of simple many-celled animal {Hydra) cut lengthwise
to show the egg cell and the testis with its sperm cells. Compare with
the photographs of the same subject, Plate II. From Attaining Womanhood, by George W. Corner, by courtesy of Harper and Brothers.
 
 
 
mals, notably the sponges and jelly fishes. In the common
fresh-water polyp, Hydra, for example (Fig. 5 and Plate I),
the buds develop from the side of the tubular parent and
ultimately break away. An interesting development of this
pattern is well seen in Obelia, a hydra-like animal often
studied in biology classes, in which the bud is not exactly like
the parent, but becomes a free-swimming medusa (jelly fish)
which in turn produces a generation of polyps like the original
hydroid.
 
In some of the sponges the buds or gemmules are formed
internally and must await the death and decay of the parent
before they can get free to begin their own career.
 
I have not space here to review all the modifications of
this general sort that occur in the more primitive part of the
animal kingdom. Some of them are decidedly bizarre. The
process of budding can, however, be considered (with certain
 
 
 
{ 7 )
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
technical reservations) as merely a variation of the fundamental process of multiplication by fission.
 
H. G. Wells, Julian Huxley, and G. P. Wells, in "The
Science of Life," summarize the whole subject of reproduction of living things when they say that "cleared of the complication of sex, reproduction is seen to be simply the detachment of living bits of one generation, which grow up into the
next." Detachment of living bits of an animal is not always
as easy, however, as in these primitive animals we have been
considering. Obviously such processes as fission and budding
can be effective only with relatively simple creatures. The
more complex the parental animals, the more awkward for
them to split in two or to produce buds. When, for example,
there is a permanent hard shell outside the body, or a complicated skeleton inside, the animal cannot well divide itself
in two. Animals with numerous special organs and tissues
cannot readily form buds in which all the special features are
represented. The new generation cannot take over the complex structure of its parent but must build its own body
anew. When the parent detaches a bit of itself for the purpose
of reproduction, that living bit must be a germinal organism,
elementary and uncomplicated but able to grow rapidly and
evolve itself into an adult like its parent.
 
I call attention to the fact that in this last sentence we
have written the specifications of an Egg.
 
This idea was adumbrated long ago by an ancient balladist :
 
How should any cherry
 
Be without a stone?
And how should any wood-dove
 
Be without a bonef
 
When the cherry was a flower
 
Then it had no stone;
When the wood-dove was an egg
 
Then it had no bone.
 
{ 8 }
 
 
 
THE GENERAL, SCHEME
 
The egg or ovum. We have already mentioned the simple
fresh-water polyp Hydra as an example of animals that
reproduce by budding. In this same animal, however, there is
another kind of reproduction that occurs from time to time,
in which the living part that is detached from the parent
to form the new generation is not a bud, made of many cells
and resembling the parent, but a single cell. As shown in the
diagram (Fig. 5, left) and the photograph (Plate II, A)
from time to time one of the cells in or near the surface of
the animal enlarges very much and stores up materials with
which it can be nourished for a while after it is cast off from
the parent. This is the egg cell or ovum. The few cells that
surround it where it grows on the side of the animal could be
called an ovary (as we call the organ of similar function in
higher animals) if it were worth while to dignify so simple
and transitory a structure as the egg hillock of Hydra by
considering it an organ. An egg, then, is a simple cell that is
set aside by the parent and destined to divide into many cells
and thus become an adult animal after the fashion of its kind.
Seen in this light, reproduction by means of an egg is merely
another case of reproduction by fission, in which the two
living products of division are very unequal, the egg on one
hand, the maternal animal on the other. If we compare a
Hydra and its egg with an animal of a single cell, say a
Cothurnia, that is going to divide, we see that the animalcule
though an adult has also the function of an egg, for it can
give rise, by division, to another animal body. In short, in
one-celled animals the same cell must necessarily carry on all
the functions of life, including reproduction ; in many-celled
animals the function of reproduction can be delegated to
special cells.
 
The Scholastics debated which came first, the hen or the
egg. Modern biology has an answer: they were contemporaneous ; among protozoans the hen is the egg. Neither came
first ; they merely became distinguishable whenever it was (the
 
{ 9 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
record of evolution has some torn-out pages at this point)
that an animal first became sufficiently complex to set aside
a germ cell, specialized for reproduction. Had a scholastic
philosopher been present on that prehistoric occasion the
only question would have been which he noticed first — probably not the egg, because it was smaller than the rest of the
animal.
 
The sperm cell. Hydras do not, however, always form eggs ;
half the time they develop not an ovary, but a testis, in which
a few cells of the animal give rise by repeated division to a
large number of very small sperm cells (diagram. Fig. 5,
right; and photograph, Plate II, C). These cells can swim
independently, when they are discharged into the water, by
means of a motile tail with which each is provided. The sole
function of such a cell is to swim until it meets an egg cell
released from another Hydra and to enter it. When the egg
is thus "fertilized" by union with a sperm cell, and then only,
it begins to divide and ultimately to become a new Hydra.
Herein we have the elements of sex, for this new polyp has two
parents, which were not exactly alike in spite of their general
similarity, because one of them furnished the egg and was
temporarily at least a female ; the other, which furnished the
sperm cell, was temporarily a male.
 
THE MEANING OF SEX
 
No characteristic of man and the other animals is so
fundamental, so completely taken for granted, as the existence of two sexes. It is the first fact the Bible mentions about
the human race: ". . . male and female created He them."
In every nature myth the animals enter two by two. In
primitive song and story every Jack that cracks his crown
has a Jill that tumbles after. Man that is born of woman finds
it impossible to think of a race with only one sex, or to
imagine other sexes than two. Nor does the biologist contradict this axiom; everywhere in nature he also sees two sexes.
 
{ 10 }
 
 
 
THE GENERAL SCHEME
 
Even in the lowest and simplest living things, in which it is
fanciful to speak of male and female, there is (as we shall
see) sexual mating or at least a process of renewal of life by
the mingling of living substances.
 
In our day, however, science makes bold more than ever
to question fundamental assumptions. The concept that space
has three dimensions is as obvious as that animals have two
sexes, but physicists do not hesitate to calculate in four, five,
or n dimensions. We may boldly ask, therefore, why sex is
necessary at all ; or why there are not several sexes. If living
things must mate in order to reproduce why could not nature
have arranged some other system, for example a state of
sexual relativity, in which an individual might be (without
any change in itself) male with respect to one potential mate,
female with respect to another.? or it might take part in
reproduction in response to another of its species, neither of
them being either male or female. Such conjectures are not
more fantastic than the concepts of mathematical relativity,
with their notions of a warp in space, and of an expanding
universe. Similar questions have indeed long been asked by
the poets and philosophers. John Milton vigorously states an
unfavorable view of the two-sex system:
 
why did God,
Creator wise, that peopVd highest Heav*n
With Spirits Masculine, create at last
This noveltie on Earth, this fair defect
Of Nature, and not fill the World at once
With Men as Angels without Feminine,
Or find some other way to generate
Mankind? This mischief had not then hefalVn.
 
PARADISE LOST.
 
and Sir Thomas Browne, the famous physician philosopher,
tough-minded as he was on many subjects, was personally
 
i n }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
squeamish about the whole matter of reproduction by physical contact of the sexes :
 
I could be content that we might procreate like trees,
without conjunction, or that there were any way to perpetuate the World without this trivial and vulgar way
of union.
 
RELIGIO MEDICI.
 
In illustration of these roving thoughts of poet and scientist, let us return for a moment to the sea-born Cothurnia.
When such an animalcule reproduces itself by division, we
find it handy to call the new animal a "daughter cell," but
this is only a figure of speech. The offspring is even closer
than a child ; it is more truly a twin of the cell that produced
it, for their relationship is exactly like that between a pair
of human identical twins, which arise by the splitting of one
cell, i.e. the human egg. Presently the parent Cothurnia will
give off another "daughter cell" ; will that be niece or sister
of the first? And if a Cothurnia is sister to its mother (i.e.
the cell that produced it) is it not equally sister to its grandmother . . . and so on, as far back as the line was reproducing
by simple division? We have here indeed a situation in which
the terminology of the human bisexual family tree breaks
down, for all the offspring of a single cell that reproduces
without mating are related together even more closely than
the members of a human family. They all have identically the
same heredity, and are all "twins" one of another, though
they may number thousands and represent many "generations." For this kind of group the biologists have had to
invent a new name; they call it a clone.
 
Such a clone, being a group of cells that all came from one
cell, may be considered something like the body of an individual many-celled animal. That too is a group of cells that
all came from one cell. Like an animal body the clone seems
to have its phases of youth, maturity, and old age. After
 
{ 12 }
 
 
 
THE GENERAL SCHEME
 
many divisions it becomes old; the vigor of its members
diminishes. Individual animals become abnormal and enfeebled, and the rate of fission slows down. The clone is in
danger of extinction. It needs a shake-up, which it cannot
get through the process of complete inbreeding (or rather,
lack of outbreeding) by which the clone develops.
 
Conjugation or mating. This seems to be the reason that even
in such simple animals a process much like sexual union occurs.
Fig. 6 shows the mating of the one-celled animal Scytomonas.
Animals of this species are not attached, like Cothurnia, but
swim about in the water. As we watch them under the microscope, two individuals that are going to mate swim near each
other, come into contact and actually cohere side to side. One
of them loses its whiplike flagellum. The protoplasmic substance of which they are made becomes continuous from one
animal to the other, and the nuclei move toward each other
and unite. In this particular species the conjugated animal
then becomes dormant for a time, but ultimately resumes
 
 
 
 
Fio. (i. Conjugation of the one-celled animal Scytomonas. Proceeding
from A, which shows a single individual, through B, C, D, and E, two
cells are seen to join, fuse their nuclei (the dark round objects) and
unite into one cell. This single individual remains dormant for a time
but ultimately becomes active again. Greatly magnified. After Dobell,
simplified.
 
{ 13 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
activity and becomes the parent of a new clone. This process
is very much like fertilization of an egg by a sperm cell in
higher animals, and we can get from it a better understanding
of the meaning of sexual union. For example, the late Professor
H. S. Jennings (a brilliant predecessor of mine in the
Vanuxem Lectures) with his fellow workers has investigated
the mating habits of a very well known one-celled animal,
Paramecium. They have discovered the remarkable fact that
two Paramecia of any one clone will not conjugate with each
other. The animal must find a mate not closely related to it.
By studying an immense number of animals of the species
Paramecium hursaria the investigators found that the whole
population of the species is distributed into several "mating
types" such that an individual of one type will mate with
one of another type, but not with one of its own.
 
Conjugation is therefore a kind of outbreeding. To use a
figure of speech taken from higher animals, it introduces
"new blood" into the family, which causes an internal rearrangement of the cell materials and gives the race a new
start. The "mating types," it will be noted, are not in any
strict sense different sexes. As Jennings points out, in one of
his examples, types A and B will mate together and type C
will mate with either of them. Such an observation shows that
type C is not of a fixed "sex." The situation indeed is one of
relative sexuality, such as we cited above when we were trying
to imagine other ways of reproduction Nature might have
tried rather than the bisexual method that universally characterizes higher animals.
 
In some other one-celled animals, however, there seem to
be only two mating types, and in many species the two conjugating types are actually somewhat different in appearance.
This is getting closer and closer to bisexuality in the strict
sense.
 
It is probable that conjugation or something like it goes
on in every kind of animal, although the details are not
 
{ u }
 
 
 
THE GENERAL SCHEME
 
always the same, and there are puzzling and obscure cases
awaiting solution. At any rate the situation is clear in the
higher animals, which always reproduce by the union of an
egg cell with a sperm cell. Just why the whole animal kingdom, except a few of the lowest and simplest creatures, settled
down so completely to the egg-and-sperm system, we can only
guess. Perhaps in some early ancestral animal, not originally
bisexual, it happened that some of the reproductive cells
were unusually well stored with nutritive substances. This
would be an advantage, for it would help to tide the embryos
over the earliest stages of their development before they
could feed themselves. Such cells would, however, be sluggish, and the chance of two of that kind meeting would
therefore be reduced. A germ cell that happened to be lighter
and more mobile would be more likely to meet the relatively
sluggish cell. Once started, such a trend toward two types
would progress and become fixed, by the familiar Darwinian
process of survival of the fittest, and ultimately we should
arrive at the characteristic arrangement, namely large eggs
laden with food (yolk) and small active sperm cells.
 
 
 
 
Fio. 7. Sperm cells of various animals and man. Greatly magnified.
 
{ 15 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
Fertilization of the Egg
 
The fertilization of an egg by a sperm cell is one of the
greatest wonders of nature, an event in which magnificently
small fragments of animal life are driven by cosmic forces
toward their appointed end, the growth of a living being. As
a spectacle it can be compared only with an eclipse of the
sun, or the eruption of a volcano. If this were a rare event,
or if it occurred only in some distant land, our museums and
universities would doubtless organize expeditions to witness
it, and the newspapers would record its outcome with enthusiasm. It is, in fact, the most common and the nearest
to us of Nature's cataclysms, and yet it is very seldom
observed, because it occurs in a realm most people never see,
the region of microscopic things. It is, moreover, in most
animals we are likely to see, a recondite event, occurring in
ponds or the sea, in the forest or the earth, wherever the
creatures lay their eggs. In mammals and birds the fertilization is hidden in the depths of the body. Nor indeed are all
eggs suitable for study ; they may, for example, be opaquely
loaded with pigment like those of the frog. Such eggs may,
of course, be killed and cut into thin slices for microscopic
study, and the process of fertilization has thus been observed
step by step in the prepared eggs of many species, but only
a few biologists ever see the whole continuous process of union
of a living egg with a sperm cell.
 
It need not be so rare a sight, however, for anyone who will
go to a seaside laboratory in summer can witness it. The sea
urchins, starfish and sand dollars which inhabit our coasts
almost seem especially created to reveal the process of fertilization with utmost clearness. While writing this chapter
I have before me a sketchbook made while a college student,
working at the U.S. Fisheries laboratory at Beaufort, North
Carolina, where I studied with amazement the finest of all
these marine eggs, those of the white sea urchin, Toxopneus
{ 16 }
 
 
 
THE GENERAL SCHEME
 
tes variegatus, first described by Louis Agassiz, and introduced to experimental biology by the cytoiogist Edmund B.
Wilson. A related species is shown in the beautiful and
instructive photographs here presented (Plates III and IV),
the work of Dr. Ethel Browne Harvey of Princeton, to whom
I am deeply grateful for the opportunity to use them. They
were made at Woods Hole from a common northern sea
urchin, Arbacia punctidata.
 
The male and female sea urchin deposit their sperm cells
and eggs, respectively, directly into the sea. For purpose of
study, however, it is quite readily possible to remove the germ
cells from the animals before they are spawned and to bring
them together in a dish under the microscope. The observer
cuts open the spiny shell of a female urchin and pulls out the
ovaries, slits them and catches in a dish of water the hundreds
of beautiful glass-clear spheres, 0.9 mm. (0.037 inch) in
diameter. A male sea urchin yields its testes, from which
exudes a fluid milky with microscopic particles, each of which
is a wriggling, dancing sperm cell — a tadpole-shaped object
with a lance-shaped head about 0.07 mm. (0.003 inch) in
length and a long tail. When the sperm cells are mixed with
the eggs, they swim about rapidly until they touch the eggs,
to which they adhere, several sperm cells about each egg,
trying to push into its substance. When one sperm cell has
actually penetrated the egg (Plate III, A, B) it causes the
surface of the egg cell to be rapidly congealed into a thin
membrane, something like the scum on a cup of cocoa. By
this means, the other competing sperm cells are effectively
prevented from entering.
 
Meanwhile the observer will have noticed the nucleus of
the egg (Plate III, A), a, rounded body about one-sixth the
diameter of the whole egg cell, eccentrically placed near one
edge and enclosed by a delicate nuclear membrane. This nucleus is the goal toward which the sperm cell is moving, and
 
{ 17 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
the object of the whole process is to secure fusion of the
sperm cell with the egg nucleus. The tail of the sperm cell is
broken oif and left behind. The head now advances through
the eggf swelling slightly as it goes. In the egg substance a
star-shaped aster or region of stiffened egg substance appears and travels with the sperm nucleus. The egg nucleus
advances to meet the sperm and within ten minutes from the
time the sperm cell enters the egg, the two nuclei have united
and blended their substance (Plate III, C). The egg is now
fertilized; it inmiediately prepares to divide, and while the
observer watches, entranced with the smooth inevitability of
these events, the divisions follow one another every twenty-five
minutes, so that one cell becomes two, the two become four,
eight, sixteen, thirty-two, and so on until the embryo is a
mass of small cells looking like a mulberry. All these events
are shown in Plates III and IV. We need not follow the fertilized egg through the subsequent complicated changes and
metamorphoses by which it becomes an adult sea urchin.
 
The meaning of fertilization. If the eggs are left alone in
the dish, they do not go ahead by themselves and turn into
sea urchins. Development cannot begin until after the entrance of the sperm cell and the fusion of the nuclei. Evidently
the sperm cell in some way is necessary to set off or stimulate
division of the egg. A great step toward understanding what
happens was made by Jacques Loeb in 1899 and 1900. Loeb
had been studying the effect upon life processes of changing
the amounts of certain minerals which are present in living
tissue. By increasing or decreasing the concentration of magnesium or calcium in sea water, for example, he could speed
up or slow down the rate of division of fertilized sea urchin
or starfish eggs. This led him to try dilute solutions of magnesium chloride on the unfertilized eggs, completely free from
sperm cells. Eggs so treated began to divide and when carefully handled often went on to form complete larvae. In later
 
{ 18 }
 
 
 
 
Plate III. Fertilization and segmentation of the egg of the sea urchin Arbacia,
as seen in eggs sectioned and stained for microscopic examination. A, sperm cell
about to enter egg. B, sperm nucleus (small black-stained object) approaching egg
nucleus. C, sperm nucleus (black object) fuses with egg nucleus, 10 minutes after
entry of sperm cell into egg. D, nucleus of fertilized egg begins to divide. E, division in progress. The black-stained objects in a row at center are the chromosomes.
F, nuclei of the two daughter-cells re-forming. G, stage of two cells. H, the first two
cells now divide again. I, stage of four cells. All magnified 375 diameters. Prepared
and photographed by Ethel Browne Harvey.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
vm
 
 
 
'H
 
 
 
 
Plate IV. Segmentation of the egg of the sea urchin Arbacia, photographed
while living by Ethel Browne Harvey. A, fertilized egg. B, beginning of segmentation. C, two-cell stage. D, four cells. E, eight cells. F, sixteen cells. G, "mulberry"
(morula) stage. H, hollow embryo (blastula) . Ij young adult sea urchin. A to H,
magnified 290 diameters; /, almost natural size.
 
 
 
THE GENERAL SCHEME
 
experiments by others, such fatherless young have actually
been raised to adult life, and to all appearances were normal
specimens of their kind.
 
Lest this experiment should seem to disparage the importance of the father, we should mention that the contrary
experiment also succeeds. If an egg is cut into two pieces, one
of which has no nucleus, and the latter is then entered by a
sperm cell, it too will divide and become an embryo, though
admittedly not as often as in the other, less drastic experiment. In this case the embryo is motherless, from the standpoint of heredity, for it has no egg nucleus in it. This shows
that egg stuff, to develop, must have a nucleus and requires
to be stimulated, but either an egg nucleus or a sperm nucleus
will do. We shall see later, however, that for reasons that
concern heredity it is decidedly better for the offspring to
get its nuclear material from both parents, as normally
happens.
 
This remarkable experiment of artificial parthenogenesis
("virgin generation") as it is called, has been repeated on
many kinds of animals, and it has been found that not only
magnesium solutions, but quite a number of different stimuli
will start division of the eggs. Exposure to sperm cells of
other species, extracts made from dead sperm cells, various
dilute acids and alkalies, sudden cooling, heating, shaking, or
pricking the eggs all can be used to initiate development in
one species or another. Mere staleness will cause the eggs of
some animals to divide. In all probability these diverse stimuli
produce some sort of common effect on the cell substances,
setting up internal changes (not as yet well understood) that
start the processes of division and growth of the egg. The
point of interest for us is that when the sperm cell acts upon
the egg in this way, it is exerting a merely physical or chemical effect. The fact that it is itself a living cell is more or less
incidental. The egg contains all the essential elements for
 
{ 19 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
the production of a perfect animal, and needs only to be
given a start/
 
The eggs of mammals, including the human species, probably do not differ in this respect from those of sea urchins
and starfish. Because they are far harder to get at and less
resistant to handling and exposure, experimental study has
not progressed very far. In very recent years, Gregory
Pincus and his associates at Clark University have worked
with rabbits, using an experimental method in which the unfertilized egg was subjected to drastic cooling while passing
through the oviduct (Fallopian tube). A few such eggs, subsequently replanted into other rabbits, are said to have
formed embryos, to have been born, and to have grown to
normal adult life. H. Shapiro of Philadelphia has still more
recently reported starting development of the rabbit's egg by
drastic refrigeration of the whole body of the female rabbit,
but up to the present none of these eggs has developed beyond
the earliest embryonic stages.
 
I hasten to add that under ordinary circumstances, when
there is no meddling by an experimenter, mammalian eggs
live in a perfectly conditioned environment. The temperature
and all other conditions to which they are subjected in the
 
1 In a brief chapter like this, in which I am deliberately selecting those
features of the natural history of reproduction which best lead up to the
higher animals, it is not possible to follow out all the ramifications of
the subject. Life processes are so richly varied that every general statement calls for a bill of exceptions. There are, for example, many animals
that can produce parthenogenetic eggs, i.e. eggs that develop spontaneously without fertilization. This is the case in a great many insects. In
some of these instances, no doubt, a stimulus akin to that of fertilization
is furnished by natural conditions, such as high temperatures, desiccation, or chemical changes within the egg, but in others there is no known
special stimulus. Indeed, when we reflect that a tendency to propagate by
division is innate in almost all animal cells, the wonder is that in most
species the eggs do have to be stimulated in order to develop.
 
Incidentally, even in the insects and other animals with parthenogenetic
generations, sexual reproduction always occurs from time to time to rejuvenate the line and start new clones, just as in one-celled animals. In
all vertebrate animals sexual reproduction is obligatory.
 
{ 20 }
 
 
 
THE GENERAL SCHEME
 
body are so closely regulated that parthenogenesis of the
sort described by Pincus would not be possible.
 
Heredity. We have not yet told the whole story of fertilization. Mere stimulation of an egg to develop, necessary as
it is, is not all the sperm cell does. It has another vastly
important task, which is to carry into the egg the male parent's contribution to the heredity of the offspring. Packed in
the nucleus of the egg and in the nuclear head of the sperm
cell are the submicroscopic chemical particles that control
the inherited characteristics of the species; when the sperm
cell unites with the egg, the nucleus of the fertilized egg
acquires an equal share of this controlling material from
each parent. When the egg divides, these determiners are
distributed to the daughter cells at each division and thus
are carried into all the cells of the embryo. This is the way
the sperm brings in "new blood" and rejuvenates the cell
lineage, as happens in the one-celled animals by means of
conjugation. In this way, moreover, two family lines are
blended, and special traits of bodily build and behavior are
exchanged and distributed, so that the young are never quite
identical with either parent.
 
This blending and assortment of hereditary characters is
the object and goal of sexual reproduction. Whatever else
follows in this book is merely the story of the arrangements
and devices of nature to assure the meeting of egg and sperm
cell and to protect the embryo that they produce.
 
How the determiners of heredity that can shape the whole
body of a man or woman, and then bequeath themselves to
another generation, are packed into the small compass of
egg and sperm cell, how they are distributed to the cells of
the body by processes of almost geometrical precision, how
they can be traced and how they guide the building of the
body — this is the subject matter of the science of genetics,
one of the grand divisions of modern biology. It is not to be
a theme of the present book. Those of my readers who have
 
{ 21 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
studied biology have mastered at least the rudiments of
genetics and the lore of the chromosomes. Unfortunately, this
important and beautiful science is almost impossible of explanation to those who have not seen animal and plant cells
through the microscope. Several writers have made brave
attempts to do so, and the reader is referred to their books.*
For us let it suffice that egg and sperm cell join ; we shall not
attempt here to see what goes on within them.
 
Meeting of the germ cells. The eggs and sperm cells of such
simple and small animals as Hydra are discharged directly
into the water, and the sperm cell swims to the egg. As
animals become larger and more complicated, the gonads
(ovaries and testes) are built more deeply into the body.
Some sort of opening or channel to the surface is then provided. The ovaries and testes of sea urchins, for example,
open through the shell by small pores.
 
When fertilization depends upon the chance meeting of
eggs and sperm cells, or upon such uncertain aids as tides
and currents, there is obviously a great risk of failure to make
contact. To compensate for this, and also for the subsequent
high loss of embryos, due to enemies and unfavorable conditions, an enormous excess of germ cells is usually produced.
There would obviously be greater economy and safety if some
arrangement were made to bring the germ cells together or
to put them near each other in the first place. A fantastic
variety of such arrangements is seen in nature. Animals that
are sluggish like the sea urchins and starfish, or actually
fixed in position, like most shellfish as well as the sponges,
corals and many ascidians (of which the "sea squirts" are
examples) are often aided, as we said above, by tides or other
currents. In higher plants, which are not only rooted to the
 
2 H. G. Wells, Julian S. Huxley and G. P. Wells, The Science of Life,
London, 1929; Charles R. Stockard, The Physical Basis of Personality,
New York, 1931; Alan F. Guttmacher, Life in the Making, New York,
1933; A. M. Scheinfeld and M. D. Schweitzer, You and Heredity, New
York, 1939.
 
{ 22 }
 
 
 
THE GENERAL SCHEME
 
ground, but have male germ cells that cannot move of their
own accord, the winds or the insects transport the pollen.
 
Most of those animals that are free to move mate by propinquity. They can at the very least deposit their eggs and
sperm cells at the same place. This is the case in many fishes,
in which the male and female place themselves close together
when they spawn, so that the sperm cells are deposited upon
the eggs. Frogs and toads provide an even better chance of
contact between the germ cells, for in the mating season the
male instinctively clasps the female with his fore limbs and
the two animals remain in close contact for days, until the
eggs are discharged, whereupon the sperm cells are deposited
directly upon the eggs. In the tailed amphibians (such as
newts and salamanders) sperm cells are not discharged externally at all. Like all other vertebrates below the mammals
(i.e. fish, amphibians, reptiles, and birds) these tailed amphibians have a combined cloacal passage into which both
the intestinal and the genital canals open. The openings of
the cloacas of the male and female are placed so close together
in mating that the sperm cells pass directly from one to the
other. They then pass up into the oviduct and fertilize the
eggs there. Much the same process occurs in many birds,
for example the common fowl and their kin.
 
An obvious advance is the development of an organ for
direct transmission of the sperm cells. The elasmobranch
fishes (sharks and rays) possess specially modified anal fins,
called claspers, which are grooved so that the seminal fluid
containing the sperm cells is guided along them from the
cloaca of the male to that of the female. This particular
method of solving the problem is, of course, not available to
land animals, since they have no fins. In snakes and lizards
there are saclike branches of the cloaca that can be turned
inside out and protruded into the cloaca of the female, carrying with them the sperm cells. In other reptiles, namely turtles
and crocodiles, and in many birds the final solution was
 
{ 23 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
attained and has become standard in mammals. This is a
special male organ, the penis, adapted to insertion into the
female genital tract. In female mammals the lower end of
the genital canal is expanded into a special canal, the vagina,
which receives the penis. The sperm cells can thus be safely
placed well within the reproductive system of the female. In
both sexes, in mammals, the intestinal outlet is separate,
leaving the genital outlets (penis and vagina respectively)
associated only with those of the urinary system.
 
In the higher vertebrates, then, the eggs leave the ovary
and pass down the egg ducts. If mating occurs, sperm cells
are put into the vagina (or into the cloaca in reptiles and
birds) and travel upward to meet the eggs in the oviduct and
fertilize them there. What is to be done next with the eggs?
Turtles coat them with a parchment-like shell (secreted by
the lower end of the oviduct), lay them, and bury them in
the sand. Birds provide a hard shell and put them in a nest.
Mammals do much more for their fertilized eggs — they keep
them in the mother's body and develop them there. We shall
have to study in later chapters the elaborate arrangements
necessary for this process of gestation.
 
Gestation
 
Although the development of the young within the mother's
body is characteristic of the mammals, and is most highly
perfected in that order of animals, it is by no means unknown
in lower orders. In some of the mollusks, for example, the
embryos are kept within the shell of the mother until their
development is well advanced. The European oyster thus
long retains its embryos in the gill chamber. The viviparous
fish which have become popular in home aquariums in recent
years raise their young in the oviduct. Some fish actually
retain them in the ovary itself. The young fish, which are
very small, live on the yolk that was in the egg from which
each one sprang, and in some species probably absorb nour
{ u }  
 
 
 
THE GENERAL SCHEME
 
ishment from the tissues of the mother, but they are not
actually attached to her. In some species of dogfish, the lower
part of the egg duct is expanded into a special chamber. In
this the embryos are retained. The lining of the chamber is
thrown into a mass of finger-like projections, between which
grow similar projections from the belly wall of each embryo.
Nutriment brought to this zone of interlacement by the blood
vessels of the mother filters through the coverings of the
two sets of projections into the blood vessels of the embryo, as
moisture filters into the roots of a tree. Much the same
arrangement prevails in the viviparous snakes.
 
In mammals the brood chamber is more than a mere dilatation of the oviduct. It becomes a special organ, the uterus,
which has thick muscular walls, to enable it to withstand the
distention produced by large embryos during weeks or months
of development, and afterward to expel them when the time
comes for their birth. The attachment between mother and
child (the placenta^ to be described more fully later) becomes
very intimate and very effective in transmitting nutritive
substances to the embryo and carrying waste products away.
Instead of being thrust into the outside world as an unprotected egg, the mammalian infant is sheltered and nourished
in the uterus for a long time — three weeks in the mouse, four
months in the pig, nine months in man, two years in the
elephant. Even after so long a period of gestation, when it
enters the world it is still dependent upon the body and secretions of the mother, for it cannot do without the milk she
provides for its nourishment.
 
A modest word about the father may be in order at this
point. It will perhaps seem from our sketch of his biological
function that in all the various races of animals his duty and
usefulness are done when he has put his sperm cells where
they can reach an ovum, serving thus to set the mechanism
of the egg into action and to contribute his equal share to the
heredity of his offspring. The rest takes care of itself in lower
 
{ 26 }  
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
animals, and in the higher orders seems a task for the female
alone. There is indeed one species in which the male animal
plays no other part at all in life than this — the marine worm
Bonellia, famous in biological lore, in which the male is nothing but a very small parasite on the gills of the female. She
carries this petty creature about with her for the sole purpose
of getting the eggs fertilized. Yet he cannot wholly be dispensed with, however brief his moment. In human history a
not dissimilar career has been that of certain prince consorts
of masterful queens.
 
Such is not altogether the case in mammals. The very fact
that gestation is a heavy burden, putting the female at a
disadvantage in the struggle of life, while she is carrying her
young and afterward mothering them, gives the male parent
another task — that of protector and leader of the family.
This finds biological expression in the fact that in almost all
mammals the male is larger, stronger, and fiercer than the
female (Rudyard Kipling to the contrary notwithstanding).
In the human race the mother's burden is heaviest of all, and
by that very fact the father becomes again biologically useful
to his offspring during the long period of gestation and
infancy, as guardian and provider of food and shelter.
 
Meaning of Sex for Human Beings
 
The gist of our preface to human reproduction is that our
own species and most of the others, high and low, reproduce
themselves by the production and union of eggs and sperm
cells. To get this essentially simple task done in the highest
animals requires the functioning of an elaborate set of
organs. In order to tell the whole story of reproduction in
man and the higher animals we shall have to discuss :
 
The anatomy of the ovary and testis and the formation
of eggs and sperm cells,
 
{ se }
 
 
 
THE GENERAL SCHEME
 
Transportation of the egg from ovary to uterus, and of
the sperm cell from testis to the egg.
 
The union of the germ cells,
 
Development of the fertilized egg.
 
The attachment of the embryo to the mother, and its
nutrition,
 
Birth and the nursing of the young.
 
These are complicated matters, which must be timed so that
each stage fits into the next. What goes on in one organ must
be coordinated with events in another. The chemical environment of the egg and the sperm cells must be kept in adjustment to their needs ; muscle cells in the oviduct, uterus and
the male reproductive system must be ready to act when
required; the lining of the uterus must be prepared for the
embryo; in short, a whole complex system of organs and
tissues must work as a unit.
 
The body has two important ways of linking the action of
its separate organs. One of these is the nervous system,
through which run innumerable signals connecting the organs
of sensation and motion and regulating many functions of
the internal organs. The other, with which we are much more
concerned in this book, is the system of the chemical messengers or hormones. A hormone is a chemical substance made
in one of the special glands called ductless glands or glands
of internal secretion, among which are the pituitary, thyroid,
parathyroid, adrenal, and parts of the pancreas, which do
not discharge their product through a duct to the outside
of the body or into another organ, as for example do the
sweat glands, the salivary glands, the liver and the kidney.
Instead, these endocrine glands (for such they are also
called) put their respective secretions into the blood as it
courses through the blood vessels which pervade their substance. The hormones are thus carried all over the body and
 
{ £7 )
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
reach the various organs and tissues which each of them is
respectively destined to affect. The hormone of the thyroid,
for instance, influences the utilization of oxygen by the tissues ; the pancreatic hormone (insulin) regulates the combustion of sugar ; adrenin affects the blood pressure by causing the arteries to contract. Just how each ductless gland
produces its own special secretion, and why certain particular tissues, and these only, respond to a given hormone, are
questions which must be solved by the physiologists and the
chemists of the future.
 
The ovaries and the testes are also glands of internal secretion, or to put the case more precisely, they include such
glandular tissue among their complicated make-up. The hormones made in the sex glands perform the function of linking
the action of the various organs of the genital system, timing
and regulating their activities. What these hormones are,
where they are produced, and how they act to accomplish the
bodily tasks of human reproduction, is the theme of this
book.
 
One more item should be added to the list of reproductive
activities cited above. This is the sexual urge, the totality of
impulses that serve to bring the sexes together for mating.
It is the most important coordination of all, for without the
union of the sexes all the other intricate processes are useless.
It, too, is partly regulated by the hormones, but we know too
little about this as yet to discuss it profitably here. The way
of an eagle in the air, the way of a man with a maid . . . are
still in part beyond the reach of science. In view of the fact
that we are still ignorant of the means by which the simplest
one-celled animal is impelled to conjugate with another of
its kind, we can only wonder at the complexity of sex psychology in the higher animals, and at all the lures that nature
has provided to insure the union of the sexes. What marvels
of color and fragrance, bird song and firefly radiance, have
been lavished to this end! and for mankind what emotions
 
{ '2H }
 
 
 
THE GENERAL SCHEME
 
are bound up with it, of young romance and mature devotion,
hope and fear, selfishness, slyness and cruelty. To the fanatic,
sex is a snare of the devil, to a Casanova a heartless game ;
to Stephen Dedalus as a young man it was torment ; to some
happier lad, it is a rosy dream. All these have much to gain
by seeing it also, with the biologist, as part of the inevitable
process of animal life. To understand is not to demean ourselves, nor to rob the human heart of virtue and the love of
beauty.
 
 
 
f s'.^ }
 
 
 
THE HUMAN EGG AND THE ORGANS THAT MAKE
AND CARE FOR IT
 
 
 
**All those parts of the Hen which are designed to Generation,
namely the Ovary, Infundibulum, the process of the Womb, and
the Womb itself, and the Privities: and also the scituation,
fabrick, quantity, and Temper of all these, and whatsoever else
relates thereto: they are all inservient, and handmaids either to
the procreation of the Egge, or to its Augmentation, or else to
Coition, and fertility received from the Male, or to the foetus:
to which they conduce either necessarily or principally, or as a
Causa sine qua non, or some other way to the better being. For
there is nothing made either vain or rash in all the operations of
Nature." — William Harvey, Anatomical Exercitations Concerning the Generation of Living Creatures, 1653.
 
 
 
CHAPTER II
 
THE HUMAN EGG AND THE ORGANS THAT MAKE
AND CARE FOR IT
 
WHAT can we say of the ovary, an organ so
remarkable that it is able to produce the Egg?
The human ovaries (Plate V, ovary) are insignificant-looking whitish, tough bits of animal tissue each
about the size of a small walnut^ hanging from the broad
ligament at the back of the pelvic cavity, beside the uterus.
They were frankly a puzzle to the ancient anatomists, who
never imagined that mammals have eggs and could not have
seen the tiny human eggs in the ovary anyway. The hen's egg
and ovary they understood much better, for they could see
in the ovary the developing yolks of various sizes and thus
they perceived the connection between the organ and the ova
it produced.
 
In another place^ I have told the story of the discovery
of the mammalian ovum — how in 1672 the brilliant young
Dutchman Regner de Graaf described what we now call
Graafian follicles or simply ovarian follicles, round eggchambers, filled with fluid, that he saw in the ovaries of cows,
sheep, swine, rabbits, and women (Plate VI, B, C, E). Familiar, of course, with the eggs of birds, he thought each follicle in the mammal was an egg. He was surprised, however,
that he could not find such "eggs" after they left the ovary,
for in large animals the mature follicles are as big as peas
or small cherries, and ought to bulge the oviducts as the hen's
eggs do. After long and futile search for the real egg by many
 
iThe human ovary is about 3 centimeters (1.25 inches) long. The
ovary of a mouse is hardly bigger than a pinhead, while that of a whale
weighs 2 or 3 pounds; but their eggs are all about the same size, as we
shall see.
 
2 George W. Corner, "The Discovery of the Mammalian Ovum," Mayo
Foundation Lectures in the History of Medicine, 1930.
 
{ 33 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
workers, Karl Ernst von Baer solved the puzzle in 1827 by
finding that the actual egg is a very small speck inside the
follicle, too small to be picked out by the unaided eye. If we
take one out of its place in the ovary and put it by itself in
a dish of clear water in a bright light it can just barely be
seen.
 
With modern instruments we can make a very thin slice of
an ovary, put it under the microscope, and photograph it.
Studying the slide from the surface down (Plate VII, B) we
see a layer of covering cells (germinal epithelium), appearing
as a dark line at the top of the photograph, with a vague
zone of connective tissue beneath it, a zone of egg cells in
reserve (c) and follicles (/) of various sizes, each containing
its egg.
 
The follicle (see again Plate VII, ^) is lined with a layer
which looks granular under low magnification, because it is
made up of small cells. Just outside this granulosa layer is
a thin layer (called thee a interna) of larger cells well supplied with blood vessels. This layer, so slight that it would
hardly be noticed, except by an experienced microscopist, is
of great importance because in all probability it is the source
of the estrogenic hormone which (next to the egg) is the most
important product of the ovary.
 
How the eggs are formed in the ovary is an unsettled problem. We know that large numbers of them are produced by
ingrowth from the surface cells of the ovary before birth. In
a newborn baby girl there are already thousands of egg cells,
many more than she can possibly need when she grows up.
Many anatomists think that these original eggs, present at
birth, furnish the supply for life ; in other words, that no new
ones are formed after birth. This means that the infant in
arms has already set aside her contribution to the heredity
of her children, and if perchance she has her last baby at
forty years of age, that particular egg will have waited all
those forty years for its opportunity to develop. This is
 
{ 34 )
 
 
 
Uterus
 
 
 
Oviduct
 
 
 
(Fallopian tube)
 
 
 
 
Rectum
 
 
 
Rectum
 
 
 
 
Plate V. The human female reproductive organs, drawn by a famous medica
illustrator, the late Max Broedel. Above, viewed from dorsal (rear) aspect. Belou
viewed from above, as seen by surgeon looking into the pelvis. One-half natura
size. From the Carnegie Contributions to Embryology, by courtesy of George B
Wislocki.
 
 
 
Tai XV
 
 
 
 
 
THE EGG
 
somewhat staggering, but not altogether preposterous, for
we have good reason to think that some other very important
cells, e.g. the chief cells of the brain and spinal cord, last a
whole lifetime without replacement. Other anatomists think
they can see scraps of evidence that new crops of eggs are
continually being formed in the ovary of the adult woman,
and that these new eggs are those which are shed from the
ovary in adult life. It is well known that the male germ cells
are formed anew continuously in adult animals (see Chapter
IX). The question, as regards the ovary is (for technical
reasons) much more difficult to solve than it might seem. I
have myself studied it quite seriously in a large collection of
monkey ovaries, and thus far have not seen good evidence that
new formation of eggs occurs. For this reason I adhere cautiously to the old view until new evidence is brought forward.
 
At any rate, some of the eggs in the reserve zone are from
time to time selected to proceed to maturity. Such an egg
sinks deeper into the ovary. The cells about it multiply to
form a thick mass, which soon hollows out to form a small
follicle. As the cavity enlarges, the egg is left in its little
hillock at one side (Plate VII, A, B,C).
 
Discharge of the egg. The follicle continues to grow and to
occupy more and more space, slowly shoving aside neighboring tissues within the ovary. Finally it enters a period of very
rapid growth, so that its volume doubles in a few hours. Plate
VIII shows the growth of the follicle in the rat. The human
follicle becomes 12 or 15 millimeters (0.5 to 0.6 inch) in
diameter when fully developed and occupies at least onefourth of the whole volume of the ovary. As it enlarges, it
pushes its way to the surface. The wall of the follicle next the
 
Plate VI. De Graafs original illustration of the Graafian follicles, in the
ovary of the cow, from De organis generationem inservientibus, 1672. A large
follicle is shown at B, smaller ones at C, C, C, C. E is & large follicle dissected
away from the ovary. The lower portion of the figure shows the oviduct
(Fallopian tube) with its funnel-like expansion. Approximately natural size.
 
{ 35 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
 
 
 
Fig. 8. The human female reproductive system. Dotted lines indicate the
position of the pelvis and other bones. From Attaining Womanhood, by
George W. Corner, by courtesy of Harper and Brothers.
 
 
 
{ S6 }
 
 
 
THE EGG
 
surface and the overlying capsule of the ovary become thinner
and thinner. The actual rupture of the follicle through the
thinned-out region has been observed repeatedly in rabbits
and sheep, following the lead of Walton and Hammond of
Cambridge, England (1928), and has been photographed in
motion pictures by Hill, Allen and Kramer of Yale Medical
School. It happens that in the rabbit these events in the ovary
can be timed very closely. The investigators anesthetize an
animal which is about to ovulate and expose one of its ovaries
under warm salt solution. Several ripening follicles are seen.
Watching or photographing one of these, they see the thin
exposed wall of the follicle weaken still more, until it bulges
to make a little bleb. Meanwhile the cells about the egg on
the inner wall of the follicle have loosened up so that the egg
is nearly free from its attachment. Finally the bleb rips open
and the contents of the follicle is expelled, carrying the egg
with it. In motion pictures, the ejection of the contents looks
like the slow rise and fall of a geyser; it is not explosive, but
actually rather a gentle occurrence. In animals like the rabbit, which produce several young at one time, the individual
follicles of one batch rupture within a few minutes of each
other.
 
The egg. The eggs of mammals, seen under the microscope,
are beautiful little spherical objects, consisting of a round
mass of cellular material surrounded by a transparent zone
or membrane (Plate VII, D). The eggs of all the higher
mammals thus far measured have been not far from 0.1
millimeter (0.004 inch) in diameter. Mouse and rat eggs are
a little smaller (0.075 mm.), those of dog, cow, and human a
little larger (0.140 mm.). Dr. Carl G. Hartman suggests a
striking comparison by which we can appreciate their size,
relative to more familiar objects: "Scatter a pinch of sea
sand on a piece of black paper — the smallest grain visible to
the naked eye is of the order of magnitude of the cow's egg.^^
 
{ 37 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
As Hartman calculates, it would require about 2,000,000 eggs
to fill an average sewing thimble.
 
We know fairly well the appearance and size of the human
ovum while it is still in the growing follicle of the ovary, but
our information about the fully mature egg (that is, during
the last hours before it leaves the ovary, and while it is in the
oviduct) is derived from a mere handful of specimens, about
ten or twelve in all, that various investigators have been able
to obtain. The Rhesus monkey has yielded to science a somewhat larger treasure of eggs. If anyone wants monkey eggs
in market lots, they might be furnished for two or three thousand dollars a dozen. To compensate for this scarcity of
primate eggs, those of the laboratory animals are fairly easy
to collect, and the domestic pig is a prime source. I have
myself handled 2,500 or more sow's eggs and used to demonstrate them annually to my medical students. Any highschool biology teacher who lives near a slaughterhouse, if
he will learn the tricks of finding and handling them, can show
his boys and girls this striking evidence of the unity of living
things.
 
The clear outer membrane of the mammalian egg is tough,
like a very stiff gelatine solution, stifFer yet than a housewife would serve for dessert. I have often pushed the eggs
of rabbits and pigs over the bottom of a dish of salt solution,
using a coarse needle which under the microscope looked like
a poker pushing a grape. The tough egg membrane easily
 
Plate VII. Structure of the ovary. A, diagram of a section through ovary,
illustrating the structures described in the text. From an article by the author,
in Physiological Reviews, by permission of the editor. B, pliotograph of small
part of a microscopical section of a monkey's ovary. The letter c indicates the
cortex of the ovary, containing egg cells not yet surrounded by follicles, o.f., an
atretic (degenerating) follicle. Photograph magnified 50 diameters. C, photograph oif section of ripe egg of Rhesus monkey, in its hillock inside a large
follicle (Corner collection, no. 100). Magnified 100 diameters. D, photograph of
living human egg, recovered from Fallopian tube at operation. Preparation by
Warren H. Lewis (Carnegie collection, no. 6289). Magnified 200 times.
 
{ 38 }
 
 
 
Retro^reoain^ corpus luteum
 
Growing follicle
 
 
 
GerminaJ. epitheliam
 
 
 
Cortex
 
 
 
Recent corpua
luteum.
 
 
 
 
 
 
 
v^r^-m.
 
 
 
 
 
 
 
THE EGG
 
resists such handling, but if a thin glass microscopic cover
slip is allowed to settle down upon an egg in a drop of water,
the clear membrane splits open under its pressure like the
skin of a grape and pops out its soft contents. It seems to
me quite remarkable that the infinitesimal sperm cell can
push its wa}' through this barrier.
 
Some eggs, like those of the pig, are heavily laden with
fat globules (yolk) ; others, e.g. those of the rabbit, are so
clear that the nucleus, inevitable part of a living cell, can
be descried in the fresh egg. The human egg, as will be seen
from our photograph (Plate VII, D), is moderately filled
with yolk granules and the nucleus cannot be seen. If the
microscopist wishes to study details of the nucleus in any
species he must "fix" the egg, i.e. kill and harden it with
chemicals, and stain the nucleus with a dye solution.
 
However different the eggs of birds and of mammals may
seem at first sight, they are fundamentally alike. Each is a
single cell, with a nucleus no bigger than that of many of the
ordinary cells of the body. The fact that the bird's egg is
very large for a single cell, and that even the mammal's egg
is the largest cell in the mammalian body, is due to the inclusion of a considerable amount of stored food substance in the
cell. In the hen this yolk is enough to feed the chick until it
hatches ; in mammals it is only a few grains of fat and protein,
sufficient to provide energy for growth and cell division for
a few days, until the fertilized egg reaches the uterus.
 
Since the bird's egg needs protection from harsh external
conditions — sunlight, dryness, a rough nest — it is provided
with a hard shell secreted about it by the oviduct after it
leaves the ovary. The mammalian egg, which is destined not
 
Plate VIII. Stages in the development of the Graafian follicle of the rat.
Note the gradual enlargement of the cavity. In G the cells holding the egg to
the wall of the follicle have begun to degenerate, and the follicle is ready to
rupture. Magnified 60 times. From the Anatomical Record, by courtesy of J. L.
Boling and the Wistar Institute of Anatomy and Biology.
 
{ 39 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
to leave a soft, moist, dark environment within its mother
until it is ready for birth, has no shell at all. The clear zone
that surrounds it is comparable with the shell membrane of
the hen's egg, familiar to everyone who has peeled the shell
off a boiled egg. The bird's egg also receives in the oviduct,
before the shell is laid on, a layer of albumen ("white of
egg") which no doubt helps to cushion the yolk and has some
nutritive value for the growing embryonic bird, but is chiefly
important because of its property of holding water and thus
preventing the egg from drying out by evaporation through
the shell. This is another protection the mammalian egg does
not require. It is therefore much smaller than the bird's egg,
because, in the first place, it lacks these massive provisions for
independent existence ; but also for a positive reason which my
mathematically minded readers may have perceived. The
mammalian egg, after only a few days of total dependence
upon its paltry yolk, gets its nourishment by absorption of
food and water by diffusion through its surface from the
uterine fluid in which it reposes. How much it gets depends
upon the area its surface presents to its surroundings. How
much it needs depends upon its volume. Geometry teaches
that as dimensions increase, surfaces increase as the square
of the radius, but volumes increase as the cube. As organic
bodies increase in size, therefore, the ratio between volume and
surface becomes less favorable. This rule, which has been
invoked to explain why animals do not grow to limitless
dimensions, probably operates also to keep all sorts of cells,
including eggs, within effective limits of size.
 
The fate of unfertilized eggs. Not all the eggs formed in
the ovary, nor even a large proportion of them, go on to
reach fruition. Most domestic mammals shed eggs from the
ovary at regular intervals, the human one egg per month
approximately, the guinea pig four or five eggs every fifteen
days, the sow an average of about a dozen every twenty-one
days. If there is no mating in a given cycle, those eggs pro
( 40 }
 
 
 
THE EGG
 
teed to degenerate while in the oviduct. Others degenerate in
the ovary, sometimes even before well-developed follicles have
formed about them, sometimes in large follicles. When this
happens, the follicle also ultimately degenerates and disappears from the ovary. Such follicles are shown in Plate VII,
A, B.
 
A Swedish investigator, Haggstrom, who counted the eggs
in both ovaries of a 22-year-old woman, found about 420,000.
Yet a woman who sheds one egg per month without interruption by pregnancy or illness during her entire life, from say
the 12th to the 48th year, cannot use up more than 430-odd
eggs. The most prolific egg producer among mammals, the
sow, might possibly shed a total of 3,000 to 3,500 eggs, allowing ten years of ovarian activity not interrupted by pregnancy, and assuming the very high average of 20 eggs at
each 3-weekly cycle ; but she has vastly more than this in the
ovaries at birth. Whether or not there is new formation of
eggs during adult life (as we discussed above), there is evidently a large overproduction of eggs in the ovaries. This,
and a corresponding but enormously greater overproduction
of sperm cells, is thought to be a survival from earlier evolutionary stages when germ cells were discharged into the water
to take the risk of enemies and mischance.
 
When the reproductive period of life is over, there are still
many eggs in the ovaries. These gradually diminish in number,
but some of them may persist to advanced ages.
 
The corpus luteum. When the eggs of a frog or fish are
spawned into the water the ovary has done its work. There is
nothing more it can do for the eggs. It shrinks back to the
insignificant bulk it had before the eggs began to ripen and
nothing more is heard from it until the next breeding season.
Not so in the mammals. Their eggs are not thrust into the
outside world. The mother is still intimately responsible for
them; they must be nourished and sheltered within her for
weeks or months to come. The uterus is to be altered to receive
 
i 41 )
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
them and keep them while they develop, the mammary gland
must be signaled to grow and prepare milk for them when
they are born. The ovary still has ahead of it the task of
getting these things done.
 
The Graafian follicle therefore does not shrivel away after
shedding the egg. Indeed, it has scarcely had time to collapse
 
 
 
The corpus luteum inthe ovaries of rabbitpl^A monkey
 
 
 
^Corpora lutea
 
 
 
Corpus
luteuKi
 
 
 
 
Life cycle of the corpus luteum (diagrammatic sections)
ess
 
 
 
Old Corp. lut
 
 
 
 
 
Ripe follicle
 
 
 
.-^MXed ->. Solid, .
follicle corpus lut.
 
 
 
Fig. 9. Diagram illustrating the structure and history of the corpus
luteum.
 
 
 
before it is being transformed into a corpus luteum (Fig. 9)
and begins to function as an organ of internal secretion for
the benefit of the embryo. The accompanying illustrations
(Plate IX) give an idea of the situation and appearance of
the corpus luteum. This remarkable change is brought about
by growth of the cells that lined the cavity, which become so
much larger that the inner wall of the follicle, folded by its
collapse, becomes thick and firm and converts itself into a
 
 
 
{ 42 }
 
 
 
THE EGG
 
glandular body occupying the site of the follicle (Plate IX,
Ai B). As the lining grows thicker, blood vessels creep in from
the surrounding part of the ovary and make a network that
carries blood past every one of the large cells (Plate IX, C).
These cells become laden with a peculiar kind of fatty material, and in animals whose fat is yellowish, for example the
cow, the transformed follicles are bright yellow in hue, becoming indeed just about the most brilliantly colored objects in
the whole body. For this reason they were long ago named
corpora lutea, yellow bodies ; but in animals whose body fat
is white, as the sow, sheep, rat, and rabbit, they appear pink
or whitish. The human corpus luteum forms a mass almost
three-quarters of an inch in diameter, with a folded wall,
bright orange in color, about a grayish core of fibrous tissue.
 
Animals which shed one egg at a time have, of course, only
one corpus luteum in each cycle of the ovary ; animals which
bear multiple litters have a corpus luteum for each egg, i.e.
for each follicle that ruptured. The sow averages ten corpora
lutea in a batch, and may have twenty-five, which is the number of the largest litter of pigs ever recorded. The rat can
have eighteen, the guinea pig two to four, dogs of various
breeds as many corpora lutea as there are puppies in the
litter of the breed.*
 
These yellow bodies of the ovary have been puzzling to
scientists ever since they were first described by Regner de
 
3 There are interesting exceptions to the statements in the foregoing
paragraph. In the first place, human females occasionally shed two eggs
at one time; if both are fertilized twins will be produced. In the case
of identical twins there is only one egg, which forms two infants.
Triplets usually come from two eggs, one of which gives twins. In the
case of the Dionne quintuplets it is conjectured from indirect evidence
(i.e. the close resemblance of the 5 sisters) that they all came from one
egg. In animals with multiple litters it is often the case that not all the
fertilized eggs develop successfully; then obviously there will be more
corpora lutea in the ovary than infants in the litter. On the other hand
it is possible, though uncommon, to have more infants than corpora
lutea, for one follicle may contain two eggs (a rare event) or one or more
of the eggs may develop into single-ovum twins.
 
{ i3 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
Graaf in 1672. A French medical student who wrote a thesis
about them in 1909 listed twenty-five different incorrect
hypotheses about their function; but already in 1898 LouisAuguste Prcnant had suggested that they might be glands
of internal secretion, making some sort of hormone for the
benefit of the eggs with which they are associated. Now that
we know more about such glands, any microscopist can see
that the corpora lutea have the signs of endocrine function
written all over them. The large, imposing cells, built into a
mass that communicates with the rest of the body only by
the blood vessels ; the delicate texture, scarcely supported by
connective tissue; the wealth of blood supply that reaches
every cell — these are the telltale evidences that the corpora
lutea are indeed organs of internal secretion, and that whatever product they secrete must be poured into the blood and
carried away to exert its effect upon some other organ. The
full story of the corpus luteum hormone, as we know it now,
will be told in Chapter V.
 
The life of the corpus luteum is relatively short. If the egg
is fertilized, the corresponding corpus luteum persists through
the greater part, if not all, of pregnancy. If the egg is not
fertilized, the corpus luteum has an active life of only about
two weeks before it begins to degenerate. In the human cycle
of four weeks a fresh corpus luteum is present, therefore,
about half the time. The older corpora are visible in various
stages of degeneration. Five or six months after the formation
of a corpus luteum all traces of it have disappeared.
 
The oviducts. When an egg is discharged from the ovary,
 
Plate IX. The corpus luteum of the Rhesus monkey. A, ovary split inty
two parts and laid open to show the corpus luteum. Magnified 4 times. Courtesy
of C. G. Hartman. B, section through ovary showing a large corpus luteum
(Corner collection, no. 187). Magnified 10 times. C, small part of corpus luteum,
magnified 250 times to show the cells. The narrow clear spaces between the
cells, bordered by small dark nuclei, are capillary blood vessels. At the \ef-t
6 cells and parts of a blood capillary have been outlined with ink to show
how each cell is in contact with a blood vessel.
 
{ u }
 
 
 
 
 
 
 
 
A w^ ^Jt
 
 
 
 
 
 
if^M.
 
 
 
'.'C]
 
 
 
 
 
 
 
D I
 
 
 
 
 
 
 
 
 
 
 
 
THE EGG
 
it is received into the open end of one of the two oviducts y
tubular conduits, each (in the human species) about 11.5
centimeters (43^ inches) long (Plates V and X). Medical
men and the general public usually call them "Fallopian
tubes," although Gabriele Fallopio (1523-1562) was not the
first to mention them and had no idea of their real function ;
he thought they were ventilators to let noxious vapors out
of the uterus. The walls of the oviducts are made, like the
intestines, of involuntary muscle cells. Their lining is a velvety
membrane which follows their channel all the way to the
uterus and joins the lining of that organ. The cells on the
surface of this membrane are beset with fine hairlike processes
("cilia") lashing continuously downward, and thus producing
a current through the oviducts toward the uterus. These cilia
may be seen in Plate X, E. At their free ends, near the ovaries,
the oviducts open directly into the abdominal cavity by
handsome trumpet-shaped expansions with fringed edges covered by the velvety red lining tissue. One of the fringes of each
oviduct runs right on to the ovary.
 
When we say the oviduct opens into the abdominal cavity,
we must not forget that the "cavity" is actually packed full
of intestines. When an egg escapes from the ovary, it does not
pop into a large vacant space ; it merely glides in a thin film
 
Plate X. ^ (at top), oviduct (Fallopian tube) of Rhesus monkey, drawn
by J. F. Didusch from preparation by author. Enlarged 4 times. B, photograph
of living eggs of a mouse, in passage through the oviduct. The eggs are seen
through the walls of the oviduct, which is exceedingly thin in this small
mammal. Magnified about 45 times. Courtesy of H. O. Burdick. C, model of a
part of the oviduct of a rat, showing eggs in passage. Magnified about 33 times.
From an article by G. C. Huber, by courtesy of the Wistar Institute of
Anatomy and Biology. D, diagram showing comparative size of the egg of the
rabbit and the folds of the lining of the oviduct. Courtesy of G. H. Parker. E,
comparative size of the human egg and the cilia of the lining cells of the
oviduct. The cilia are seen as little brushlike clumps on the free ends of some
of the tall cells. Enlarged 600 times. This drawing was made by combining part
of a human egg described by Warren H. Lewis (see Plate VII, D) with a
picture of the epithelium of the oviduct from a paper by F. F. Snyder in the
Bulletin of Johns Hopkins Hospital.
 
{ 45 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
of moisture between the smooth surfaces of the organs in the
region of the ovary. The open funnel of the oviduct is directly
at hand, and moreover the moisture in which the egg drifts is
constantly drawn into the oviducts, carrying the egg with it,
by action of the cilia mentioned above. Small particles of
carmine or even foreign eggs, introduced into the lower abdominal cavity by the experimenter, are within a few hours
carried down the oviducts toward the uterus.
 
It is even possible for the egg to drift across from one ovary
to the opposite oviduct, a distance of roughly 3 or 4 centimeters (1 to 2 inches), and therefore a woman who has had
one ovary and the opposite Fallopian tube removed is not
necessarily sterile. In some animals, e.g. the sow, the oviduct
expands into a voluminous sac partly enclosing the ovary;
in the dog and cat the enclosure is almost complete; in the
rat and mouse it is quite complete and eggs are obliged to
travel down the oviduct corresponding to the ovary from
which they came.
 
How are the eggs transported? We know that this trumpetlike capsular part of the oviduct, just mentioned, throws
itself during life into squirming movements which are especially active at the time the eggs are discharged. This may
help draw the eggs into the oviduct. How they are pushed
along toward the uterus, once they are in the tubular canal
of the oviduct, is at present under discussion. When there are
several eggs (that is, in animals which bear several young at
a time) the eggs travel together at first, sticking together in
a little web of cellular debris they have brought with them
from the ovary, but after a few hours this entanglement dissolves and the eggs travel free and bare, though still more
or less closely together. As will be seen from Plate X, C, Dy
the lining of the tubes forms voluminous folds, so that the
available space is hardly larger than necessary to permit
passage of the eggs. It used to be thought without question
that the eggs are brushed along by action of the lashlike cilia
 
{ 46 }
 
 
 
THE EGG
 
of the surface cells. This is still not out of the question, in
spite of the relatively small size of the cilia as compared to
the eggs — about in the proportion of an eyelash to an orange
(Plate X, jE). With a bunch of eyelashes or something similar,
for example a tiny camel's hair brush, it does not take much
effort to roll along an orange floating in water, as the eggs
float in the fluid contents of the oviduct.
 
This supposition, however, has its weak points. In the first
place there are animals in which the oviduct is not provided
with cilia throughout its entire length. In the second place,
there is a remarkable fact which cannot easily be explained
on the basis of ciliary transport, namely that the oviducts of
different species of animals are of very different lengths, and
yet with only a few known exceptions, the eggs make their
journey through them in about the same time, reaching the
uterus in 3 to 3% days. The oviduct of the sow is about forty
times as long as that of the mouse, therefore the eggs must
travel forty times as fast. The cilia, however, certainly do not
beat that much more rapidly.
 
What is more, the cilia beat with more or less uniform
motion, while the eggs do not travel at uniform speed. A
former colleague of mine. Dr. Dorothy Andersen, once collected at a packing house a very large number of oviducts
of swine containing eggs. She cut up each one into 5 segments
and examined each segment separately to see whether it contained eggs. She found that it is common to find eggs in the
middle segments, but rare to find them in the first and in the
last parts of the tube — in other words, the eggs are rushed
through the first fifth, transported very slowly through the
middle stretch, and then hurried through the last part into
the uterus. A similar and even more accurate observation
has since been made in the mouse (W. H. Lewis and Wright).
 
All these difficulties lead us to suppose that the eggs are
really transported by contractions of the muscle fibers in the
walls of the oviducts, which move them along by a "milking"
 
{ 47 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
action. Such a mechanism is common in the body. That is how
food is shoved along in the intestines. That is how a horse
gets water through his esophagus up to his stomach when
his mouth is away down in the pond. Similar contractions of
the walls of the ureter force urine from kidneys to bladder,
no matter what position the body may be in with respect to
gravity. We know that the muscular walls of the oviducts
undergo contractions which could move the eggs, and we
know also that these contractions are under the influence of
the hormones of the ovary, changing their rhythm and intensity at the very time the eggs are in transport. Burdick,
Pincus, and Whitney have been able to lock the ova in the
oviducts by administration of an ovarian hormone. Most students of this problem now think, therefore, that the chief
method of transport of the eggs is by rhythmic contractions
of the tubal muscles, and that the cilia play at most only a
secondary role.
 
I have long thought that we ought not to emphasize the
oviduct solely as an organ for transporting the ova, but
rather as a means of delaying their transportation. We are
going to see (in Chapter V) that the mammalian embryo,
reaching the uterus naked, delicate, and yolkless on the fourth
day after leaving the ovary, requires immediate nourishment
and a soft succulent place in which to grow. The uterus must
have time to get ready for its exigent tenant. If the embryos
arrive too early they cannot develop. I believe that one of the
most important functions of the oviduct is to hold back the
eggs until the uterus is ready for them.
 
The uterus. When the eggs pass from the oviduct into the
uterus they find themselves in a chamber of larger size, with
heavier and more muscular walls.
 
The uterus is built on fundamentally the same plan in all
mammals, although its form varies a great deal in different
species. It consists basically of two tubular canals, one right
and one left, corresponding to the two ovaries and oviducts.
 
{ 48 }
 
 
 
THE EGG
 
 
 
 
Fig. 10. Form of the uterus in a series of mammals, illustrating the
various degrees to which the two horns of the uterus are separate or
fused. Ay monotreme (Echidna); B, marsupial (opossum); C, rodent
(rabbit); D, carnivore (dog); E, ungulate (mare); F, primate (Rhesus
monkey). From Physiology of the Uterus, with Clinical Correlations, by
S. R. M. Reynolds, by courtesy of the author and Paul B. Hoeber, Inc.
 
 
 
{ 49 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
Each canal is really the continuation of one of the oviducts.
At their lower ends the uterus enters the last part of the
genital tract, namely the vagina. In most animals the two
canals of the uterus unite before they enter the vagina, forming a Y-shaped organ, with a single stem and two horns
 
 
 
UTERUS
 
 
 
OVIDUCT
(FALLOPIAN TUBE)
 
 
 
 
Fig. 11. Diagram of the human female reproductive tract. The uterus,
and the oviduct at the right, are depicted as if laid open by removing the
nearer half. The vagina is drawn as if fully distended. In part after a
drawing by R. L. Dickinson in his Human Sex Anatomy.
 
(Fig. 10, E), but the extent of this fusion differs very much
in different animals. In rabbits the two horns remain entirely
separate and enter the vagina independently, side by side
(Fig. 10, C). In monkeys, apes, and humans the opposite
extreme is found, for even the horns fuse together, closing
the Y and making a single-chambered uterus into which the
two oviducts are inserted as shown in the diagram, Fig 11.
 
{ 50 }
 
 
 
THE EGG
 
Even in these animals, however^ the uterus is double in its
embryonic development. In Rhesus monkeys (Fig. 10, F) and
in human infants there is a little notch at the top of the
organ, marking the last trace of the doubling. In the other
species shown in Fig. 10, namely echidna (A), opossum
(B), dog (D), and mare {E) we find various degrees of
fusion of the two horns. Sometimes in women the process
of fusion fails to be completed, leaving a bicornuate (twohorned) uterus which under certain circumstances may puzzle
the gynecologists or even be mistaken for a tumor. In a
general way it may be said that animals which bear a single
infant, or twins, at one time, have one-chambered uteri or
short uterine horns, while those that bear multiple litters
have well-separated horns. I hardly know which of these
types offers the most striking picture, late in pregnancy
when the uterus reaches its largest dimensions — the human,
for example, with its infant ensconced in a single huge chamber, the cow with an unborn calf in one enormous sac with a
little empty horn beside it, or a sow with two long uterine
horns each distended like two great strings of sausage, with
five to eight 12-inch pigs in each link.
 
The lining of the uterus. The longest act of the drama of
reproduction is played in the cavity of the uterus. From the
first week after the egg is shed from the ovary, until the day
of birth, the infant knows no other environment, and depends
absolutely upon the reactions of growth and chemical exchange that take place in these walls that shut it off from
everything else in the world. Here occur, as we shall see, some
of the most remarkable and important interactions of the
hormones of the ovary and the tissues that guard the embryo,
and here is the seat of the process of menstruation, strange
phenomenon that is an outward sign of human participation
in the cosmic tides.
 
Because the inner layer or lining of the uterus and what
goes on in it will occupy much of this book, we may as well
 
{ 61 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
introduce its technical name at this point, to save printing
two words for one every time it is mentioned: endometrium,
from Greek endo, within, and metron, the uterus. It is a
layer about 5 millimeters (1/5 inch) thick, lining the cavity
and therefore applied to the inner surface of the pear-shaped
muscular parts of the organ. At the upper end of the uterus
it blends with the lining of the oviducts as they enter, at the
lower end it continues on to become the lining of the vagina.
It looks rather like pink or red velvet, slightly moistened.
In most animals it is thrown into delicate folds, but in the
human uterus it is relatively smooth. Upon the cells and
secretions of this layer the embryo is to depend for everything it needs during gestation.
 
It is always difficult to convey in nontechnical terms an
idea of the finer structure of the tissues of the body. In a
book for general readers, microscopical anatomy is like
mathematics in books on astronomy or physics — something
to be avoided if possible. Yet physiology without cell structure means less than Einstein without calculus. Therefore
let us buckle down together for a few pages and try to build
up a picture of the cell structure of the endometrium for
subsequent use.
 
The effort would be much easier if we could sit down together in my laboratory and prepare a specimen as shown
in Fig. 12. Taking a preserved human uterus from a jar of
formalin, we cut it in two lengthwise with a sharp knife so
that we can look into the cavity (Fig. 12, A). Then we cut
out a horizontal slab of uterine tissue {B) and from this
we detach a little block running down through the endometrium into the muscle (C). This we shall place on the
table, so that its upper side will be that which formed the
surface of the lining, facing the cavity; i.e. like a cube of
melon with the rind downward and the pulp upward (Fig.
12, C). After we have studied and sketched it under low
magnification, we shall cut off a very thin slice (technically
 
 
 
THE EGG
 
 
 
 
Fig. 12. Block diagram showing construction of the lining of the
uterus (endometrium). At A the uterus is represented as if cut in two
lengthwise, to show its lining. At B is shown a block cut from the uterus ;
a small part of this is represented at C, turned so that the inner surface
of the endometrium is upward, showing the glands. At D a small part
of C is drawn still more enlarged, to show that the glands are really
cell-lined tubes dipping down from the surface epithelium.
 
i 63 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
section) from one side, stain it with appropriate dyes and
photograph it through the microscope (Plates XVII, XXI).
When studying the two-horned uteri of small animals such
as the rat, rabbit, or guinea pig, we usually cut our blocks
from the whole thickness of the tubular horns, as one slices
a banana, and therefore the thin sections for microscopic
study are round, with the uterine cavity showing in the
center (see Plate XVII, B, in comparison with A of the
same plate).
 
We find that the surface is paved with a single layer of
tall cells, and that at frequent intervals this surface layer
pushes down into the depth of the endometrium, forming
fingerlike tubes, closed at the end, which reach almost to the
muscle (Fig. 12, C, D). These tubes are supported by spongy
connective tissue, and between them there is a network of
capillary blood vessels supplied by arteries. They are in fact
actually glands, able as shown in Fig. 13, to take water and
the "makings" of nutritive substances from the blood vessels,
build them up into foodstuffs for the early embryo, and discharge the resultant secretion into the cavity of the uterus.
The endometrium is therefore something like a quick-lunch
counter, with a supply of raw foods in the rear (in the blood
stream), a row of cooks and waiters (the gland cells) and
a line of customers (the cells of the embryo). The outfit does
not however function in this way all the time; it secretes
nutritive materials, practically speaking, only when an egg
is likely to be present. How all this is regulated by the
hormones of the ovary will be explained in Chapter V. To
paraphrase a saying of Robert Boyle, the endometrium
looks like so much velvet, yet there are strange things performed in it.
 
The cervix and vagina. The lower end of the uterus projects downward into the vagina as shown in Fig. 11. This
part of the organ is known as the neck or cervix. Its lining
is full of glands which secrete mucus.
 
{ 54 }
 
 
 
THE EGG
 
 
 
The lowest part of the genital canal, the vagina, is lined
with a membrane made of cells many layers thick (Plate
XIII, A)f closely resembling the structure of skin, except
that the latter is dry and somewhat scaly, while the vaginal
 
 
 
 
Secretion.
 
 
 
Fig. 13. Diagram representing a gland like those of the uterus, consisting of a tube of cells dipping down from the surface. This is surrounded
by a network of capillary blood vessels, from which water and other
substances pass through the gland cells, undergoing chemical elaboration,
and are discharged into the central channel of the gland and thus reach
the cavity of the uterus.
 
 
 
lining is moist. The lining of the vagina, in fact, becomes
continuous with the skin of the outside of the body, at the
vaginal orifice, just as the membranes of the nose, mouth, and
lower intestine become continuous with the skin.
 
Fertilization and segmentation of the egg. Sperm cells
deposited in the vagina by the male make their way up
 
{ 55 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
through the canal of the cervix and body of the uterus and
into the oviduct. This journey is accomplished in a few hours,
so that the descending egg and the ascending sperm cells
meet in the Fallopian tube. There the process of fertilization
takes place by entry of one sperm cell into the egg, as described for the sea urchin in the last chapter.
 
The egg now begins to divide. The process of division has
not yet been observed in the human egg, but it has been well
studied in many animals by the drastic and expensive method
of killing animals at successive stages, a few hours apart,
after mating so that the eggs can be found and studied under
the microscope. In recent years the dividing eggs of rats, mice,
rabbits, and monkeys have, through the skill of Warren H.
Lewis of the Carnegie Embryological Laboratory and his
various associates, been successfully removed, kept in dishes
of salt solution at body temperature, and photographed in
motion pictures. Our illustration (Plate XI) is taken from
an excellent series of still photographs of the rabbit egg
taken by P. W. Gregory in the same laboratory. To those
who have not seen such pictures, this series will cause surprise
chiefly by its resemblance to the dividing sea urchin eggs of
Dr. Ethel Browne Harvey's series (Plate IV).
 
In most mammals the embryos pass from the oviduct to
the uterus late on the third day or on the fourth. There is
some reason to think the same is true in the human. By this
time the embryos are at least in the four-cell stage and in some
animals (e.g. the rabbit) they have divided even more fully,
entering the uterus as little clumps of cells called morvlae
from the Latin word for mulberry^ which they resemble. The
 
Plate XI. Division of the fertilized egg of the rabbit. A, one cell stage.
B, two cell stage, 25 hours after mating. C, four cells. D to G', 4 to 32 cells.
H, morula stage (solid mass of cells). /, first signs of hollowing. /, K, hollow
stages (blastocysts) 90 and 92 hours after mating. Magnified about 140 times.
From Contributions to Embryology, Carnegie Institution of "Washington, by
courtesy of P. W. Gregory.
 
i 56 }
 
 
 
p
 
 
 
^x'?m)msms&^siw
 
 
 
 
 
k^
 
 
 
 
 
 
 
 
 
\
 
 
 
#
 
 
 
 
 
V^^
 
 
 
 
 
 
 
 
THE EGG
 
embryo soon becomes a hollow sphere, with a little mass of
cells at one side (Plate XI, J and K), This inner cell mass
is to become the embryo proper ; the remainder of the spherical cyst becomes the embryonic membranes.
 
During the first few days after arrival in the uterus the
embryos are free and unattached. In animals bearing only one
infant at a time, as usual in the human species, the embryo
simply settles down somewhere on the inner wall of the uterine
cavity. Species bearing several young have long uterine horns
to provide room for them all. In such animals the free embryos
must be moved along the uterus, by a kind of squirming movement of the uterine walls, until they are spaced at regular
intervals.
 
Implantation. Attachment or implantation begins, in most
species, about the 7th day, but in some (e.g. the sow) as late
as the 13th. The nature and extent of the attachment of
infant to mother, though fundamentally the same in all mammals, varies a good deal, in its structural character, in the
various orders of the Mammalia. In the ungulates (hoofed
animals), for instance, the attachment is not very intimate.
In the sow the voluminous membranes of the embryos are
simply apposed to the inside of the uterus, like a string of
crumpled bags fitted inside the long uterine horns, and the
embryos get their nutritive fluids and the oxygen they breathe,
 
Plate XII. Implantation of the embryo in the primate uterus. A^ embryo of
Rhesus monkey (Carnegie C. 610) in the blastocyst stage, 9 days old, just
settling down on the lining of the uterus. The little white spot in the center is
the "inner cell mass," destined to become the embryo proper. Magnified 60
times. B, human embryo about 12 days old (Carnegie 7700) which has burrowed
into the uterine lining. Magnified 12 times. C, section of a very similar human
embryo (Carnegie 7802) showing how it lies within the endometrium. The
glands of the uterus are in a state of progestational proliferation under the
influence of the corpus luteum hormone (see Chapter V), Magnified 10 times.
D, portion of same section magnified 30 times, to show the embryo proper
{emh.) and the placental villi, which are beginning to grow out from the envelope (chorion) of the embryo. A by courtesy of G. L. Streeter, C. H. Heuser,
and C. G. Hartman ; B, C, and D, by courtesy of A. T. Hertig and John Rock.
Photographs by Chester Reather.
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
by filtration through these apposed membranes. When the
pigs are born the membranes ("afterbirth") simply peel off
the lining of the uterus leaving the latter more or less intact.
In most mammals, however, the contact becomes much more
intimate. The membranes send down long rootlike processes
 
 
 
 
5 ImplantQllon of the Imman embryo
 
 
 
Fio. 14. Diagrams showing implantation of the embryo, in the rabbit
and human. In the rabbit figures the uterus is represented as if cut transversely, as one slices a banana; in the human figures the uterus is cut
lengthwise as one halves a pear. From Attaining Manhood, by George W.
Corner, by courtesy of Harper and Brothers.
 
into the uterine lining or endometrium. This is illustrated in
the diagram of the rabbit's implantation (Fig. 14). In the
human and a few other animals, the early embryo settles down
not merely on the inner surface of the uterus, but actually
burrows down into the lining, and sends out its rootlike
 
 
 
{ 68 }
 
 
 
THE ILGG
 
processes (villi) all about it. As it grows it bulges into the
uterine cavity, remaining rooted at its base, and thus forms
a definite organ of attachment, the placenta. The sketch,
Fig. 14, gives a diagrammatic idea of this arrangement, and
Plate XII illustrates some of the details of implantation in
man and monkey, from the unique specimens of the Carnegie
Embryological Collection.
 
Within the placenta, blood vessels of the embryo ramify
in close proximity to the blood stream of the mother. Nutritive substances and oxygen filter from the uterus through
these blood vessels into the infant's blood; waste substances
and carbon dioxide filter out. The infant, completely immersed in the fluid contents of its dark chamber, thus gets
only such substances as can be brought to it dissolved in the
mother's blood and filtered through the placenta.
 
Preparation of the uterus for implantation. It may make
the next chapters clearer if we anticipate slightly at this
point our discussion of the corpus luteum hormone (Chapter
V). While the embryo is floating into the uterus prior to its
attachment, it requires nourishment from the uterus. To
provide this, and also to favor the invasion of the maternal
tissues by the placenta, the hormone made by the corpus
luteum (progesterone), acts on the uterus, causing great
activity and growth of its tubular glands. Without this
preparation the embryo, arriving in the uterus, would be
unable to develop, like the seed told of in the Biblical parable,
that fell on stony ground.
 
 
 
{ '59 }
 
 
 
THE OVARY AS TIMEPIECE
 
 
 
'They hounded to the horizon s edge
And searched with the sun's privilege
 
Saw the endless wrack of the firmament
And the sailing moon where the cloud was rent,
And through man and woman and sea and star
Saw the dance of Nature forward and far.
Through worlds and races and terms and times
Saw musical order and pairing rhymes."
 
Ralph Waldo Emerson^ The Poet.
 
 
 
CHAPTER III
 
THE OVARY AS TIMEPIECE
 
OUR western plainsmen used to watch, in August
I and September, milling herds of bison, blackening
the prairie for miles. It was no uncommon thing to
see thousands of them, eddying and wheeling about under a
dense cloud of dust raised by the bulls as they pawed in the
dirt or engaged in desperate combat. In these herds the males
were continually following the females and mating with them.
The whole mass was in constant motion, all bellowing at once
in deep and hollow sounds, which mingling together seemed
at the distance of a mile or two like the noise of distant thunder.^ This was the yearly period of estrus,^ the mating time,
when the females were ready to produce their eggs, and the
 
1 This passage is largely a quotation from George Catlin, The North
American Indians, vol. 1 (p. 280 in the Edinburgh reprint of 1926).
Catlin's rather discreet painting of such a scene occurs in the same
volume, fig. 105.
 
2 Estrus is the technical term for recurrent periods of sexual excitement in animals, popularly called "heat." It was introduced in 1901 by
Walter Heape, a prominent student of the physiology of reproduction.
The word comes from the insect described by Virgil:
 
"About the groves of Silarus and Alburnus evergreen
In holm-oak swarms an insect
 
We call the gadfly ('oestrus' is the Greek name for it) —
A brute with a shrill buzz that drives whole herds crazy
Scattering through the woods, till sky and woods and the banks of
Bone-dry rivers are stunned and go mad with their bellowing."
 
{Georgics, Book III, C. Day Lewis's translation.)
In its Latin neuter form oestrum this word long ago became an English
word meaning any recurrent excitement, e.g. the poetic frenzy. Heape
adopted the masculine form as his special technical term. In England
it is spelled oestrus and the first syllable is pronounced e as in "me." In
the United States, following a general trend of our language, it is now
commonly spelled estrus and pronounced with e as in "west." The
adjectival form is estrous; cf. mucus, m,ucous. The interval between two
estrous periods, in Heape's terminology, is diestrus; a long period between sexual seasons (as for example in sheep during the winter) is
anettrus.
 
{ 63 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
males to fertilize them. Such a season of mating is well-nigh
universal in nature, though fortunately not all the denizens of
earth react as violently as the bison. The rhythm of sex is
manifested in infinite variety, assuming every aspect ; now to
our human eyes tensely dramatic, now gently romantic, now
bestial or merely matter-of-fact, sometimes even comical.
 
In springtime two robins nest beneath my window, and
soon a group of eggs in the nest gives evidence that the ovaries
of the female bird have responded to the rhythm of the year.
Twice a year my neighbor's spaniel gives unmistakable signs
that she is ready to mate, and I know, being an anatomist,
that if we could inspect her ovaries we should see the Graafian
follicles enlarging, and the microscope would show us a crop
of ripening eggs.
 
The ovary as a timepiece runs at curiously different rates
in different animals. Many creatures living wild, both plants
and animals, necessarily time their breeding with the seasons
of the year, because their offspring must begin life when conditions of temperature, shelter, light and food are most favorable. Hence the vernal growth of plants and all the annual
breeding seasons of animals such as those of migratory birds
and of the fish, salmon and shad for example, that swarm into
the bays and rivers every spring, teeming with roe and milt
and seeking a sheltered place in which to spawn. Many marine
plants and animals have reproductive cycles controlled by the
tides and therefore breed at intervals of a month or multiples
of a month. There are seaweeds, for instance, that fruit only
on the highest tides, and worms that breed at particular
phases of the moon. The Japanese palolo, an annelid worm
living on the sea bottom, swarms to the surface to breed on
four nights of every year, namely on the new moon and the
full moon of October and November (Appendix II, note 2).
 
In the course of evolution, however, many animals have
adopted cycles not directly related to the yearly seasons or
the tides. Some of these are domesticated species which man
 
i 64 }
 
 
 
THE OVARY AS TIMEPIECE
 
has freed from dependence upon the wild crops and has improved for more rapid breeding; others have acquired their
cycles for no obvious reason. The shortest cycle is that of
the domestic fowl, which lays an egg once a day ; the longest,
that of the locusts that come swarming from the ground at
intervals of seventeen years, in obedience to some obscure
signal, to deposit their eggs and then to die.
 
In mammals, and in the human race, the ovary is no less
cyclical than in lower animals. Many wild mammals have an
annual cycle so timed that they may bring forth their infants
when food is plentiful for the mothers. Other species have
estrous cycles at intervals throughout the year, or a sexual
season of several cycles at a favorable time of the year. Rats
and mice have very short cycles, ovulating every 4^ to 5
days, except when the cycles are interrupted by pregnancy.
The guinea pig has a 15-day cycle. Cows, mares, and swine
have estrous periods at 21-day intervals throughout the year.
Sheep have several cycles in the late summer; during the
winter they are anestrous. Dogs and cats have two or three
estrous periods each year ; so, apparently, have lions. Many
other carnivores are monestrous (having one period each
year). Not only do the time intervals vary in different species,
but fhere are all sorts of different behavior patterns at estrus
and a good many differences in the details of internal physiology.
 
The cycle of the sow. To make this matter clear, let us
follow through the cycle of one particular species and then
discuss some of the variations. That valuable creature, the
domestic sow, will serve us admirably for this purpose. She
has an estrous cycle of 3 weeks' duration. During 2% weeks
of each cyclic interval she goes about her usual program of
eating and sleeping and if there is a boar in the herd she shows
no interest in him. Then there is a change of mood and behavior. For 3 days she undergoes a well-marked phase of
estrous excitability, marked by restlessness, diminished appe
{ 65 )
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
tite, and heightened sexual interest. If there is no boar present
she sniffs and nuzzles at the genitals of other sows, but if
there is a boar she promptly accepts mating and in the normal
course of events becomes pregnant. The cycles then cease until
the young are born. If she does not mate, or if the mating is
not fertile, cycles continue as usual every 3 weeks throughout
the year.
 
These events in the life of the sow have been known to every
swineherd for ten thousand years, but nobody knew until the
present century just what is going on inside the animal every
21 days to stir her two hundred pounds of meat, bones, and
fat into three days of such specialized conduct. It turns out,
when we investigate the matter, that during the diestrous
phase of the cycle (the 21/2 weeks of no sexual activity) the
Graafian follicles in the ovaries are all small, with unripe eggs
in them. About two days before the onset of estrus, a crop of
follicles begins to grow. The ovaries of sows killed on the first
day of estrus contain large follicles with mature eggs. Late on
the second day we find that the follicles have ruptured and the
eggs are on their way down the oviducts. The follicles are
being converted into corpora lutea (see diagram, Fig. 15).
By the sixth or seventh day after ovulation the corpora lutea
are fully developed and (as we shall see in Chapter V)' are
at work producing their hormone, progesterone. This hormone acts upon the uterus, altering its lining to make it ready
to receive the eggs, as a plowman tills the fields to receive the
seed. If the sow has mated while she was in estrus, the eggs
will be fertilized and they will settle down in the uterus and
develop there. Once the pregnancy is well established, the
cycles cease, possibly because a hormone produced by the
placenta (or rather the outer part of the embryonic tissues,
destined to form the placenta) signals the ovary, via the
pituitary gland, to stop development of follicles for the time
being. If not fertilized, the eggs will degenerate and go to
pieces; then the corpora lutea, no longer useful, begin to
 
{ 66 }
 
 
 
THE OVARY AS TIMEPIECE
 
 
 
 
 
{ 67 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
degenerate on the 15th day of the cycle (i.e. 14 days after
ovulation) and shrink out of existence. About the 19th day
a new crop of follicles begins to mature and the cycle repeats
itself.
 
The whole process of the estrous cycle is therefore a beautifully timed arrangement by which, first, the eggs are matured and discharged from the ovary; second, the sow is
induced to mate at just the right time to get the eggs fertilized; and third, the uterus is prepared to receive the embryo, by action of the corpus luteum, which is formed and
thrown into action at just the right time. If all this preparation for maternity fails for lack of opportunity to mate,
then the cycle repeats itself as soon as the changes in the
ovary and uterus have cleared away.
 
Variations of the cycle in other mammals. What I have
described in the sow is the fundamental plan of the cycle ; this
animal happens to illustrate it with diagrammatic simplicity.
A whole book could be filled with variations displayed by various animals.* In guinea pigs, for example, the female not only
will not mate between estrous periods, but actually cannot,
because the skin grows over the vaginal orifice and blocks
entry of the male, except during estrus, when it temporarily
opens. Such an arrangement exists in no other animal. In
cats and ferrets the ovarian follicles behave peculiarly; although they ripen in each cycle, they will not rupture and
discharge their eggs unless mating occurs. In rabbits the follicles will not even ripen without mating. This means that in
these three species the corpus luteum phase of the cycle does
not occur if the animal does not mate. In all other animals
known at present, including man, the follicles ripen and rupture spontaneously.
 
In rats and mice there is a very peculiar situation, first
 
3 See S. A. Asdell, Patterns of Mammalian Reproduction, Ithaca, N.Y.,
1946.
 
{ 68 }
 
 
 
THE OVARY AS TIMEPIECE
 
worked out by Long and Evans.* The cycles are rapid, averaging less than 5 days in length. Since it takes about 7 days
to get the embryos down into the uterus and safely implanted
there, we see that unless something were done to prevent it,
there would be two batches of early embryos on their way at
once. Before the first were soundly attached, the second lot
would be claiming space and nourishment in the uterus, with
resultant confusion and damage. To prevent this a special
mechanism has developed in rats and mice : the act of mating
signals the ovary to postpone the next cycle 10 days instead
of five, thus giving time to get the pregnancy under way. This
can be imitated experimentally by simply inserting a smooth
glass rod deeply into the vagina during estrus, in lieu of the
male organ.
 
The human cycle: menstruation. The most peculiar variation of all occurs in the human species and in our near kin,
namely the apes and higher monkeys. The length of the cycle
is about 4 weeks, but in these animals there is no well-defined
estrous period. Mating can occur at all times of the cycle.
 
The follicle matures and discharges its egg silently, without
any marked changes of behavior. The corpus luteum forms
from the discharged follicle and functions as in other animals,
but when it breaks down, about two weeks after ovulation, its
effect upon the lining of the uterus does not merely subside.
There is, instead, a sharp breakdown of the endometrium with
hemorrhage. This periodic menstruation occurs only in the
higher primates ; nothing like it is seen in other animals. The
question of its relationship to the estrous cycle of non-menstruating animals has puzzled and confused naturalists and
physicians since the days of Aristotle. Because animals like
the sow and mare have in their cycles one prominent event,
namely estrus, and humans display also one definite cyclic
 
* J. A. Long and H. M. Evans, "The oestrous cycle in the rat and its
associated phenomena." Memoirs of the University of California, vol. 6,
1922.
 
{ 69 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
change, namely menstruation, the two phenomena were
thought to be the same. Serious misconception of the human
cycle caused by this error has been cleared up only in the
twentieth century.
 
For the sake of perfect clearness on this point, let us compare diagrams of the estrous and the menstrual cycles (Fig.
 
 
 
THE CYCLE IN GENERAL
 
 
 
 
ESTRUS
 
 
 
CORPUS LUTEUM
 
 
 
PRIMATE CYCLE
 
OVULATION
 
-I
 
 
MENSTauATION
 
 
 
Fig. 16. Diagram comparing the estrous cycle in general with the
menstrual cycle of the higher primates.
 
16) . It will be seen that the two are fundamentally alike, since
the important feature of each is ovulation followed by the
corpus luteum phase. In lower animals ovulation is accompanied by an outspoken period of sexual receptiveness, in the
primates (man, apes, and higher monkeys) it is not; in the
primates the end of the corpus luteum phase is accompanied
by menstruation, in the other animals there is no bleeding at
this time.
 
 
 
{ 70 }
 
 
 
THE OVARY AS TIMEPIECE
 
How menstruation is brought about by the ovarian hormones, and what purpose it may serve, we shall discuss in
Chapter VI.
 
The vaginal cycle. Obviously, the periodic ripening of the
ovarian follicles sets in action large forces that can alter the
state of other organs, change the reactions of the body, and
determine the behavior of the female animal. By means of the
ovarian hormones released at this time, there are ( as we shall
see) cyclic changes in the whole reproductive tract. Not only
is the lining of the uterus modified, but the Fallopian tube,
the vagina, and in some species even the external genital
organs also take part in these rhythmic alterations. This fact
led to the discovery, twenty-five years ago, of an extraordinarily useful method of research, which greatly increased
our rate of progress in unraveling the problems in this field ;
and because it was made in the United States, helped put the
American investigators of this generation in the forefront.
 
To grasp the importance of this discovery, we must remember in the first place how very helpful to science in general
are the rat, mouse, and guinea pig. These little rodents are
hardy, inexpensive, and easy to feed, house, and handle in the
laboratory. Their small size is also a great advantage when
experiments call for treatment with scarce or expensive hormones and other chemical reagents. Unlike cats, they breed
freely in cages. Unlike dogs, they have rapid cycles, requiring
no long waits in the course of experimental study. Unfortunately, among all the mammals they give the least conspicuous signs of estrus. They show no genital swellings like the
bitch, no excitement like the sow. They normally mate only
at night, and to be certain they are in estrus, the investigator
had to put them with males and sit up all night watching them,
or else use roundabout methods of observation which were not
perfectly reliable. As an illustration of the difficulties, I recall
that before 1917 a distinguished biologist who was working
chiefly with guinea pigs supposed their cycle to be 21 days
 
{ 71 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
instead of 16, and a first-class embryologist who made a
determined effort to work out the estrous cycle of the rat by
the best means at his command, came out with a result of 11
days, just twice as long as the correct figure, having somehow
missed alternate cycles.
 
It can be imagined with what enthusiasm those of us who
were working in the field learned of the simple discovery
announced in 1917 by C. R. Stockard 6f Cornell Medical
College and his colleague G. N. Papanicolaou." These men
found that in the guinea pig the cyclic changes, which take
place in the reproductive tract under the influence of the
ovarian hormones, are seen with especial clearness in the
lining of the vagina. Here there is a cycle of growth and shedding of the surface cells, which follows events in the ovary so
closely that the time of rupture of the follicle can be determined within one hour. It is only necessary to scrape the
vaginal lining gently with an instrument, or to wash the
cavity out with a medicine dropper and a little salt solution,
and study the findings under the microscope. This can be done
in a few minutes and does not harm or upset the animal in any
way. The vaginal closure membrane, mentioned on page 68,
as a peculiarity of the guinea pig, is of course kept open by
these daily examinations.
 
In justice it ought to be added here that something of what
Stockard and Papanicolaou found had been described in the
1890's in more or less forgotten papers by several investigators, particularly the French observer, Lataste; but it was
their masterly and complete investigation of the matter which
made it available to science.
 
By the use of this method Stockard and Papanicolaou
promptly ascertained the correct length of the guinea pig's
cycle and secured a much more accurate timing and description of the subsequent events of the cycle than we had before.
 
5 C. R. Stockard and G. N. Papanicolaou, "Oestrous cycle in the
guinea pig," American Journal of Anatomy, vol. 22, I9I7.
 
{ 72 }
 
 
 
THE OVARY AS TIMEPIECE
 
The method was soon applied to the rat by Long and Evans
of the University of California and to the white mouse by
Edgar Allen of Yale Medical School, then at Washington
University, St. Louis. We shall see in subsequent chapters
some of the important work that was made possible because
the cycles of these three animals were now so much better
known. The detection of the ovarian estrogenic hormone by
E. Allen and Doisy (1923) was a direct result; so was the
discovery of Vitamin E by H. M. Evans and his colleagues
(1922). In conjunction with the growing knowledge of the
cycle of the sow and of reproduction in the rabbit, it led
indirectly to the discovery of the corpus luteum hormone and
to a far clearer general comprehension of the whole field than
was possible before.
 
The exact details of the vaginal changes are of no particular importance except to those who need to follow them in the
laboratory. Briefly stated, there are two kinds of cells that
get free in the vagina. One kind is of course the cells of its
lining. These are epithelial cells like those of the external
skin except that they are ordinarily moist. Those that lie on
the surface of the lining are not infrequently shed into the
cavity. The cyclic changes can be followed in the accompanying figure, taken from the monograph on the rat's cycle by
Long and Evans. In Plate XIII, B we see the vaginal cells
as they are in the interval or diestrous phase ; there are fairly
large numbers of white blood cells or leucocytes (the small
rounded cells with irregular nuclei) intermingled with a few
large flat epithelial cells. At C we see signs of approaching
estrus; the leucocytes have disappeared, and the epithelial
cells are swollen and rounded, by action of the ovarian hormone upon them before they were shed from the wall into the
cavity of the vagina. In figure D of Plate XIII we see that the
epithelial cells now being shed are dry, scaly, and lack nuclei
— they are cornified, as we say, like the cells on the dried-out
surface of ordinary skin. At the time when the ripe follicles
 
[ 73}
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
are about to rupture, the process of cornification of the
vaginal wall is very active, and cornified cells are shed in
thousands, yielding thick caseous scrapings that can be identified without a microscope. The next day the leucocytes come
back (E), the masses of cornified cells disintegrate, and the
interval picture reappears. In sexually mature rats and mice
this change repeats itself every 5 days, in guinea pigs every
15 days.
 
Vaginal cycles in other animals. If such clear-cut vaginal
changes occurred in all mammals, it would be of great advantage in studying their cycles. If they occurred in women, it
would be of priceless value to gynecologists, especially in the
serious business of diagnosing the cause of sterility. At present we have no certain way of finding out whether a woman is
ovulating or not, except by operative exploration. Unfortunately, the vaginal changes are far less clear than in the
small rodents. Extreme differences, such as that between
normal activity of the ovary on one hand and total inactivity
on the other, can be detected, but such changes as occur from
day to day in the cycle are faint. The latest word thus
far is in volume 31 of our Carnegie Contributions to
Embryology, recounting studies made on human patients by
Ephraim Shorr of Cornell Medical College and observations
of the Rhesus monkey made in the Department of Embryology
of the Carnegie Institution by Ines de AUende in consultation
with Carl G. Hartman. Dr. de Allende was generally able to
diagnose the occurrence or nonoccurrence of ovulation in
monkeys, as confirmed by surgical exploration. It seems not
improbable that by refining the study of vaginal cells it may
ultimately be possible to diagnose ovulation in humans.
 
The cause of the cycle. Some day no doubt we shall understand the whole mechanism of the ovarian rhythm, and know
why and how the cycle is short or long in various animals and
why its manifestations vary in so many ways. At present we
can do hardly more than guess. We think the alternations of
 
{ U }
 
 
 
 
 
 
'05:
 
 
 
' 5
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* *^ ♦it ii
 
^ M
 
 
 
s
 
 
 
>
 
^ ^
 
 
 
^
^
 
 
 
!i;*^
 
 
 
««^'
 
â– ^s
 
 
 
c
 
 
 
Plate XIII. The vaginal cycle in the white rat. A, section of lining of the vagina.
The inner surface, from which cells are shed as seen in following pictures, is at the
right. B, cells shed into cavity of vagina during interval part of cycle. The larger
masses are the epithelial cells; the small rounded objets with gnarled nuclei are
white blood cells (leucocytes) . C, just before estrus. D, during estrus (at time of
ovulation) showing complete cornification, with loss of nuclei. The section of the
wall of the vagina pictured at A was taken at this time, and shows the cornified
cells in place, forming a clear layer at the right. E, at end of estrus, showing return
of leucocytes. All magnified about 650 times. From J. A. Long and H. M. Evans,
"The Estrous Cycle in the Rat," University of Ccdifomia Memoirs, No. 6.
 
 
 
 
Plate XIV. Castrate atrophy. Left, normal uterus of young adult rabbit. Righti
uterus of litter-mate sister one month after removal of both ovaries. Note thmner
horns and vagina, with paler and flabbier walls, in specimen on right. (One Fallopian tube of this specimen has been cut off.) Preparation by author. Natural size.^
 
 
 
THE OVARY AS TIMEPIECE
 
the cycle are due to an interplay or see-saw action between the
hormones of the ovary and of the hypophysis or pituitary
gland. To make this clear let us continue to anticipate the
next chapter by postulating that the ovary produces an
estrogenic hormone that acts upon the uterus and the rest
of the reproductive tract, producing among other effects the
estrous changes of the vagina referred to above. Another
fundamental fact is that the whole activity of the ovary,
including the production of the estrogenic hormone, is under
the control of the pituitary gland (see Plate XIX and Fig.
20). If this remarkable bit of glandular tissue is removed, the
ovary quits functioning altogether. By chemical extraction
the pituitary yields hormonal substances which can restore
ovarian function in the absence of the pituitary gland, or
cause the ovary of the immature animal to grow and begin
functioning. It has been shown, however, that if we inject
the ovarian estrogenic hormone into a female animal, the
pituitary hormones that stimulate the ovary are reduced in
amount. Here we have, in all probability, the fundamental
mechanism of the ovarian timepiece. The pituitary stimulates
the ovary, but the latter then sends out its estrogenic hormone and this depresses the pituitary. Then the ovary loses
pituitary support. Up goes the pituitary again like the other
end of a see-saw. There must of course be other factors in the
situation, for such a mechanism, like the see-saw, will come
to balance unless it gets a push from time to time. In Chapter
VI we shall return to this subject after a more detailed account of the ovarian hormones.
 
 
 
i 76 }
 
 
 
THE HORMONE OF PREPARATION AND MATURITY
 
 
 
**The hierarchy [of ike organs] is such that incessantly one borrows from another, one lends to the other, one is the other's
debtor . . . each member prepares itself and strives anew to purify
and refine this treasure . . . each doth cut off and pare a portion
of the most precious of its nourishment; and dispatch it downwards where Nature hath prepared Vessels and Receptacles
suitable . . . to preserve and perpetuate the Human Race. All this
is done by Loans and Debts from one to the other." — Rabelais,
Pantagruel (Book III, Chapter 4).
 
 
 
CHAPTER IV
 
THE HORMONE OF PREPARATION AND MATURITY
 
THE ovary was very slow to yield the two great secrets
of its function. The fact that mammals and man
breed by means of eggs, and that the ovary is the
source of the eggs, was not even conjectured until 1672, and
was not proved (as we have seen, p. 34) until 1827. The fact
that the ovary is an organ of internal secretion was not
clearly stated until 1900.
 
The ancients knew of course that the organs we now call
the ovaries are homologous with the male testicles and have
something to do with reproduction; in fact, the Greeks and
Romans called them "the female testes." Castration of female
animals to prevent them from breeding is a very old practice.
The verb "to spay," meaning to castrate the female, goes
back to late Middle English, and practitioners of that art
were called "sow-gelders" as early as 1515, judging from a
citation in the New English Dictionary. These men must have
known that removal of the ovaries stops the estrous cycles,
and anybody who butchered a spayed sow would surely notice
that in the absence of the ovaries the uterus shrinks far below
its normal size. But these facts, even if known from observations on animals, did not get into the textbooks of human
physiology until the surgeons began to remove human ovaries.
That operation, first made possible in 1809 by the courage of
Ephraim McDowell and of his patient, Jane Crawford, was
fairly common by 1850. The great physiologist Carl Ludwig
said, in his textbook of 1856, that in humans loss of the
ovaries not only stops the menstrual cycles, but also causes
the uterus to shrink.
 
This matter of castrate atrophy furnished a really important clue. It deserves careful explanation. When the ovaries
of an adult female are removed, the oviducts, uterus, and
 
{ 79 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
vagina undergo rapid reduction in size. In the rabbit, in which
the phenomenon has been quite fully studied, the uterus loses
half its weight in two or three weeks and its tissues become thin
and flabby (Plate XIV). This atrophy of the uterus produced
by castration of the adult female is obviously just the reverse
of what happens at the time of puberty, when the ovaries first
become mature. The uterus and the other accessory reproductive organs (oviducts, vagina and mammary glands)
which in infancy are small and undeveloped, grow to adult size
when the ovaries begin to function. Both pubertal growth and
castrate atrophy indicate clearly that the adult uterus is
dependent upon the ovary.
 
It is difliicult to realize that less than fifty years ago nobody
could guess how this action of the ovary upon the uterus is
produced. Some thought that castrate atrophy was due to
interference with the blood supply of the uterus when the
ovaries were removed, others thought the nerve connections
were upset.
 
A Hormone of the Ovary?
 
The first step toward demonstrating the endocrine function
of the ovary was taken in 1896 by Emil Knauer of Vienna,
who took out the ovaries of guinea pigs and grafted pieces
of them back into the same animals, at new sites. He demonstrated that such grafted ovaries prevent the occurrence of
castrate atrophy. It must be, then, that the ovary makes some
sort of chemical substance which acts upon the uterus. This
is lost when the ovaries are removed, but again becomes available if the ovary is successfully regrafted, no matter where,
in the animal's body.
 
In 1900 Knauer definitely suggested this idea of an internal
secretion of the ovary. In the same year Josef Halban, also
of Vienna, took three infantile guinea pigs, grafted bits of
adult ovaries of the same species under their skin, and found
that their uteri promptly grew to adult size. On the basis of
 
{ 80 )
 
 
 
THE HORMONE OP PREPARATION
 
Knauer's work and his own he stated the hypothesis of an
internal secretion in perfectly clear terms : *'We must assume
that a substance is produced by the ovary, which when taken
into the blood is able to exert a specific influence upon the
genital organs ; and that the presence of this substance in the
body is absolutely necessary for the maintenance — and, as my
researches show, for the development — of the other genital
organs and the mammary glands."
 
With such a downright challenge as this, the inevitable next
step was for somebody to try to make a chemical extract of
ovarian tissue which should contain the potent substance
postulated by Halban, and which could be injected into castrated animals instead of grafting ovaries into them. Several
investigators actually tried it, but they were working in the
dark and failed to hit upon the proper chemical steps. Thereafter for a few years experimenters went off on another trail.
From 1911 to 1914 several Viennese and German gynecologists spent a great deal of time and effort searching for chemical extracts of the ovary which should produce menstruation
in animals. This was a bad idea, for apparently these doctors
never stopped to think that the rabbits and guinea pigs they
were using do not menstruate anyway. We can see now that if
they had used monkeys, which do menstruate, they might have
found a clue. As a matter of fact, these men — Adler, Aschner,
Schickele — did get a clue, but not exactly what they were
looking for. They did not accomplish the miracle of making
guinea pigs menstruate, but many of their extracts did have
the property of increasing the blood flow through the vessels
of the immature uterus, thus making it grow. Unfortunately
they did not all use similar methods, and, what was more confusing, some of the extracts were made from whole ovaries,
some from the corpora lutea (of swine or cows) and some
even from human placentas. The situation was so confused
that the results were almost meaningless.
 
In 1912 and 1913 two workers, Henri Iscovesco in Paris
 
{ SI }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
and Otfried Fellner in Vienna, found that a really potent
preparation could be made by extracting the ovary with fat
solvents (alcohol, ether, acetone). Their products readily prevented castrate atrophy, developed the infantile uterus, and
enlarged the mammary glands. In the last year or two before
the War of 1914-1918 these results were refined and standardized by several workers, the best work being that of Robert
Frank of New York and Edmond Herrmann of Vienna.
 
The sum total, then, of twenty years of investigation was
the demonstration that there is a substance in the ovary in
general, in the corpus luteura, and in the placenta, which has
the property of causing growth of the uterus of the infantile
animal and of preventing castrate atrophy in adult animals.
The relationship of this substance to the estrous cycle and to
menstruation was decidedly a problem for the future, and
its presence in so many tissues hindered rather than helped
the effort to untangle the specific endocrine functions of the
ovary and of the corpus luteum.
 
The Vaginal Test; Isolation of the Hormone
 
During the war the European laboratories dropped such
problems as this, but in the United States the discovery (or
rather, rediscovery and clarification) of the vaginal cycle of
rodents by Stockard and Papanicolaou turned the work in
another direction. I mentioned in Chapter III that Edgar
Allen in 1922 described a similar cycle of vaginal changes in
the mouse. Allen was very much impressed by the striking
coincidence of the peak of the vaginal changes with the presence of mature follicles in the ovary. This led him to consider
the possibility that there is a hormone in the follicles and particularly in the follicle fluid. The hypothesis that the special
events of estrus are due to a secretion of the follicle, rather
than of some other element of the ovary, was already widely,
if somewhat vaguely entertained, because various observers
had noticed that the mature phase of the follicles is closely as
{ 82 }
 
 
 
THE HORMONE OF PREPARATION
 
sociated with the phenomena of estrus. The pioneer American
worker, Leo Loeb, said in 1917 that some of the cyclic changes
in the uterus might be due to a secretion of the follicles.
Arthur Robinson of Edinburgh in 1918 went so far as to
write "It can scarcely be doubted that the phenomena of heat
are due to something produced by the follicles." Edgar Allen
now had the added evidence of the vaginal cycle pointing him
in the same direction. Enlisting the collaboration of Edward
A. Doisy, then a young biochemical colleague at Washington
University (St. Louis), he proceeded to test this hypothesis
by injecting a few drops of fluid, drawn from mature follicles
of the sow, under the skin of castrated female rats and mice.
In such animals, of course, cycles do not occur, and the
vaginal lining becomes very thin and undeveloped and remains
unchanged from day to day. An injection of follicle fluid,
however, produced in 48 hours a typical estrous condition of
the vagina, which could be easily detected by scraping or
washing out the vagina and looking at the cells under the
microscope. This result is shown in Plate XV, originally
published in illustration of Allen and Doisy's earliest results.
When administered to infantile rats and mice, the injections
caused the uterus to grow to adult size and the vagina to open
as in sexually mature animals (see Plate XVI, illustrating
similar growth of the uterus in monkey and rabbit).
 
This astonishing result provided at once a new test, simple,
precise, and rapid, by which the chemists could follow the
hormone through various steps as they attempted to purify it.
A sample suspected to contain it can be injected into a castrated rat or mouse and the vaginal cells examined under
the microscope at intervals until the estrous change is seen.
By giving graded doses to a series of animals the amount of
hormone in a sample can be measured.
 
Follicle fluid is a complicated mixture of water, salts, a
little fat, a lot of protein. Doisy faced the task of extracting
from this "soup" a substance that could be present, as he
 
{ 83 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
knew well, only in very slight amounts. He guessed that like
Iscovesco's, Fellner's, and Herrmann's materials it might be
soluble in fat solvents. Fortunately this was correct, and he
found at once that the potent substance is soluble in alcohol,
a very helpful thing because when strong alcohol is added to
a beaker of follicle fluid it throws down the troublesome proteins but leaves all the potency in the clear supernatant fluid,
which can be decanted and subjected to further analysis. The
hormone is also soluble in ether, chloroform, and acetone. In
this respect it resembles the fats and therefore goes along
with them through the various solutions ; but Doisy was able
to get rid of these substances by the familiar expedient of
cooking the extract with a little alkali. The fats were thus
converted to soaps and could be washed away with water,
leaving a small amount of non-saponifiable oil, in which was
now concentrated almost all the potency of the original follicle
fluid.
 
For theoretical reasons not now important, Allen and
Doisy believed their active principle was peculiar to the large
ovarian follicles, but other workers soon found it in the rest
of the ovary. There is a little in the corpus luteum, and very
much in the placenta. Robert Frank and his colleagues found
it in the blood of female animals. It even turned up in the
sex organs of plants, for example in the catkins of willow trees
and in palm kernels.
 
Incidentally, it was now obvious that this estrogenic hormone (as we may call it, because it initiates the estrous
 
Plate XV. Effects of the estrogenic hormone on the vagina of the rat. A^
section of vagina 10 days after castration. B, cells from contents of vagina at
this time; leucocytes only are seen. C, section of vagina of castrated animal
36 hours after an injection of estrogen. Note thickening of vaginal lining.
D, cells from vaginal contents of same animal. Epithelial cells now predominate
in the vagina. E, section of vagina in estrous condition 48 hours after beginning
of treatment with estrogenic hormone. Surface cells cornified, forming clear
surface layer. F, vaginal cells of same animal, showing cornified cells only.
Greatly magnified. From Sex and Internal Secretions, by courtesy of Edgar
Allen and the Williams and Wilkins Company.
 
{ 84 }
 
 
 
 
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'H^^
 
IK^
 
 
 
Â¥
 
 
 
V
 
 
 
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W
 
^^f"*^
 
 
 
**'*' 'i^
 
 
 
 
THE HORMONE OF PREPARATION
 
changes in the vagina) is the very same substance that Halban
had predicted and that Iscovesco, Fellner, Frank, Herrmann
and many others had extracted, in varying degrees of impurity, from ovaries and placenta. It not only acts upon the
vagina and makes the immature uterus grow with remarkable
speed, but it also stimulates growth of the external genital
organs and of the mammary glands.
 
Complete chemical purification proved very difficult. After,
collecting a supply of follicle fluid by tapping hundreds of
ovaries, or grinding up a batch of ovaries or placentas,
extracting with alcohol and putting the extract through
twenty chemical steps, it was disheartening to find that various oily contaminants, some known and some unknown,
insisted upon following the hormone through all the processes
of purification.
 
At this point another unexpected discovery came to the rescue. In two European laboratories (Loewe, 1926, and Aschheim and Zondek, 1927) it was found that a substance having
the same potencies is excreted in the urine of adult human
females. Especially during pregnancy, when the hormone is
present in the placenta in large quantities, it passes through
the kidneys and into the urine in large amounts. Investigators
now began to look for it in the urine of other animals, and
Aschheim made the almost incredible discovery that it is present in enormous amounts in the urine of stallions, surely the
least feminine of animals. The reasons for this strange fact
 
Pi,ATE XVI. A, cross sections of uteri of immature Rhesus monkeys showing
the eflPect of estrogenic hormone. Left, untreated anftnal. Right, treated animal.
Note growth and differentiation of tissues. Magnified 8 times. From the Journal
of Morphology, by courtesy of Edgar Allen and the Wistar Institute of
Anatomy and Biology.
 
B, uteri of immature rabbits, showing effect of estrogenic hormone. Left,
untreated rabbit, 6 weeks old. Right, litter-mate sister after 10 days' treatment.
Note growth (thicker horns), increased circulation of blood (shown by darker
color of horns), and improved muscle tone (shown by coiling of the horns).
2/3 natural size. Preparation by author.
 
{ S3 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
may be put aside for the moment ; the important thing is that
a watery source of the hormone is very much easier to work
with than follicle fluid or chopped-up placenta. Starting with
human pregnancy urine or stallion's urine, the biochemists
did not have to contend at all with fats and proteins, the
most troublesome ingredients of their former sources of supply. When the kidney secretes urine it strains out and retains
these substances in the body. With the aid of this great simplification, Doisy was able to announce in 1929 that he had
obtained the active principle in crystalline form, that is to
say, absolutely pure; in the same year the great German
biochemist Butenandt produced it and in 1930 it was announced at Amsterdam by Dingemanse, de Jongh, Kober and
Laqueur and from Denver by d' Amour and Gustavson. All
four laboratories had found exactly the same substance.
 
The Chemical Nature of Estrone
 
It was now up to the organic chemists to tell us the chemical nature of this hormone from pregnancy urine, or estrone,^
as it came to be called. What they found, I shall have difficulty in stating for my readers, except those who are familiar
with the chemistry of hydrocarbons, because estrone belongs
to a group of substances not within the ken of the general
public, nor even indeed, of many chemists. It is a sterol. To
explain this by saying that sterols are complex higher cyclic
alcohols is correct but not very helpful. They are colorless
solids occurring in crystals ; in bulk they look a good deal like
powdered sugar or table salt, but when compressed into a
 
1 The term estrogen, or estrogenic hormone, has been adopted to signify
any and all of the hormones giving eflFects such as described in this
chapter. Estrin, now little used, has the same significance. The terms
estrone, estradiol, estriol, stilbestrol, equilenin, etc. refer to individual
hormones of the series, each of which has its own particular chemical
formula. Allen and Doisy, the discoverers of estrone, called it theelin,
and this name, with its derivatives, is by agreement of a committee of
American scientists alternatively used in this country. Each drug manufacturer making these hormones has his own trade name.
 
{ 86 }
 
 
 
THE HORMONE OF PREPARATION
 
mass, a quantity of sterol looks and feels more like a hard
white crystalline wax. Sterols are plentiful in yolk of eggs,
brain tissue and many plant tissues. Wool fat (lanolin) is
largely composed of sterols mixed with softer, greasier fatty
substances. Most of the sterols have no hormone action; in
fact they tend to be rather inert substances, but since the
identification of estrone it turns out that several particular
sterols that are found in the male and female reproductive
systems and the adrenal gland, as well as related substances
prepared synthetically, have powerful effects in the animal
body. Estrone is one of this group.
 
Readers who are interested in the chemical structure of
estrone and the other sex gland hormones will find in the
Appendix of this book a detailed account, written for those
who remember a little of their elementary chemistry. What
follows here will be intelligible to those who are familiar with
organic chemistry ; other readers are advised to read Appendix I before proceeding further. The structural formula
of estrone is as follows :
 
 
 
 
ESTRONE
 
The molecule contains 18 atoms of carbon, 22 of hydrogen,
2 of oxygen, arranged as 3-hydroxy, 17-keto estratriene. In
1936 Marker, Kamm, Oakwood and Laucius gave us absolute
and final proof of this structure, by producing estrone artificially in the laboratory (at Pennsylvania State College) by
conversion of one of the sterols obtained from vegetables, of
which the formula was already known. This was of course a
partial synthesis or rearrangement, the investigators having
taken advantage of Nature's work in building up the substance with which they started. Bachmann, Cole and Wilds of
the University of Michigan reported in 1939-1940 that they
 
{ 87 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
had achieved the total synthesis of an estrogenic hormone,^
building it up in the laboratory from simple materials. These
examples of chemical magic made a fitting climax to years of
brilliant work on estrogenic hormones by the chemists of many
nations.
 
A substance as complicated as this affords many opportunities for slight modifications by rearrangement, addition,
or subtraction of the constituent atoms. It is not surprising,
therefore, that a whole series of estrogenic hormones has
been found, each differing slightly from estrone in chemical
structure and in potency or even in details of physiological
action. These have been obtained from the urine of other
species (as for example equilenin from the mare), from male
urine and from the human placenta.
 
It is a curious fact that Allen and Doisy's originally discovered hormone of the swine ovary, being immensely difficult
to purify because of all the fats, oils and proteins of the tissues that come out in the extract with the hormone, was not
actually identified for a long time. Finally MacCorquodale,
Thayer and Doisy in 1935 extracted two tons of ovaries and
obtained as the chief active substance a few milligrams of a
compound differing from estrone only in having an OH group
at position 17 instead of the doubly-bonded oxygen. This is
estradiol. It is probably the form which is actually made in
the ovary.
 
It has been found that esters of these hormones, i.e. combinations of estrogens with organic acids, are more slowly
eliminated from the body than the estrogens themselves and
therefore give longer and more intense effects. The propionic
and benzoic esters have been widely used in the treatment of
human patients.
 
Chemists are always interested to know just what part or
feature of such a molecule is responsible for its effects. They
 
2 Actually not estrone, but equilenin, referred to in the following
paragraph.
 
{ 88 }
 
 
 
THE HORMONE OF PREPARATION
 
learn this (if they can) by making up similar but definitely
different substances until they find the simplest substance that
has the same action. E. C. Dodds of the Courtauld Institute
of Biochemistry, Middlesex Hospital, London, and his fellow
workers have thus found a long series of synthetic estrogens,
of which the most important is diethyl stilbestrol:
 
oicTHn.$ricicsTiiOL
 
This compound is practically identical in its effects with
the naturally occurring estrogens and is being tried by physicians in place of them. Students of chemistry will be interested
in the fact brought out by Dodds, that the formula of diethyl
stilbestrol can be written so that it resembles, in spatial
relations, the formula of estrone and the other natural estrogens.
 
fxy
 
DIETHYLSTILBESTROL
 
The outstanding difference is that in stilbestrol two of the
rings are open. Dodds compares this sort of similarity to
that of a particular key, made for a given lock, with the
skeleton key which will also open it. When, however, the
molecules of diethyl stilbestrol and estrone are represented by
3-dimensional models, as was kindly done for me in connection
with the Vanuxem Lectures, by Mr. MuUer of the Princeton
Chemistry Department under the direction of Professor Hugh
Taylor, they do not show the same degree of similarity as do
the two diagrams on paper. The relation between the chemical structure and the action of these substances can hardly,
therefore, be explained by a hypothesis as simple as that suggested by Dodds. All we can say is that all the estrogens thus
far known, both natural and synthetic, have a ring structure
 
{ 89 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
more or less like these examples and possess phenolic properties, as indicated by the OH group in at least one ring.
Until we know definitely just what the hormones do when
they reach the cells upon which they act, these facts will have
to suffice us.
 
Potency of estrone. Estrone is a very powerful substance;
that is to say, only a very small amount is required to produce
large effects. It has to be used and talked about in quantities
too small for ordinary measures of weight, and so we mention
it in terms of the chemists' tiny unit, the gamma (y) which
is 1/1,000 of one milligram. An ordinary U.S. postage stamp,
gummed, weighs 60 milligrams ; one gamma is therefore
1/60,000 part of the weight of a stamp. As little estrone as
1/100 gamma, or 1/6,000,000 of a postage stamp, per day
for 3 or 4 days may be enough to produce estrous changes
in a castrated mouse, and even in a woman 20 gammas per day
(1/3,000 of a postage stamp) for 10 days may be sufficient
to produce certain profound effects upon the uterus which
we are going to consider in Chapter VI. Some of the other
estrogens are three or four times as potent as this.
 
The total amount produced in one day by the two ovaries
of an adult woman is believed to be equal in potency to about
300 to 400 gammas of estrone, or something over 1/200 of
the weight of a postage stamp.
 
By worldwide agreement through the League of Nations
an international unit of estrone was set up, for the benefit of
scientists and the drug industry. This is the amount of potency in 0.1 gamma of the pure hormone. At first the League
of Nations Committee on Standardization of Drugs and Hormones set aside in London a stock of the pure hormone to
serve in much the same way as the international standards of
weight and length (metric system) in Paris. Any responsible
person who wished to test his own product could get a few
units from London and compare the effectiveness of the two
samples in rats or mice. It is good to know that if the precious
 
{ 90 }
 
 
 
THE HORMONE OF PREPARATION
 
store of standard estrone should ever be lost the hormone can
be recreated to the exact formula and as long as the powers
of destruction leave us a good organic chemist alive on earth
this product and symbol of constructive international effort
will survive.
 
Administration of the hormone. Most of the pure estrogens
must be administered hypodermically, because they are not
well absorbed from the digestive system and are therefore not
effective when given by mouth. Some of them can be dissolved
in water for hypodermic injection, but the effects last longer
when they are injected in oil. For this purpose bland vegetable
oils such as corn (Mazola) oil and sesame oil are used. The
neutral triglycerides are also coming into use as solvents for
injection; they dissolve the hormones better than do the oils
and are generally better tolerated by the tissues into which
they are injected. It has been a great surprise to find that the
oil-soluble sterol hormones will enter the body through the
skin if made up into ointment and applied by thorough rubbing (inunction). This is not a very exact way of giving a
drug, for we can never be sure how much is lost or not absorbed, but at least it avoids disagreeable hypodermic punctures. Some of the new synthetic estrogens of relatively simple
form, such as stilbestrol (mentioned above) can be given by
mouth. There are also certain new compounds of the higher
estrogens (e.g. ethinyl estradiol) which are effective by mouth.
We may expect that after a due period of experiment, injections of the hormones will give way, at least to a considerable
degree, to medication by mouth and by inunction.
 
The English investigators Deanesly and Parkes suggested,
a few years ago, a brand new method of administering the
estrogenic hormones (and equally well the other sterol hormones, whether from corpus luteum, testis, or adrenal gland,
or from the chemist's beaker). This is to compress the hormone into a little rod-shaped pellet like a short segment of
graphite from a lead pencil, and to bury this pellet under the
 
{ 91 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
skin. A hypodermic needle of large diameter can be inserted
and the pellet pushed through its canal. Once buried, the surface of the pellet is slowly dissolved and the hormone is thus
received by the animal in very small but continuous dosage.
In this way it acts very effectively over long periods of time
with the minimum disturbance of the animal. The method is
extremely useful in laboratory experiments and there are reports of its successful use in certain human cases. There is
still much to be learned, however, about the rate of absorption
of these pellets, before we can know what daily dose we are
actually giving when we administer the hormone in this way.
 
What part of the ovary makes the estrogenic hormone?
After a great deal of investigation it is generally considered
by the experts that the estrogenic hormone is probably made
in the walls of the follicles, both large and small. The evidence
for this conclusion is indirect, for there is no way to locate
the hormone directly. The best we can do is to put little fragments, taken from various parts of the ovaries of large animals, under the skin of castrated mice to see if they contain
estrogenic potency. Some years ago A. S. Parkes of London
astonished his fellow workers by reporting that he had found
a way (by use of X-rays) to break down the follicles in the
ovaries of mice and thus to reduce the ovaries to masses of
nondescript cells. Such mice became sterile, of course, because
they could not produce eggs, but they went on having estrous
cycles more or less regularly. This teaches us that the ovarian
cells which make the estrogenic hormone can do so even when
not actually organized into follicles.
 
I have already mentioned that during pregnancy the human
placenta contains a large amount of estrogenic hormones. We
know that these are not made in the ovary but in the placenta
itself. There are several cases on record in which the ovaries
were removed during pregnancy but the supply of estrogen
continued. In humans and animals that are not pregnant the
 
{ 92 }
 
 
 
THE HORMONE OF PREPARATION
 
ovaries are the only effective source of estrogenj and if they
are removed all evidence of estrogenic action disappears.
 
Recent investigations begin to hint that under special circumstances the adrenal glands may produce estrogenic hormones. It is too early however to see what relation this has
to the general theory of the estrogenic hormones.
 
Action of the Estrogenic Hormones
 
Once the hormone gets into the blood stream, whether from
the subject's own ovaries, or by the experimenter's needle, it
is carried all over the body, through all the organs and tissues.
But — and this is characteristic of all the hormones — it is
selective in its action, like a key that opens certain locks and
not others. The major point of attack of this particular
hormone is the reproductive tract. This is strikingly seen if
we give small doses to an immature female animal, whose
uterus has never yet been subject to the action of estrogen.
Half an hour after an injection of the hormone the blood
vessels in the uterus begin to dilate and the blood to flow faster
through them, reddening the whole organ. The microscope
tells us that the rate of cell multiplication in uterus, Fallopian
tube and vagina is sharply increased. All the constituent tissues of these organs become better defined or differentiated,
as the histologists say (see Plate XVI, A). The muscle cells
of the uterus grow longer and thicker and the uterine glands
increase in size. Plate XVI, B shows the remarkable stimulation of growth and intensification of blood supply, produced
in a young rabbit, 10 weeks old, by treatment with estrogen
for 10 days. In two weeks or thereabouts, if the treatment is
continued, the baby rabbit develops a uterus of adult size;
but to the best of my knowledge, the hormone will not carry
the growth of the uterus beyond the normal mature state.
Further treatment, if forced, might cause damage to the
uterus but would not make a larger-than-normal organ. The
 
{ 93 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
old hereditary pattern of the body does not yield readily to
these upstart hormones.
 
As will be understood from the introductory discussion of
castrate atrophy (at the beginning of this chapter), these
same effects of estrogens occur in adult animals that have
been deprived of their ovaries, just as in immature animals.
In short, the action of estrogens is to bring up the immature
uterus to the full adult stage, and then to keep it up, ready
and waiting for the further changes that will be imposed upon
it by the action of the corpus luteum. All this has been amply
confirmed in the highest animals ; in monkeys by direct experiment on immature and castrated animals, in human patients
by therapeutic treatment of women whose ovaries had been
removed for surgical reasons.
 
We once saw a fantastic outcome of estrogen treatment.
Thomas R. Forbes, while a student in my laboratory at the
University of Rochester, tried estrone on some 18-inch
female alligators. These creatures were still several years
short of sexual maturity, and their oviducts (they have no
uteri, being oviparous) were very immature. The heavy
dosage of estrone crowded years of development of the
oviducts into a few weeks, while the rest of the alligator's
body remained small. Before long their bellies began to bulge,
they sickened and died. At post-mortem Forbes found the
abdominal cavities full of nothing else but coil after coil
of hypertrophied oviducts, which had pushed the liver up
toward the head, jammed the intestines into the flanks, and
finally killed the unfortunate creatures when they could no
longer find room for these redundant viscera. It would not be
possible (I hasten to add) to produce such tragically disproportionate growth in humans or other mammals except
perhaps by treatment during the embryonic period.
 
In mammals, of course, the vagina shares in all this response of the reproductive system to estrogenic hormones,
and in the rat, mouse and guinea pig it gives tell-tale signs
 
{ H }
 
 
 
THE HORMONE OF PREPARATION
 
of its response by such changes in the vaginal wall and in
the free vaginal cells as we have already discussed and
illustrated (page 83; Plate XV). In human females who
have passed the menopause, and younger women whose
ovaries have been removed surgically, the vagina shows the
effect of diminished or absent estrogenic hormone. When
such patients are given the hormone, its effect can be detected
by studying the vaginal cells. This method is now used to
diagnose loss of ovarian function and to follow the progress
of treatment with hormones.
 
The estrogenic hormones act on the mammary glands in
a very definite way. These glands, when fully developed,
are constructed on a plan resembling a little cluster of trees,
in which the trunks come together at the nipple, forming
the main milk canals. The branches form the general duct
system, and the leaves are the milk-producing units (see
Fig. 29). In immature animals the twig-like terminal units
are scarcely or not at all developed, and even the duct system is rudimentary. Estrogenic hormones make the ducts
grow until the gland is a wide-spreading tree, but still without much development of the actual milk-producing terminations on the ends of the twigs. In short, the estrogens bring
the infantile mammary glands up to the normal stage of
development of a mature virgin animal. As we shall see in
Chapter VIII, during pregnancy other hormones, namely
the pituitary hormones and in some animals the corpus
luteum hormone, carry on the development of the gland and
bring about the production of milk.
 
The estrogens and puberty. When the time approaches for
a young girl to become mature, the pituitary gland begins
to put out its gonadotrophic hormones (see p. 141). These
in turn stimulate the ovary to produce its estrogenic hormone. All the accessory reproductive organs (uterus, oviducts, vagina, external genital organs, mammary glands)
begin to grow toward mature size. The menstrual cycle
 
{ 96 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
begins. Hair grows in the armpits and the external genital
region. All these changes are due directly to the estrogenic
hormone. If the ovaries are removed before puberty they
do not occur, and on the other hand they can be brought
out in experimental animals and in castrated women by
suitable injections of the hormone. Other signs of mature
femininity, namely the female type of skeleton and bodily
contours, the adult type of voice, are more deeply innate
characteristics. It would be a mistake to think that the estrogenic hormone and the male hormone make all the difference
of bodily type between men and women, or between male
and female animals. Sex is determined when the egg is fertilized.^ The animal develops ovaries because she is a female
already. When they begin to function as endocrine organs
they make her sex effective by developing the accessory
sexual organs so she can ultimately bear her young. In this
sense the estrogenic hormone is a sex hormone; but if the
ovaries fail to develop or are removed in childhood, and
the ovarian hormones are thus unavailable, the girl still
becomes a woman — infertile of course, usually somewhat
immature or boyish, but still physically a woman, not a
male or a neutral individual. For this reason the term "female
sex hormone" has been generally abandoned and the safer
name, estrogenic hormone, used instead (Appendix II, note 3) .
 
Estrogens and the estrous cycle. Given a castrated female
guinea pig and a syringe of estrogenic hormone, the experimenter can reproduce cyclic changes in the vagina exactly
like those found at estrus in the normal animal whose ovarian
timepiece is ticking properly; and if he times his injections
carefully he can set up a regular vaginal rhythm every 15
days (the normal rate of this species), so that an observer
following the cycle by examining the vaginal cells, could
not discover the absence of the animal's own ovaries.
 
This artificial cycle wiU also affect the uterus. The fort
8 See any of the books on heredity cited in note 2 of Chapter I.
 
{ 96 }
 
 
 
THE HORMONE OF PREPARATION
 
nightly injections of estrogenic hormone will cause it to
undergo the changes characteristic of estrus. The ovaries
being absent, there will be no follicles to ripen and hence
no corpus luteum. If the experimenter wants to make his
artificial cycle complete, he will have to follow up his estrogen
with injections of the corpus luteum hormone — but that is
next chapter's story.
 
I have chosen the guinea pig as my example, but I might
well have spoken of other animals. In the spayed female dog,
for example, all the physical signs of "heat" characteristic
of that species are brought on by estrogenic hormones, including the swelling of the external genital region and the
sanguineous discharge normally seen at estrus or shortly
before. In short, we can say that the physical changes of
uterus and vagina that go with the ripening follicle of the
ovary, are caused by the estrogenic hormone. In the life
of the normal animal, however, these changes are accompanied also, during the estrous period, by the psychological
urge to mate. Is this also produced by the estrogenic hormone
of the ovary? Not all the necessary evidence on this important question is at hand. Psychic reactions are notoriously difficult to study. It is not easy to observe, test, and
measure the sex behavior of animals in the laboratory. We
know of course that if the ovaries are removed, the female
is no longer receptive sexually, but even this statement requires reservations, especially in the case of our own unpredictable species. In many animals that have been studied
(e.g. rat, mouse, dog, cat, sheep) there is evidence that the
administration of estrogenic hormone to castrated females,
or to intact females outside of the mating season, will awaken
sexual receptivity. Josephine Ball found the same result
in the Rhesus monkeys in the colony of the Carnegie Embryological Laboratory. In the guinea pig, recent work by William Young and collaborators at Brown University and
Yale Medical School strongly suggests that not only the
 
{ 07 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
estrogenic hormone but also that of the corpus luteum is
necessary. At any rate, these investigators obtained more
frequent and more normal responses in castrated female
guinea pigs if they added a little corpus luteum hormone
after a course of the estrogen. This sets up a neat dilemma :
there is of course no corpus luteum, in the ordinary cycle
of normal animals, until after the animal has been in estrus.
We can only conjecture that in the guinea pig at least, the
mature follicles must secrete a little corpus luteum hormone
before they rupture and become actual corpora lutea.
 
Important as this question of the relation between estrogens and the estrous urge is, we simply do not know
enough as yet to apply the above results to human beings.
To what extent the sex urge in women is controlled directly
by the estrogenic hormone is a question too complex for
analysis at present. The behavior of rats and guinea pigs
is difficult enough to understand. Human behavior involves
all sorts of mental processes not subject to experimental
control. We may be sure, however, that the hormones have
an important part in the matter, directly or indirectly, and
that without them there could be no human mating.
 
The estrogenic hormone as a medicinal drug. When a
physician administers an estrogenic hormone he is giving
the patient a substitute for her own hormone. He thinks her
supply of estrogen is too low for current needs. This lack
is, however, not easy to determine or to measure. The signs
of hormone deficiency are not very clear, and laboratory
tests by examination of the patient's blood, to see how much
hormone it is carrying, are expensive and in our present state
of knowledge not necessarily decisive. Upsets of the menstrual
cycle and other disorders of the female reproductive system
may or may not be due to hormone lack; the theory of
menstrual disorders is not yet clearly worked out. For this
reason their treatment with hormones is at present a matter
for very cautious study by specialists who have the facilities
 
{ 98 }
 
 
 
THE HORMONE OF PREPARATION
 
to treat their patients as laboratory subjects, which means
more attention, more examination and more testing than
patients with better-understood diseases usually require, and
more expense for somebody, either the patient herself or the
research budget of a clinic. The pages of medical journals
are, however, nowadays full of reports of research, and day
by day the subject is being advanced.
 
There is one disorder of health in which it is perfectly
clear that the trouble is caused by the ovary failing to put
out enough hormone and that a supply from the drug store
will be helpful. This is the distress that often follows the
cessation of the menstrual cycle, both the natural menopause
of women at 45 or 50 years of age, and the so-called "surgical
menopause" produced by operative removal of the ovaries.
When the characteristic symptoms of a stormy menopause,
such as hot flushes of the skin and general nervousness, become almost intolerable, large doses of estrogenic hormones
often give genuine relief.
 
Another helpful use of estrogenic hormones is in the treatment of retarded sex development caused by ovarian insufficiency. In certain cases, selected by experienced physicians as likely to be helped, and carefully treated over long
periods, the aspects of femininity have been given to underdeveloped girls, with great benefit to their social adjustment
and their morale.
 
These hormones are powerful agents. We have seen that
they affect many organs, and even yet we do not know all
they may be doing in the body. In careful experienced medical
hands they can be beneficent drugs. Used recklessly they
may do great damage.
 
The estrogenic hormones and cancer. There is a whole
series of chemical substances that cause cancer or other
tumors, malignant and benign, when injected or rubbed
into the skin. Some of these are chemically similar to the
estrogenic hormones and indeed there are a few synthetic
 
{ 99 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
cancer-producing (carcinogenic) substances that are also
estrogenic. It becomes therefore a burning question, whether
or not the familiar and commonly known estrogens are
carcinogenic. This question cannot be answered "no" or
"yes" without explanation. Briefly the situation is as follows : The estrogens commonly used in medical practice and
in the laboratory do not ordinarily produce cancer by their
own direct action. In experimental animals cancer may follow their use under special circumstances, of which the
following is a good example. In a certain pure-bred strain
of mice, the females have a high tendency to develop cancer
of the mammary glands. The males inherit the same tendency
but do not suffer from it because the male mammary gland
is too scanty to become cancerous. If the males are given
large doses of estrogenic hormone, their mammary glands
grow larger and then they often develop cancer of the
breast.
 
In our Carnegie Embryological Laboratory, Hartman
and Geschickter have given sixteen Rhesus monkeys enormous
doses of estrogenic hormones over periods of many months,
even for two or three years, and have not found a single
tumor. On the other hand Alexander Lipschiitz of Santiago,
Chile, with Rigoberto Iglesias, Luis Vargas Fernandez and
others has found that in guinea pigs it is very easy to produce
fibrous tumors in the abdominal cavity with estrogens. These
are not malignant but may kill the animal by their mere size.
There is even a recent report (from Gardner and E. Allen
of Yale) of tumors of the uterus in mice, which may be
malignant, produced by injection of estrogenic hormones in
non-cancerous pure-bred strains.
 
The present definite medical consensus is that in human
beings cancer is not produced by ordinary doses of estrogens.
The whole subject, however, demands and is getting further
investigation.
 
{ 100 }
 
 
 
A HORMONE FOR GESTATION
 
 
 
"In general estrogen is the hormone of the woman, it assures
the development of the genital and mammary apparatus ; progesterone is the hormone of the mother, it is indispensable for
reproduction/* — Robert Courrier, Biologie des Hormones Sexuelles Femelles, 1937 (translation).
 
 
 
CHAPTER V
 
A HORMONE FOR GESTATION
 
IF this were a detective story, not merely a story of
detection, the reader would at this point be directed to
turn back to pages 41-44, in which (he would solemnly
be informed) he will find all the clues necessary to solve the
great Corpus Luteum Mystery. Having reread those pages
and having inspected the photographs of the corpus luteum,
Plate IX, he will be in possession of all the information that
enabled Louis-Auguste Prenant of Nancy in 1898 to suggest
that the corpus luteum, subject of so much previous conjecture and so little fact, is actually an organ of internal
secretion. This guess, I admit, required sharp wits. Today
every reader who has studied biology ought to get the same
idea when he sees this small but vivid organ, walled off from
the rest of the ovary by its fibrous capsule, drained by no
secretory duct but obviously equipped with a rich network
of blood vessels, and composed of large and characteristic
cells resembling those of the adrenal gland. Seen under the
microscope as pictured in Plate IX, C, this arrangement
fairly shouts "I am a gland of internal secretion" ; to recognize that fact forty-four years ago was a real feat of scientific detection.
 
But even in novels of crime the sleuth's clever guess must
be followed by careful accumulation of evidence for the
jury; still more is this the case when the object of detection
is the function of an important gland and the seeker's reward
a valuable addition to scientific knowledge and human
welfare.
 
I do not pretend to write this chapter in cool detachment.
Its theme-word progesterone has for me connotations that
will never be found in the dictionary. In the first place I
invented the word myself, as far at least as the letter "t,"
 
{ 103 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
as will be explained hereafter. In the second place, it recalls
memories of bafflement, comedy, hard work, and modest success. Can I forget the time I went racing up the steps of
the laboratory in Rochester, carrying a glass syringe that
contained the world's entire supply of crude progesterone,
stumbled and fell and lost it all.? Or the day Willard Allen
showed me his first glittering crystals of the hormone, chemically pure at last?
 
In the third place, I am writing largely about the work
of personal friends. Prenant and Born I did not know,
for chronological reasons ; but Paul Bouin received me in
his laboratory at Strasbourg many times in the summer
of 1924), looking like a Frenchman out of a storybook,
writing and teaching like the grand scholar and gentleman
he is. The story of Born's legacy I heard from Ludwig
Fraenkel himself, to whom in Montevideo may this book
carry a special greeting. Dispossessed of his famous clinic
in Breslau, driven from his country, he can never be exiled
from a world that honors great minds and great hearts
wherever they are. Karl Slotta and Eric Fels, when at last
I met them in their South American homes, proved no less
distinguished in hospitality than in chemistry. Adolf Butenandt of Berlin sat happily at my own fireside and dinner
table in 1935, and there he will be welcome again now that his
country's guns are silenced.
 
Nor can I possibly write with detachment of Willard
Allen's work, which at first I shared and afterward watched
with affectionate admiration. The American pioneers in
this work, Leo Loeb and Robert T. Frank, early honored
me with their acquaintance and good will. Likewise the names
of our Wisconsin fellow-workers, Frederick Hisaw (now at
Harvard), Harry Fevold, Charles Weichert, Samuel Leonard, Roland Meyer (the latter for three years also in my
laboratory at Rochester) are written not only in the formal
list of investigators to be mentioned here, but also in mem
{ 104 }
 
 
 
A HORMONE FOR GESTATION
 
ory's record of friendly rivalry and mutual enthusiasm.
Without apology, then, let these personal feelings color
(for so they must) the narrative of research.
 
The collection of evidence begins with a scene poignant
enough, indeed, for a novel. In 1900 the great embryologist
of Breslau, Gustav Born, lay dying. Scientist to the last,
his mind was full of a hypothesis he knew he could not live
to test and which he could not bear to leave untried. To his
bedside, therefore, he summoned one of his former students,
the rising young gynecologist Ludwig Fraenkel. To him
Born imparted his thought that the corpus luteum is indeed
an organ of internal secretion, and moreover that its function
must be concerned with the protection of the early embryo.
This guess about its specific function, like Prenant's about
its general nature, was brilliant and novel in its day, even
though to us in retrospect when we consider that the corpus
luteum is present only when the egg is available for development, such a function seems probable indeed. So it seemed
then to Fraenkel, whose task it was to devise the experiments
by which Born's conjecture could be put to rigorous test.
 
He knew that in the rabbit the embryos become implanted
in the uterus on the 8th day after mating. They spend 3
days in the oviduct and then 4 days more as free blastocysts
in the uterus, before they become attached. To test the
function of the corpora lutea, Fraenkel planned to interfere
with the natural course of events by removing them while
the embryos were still unattached. The simplest way of
removing the corpora lutea is of course to remove both
ovaries, by surgical operation under an anesthetic. Since
this might, for all he knew, remove some other useful or
necessary factor, Fraenkel tried also cutting out the corpora
lutea alone, or burning them out with a fine cautery, of
course always under an anesthetic. This operation is more
difficult than simple removal of the ovaries. The rabbit sheds
many eggs at a time, up to 10 or even 12, and a correspond
{ 105 )
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
ing number of corpora lutea have to be searched for and
removed at the operation.
 
As already explained on p. 68, rabbits are peculiar in
that the ovarian follicles ripen only after mating, not
spontaneously at more or less regular intervals, as in other
animals. This is a great advantage for the present purpose,
for it means that we can time our experiments at will.
Fraenkel simply mated his females to buck rabbits of known
fertility. He knew they would ovulate next day and that
while the eggs were being fertilized and beginning to develop,
the ruptured follicles would be transformed into corpora
lutea. Sometime during the next 6 days he intervened surgically and destroyed the corpora lutea. Then he simply waited
to see what happened. If loss of the corpora did nothing,
he could expect that after 3 weeks the rabbit would show
signs of pregnancy and about the 33rd day, as is the
rule in this species, she would give birth to her litter of
young. Actually, when the experiment was performed as
described, no pregnancy ensued. Something had interfered
with the embryos. Fraenkel checked this result by careful
control experiments; he removed only one ovary, or cut
into both ovaries without removing the corpora lutea. Thus
he had experiments in which there was no endocrine loss, but
just as much upset and damage as if the corpora lutea had
been removed. The results were decisive. If the corpora lutea
were not completely removed, the pregnancy went on. If
they were removed, the pregnancy failed. In many cases he
did not wait for the time of birth, but autopsied the rabbit
3 or 4 weeks after operation, always finding that the embryos
had disappeared from the uterus. He did not learn what had
actually happened to them, nor when the blow fell. He only
knew they could not survive the loss of the corpora lutea.
 
These results were presented to the German Gynecological
Society in 1903, but they met a good deal of criticism and
disbelief. Some of the experiments were for technical reasons
 
( 106 }
 
 
 
A HORMONE FOR GESTATION
 
not perfectly convincing, although we know now their outcome was correct. Fraenkel returned to his laboratory and
after seven years was able to present in 1910 completely
acceptable results.
 
At about the same time as these later experiments, and
apparently without knowledge of Fraenkel's work, the
French histologist Bouin and his colleague Ancel had under
way experiments (published in 1910) which demonstrated
another aspect of the activity of the corpus luteum. They
found that during early pregnancy the lining of the uterus
undergoes a remarkable change. This is shown in Plate
XVII, B, which reproduces one of Ancel and Bouin's actual
figures.^ The tubular glands of the uterus begin to grow
longer, to secrete fluid and therefore to become dilated. Their
cells multiply so fast that there is no longer enough room for
them in the simple tubular wall, and the glands begin to
become folded or pleated. The folds of the endometrium are
deeply pervaded by these glands ; and finally in a section of
the uterus one sees a beautiful lacelike pattern (Plate XVII,
B, right) representing the cross-section of this gland-filled
tissue.
 
This change in the condition of the lining of the uterus,
described by Ancel and Bouin, gave the key to the discovery
of the corpus luteum hormone. We shall have to mention it
again and again. W^e can therefore save words by using the
technical name of this change, i.e. progestational proliferation, that is to say "growth and change which favors gestation." Obviously, as the picture shows, it is growth and
change; that it favors gestation will be proved as we go
along.
 
Anticipating our story again, so that we may be perfectly
clear about this important matter, let it be said that progestational proliferation does not occur in the rabbit only, but
 
1 Photographs of the rabbit's uterus magnified, shown in this book,
represent sections (slices) across the uterus, as one slices a banana.
 
{ 107 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
in all mammals, in the first days of pregnancy and also
without pregnancy, whenever a recent corpus luteum is
present in the ovary. This means that in animals with regular
cyclic ovulation, for example the guinea pig, dog, cat, pig,
human, and indeed most mammals, progestational proliferation occurs in each cycle. It is not exactly alike in all
animals ; it is very elaborate in some, such as the rabbit
and the primates (monkeys, apes, and humans) but in others,
e.g. rat, mouse, and guinea pig, it is relatively slight. Plate
XVII shows it in three kinds of animals.
 
Ancel and Bouin guessed that this progestational proliferation is caused by the corpus luteum, and they took
steps to prove it by an ingenious plan. They mated their
female rabbits, not to fertile bucks, but to males rendered
infertile by tying off their seminal ducts. Such rabbits
ovulated and formed corpora lutea but, of course, did not
become pregnant. The only respect in which they were different after mating was that their ovaries now contained
corpora lutea. Since their uteri developed typical progestational proliferation, the corpora lutea must have been responsible. The two experimenters then repeated their experiment of mating their rabbits to infertile males, but
within a day or two they removed the ovaries or cut out the
corpora lutea. Progestational proliferation did not occur.
Obviously the corpus luteum controls the condition of the
 
Plate XVII. Preparation of the uterus for implantation of the embryo
(progestational proliferation) in human, rabbit, and pig. In each case the
left-hand figure shows the interval stage, the right-hand figure shows the effect
of the corpus luteum hormone. A^ this process in the human uterus, from the
first description by Hitschmann and Adler, 1908. Magnified about 15 times.
B, the first pictures of progestational proliferation of the rabbit's uterus, by
Bouin and Ancel, 1910. Magnified about 10 times. C, the same change in the
uterus of the sow, from preparations by the author. The left-hand figure represents the day before ovulation, the right-hand section was taken 8 days after
ovulation. Magnified 10 times.
 
{ 108 }
 
 
 
r
 
 
 
 
 
 
^^^s^f^:o*iA>>^ ^i.^^^^^
 
 
 
m
 
 
 
 
 
 
-:^ ' ^•
 
 
 
o-i^^;^ A
 
 
 
 
 
 
 
A HORMONE FOR GESTATION
 
uterus and determines the occurrence of progestational
proliferation.
 
The American investigator Leo Loeb had indeed already
shown (1909), in another way, that the corpus luteum
controls the state of the uterus. In the guinea pig the embryo
settles deeply into the uterine lining (endometrium) as it
does in the human species, and the maternal tissue responds
by active growth at the site of attachment, so that the placenta contains a great mass of maternal cells. Loeb showed
that the maternal response is caused to occur by the irritation, so to speak, produced by the embryo as it settles into
the lining of the uterus. In his experiments he imitated this
irritative action, in nonpregnant animals, by putting into
the uterus, not embryos, but bits of foreign material, such
as tiny pieces of glass or collodion. In his simplest trials he
ran a silk thread through the uterus and tied it in place,
or merely inserted a needle into the uterus and scratched the
endometrium. At the points of irritation, the interior of
the uterus promptly developed within a few days, little
tumors made up of cells closely resembling, under the microscope, the maternal part of the placenta.
 
Now we come to the point of all this. Loeb discovered that
he could get his tumors only during a limited part of each
cycle, when the corpora lutea are present. If he tried at other
times, or if he tried it at the right time but took away the
 
Plate XVIII. Action of progesterone, the hormone of the corpus luteum.
Af normal litter of embryos of rabbit in uterus, 5 days after mating. B, dead
and degenerating embryos (same age as those in ^) in uterus of rabbit whose
ovaries were removed the day after mating. Magnified 20 times. C, section
of uterus at time of ovulation. D, uterus of rabbit castrated just after ovulation
and given injections of progesterone for 5 days. Magnified 7 times. E, at (1)
section of uterus of infant rabbit 8 weeks old; at (2) same after 5 days' treatment with estrogenic hormone; at (3) same after 5 more days' treatment
with progesterone. All magnified 7 times. F, two litters of rabbit embryos
6 days old, from mothers deprived of their ovaries one day after mating but
injected with progesterone daily. Magnified 71/2 times. Preparations by author.
Courtesy American Journal of Physiology.
 
{ 109 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
corpora lutea, then he got no placenta-like tumors. In short,
when the corpora lutea are present, the uterus is in a special
state in which it can respond to the need of the embryos for
maternal protection.
 
Reviewing the story, we see that Fraenkel demonstrated
that the implantation of the embryos depends upon the
corpus luteum, while Ancel and Bouin had shown by one
experiment, and Loeb by another, that the functional state
of the uterus depends upon this same gland. We cannot
escape the conclusion that these two facts are connected;
in other words, that the corpus luteum fosters the embryos
by setting up progestational proliferation. No doubt this
would have been proved very promptly had not the World
War of 1914-1918 interfered with such investigation.
 
It fell to my own lot (in 1928) to conduct the experiments
which tied together the discoveries of Fraenkel and of Bouin
and Ancel, by showing exactly what happens, and when,
to embryos deprived of the support normally afforded them
by the corpus luteum. In the first of my experiments I mated
seven female rabbits to fertile males. Fourteen to eighteen
hours thereafter the ovaries were removed by surgical operation under complete anesthesia. At this time, as we know
from previous studies by embryologists, the eggs were in
the 2-cell stage and were in the oviducts. Five, six, or seven
days thereafter the animals were killed and examined. Progestational proliferation had of course not occurred, because
the corpora lutea had been removed. When the embryos were
recovered, by washing them out of the uterus, it was found
that they had died in utero. From their measurements and
stage of development, as compared with normal embryos
(Plate XVIII, B, A), it could be ascertained that they had
ceased to grow on the fourth day, i.e. as soon as they had
entered the uterus. These embryos died because the uterus
was unprepared to receive them.
 
A control experiment was done with seven more rabbits.
 
{ no }
 
 
 
A HORMONE FOR GESTATION
 
In these everything was done as before, except the ovaries
were not removed. Parts of them were removed, or they were
cut in two, leaving their blood supply intact; in short, as
much interference and damage was produced as in the first
group, but in each case several corpora lutea were left in
place. In these rabbits, progestational proliferation of the
uterus occurred normally; and in six of the seven, normal
embryos were found when the rabbits were killed for study
on the 5th to the 8th day.
 
To sharpen the results, and pin them directly to the
corpus luteum, I was luckily able to find seven rabbits in
which, when I explored them, the corpora lutea were found
to be grouped all together in one end of an ovary. When
this chanced to be the case, in either the right or the left
ovary, I could take out one ovary entirely and all the
grouped corpora lutea from the other, still leaving a large
amount of ovarian tissue. In all these, progestational proliferation failed to occur and the embryos died.
 
We have proved two points. First, we have shown that
successful care of the embryos in utero depends upon a chain
of events. The corpora lutea prepare the uterus, the uterus
then cares for the embryos. The reason, unknown to Fraenkel,
that his embryos died was that he had prevented Ancel and
Bouin's progestational proliferation, by removing the corpora lutea.
 
Second, we have found that the corpora lutea are necessary
not only for implantation (as indicated by Loeb's experiment), but also still earlier, for the nutrition and protection
of the embryos during the time when they are lying free in
the uterus. How they do this is another question which will
be considered later; obviously it is a matter of chemical
substances secreted by the glands of the uterine lining under
the influence of the corpus luteum (Appendix II, note 4).
 
If the corpus luteum can do these remarkable things by
hormone action, we ought to be able to get the hormone out
 
{ in }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
of the gland and purify it ; but how are we to know when we
have it and how much we have? This question is answered by
our experiments on rabbits, just cited. All we need to do is to
mate a rabbit, remove the ovaries next day, and then administer our extract to see whether it will cause progestational
proliferation, and if so, how much extract is required.
 
THE HORMONE OF THE CORPUS LUTEUM
 
From this stage on I was fortunate indeed in having the
collaboration of Willard M. Allen, then a medical student^
equipped with an excellent knowledge of organic chemistry.
We began, of course, in the dark. All we knew for certain was
that we had to extract something; we did not know what it
was or what its chemical properties might be. We had two
clues. In the first place, practically all the known important
chemical substances in the animal body can be dissolved and
therefore extracted by either water or alcohol, provided they
are protected from breaking down, spoiling, or being digested
in the process. (Incidentally, how can you protect a substance
from spoiling if you do not know what it is?) In the second
place, we had a hint from the work of Edmund Herrmann,
mentioned in Chapter IV, p. 82. Some of his photographs,
published in 1915 in the report of his work on the ovarian
hormone (i.e. estrogen) showed that without realizing it he
had produced progestational proliferation with some of his
extracts. From his report we knew that whatever he had in
his extracts must be soluble in alcohol. Willard Allen and I
began therefore by collecting corpora lutea of sows' ovaries
from the slaughterhouse. We minced them up in a meat chopper and extracted them with hot alcohol. Very luckily for us,
Walter R. Bloor, then professor of biochemistry at Rochester,
is a great expert on animal fats and allied substances. We
built our extractors from his design and sought his advice on
 
2 Now Profepsor of Obstetrics and Gynecology, Washington University,
and head of the St, Louis Maternity Hospital.
 
{ 112 }
 
 
 
A HORMONE FOR GESTATION
 
many details of the chemical manipulation. After various
tribulations, one of which I shall narrate below (page 118),
we found (1929) that we could obtain a crude oily extract,
looking like a poor grade of automobile grease, which when
injected into experimental rabbits was a perfect substitute
for their own ovaries in tests such as described above. After
5 days' injection, progestational proliferation was complete.
This is well illustrated by comparison of Figures C and D
on Plate XVIII, which show sections of the uterus of a castrated rabbit before and after treatment.
 
In some of our experiments, in which a large dose was used,
we even improved upon nature by producing more extensive
progestational proliferation than normally occurs. What was
even more striking, the embryos at 6 days were just as well off
as if their mother's own ovaries had seen to their welfare.
Plate XVIII, F shows two such litters of embryos 6 days old,
in rabbits castrated more than 5 days before. Evidently our
crude oily extract contained the long-sought hormone.
 
At the University of W^isconsin, at the same time, F. L.
Hisaw and his associates, Meyer, Weichert and Fevold, were
also engaged in the extraction of sows' ovaries in the search
for an active substance. Their reason for looking for a hormone was, however, curiously different. In the pregnant
guinea pig, as the time of birth approaches, the two pelvic
bones, right and left, become separated where they join in
front ; that is, on the belly side of the animal. The bony junction in fact almost melts away, in order to allow birth of the
infant guinea pigs, which are so large in proportion to the
mother that they cannot pass through the pelvis as it normally exists. This is one of the strangest of those strange
adaptations which make the reproductive functions of one
species different from those of another, and which puzzle and
confuse the investigator, but sometimes offer unexpected clues
if he is sharp enough to see them.
 
Looking for the cause of this pelvic relaxation in the
 
{ 113 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
guinea pig, Hisaw and his young fellow students sought for
a hormone ("relaxin") in the corpus luteum. In the course of
this quest they obtained, and were the first to mention (1928),
although without exact definition, extracts having some of
the properties now known to be those of the corpus luteum
hormone. The matter of the supposed relaxative hormone,
incidentally, still remains a puzzle about which too little is
known to discuss it in this book.
 
With one of these preparations Weichert (1928) was able
to duplicate Leo Loeb's experiment (described above) in a
castrated guinea pig; that is, the corpus luteum extract acted
upon the guinea pig's uterus so that in response to irritation
of its lining it produced masses of maternal cells as in pregnancy. This was confirmed by several of my students. Thus
the basic functions of the corpus luteum suspected by Ancel
and Bouin and by Loeb were confirmed by the use of extracts.
Fraenkel's findings were also soon repeated with the hormone,
for as soon as Willard Allen and I could prepare enough of
the extract, we were able (1930) to castrate female rabbits
at the eighteenth hour after mating and to carry the embryos,
by use of our extract, all the way to normal birth at the usual
term of pregnancy, in seven of our first fourteen attempts.
 
It should be added that this is a tricky experiment about
which even yet we do not have full information. It seems to
require just the right amount of estrogen along with the progesterone. Perhaps we were lucky that our extract was just
sufficiently impure. At any rate it has turned out to be much
harder to accomplish the same result with chemically pure
progesterone.
 
Although the experiments thus far cited were all done upon
the rabbit and guinea pig, there is no doubt that similar
effects are produced in other species, including the human.
In 1930 Hisaw and Fevold were able to produce progestational proliferation in the monkey, and the same result has
since been achieved many times in women by gynecologists
 
( lU )
 
 
 
A HORMONE FOR GESTATION
 
who had occasion to administer progesterone to human patients whose ovaries had been removed. There will be much
more to sa}'^ about this when we come to discuss the menstrual
cycle in Chapter VI.
 
Meanwhile Willard Allen was makmg successful efforts to
purify the hormone. Our crude extracts were already free of
protein and we had got rid of the phosphorus-containing fats,
always a bother in alcoholic extracts. The next stages were
much harder than it was to purify estrone, because unfortunately the corpus luteum hormone is destroyed by alkalies.
The chemists, therefore, could not get rid of fatty contaminants by merely turning them into soap and washing them
away. By one trick and another, however, Allen successively
got rid of the major contaminants, namely fats, fatty acids,
and the inert sterol known as cholesterol. He began to get the
hormone in crystalline form. Fels and Slotta, then (1931) in
Breslau, Fevold and Hisaw (1932) and Allen (1932) ultimately obtained an almost perfectly pure crystalline substance of high potency. For his part of this work Willard
Allen received the 1935 Eli Lilly Award of the American
Chemical Society for the best work in biochemistry done by
an American under thirty-one years of age. We now called
into consultation Dr. Oskar Wintersteiner of Columbia University, a skilled microanalyst. Allen gave him 75 milligrams
of the crystals, not much more than the weight of a postage
stamp. He completed the purification and found that the
hormone is a sterol having 21 atoms of carbon, 30 of hydrogen and 2 of oxygen. Practically at the same time Slotta,
Ruschig and Fels at Breslau, and Butenandt and Westphal,
then at Danzig, also reported ultimate purification of the
hormone and announced, as probably correct, the formula
printed below. Butenandt told me later that the total amount
of the hormone he had available with which to work out its
structure was 20 milligrams, one-third of the weight of a
 
{ 116 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
postage stamp. The same year (1934) Butenandt and two
colleagues succeeded in making the hormone synthetically by
chemical manipulation and rearrangement of a better known
and more widely available sterol and thus confirmed the formula.
 
The chemistry of progesterone. This hormone is also a
sterol, and is put together in a way not greatly unlike the
estrogenic substances. Students of organic chemistry will
recognize it as 3, 20 diketo 4, 5 pregnene :
 
 
 
 
PROGESTERONE
 
A more detailed explanation of its chemical relationships will
be found in Appendix I. This substance has not yet been
synthesized from simple materials, but it has been made by
rearranging the structure of somewhat more complicated
sterols built up by plants and animals. For some years a
vegetable sterol from soy beans was the most readily available
source for the synthetic chemist, but it is now being made
from cholesterol, which occurs plentifully in the spinal cord
of oxen.
 
The name 'progesterone. It finally became necessary to
name this substance, even before we knew what it was, in order
to avoid long phrases in talking about it. Our experiments
had proved that its effects are progestational, i.e. it favors
gestation; for this reason I decided, with Willard Allen's
approval, to call it progestin. This word is easy to spell and
pronounce in many tongues, means something but not too
much, and did not commit us to any theories that might prove
untenable later. When the exact chemical nature of the hor
( 116 }
 
 
 
A HORMONE FOR GESTATION
 
mone became known, the chemists, led by the amiable and
diplomatic Butenandt, suggested the suffix -sterone. This
tells us that the substance is a sterol containing doubly-linked
oxygen.
 
Progesterone it is, then; and my original name progestin
is retained for use as a general term when we need to talk
about such a hormone without specifying its exact chemical
structure. As a matter of fact, some of the other sterols have
been found to produce progestational proliferation, though
rather feebly in comparison with progesterone itself, and as
a group we can call these "progestins," just as we use estrogen as a general term and specify estrone, estradiol, etc. as
individual substances.
 
Natural sources of progesterone. The corpus luteum is the
only important natural source of progesterone. It has been
extracted not only from the sow, but also from the whale,
whose 2-pound corpus luteum contains a large amount. A
progestin (probably progesterone) has been extracted from
the cow. There is a little in the human placenta, and most
curiously of all, the adrenal gland contains something that
gives similar effects in animals.
 
Potency of progesterone; administration. This hormone is
not as potent, weight for weight, as the estrogens. Direct comparisons are scarcely possible, for the two kinds of substances
do different things ; but if we compare the amounts necessary
to produce definite effects in the whole uterus and whole
vagina of an animal respectively, we have to use doses of
progesterone several hundred times larger than of estrogen.
Like coal and dynamite, they exert their power in different
ways.
 
In 1935 the League of Nations Commission on Biological
Standardization agreed upon an international unit of progesterone, namely the amount of potency in 1 milligram of the
chemically pure hormone. This is 1/60 of the weight of a
 
{ X17 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
postage stamp. To compare an unknown preparation with
this, it must be tested on rabbits under standard conditions.
 
Progesterone is soluble in oils and fats as well as in fat
solvents like ether, and therefore it is generally injected hypodermically in a bland vegetable oil, such as sesame oil. It is
ineffective when given by mouth, as shown by extensive trials
on rabbits. Recently some of the drug manufacturers have put
out another substance, a progestin of slightly different chemical structure, which is reported to give progestational proliferation in rabbits when given by mouth. Its usefulness in
human patients is now being established (Appendix II,
note 5).
 
A failure and what it taught. Willard Allen and I had a
queer experience with our first extracts, from which we learned
something important, so that the story is not only amusing
but useful. The beginning of this tale is that when we started
we followed (as I said before) a hint from the work of Edmund Herrmann, who had obviously produced progestational
proliferation in a few of his experiments without knowing it.
He had used very young rabbits, roughly 8 weeks old. They
react more readily than adults to the estrogen which was the
chief ingredient of his extracts. Since we wanted to follow his
methods closely at first, we used infant rabbits too, and with
them our first successes were obtained. In the spring of 1929
we were all ready to report the first steps in print. The paper
was being written, when it occurred to me that our directions
for extracting the hormone ought to be tried out by a nonetoo-good chemist, just to make sure they were foolproof. We
did not want others to think our work could not be repeated,
just because our directions were not clear. It was agreed that
I was a bad enough chemist for the test : if I could make the
extract all by myself, then anybody could. So Allen went on
his vacation and I went back to our extractors and vacuum
stills. In a week I had a batch ready; to my horror it was
ineffectual. I made another batch; it, too, was worthless. I
 
{ 118 }
 
 
 
A HORMONE FOR GESTATION
 
suppressed the paper and telegraphed for Allen. We decided
that I needed a vacation and that we would look for the
trouble in the fall. In September I made another batch with
Allen watching every step, but not touching the apparatus.
It was no good. What could be wrong.'' Since my laboratory
was sunnier than his, perhaps my hormone was being spoiled
by sunlight. I had a room blacked out and made a batch in
the dark. That failed. Then we remembered that Allen, being
a better chemist than I, usually got his extracts freer of superfluous grease and therefore had to mix them with corn oil
(Mazola) so that he could inject them. Mine were greasy
enough to inject without added oil. Perhaps the corn oil protected his hormones somehow while mine spoiled. We checked
that idea — another two weeks gone — and that was not the
answer. Then in desperation we made a batch together, side
by side and almost hand in hand, each watching the other. We
divided it into two lots and tested it separately — Allen's
worked ; mine did not ! Eureka, my trouble was in the testing,
not in the cookery.
 
The explanation will seem so silly that I almost hesitate
to admit what it was. The fact is that rabbits do not respond
well to progesterone until they are about 8 weeks old and
weigh about 800 grams. We did not know this, and our rabbits ranged from 600 to 1,200 grams. When we went to the
cages to inject them, Willard Allen's idea of what constitutes
a nice rabbit led him to choose the larger ones, while I must
have had a subconscious preference for the infants. My extracts had been as good as his all the while, but my rabbits
were insensitive. It is staggering to think how often the success
or failure of research may hang upon such an unimaginable
contingency.
 
We thought very hard about this experience, and decided
that after all we should not have expected that the hormone
of gestation would act upon an infant's uterus. Caring for
 
{ 119 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
embryos is a job for a grown-up uterus. Thereafter we used
only adult rabbits and never had another failure. Before we
published the method one of our laboratory technicians made
a lot of the extract unassisted and it worked.
 
Meanwhile the Wisconsin workers, Hisaw and his colleagues, had found that their extracts that relaxed the guinea
pig's pelvic bones would not work in infant guinea pigs unless
the animal was first "primed" with estrogenic hormone. Following up this clue, Allen learned that if we make the infant
uterus grow larger by a few days' treatment with an estrogen, it will then respond fully to progesterone. A very striking
experiment illustrating this is shown in Plate XVIII, E, An
infant rabbit has, of course, a very small uterus. After 5 days'
treatment with estrogenic hormone, the uterus becomes large
and well differentiated. If progesterone is then given for 5
days, the uterus shows full progestational proliferation like
that of an adult in early pregnancy. Meanwhile the rabbit
herself remains a baby small enough to hold on the palm of
one's hand.
 
By what means does progesterone affect the uterus? Just
how the various hormones exert their action upon the organs
which they control is very obscure. About the action of progesterone we have at present only a very remote idea. We
can guess that in some way the hormone alters the general
nutritional state of the cells of the uterus by way of a change
in their metabolic rate or some other deep-seated effect on
cellular physiology.
 
What happens to progesterone after it acts? In 1936 a
discovery of great importance was made by Ethel H. Venning
and J. S. V. Browne of Montreal. This is that in the human
body used-up progesterone is converted into another substance called pregnanediol (preg-nane-di-ol). The conversion
takes place by the addition of six atoms of hydrogen. I give
the chemical formula for those who are interested:
 
{ 120 }
 
 
 
A HORMONE FOR GESTATION
 
 
 
 
PREGNANEDIOL
 
Pregnanediol is an inert substance as far as hormone action
is concerned. The body gets rid of it by attaching it to another
substance readily available from the starches and sugars of
the food, namely glycuronic acid (see Appendix, p. 253).
To this an atom of sodium is added, and the combined
substance, sodium pregnanediol glycuronidate, passes out
through the kidneys. It happens to be easily separable from
the urine and can thereafter be detected and measured by
relatively simple laboratory tests. Each molecule of this
waste product in the urine means that a molecule of progesterone was available for conversion. If ten milligrams, for
instance, of pregnanediol is recoverable from a single day's
urine, then we know the patient produced at least that much
progesterone — in fact a little more, for there is some loss in
the chemical process of measurement and possibly some loss
in the body, i.e. some of the progesterone may be broken down
and eliminated in other ways. The method is good enough,
however, to help very much in estimating the functional activity of the corpus luteum in women and is beginning to be
used as a method of diagnosing ovarian deficiencies.
 
All this information about the conversion and excretion of
progesterone unfortunately holds good only for the human
species and (apparently) the chimpanzee. It is enough to
make a laboratory experimenter tear his hair, when he realizes
that in other animals progesterone is excreted in some other
way, which nobody has been able to discover. Pregnanediol
has not been found in the urine of rabbits and monkeys, nor
in any other animal. Nor has any other substance that might
 
{ 121 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
be derived from progesterone and from nothing else been
found in the urine. Either it escapes from the body, in lower
animals than man, in some elusive form ; or it is broken down
so completely that its chemical fragments are undistinguishable among the simple remnants of bodily chemicals that make
up the excretions (Appendix II, note 6).
 
Action of progesterone on the muscle of the uterus. In
1927 a well-known Austrian scientist, Hermann Knaus, dis
 
 
 
Fio. 17. Arrangement of apparatus for maintaining excised pieces of
uterine muscle under physiological conditions and recording its contractions.
 
{ 122 }
 
 
 
A HORMONE FOR GESTATION
 
covered another action of the corpus luteum. To make this
clear let us imagine an experiment such as is shown in Fig. 17.
A rabbit is killed, the uterus is removed, and a portion of one
horn is suspended in a cylinder of salt solution so that one
end is tied down and the other is fastened to a writing lever
that writes on a revolving drum. The salt solution is kept at
body temperature by standing in a bath of warm water.
Oxygen is bubbled through the salt solution, and a little sugar
is put into it as food, providing energy for the tissues. The
whole thickness of the uterus, except its inner lining, is composed of involuntary muscle, as explained on page 48. Placed
in an apparatus of the sort just described, which imitates the
natural conditions within the body, any such piece of living
involuntary muscle, whether from the uterus, intestine, stomach, bladder, blood vessels, or elsewhere, will undergo rhythmic contractions every minute or two and will write them on
the revolving drum as shown in the illustration. The experimenter, if he likes, can induce larger, more sudden contractions by putting into the salt solution one or another of those
substances that are known to stimulate involuntary muscle.
A drop of adrenalin solution will make the uterine muscle pull
so strongly that it will almost yank the lever ofF the drum. So
will a drop of pituitrin solution (subject to a very important
reservation which is about to be mentioned) — indeed, pituitrin is such a powerful stimulant of uterine muscle that it is
often used by obstetricians to make the human uterus contract
after childbirth.
 
Knaus found that the uterus of a pregnant rabbit, set up
in salt solution as described, will not react to pituitrin. He
had just learned this when the first reports of the isolation of
progestin reached Austria ; he made up some crude progestin
(the first in Europe) and found that when he gave this by
injection to a castrated adult rabbit for 5 days, the uterus
became absolutely insensitive to pituitrin, exactly as if she
were pregnant.
 
{ 123 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
This experiment works with some species of animals and not
with others ; we do not know surely about the human uterus in
this respect. In cats, strangely enough, progesterone suppresses the action of adrenalin on the uterus (something that
never happens in the rabbit) but does not suppress the action
of pituitrin. These differences present a remarkable and probably very subtle problem in the physiology of muscle. When
it is answered we shall know much more than we do now about
involuntary muscle and also about hormones. Details aside,
however, the experiment of Knaus shows us that progesterone
can act in a striking way on involuntary muscle. We owe to
S. R. M. Reynolds a very ingenious method of studying uterine
contractions in living rabbits. By a simple plastic operation,
done in a few minutes under complete anesthesia, the twin
cervices of the uterus are stitched to the belly wall and thus
made accessible. A rabbit so prepared suffers no inconvenience if properly cared for, and like any other healthy unfrightened rabbit will lie quietly on her back for hours if
gently tied down. A tiny rubber balloon is carefully inserted
inside the uterus. From this a tube leads to a little bellows
which actuates a lever writing upon a revolving smoked drum.
Whenever the uterus contracts, the balloon is squeezed, the
bellows is inflated, and the lever goes up. With this apparatus
Reynolds found that the normal uterus of an adult female
rabbit undergoes more or less regular contractions. Castration suppresses the contractions, for the uterus which is
enfeebled by castrate atrophy (see page 79) becomes inactive.
Administration of estrogenic hormone, however, restores the
contractions. Progesterone promptly and effectively quiets
the uterus. The graph shown herewith (Fig. 18) illustrates
the effect of an injection of progesterone. At 10:20 a.m. the
uterus was contracting regularly. The hormone was given a
few minuteis later. In one hour (see third line of the graph)
the contractions became definitely smaller and less frequent.
 
{ lU }
 
 
 
A HORMONE FOR GESTATION
 
By 12:20 p.m. the uterine muscle was practically not contracting at all. This effect wears off in a few hours.
 
Such a sedative action of progesterone upon the uterine
muscle has been observed in many animals and there seems to
be good evidence that it occurs in the human species. In all
probability it serves to keep the uterus quiet in early pregnancy so that the embryos can become safely implanted.
 
10'*'* '1'
 
 
 
{AJJULJLJUlA-A.Aj^'<jyULAA..A^
 
 
 
IZ"p^
 
 
 
Fio. 18. Effect of progesterone on the contractions of the living rabbit's
uterus. A tiny rubber bulb in the cavity of the uterus is compressed each
time the uterine muscle squeezes down, so that the rhythmic contractions
are recorded on a revolving drum. Progesterone administered at 10:20
a.m. By 12:20 p.m. the uterus is quiescent. From an article by S. R. M.
Reynolds and W. M. Allen, 1935, by courtesy of the American Journal
of Obstetrics and Gynecology and the C. V. Mosby Company.
 
Is the corpus luteum necessary throughout pregnancy?
In the rat and mouse, removal of the ovaries at any time in
gestation causes termination of pregnancy. The embryos are
cast off prematurely or they break down in the uterus and are
absorbed in situ. Guinea pigs do not always lose their young
if the ovaries are removed after implantation has occurred.
In humans it seems certain that both ovaries, including of
course the corpus luteum, can be removed after the first few
weeks without harm. ^Vhether the pregnant human female,
and other animals having long terms of pregnancy, do not
need progesterone after the embryos are safely implanted, or
 
{ 125 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
whether perhaps the placenta makes enough to serve in place
of the corpus luteum, we do not yet know (Appendix II,
note 7).
 
Progesterone as a medicinal drug. Progesterone is already
in the drugstores. It comes in neat little boxes of glass ampoules filled with a bright clear oily solution, duly labeled
with the hormone content in international units. Tablets of
the similar substance that acts by mouth (page 118) are also
available for trial. Prescriptions for these drugs will be filled
no less readily, though somewhat more expensively, than for
digitalis or belladonna.
 
Before we expect the doctors to cure people with the
ovarian hormones, however, let us consider the special circumstances. To take a quite different case, when Banting, Best,
Collip, and McLeod handed over the pancreatic hormone,
insulin, to the medical profession, they were filling a specific,
clearly understood need. They had worked out the insulin
problem by experiments on dogs. Sugar is sugar, whether a
dog burns it or a man, and the way in which different animals
use sugar is the same, regardless of the species. Diabetes,
moreover, was a well understood disease, and in the minds of
the medical profession it was waiting to be treated with this
hormone as a lock waits for the key.
 
To take another example, the hormone of the adrenal
medulla, epinephrin (trade name Adrenalin) has a relatively
simple, direct action. What it will do, what it is needed for, is
fairly clear. It can be used for acute asthma, or for bleeding
from mucous membranes, with understanding and with reasonable hope that it will be effective under the circumstances.
 
This is unfortunately not the case with endocrine disease
of the reproductive system. The human uterus and the rest
of the system behave quite differently from those of most
other animals. We cannot, for example, apply directly to
humans with regard to disturbances of menstruation or pregnancy, information gained from the lower mammals, because
 
{ 126 )
 
 
 
A HORMONE FOR GESTATION
 
the latter do not menstruate and in pregnancy they differ in
many ways. It will be clear enough when we deal with the
menstrual cycle, in Chapter VI, that we do not even yet fully
understand the way the ovarian hormones take part in menstruation. We know that the monthly cycle and the process of
gestation require not only the individual hormones but also
an exact balance between them. When these things go wrong,
they do so in complex and devious ways. When a young woman is cramped with menstrual pain or a wife goes childless
against her will, in many cases neither her physician nor the
investigator in his laboratory can say exactly what is wrong
or how to redress it. They can only try their best ; often the
treatment works, often not. Only by the slow pathway of
experiments on monkeys and cautious observation and trial
directly in humans shall we ever comprehend the normal physiology of reproduction in our own species and those vexatious,
oftentimes tragic disturbances that lead to disorders of menstruation, miscarriage, and sterility.
 
It is therefore only in small degree possible as yet to apply
progesterone and estrone, and the other potent steroidal
hormones, to human disease. We must leave the problem in
the hands of competent gynecologists and obstetricians, particularly in the clinics of the medical schools and research
hospitals. When these men give the word, hormone treatment
becomes justifiable. The work is going forward daily; I do
not mean to be discouraging, but only to avoid false promises
of quick magic like that of insulin. Incidentally some cases
of diabetes still defy insulin, and the specialists in that disease
have by no means been able to declare their treatment perfected and their researches complete.
 
The maintenance of pregnancy. What can we hope for from
progesterone in the long run ? The great dramatic thing about
this hormone as seen in the laboratory is of course its power
to maintain pregnancy after the loss of ovarian function. One
of the greatest problems of medical practice is that of spon
{ 127 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
taneous abortion of the embryo or fetus ("miscarriage").
About one pregnancy in three terminates prematurely, according to generally accepted figures.^ These accidents have
many causes. Sometimes the embryo is itself unhealthy,
through some mischance of heredity or development, like a
seedling plant that will not grow. Sometimes illness or accident to the mother upsets the course of events. Sometimes, we
may suppose, the hormones go wrong. Perhaps the supply of
progesterone from the corpus luteum or placenta is not adequate. In such cases it might conceivably be useful to supply
the hormone by injection, thus making up the lack. The main
difficulty at present is to diagnose such cases in time to treat
them.
 
There is another way in which progesterone might help.
No matter what the cause of an abortion, it is always accompanied by spasmodic contractions of the uterus, trying to get
rid of its burden. Sometimes, we think, the contractions come
first, as the result of injury or illness, and dislodge a normal
embryo. We have seen that progesterone will quiet the uterine
muscle; by reason of this, we may hope that it will help to
steady the uterus in the case of a threatening abortion. With
these thoughts in mind, the doctor tries progesterone in the
face of such a disaster. Sometimes the pregnancy goes on,
sometimes not. How can he tell whether his hormone worked
the cure ? His case records are not altogether helpful, for no
two cases are alike; and what is more, the physician in his
anxiety generally tries two or three remedial measures at
once, any one of which might have been responsible. If he
controls a large clinic with many such patients, he can use
the treatment on alternate cases only until he is satisfied
which group does better. By this method, while the physician
 
3 This statement need cause no alarm to any prospective mother who
happens to read it. Once pregnancy is past the first weeks and under
medical care, it goes safely on in an overwhelming majority of cases.
The figure of one loss in three includes many pregnancies of the earliest
weeks, and even some that occur so early as to be recognized only by
microscopic methods.
 
{ 128 }
 
 
 
A HORMONE FOR GESTATION
 
is being scientific he is (if the drug is really useful) condemning half his patients with threatened abortion to the risk of
losing their babies — a dilemma similar to that dramatically
expounded in Sinclair Lewis's great novel of medical life,
Arrowsmith. A clever method of testing this question was
recently suggested by the British physicians Malpas, McGregor and Stewart, who pointed out that women who are
unfortunate enough to have three or more successive spontaneous abortions are (statistically speaking) almost certain
to miscarry in the next subsequent pregnancy. If, then, any
kind of treatment is followed by the birth of a living infant,
the odds are great that the medical procedure, and not mere
chance, was responsible. By this severely critical test, it
appears that progesterone is saving some of these babies.
Needless to say, a treatment which is still so largely experimental requires skilled and thoughtful handling, by physicians
thoroughly familiar with the proper dosage and other problems.
 
Post partum pain. The most clear-cut use of progesterone
involving its sedative action on the uterine muscle is for the
relief of spasmodic pain due to excessive contractions of the
uterus after childbirth. This is sometimes severe enough to
require relief. Lubin and Clarke, of Brooklyn, found that a
single dose of one international unit of progesterone will
relieve these afterpains in about 90 per cent of the cases.
 
Menstrual cramps. Painful menstruation is one of the commonest of human ills, and one of the least understood. Knowing as little as we do about normal menstruation, it is no
wonder that we also know all too little about its disturbances.
In the case of painful menstruation (dysmenorrhea) we are
not even sure of the exact seat of the pain in all cases. It is
probably due to cramping of the muscular wall of the uterus ;
but there is reason to think that in some cases the pain may
be produced in the lining of the uterus rather than in the muscular substance of the wall. All sorts of treatment have been
 
( 129 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
tried, from psychological analysis to operations designed to
correct faulty positions of the uterus. The fact that each of
these widely different measures sometimes succeeds and sometimes fails, suggests strongly that dysmenorrhea is not a
single disease, but rather a symptom due to different causes in
different cases. The whole situation creates a problem for
investigation by the combined forces of clinical gynecology
and the laboratory investigators. Unfortunately, we can expect to get very little help, in such a problem as this, from
study of animals. Even the female Rhesus monkey, so useful
for study of the physical aspects of menstruation, cannot
help us in this investigation, for even if she suffered from
dysmenorrhea or could be made to experience uterine cramps
for the purpose of our studies, she cannot report her symptoms or help us evaluate the results of treatment.
 
When it was discovered that progesterone can quiet the
normal contractions of an animal's uterus and even the violent
spasms that cause post partum pain in human patients, many
physicians thought of trying it in dysmenorrhea, thinking
that it might relieve a crampy state of the uterus. As usual
whenever a new treatment, no matter what, is tried in one of
the old reliable guaranteed-to-baffle diseases, some of the
doctors and patients reported hopeful results. A little later
skeptical reports began to be published. Critical observers
reminded us anew that dysmenorrhea is such a peculiar thing
that we must be very cautious about accepting a new cure.
For example, there are undoubtedly some cases in which the
pain is largely subjective, arising from psychic causes. These
people will be helped by any treatment that happens to win
their confidence. Depending upon the patient's turn of mind,
a hypodermic injection of sterile water given with due assurance, any new hormone in an impressive package, psychological or religious comfort — any of these may give genuine
relief. With equal certainty there are other cases produced
by some sort of actual physical or chemical disorder in the
 
{ 130 }
 
 
 
A HORMONE FOR GESTATION
 
reproductive system, and these must be attacked, if possible,
by treatment aimed directly at the cause. The physician,
however, cannot definitely classify these cases before he treats
them. Being a merciful man and anxious to give relief as soon
as possible, he generally prescribes what has worked best in
his last few cases. He usually tries several things at once, thus
spoiling a good experiment in the hope of more relief. As a
result, it is very difficult to judge the effects of progesterone
when used in the treatment of dysmenorrhea. What is badly
needed is a large-scale report from one of the university hospital clinics, based on a long series of cases in which progesterone has been used in alternate patients, and in alternate
periods in the same patient, so that really scientific checkup
of the effects can be provided. Meanwhile, there have been a
good many reports of relief of menstrual cramps, some of
them almost magical, and other reports of failure. It certainly
ought to be tried in cases that have resisted other forms of
treatment, and that are severe enough to warrant the necessary hypodermic injections, as well as the expense, which may
run up to several dollars at each period if large doses are
necessary. If the new progesterone-like drugs for administration by mouth prove to be successful, they will simplify the
problem.
 
Control of irregular or excessive menstrual bleeding. Progesterone has the property of preventing menstruation, as
we shall see when we discuss that subject in Chapter VIII. For
this reason it is being tried in cases of excessive menstrual
bleeding and irregularity. It looks as if this hormone and
some of its chemical relatives are going to be really useful in
these distressing ailments, as we come to understand them
better ; but this is decidedly a matter for trained specialists.
No drug can safely be used to stop uterine bleeding except
after a thorough examination, to rule out the possibility of
bleeding from cancer or other tumor of the uterus. Once such
 
{ isi )
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
causes of bleeding as these are ruled out, the physician may
safely try progesterone.
 
At the present time each case of menstrual disorder is a
separate problem and both doctor and patient must realize
that hormone treatment is experimental. It brings relief from
debilitation and misery to some women even now. As we learn
more through cautious trial, more will be helped. Meanwhile
those of us who have had something to do with the finding of
this hormone wish to see it exploited with care and understanding, not discredited by premature advertising and incautious use (Appendix II, note 8).
 
 
 
{ 132 }
 
 
 
THE MENSTRUAL CYCLE
 
 
 
*'In this Enquiry indeed, tvhich we are now attempting, no less
useful than agreeable, the Wits of almost every Age have toiVd:
hut as there is hardly any Argument, on which Physicians have
wrote more; so is there no one, in which they have given less satisfaction to their Readers. . . . I shall not appear to have employed
my Time ill, in endeavoring to set the Nature of the Menses in a
clearer Light, than I find it hitherto done by Authors. In which
Performance the Reader will find nothing abstruse, nothing far
removed from common sense: inasmuch as it has been my only
Care to find out the Truth, as much as possibly I could." — John
Freind, Emmenologia, translated into English by Thomas Dale,
1729.
 
 
 
CHAPTER VI
 
THE MENSTRUAL CYCLE
 
SURELY the process of menstruation is one of the
strangest things in all Nature. An important organ —
the uterus — serving an indispensable function, is overtaken at regular intervals by a destructive change in the
structure of its lining, part of which undergoes dissolution
with hemorrhage, and must be reorganized in every monthly
cycle. The loss of blood from organic tissues, everywhere else
in the animal kingdom a sign of injury, even of danger, is in
this one organ the evidence of healthy function. To make the
puzzle greater, menstruation is by no means general in the
animal kingdom, or even among the mammals. It occurs,
indeed, only in the human race, in the anthropoid apes
(having been observed in chimpanzees and in the gibbons), in
the baboons, and in the Old World monkeys ; in short, in a
closely related group of primates, one little portion only of
the great class of Mammalia. No other animals, in forest,
plain, or sea, hiding in dens or grazing the fields, undergo in
the course of their cycles any such phase of hemorrhage. It is
a paradox indeed that this curious phenomenon of periodic
breakdown, seemingly an imperfection, a physiological flaw, is
characteristic solely of the females of those very animals we
are pleased to think the highest of earth's creatures (Appendix II, note 9).
 
The periodicity of menstruation. In human females, menstruation recurs at intervals of about 4 weeks. There is a
common impression that the cycles are normally quite regular,
but any woman who will keep an accurate calendar of her
cycles will find a surprising variability.
 
A recent statistical analysis of thousands of records^ shows
in fact that the commonest average cycle length (the "mode"
 
1 Leslie B. Arey, "The degree of normal menstrual irregularity."
American Journal of Obstetrics and Gynecology, vol. 37, pp. 12-29, 1939.
 
( 135 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
as statisticians say) in adult European and American women
is 28 days, but it is also very common for a woman to average
cycles of 25, 26, 27, 29, and 30 days. The individual woman,
moreover, often varies several days, in any one cycle, from
her own average. To state this in exact terms, so as to make
clear just how much variation a woman may consider normal,
is rather difficult, for it is a matter of statistics and such
things are hard to translate into everyday language. The
clearest statement is that of Professor Arey, already quoted,
whose words I paraphrase as follows: let a woman keep a
record of her cycles for several years, so that she has enough
observations to strike an average. Say, for example, that her
personal average is 28 days. Arey's figures show that with
this information she cannot hope to predict the onset of any
given period with accuracy closer than 2.5 days plus or minus,
i.e. she may expect it any day between the 25th and 30th
after onset of the last period, and even then one-third of all
her cycles will depart still more widely from the average
length, say another day or two, and sometimes more. The
statement that she averages a 28-day cycle has the same kind
of meaning as the average price of eggs during the year,
which may be very different from the price at any one time,
or a baseball player's average of home runs per game. All it
means is that the length of her successive cycles will be within
a few days, more or less, of 28 days, seldom however coming
out at that precise length. In fact a woman whose cycles were
perfectly regular to the day, during many months or years,
would be a medical curiosity. No such case has ever been
reported.
 
When we come to consider, a little later, the intricate interplay of hormones that goes to produce the cycles, we shall
not be surprised that the timing is not perfectly regular. Nor
will we be surprised to learn that in young girls, during the
first few months or years of menstrual function, while the
endocrine mechanisms are becoming adjusted, the cycle length
 
{ 136 }
 
 
 
THE MENSTRUAL CYCLE
 
is extremel}'^ variable. Arey compiled the records of 100 girls
during about two years after the onset of menstruation, and
calculated the average cycle length of each during this epoch
of their lives. One-third of these girls actually never had a
cycle that corresponded exactly to the day with their own
personal averages ; in other words, every single cycle varied
from the arithmetical norm. During the latter part of adolescence there is considerably greater regularity.
 
The first menstruation most commonly takes place sometime
between the ages of 12 and 14 inclusive. The average age at
the time of onset, in the white race at least, is 13% years, but
onset at any age from 11 to 16 may be regarded as normal.
Delay beyond 16 is a matter for medical investigation.
 
The normal duration of the menstrual flow may be from
one day to one week ; the modal duration is 5 days.
 
Among the infrahuman primates there is only one, the
Rhesus monkey, which has been studied in numbers large
enough for positive statement. In this species, observed in
captivity in the United States and England, the mode, i.e.
the most frequent cycle length, is 28 days, as in women.
Individual animals have average cycle lengths of 25 to 31
days, and single cycles vary from 14 days up. Rather scanty
observations on chimpanzees, baboons, and a few species of
monkeys mostly show averages a little longer than 28 days.
This statement might or might not hold good if the statistics
were more extensive (Appendix II, note 10).
 
The poetic suggestion quoted at the head of Chapter III,
that the reproductive cycles of living things are part of the
rhythms of the universe, must not be taken too literally.
Menstruation is not regulated by the moon. It happens that
the lunar cycle has the same length to the day as the modal
human cycle, but we have seen that the human cycle frequently deviates from the mode, and if, for example, the start
of the period coincides with the new moon or any other given
lunar phase, the odds are it wiU be off cycle by at least a day
 
{ 137 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
or two next month and perhaps completely out of phase next
season. I once had 4 females of the Java monkey (Macaca
irus) in a cage adjacent to a large group of the closely related
Rhesus monkeys. While the latter were running cycles of 28
days' modal length, their Javanese cousins, living under the
same moon, were exhibiting a modal cycle length of 35 days.
As mentioned in Chapter III, the cycles of other mammals
may vary from 5 days to a year in length, and if we consider
the birds and insects we finds cycles of one day to 17 years.
If the heavenly bodies are to control these rhythms, the cycle
of the 17-year locust calls for a hitherto unknown comet !
 
The idea of a relation between human menstruation and
the moon is, however, ancient and widespread. It was, no
doubt, suggested by the obvious and inescapable relation
between the moon and the tides of the sea. If the moon can
control the ebb and flow of great waters, why not also the
tides of human life .'' Perhaps the popular mind has also been
influenced by the fact that outbursts of insanity in women
sometimes accompany the menstrual cycle ; this seems again
to link menstruation with the moon, which has long been considered a cause of lunacy. Then there are, of course, certain
special cases in nature in which the life of an animal is directly
influenced by the moon or the tides (e.g. the palolo. Chapter
III) . These cases may have helped to foster the notion we are
discussing. As lately as 1898 the eminent Swedish physicist
Svante Arrhenius thought he had proved the connection of
lunar and menstrual cycles by mathematical evidence, but
this has been completely disproved, notably by the English
physicians Gunn, Jenkin, and Gunn (1937). It is indeed difficult to conceive of any direct participation of the moon in the
reproductive cycles of the land-dwelling primates, for if it
were really efl*ective we should expect menstruation to occur
at the same phase of the moon in all females of a given species,
a state of aff"airs that would have made the social organization of mankind unthinkably different from what it is.
 
{ 138 }
 
 
 
THE MENSTRUAL CYCLE
 
NATURE OF THE MENSTRUAL CYCLE
 
Events of the cycle in non-menstruating animals. To get
a clear understanding of the process of menstruation, it is
necessary to understand first what takes place during the
cycle in animals which do not menstruate. This has already
been discussed in part and illustrated in previous chapters,
and is summarized in the diagram herewith (Fig. 19) which
represents the typical or generalized cycle of mammals. If
we wish to talk about any one species, we shall have to introduce modifications into this scheme, but as it stands it can
be used as a basis for understanding them all. In the upper
portion, which shows events in the ovary, we see (beginning
at the left) the growth and ripening of the follicle. The moment of rupture of the follicle and discharge of the egg gives
a convenient point of division, which we may consider as the
start of a new cycle. Looking at the third part of the diagram,
that indicating sex activity, we see that ovulation occurs
during estrus, an arrangement which is adapted to secure
fertilization of the egg. Next, the follicle is converted into a
corpus luteum. This in turn runs its course, secreting progesterone for about two weeks (in typical species) and then,
if the Ggg is not fertilized, the corpus luteum suddenly begins
to degenerate and ceases to secrete its hormone. Thereafter,
a new crop of follicles begins to develop. In some animals the
new cycle follows at once (e.g. the guinea pig, which has a
cycle of only 15 or 16 days) ; in others several months may
elapse, during which the ovaries are relatively dormant (as
in dogs and cats) or a whole year, as in many wild animals.
 
Digression about the cycle in general. We come now to the
fundamental question of the female reproductive cycle,
namely what causes the alternations of structure and function
in the ovary. When the cycle was first discussed, in Chapter
III, we could deal with it only as an observed phenomenon
of natural history, but we are now in a position to consider
 
{ 139 }
 
 
 
THE HORMONES IN HUMAN KEPRODUCTION
 
 
 
 
{ UO }
 
 
 
THE MENSTRUAL CYCLE
 
the problem in the light of our knowledge of the hormones.
To resume this subject where we left off on page 75, there is
scarcely any doubt at present that the cycle is somehow
produced by interplay of hormones from the ovary and the
pituitary gland.
 
If we look at the pituitary gland or hypophysis (Plate
XIX and Fig. 20) we find that this gland of internal secretion
is composed of two major parts, the anterior and the posterior lobes. It is the anterior lobe which produces hormones
(probably two in number) having the power of stimulating
the ovary to produce estrogenic hormones and of promoting
the growth of ovarian follicles. They also affect the male
organism, causing the testes to grow and produce sperm cells.
Because of these actions the hormones we are discussing are
called gonadotrophic, a name which signifies "producing
growth of the sex glands." From the brilliant work of P. E.
Smith, Bennett Allen, H. M. Evans, Zondek and Aschheim,
and many others between 1915 and the present time, we have
learned (as mentioned in Chapter III) that removal of the
anterior lobe of the pituitary stops growth of the ovaries and
puts an end to the cycles of the animal. By implanting bits of
anterior pituitary, or better by injecting extracts of the gland
into immature animals, the ovaries are caused to grow and
the cycle to begin. The ovary is thus absolutely dependent
upon this action of the pituitary. Removal of the anterior
lobe produces all the effects of castration, for without it the
sex glands, ovary and testis, deteriorate to inactivity. On the
other hand, there is a good deal of evidence that the estrogenic hormone of the ovary represses the production of the
pituitary gonadotrophic hormones. After removal of the
ovaries, the pituitary gland is found to contain more gonadotrophic potency than before; after injection of estrogenic
hormones it contains less (Appendix II, note 11).
 
When these facts became known, a fairly clear explanation
of the reproductive cycle suggested itself almost simultane
{ m }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
 
 
Post.
 
 
 
 
 
Fig. 20. Above, the pituitary gland, showing the anterior lobe and the
posterior lobe with its stalk by which the gland is connected to the brain.
Enlarged approximately 5 times. Below, median section showing position
of pituitary gland in its bony cavity at the base of the skull; compare
with the X-ray photograph, Plate XIX.
 
{ m }
 
 
 
w
 
 
^S, ^I^^^H
 
 
 
 
i]
 
 
^^^^^^|R^ ''â– â–  â–  iiiiiiilMr
 
 
^^
 
 
 
 
I^H
 
 
 
 
1
 
 
 
Plate XIX. X-ray photograph of the human skull, to show the location of the
pituitary gland. The arrow points to the little hollow (sella turcica) in the bone
below the brain, in which the gland lies. About 2/5 natural size. Courtesy of the
Eastman Kodak Company, Rochester, N.Y.
 
 
 
T^vii
 
 
 
 
Plate XX. The human infant at birth, with the placenta and membranes.
From the anatomical plates of Julius Casserius, published by Adrianus
Spigelius in 1626.
 
 
 
THE MENSTRUAL CYCLE
 
ously, about 1931-1932, to a number of investigators, among
them first perhaps Brouha and Simonnet in Paris, then to
Leonard, Hisaw and Meyer in Wisconsin, and Moore and
Price^ in Chicago. This hypothesis suggests that the cycle is
Hke a clockwork in which the pituitary is the driving force
and the regulatory escapement is the reciprocal action of
ovarian and pituitary hormones (Fig. 21). The pituitary
 
 
 
ESTRUS
 
 
 
E5TRU5
 
 
 
HYPOPHYSIS
 
 
 
ESTRIN
 
 
 
 
Fig. 21. Diagram illustrating the alternation or "push-pull" hypothesis
of the ovarian cycle discussed in the text.
 
 
 
makes the follicles grow, ripens the follicles and eggs, and
causes the production of estrogenic hormone. The rising tide
of estrogenic hormone thus checks the production of pituitary
hormone, which begins to fall off as estrus occurs. The estrogenic hormone is used up, and as it reaches a low ebb, the
pituitary, now freed from the repressive action of the ovary,
again begins to secrete its gonadotrophic hormone. Up goes
the pituitary and then up goes the ovary again, thus getting
another cycle under way. This scheme, however, cannot fully
explain the cycle. As Lamport has shown, a push-pull action
of the two hormones would naturally tend, not to effective
cyclic fluctuations of estrogen, but to ever smaller changes
approaching equilibrium. We must therefore postulate some
other event which occurs from time to time to break the bal
2 For a discussion of this theory, see Carl R. Moore and Dorothy Price,
"Gonad hormone function." American Journal of Anatomy, vol. 60, pp.
13-72, 1932, and Harold Lamport, "Periodic changes in blood estrogen."
Endocrinology, vol. 27, pp. 673-680, 1942.
 
{ 143 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
ance of the two hormones. Under the push-pull hypothesis it
is in fact easier to understand the long diestrous phase of
cycles like those of animals that have an annual cycle, when
(as we may suppose) the estrogenic and gonadotropic hormones are balancing each other, than to explain what happens
to set the see-saw swinging again, or to bring on cycles, in
some animals, every few days or weeks. At present we can
only make vague conjectures about the possible role of other
hormones, e.g., progesterone or another pituitary hormone.
 
Events of the cycle. To resume the main theme of our discourse, during all these changes in the ovary the uterus is,
of course, constantly under the influence of the ovarian hormones. Even when there is a long anestrous interval between
one ovulation and the next, the ovary produces enough estrogen to protect the uterus from atrophy. As the follicles enlarge and ripen, there is a period of growth and development
of the lining of the uterus (endometrium). When the corpus
luteum is formed and begins to produce progesterone, the
uterine lining is rapidly brought into the progestational condition, as described in Chapter V and illustrated in Plate
XVII. About one week is required to complete these changes.
The favorable environment thus prepared for the embryos
(pages 107-111) is maintained about one week longer, making
two weeks in all between the beginning and the end of the
active life of the corpus luteum. This is the progestational
phase of the cycle. If the animal mated while in estrus, the
embryos arrive in the uterus about the 4th day (later in
some species) and begin to attach themselves sometime between the 7th and the 13th day, according to the species. It
will be seen that the corpus luteum functions long enough to
give time for implantation of the embryos. If this occurs,
some sort of signal, probably via the pituitary gland, causes
the corpus luteum to survive and maintain the uterus in a
state favorable to early pregnancy.
 
Retrogression of the uterine changes. We are considering
 
{ lU }
 
 
 
THE MENSTRUAL CYCLE
 
here, however, a cycle in which the eggs are not fertilized. In
such a case they are transported through the oviduct to the
uterus, where about 8 or 9 days after they first left the ovary
they go to pieces and disappear. The corpus luteum holds on
until the 14th or 15th day, then degenerates and ceases to
deliver progesterone to the blood stream. The endometrium
is thus deprived of its hormonal support. The changes induced
by progesterone disappear in the course of a few days. The
blood flow through the uterus diminishes, the lining becomes
thinner, the cells of its surface epithelium and glands diminish
in number and height, and the glands resume the simpler form
that characterizes the interval and follicular phase of the
cycle. Generally speaking, the steps of this reversion are
gradual ; it is spread over several days, and gives no outward
sign to let us know it is in progress.
 
In our diagram (Fig. 19) the whole sequence of changes
in the lining of the uterus is illustrated by the middle portion,
which is a conventionalized representation of the glands in
their successive phases.
 
The cycle in menstruating animals. The cycle of the menstruating animals and the human species is fundamentally
similar to that of other animals. Two important difl*erences,
however, exist. In the first place there is not a sharply defined
phase of sexual receptivity like the estrus of other mammals.
Although cyclic fluctuations of sex activity occur in some of
the apes and monkeys, this is by no means as well defined as
in most other animals, and in the human female sex desire is
obviously much more influenced by all sorts of moods, social
situations, domestic ups-and-downs, and the like, than by any
tendency to cyclic alternation. Mating may occur on any day
of the cycle. There is no outward sign, like the estrous behavior of lower mammals, to indicate the time of ripening of
the ovarian follicle and its ^gg.
 
It is interesting to speculate about the effect of this suppression of estrous rhythm upon human life and the progress
 
{ us }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
of the race. Certainly our customs would be very different
from what they are if the sexual compulsions of women were
like those of animals with strongly marked estrous periods.
In these creatures the sex response, intense and irresistible
in the female during estrus, is wholly absent at other times ;
in the human species it is moderated but diffused over a
larger proportion of the time. In their various aspects and
sublimations, from downright sex desire to affection and
vague romantic yearnings, the impulses of sex color in some
degree our entire adult lives, teach us to love nature and art,
and call us to sacrifice and devotion. In this respect above all
mankind differs from the beast.
 
Regardless, however, of this all-important difference of
behavior, the cycle of the ovary proceeds in the human species
as in the others (Fig. 22). The follicle ripens and ruptures,
the egg passes to the uterus, the corpus luteum forms and
takes up its endocrine function. The lining of the uterus
undergoes a profound progestational change. The epithelial
cells of its glands multiply so greatly that the glands have
to become sinuous and pleated, in order to be accommodated
in the available space. The glands fill up with fluid secretion
and therefore become dilated. The result is a very characteristic appearance, when seen in sections of the uterus. This
progestational or "premenstrual" state is well shown in
Plate XXI, C.
 
Inspection of the diagram (Fig. 22) will show that the
premenstrual phase is at its height during the second week
after discharge of the egg from the ovary, just as in other
mammals. If there is a mating, and the egg is fertilized and
becomes an embryo, it will reach the uterus when the endometrium is fully under the influence of the corpus luteum and
ready to take care of the new arrival.^ This is clearly illus
3 We do not actually know the time of arrival of the human embryo
in the uterus, nor the precise time of its implantation, since no normal
 
{ U6 }
 
 
 
THE MENSTRUAL CYCLE
 
 
 
 
 
 
 
human embryos younger than about 7 1/2 days have as yet been seen.
Information from other animals, together with what is known of the
human embryo at the 8th day, makes it highly probable that the human
embryo becomes attached about the 7th day after ovulation.
 
 
 
{ U7 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
trated in Plate XII, C, a photograph of one of the earliest
known human embryos, obtained by Dr. Arthur T. Hertig of
Boston, and preserved in Baltimore at the Department of
Embryology of the Carnegie Institution of Washington. The
uterus in which this 11 -day embryo has attached itself is in
the typical progestational phase, as shown by the form of
the glands.
 
The menstrual breakdown. About the 14th or 15th day
after ovulation, the corpus luteum begins to degenerate, as in
other animals. The uterus, thus deprived of support by progesterone, undergoes a violent reaction. In its innermost layer
the circulation of blood is disturbed, the surface epithelial
cells, the glands and the connective tissue are damaged, and
the tissues break down. Blood from small ruptured vessels fills
the cavity of the uterus and trickles toward the vaginal canal.
A section of the endometrium at this time shows a remarkable
picture ; the surface layer has sloughed away, and the stumps
of the glands jut into the central mass of blood and cellular
debris. In the course of a few days a process of repair sets in,
the lost surface cells are replaced, the glands restored and the
debris cleared up.
 
The various stages of the uterine cycle are shown in
Plates XXI and XXII, which present a series of specimens
from the Rhesus monkey.
 
The sequence of these events is summarized in the diagram,
Fig. 22. From this it will be seen that ovulation takes place
about the middle of the interval between the two menstrual
periods. It is customary to count the days of the primate
 
Plate XXI. Three stages of the cycle of the uterus of the Rhesus monkey.
 
A, 16th day of cycle, just after ovulation; interval stage. B, 23d day of cycle.
Effect of corpus luteum hormone appears in the glands; early premenstrual
stage. C, 27th day of cycle. Menstruation due one day later. Full progestational
(premenstrual) stage. All magnified 10 times. A, Corner collection (no. 2)}
 
B, courtesy of C. G. Hartman (H. 326); C, courtesy of G. W. Bartelmea
(B. 123).
 
{ U8 }
 
 
 
THE MENSTRUAL CYCLE
 
cycle from the first day of menstruation. Ovulation most
commonly takes place about the 12th to the 16th day,
although in individual cases it may be earlier or later than
this. The corpus luteum is active for about 13 or 14 days,
and therefore its degeneration brings on menstruation again
25 to 30 days after onset of the last period.
 
The "safe period.** Let us digress again for a moment, to
discuss, in passing, an interesting and important deduction
that follows from the schedule of the human cycle, as shown
in the diagram, Fig. 22. There is evidence from many species
of animals that the eggs can be fertilized only while in the
oviduct, during the first two or three days after their discharge from the ovary. We know also that the sperm cells
cannot survive more than a few days in the female reproductive tract. It follows that the only part of the human
cycle during which fertilization of the egg can occur is
the few days following ovulation. Since, however, there is
no way of ascertaining the date of ovulation and it may vary
by several days, we shall for the sake of caution estimate
the presumably fertile period as a few days longer each
way, say from the 8th to the 20th day of the cycle, counting
from the first day of the menstrual period. All the rest of the
cycle, i.e. from about the 20th day to the 8th of the next
cycle, will be a period of sterility, during which mating will
not result in pregnancy. This is the theoretical basis of the
so-called "safe period" method of birth control. If all women
had regular cycles and things never happened out of turn,
it would no doubt be a fully effective method, but irregularity
 
Plate XXII. The uterus of the Rhesus monkey during menstruation. A^ first
day of flow; at bl., small collections of blood in the lining of the uterus. B,
third day; note loss of surface tissues of lining and disappearance of progestational pattern of glands. C, anovulatory menstruation, first day. Note, in comparison with A, that there is no progestational change of the glands. Magnified
10 times. Ay B, Corner collection (nos. 39, 22) ; C, courtesy of G. W. Bartelmez
(B. 128).
 
{ U9 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
of cycles and unpredictable variations make it much less
than certain.*
 
Role of the blood vessels of the uterus in menstruation.
Within the past few years a good deal has been learned
about what actually happens to produce the menstrual breakdown. Much of this advance we owe to G. W. Bartelmez of
the University of Chicago, and to his former associate,
J. E. Markee, now of Duke University. To make it clear we
must first understand the arterial blood circulation of the
lining of the uterus. The endometrium is fed by arteries which
come up into it from the underlying muscle (Fig. 23). These
have branches of two kinds. Those of one kind are very
pecuhar, for they are wound into coils, making their extremely tortuous way toward the surface, where they break
 
 
 
 
Fig. 23. Diagram of the arteries of the uterus, from the description of
Daron. Enlarged about 20 times.
 
* Carl G. Hartman, Time of Ovulation in Women. Baltimore, 1936.
 
{ 150 }
 
 
 
THE MENSTRUAL CYCLE
 
up into tiny capillary vessels (not shown in the diagram)
that supply the inner one-third of the endometrium. The
other kind of branching is that of the straight arteries, which
run a short course directly to supply the basal two-thirds
of the endometrium.
 
By studying under his microscope a series of uteri of
women and monkeys, collected at successive stages of the
cycle, Bartelmez showed that the fundamental step in the
menstrual breakdown is a shut-off of the coiled arteries.
With such material, however, it is possible to see only interrupted stages of the process ; the sequence cannot be seen
in full. Markee has therefore made use of a remarkably
clever means of watching menstruation in progress.^ Since
we cannot see into the uterus, he undertook to put that organ
(or rather, small pieces of its lining) into a situation where
it can be watched. He grafted bits of endometrium into the
anterior chamber of the same animal's eye, thus applying a
method already used by a few investigators for other purposes. The small grafts are placed just behind the clear
cornea, and get their blood supply through vessels which
grow into them from the iris. The operation of grafting,
which is done under complete anesthesia, is relatively simple,
though, of course, it requires deft hands. The animal suffers
no discomfort from the graft and is inconvenienced only by
the fact that while under observation she has to sit in a
tight wooden box, something like a pillory (but more comfortable), while the investigator studies her eye through
a microscope. He is, by the way, at least as uncomfortable as
the monkey, because the task of watching the winking, roving eye of the animal, changing the focus and moving the
microscope and light whenever necessary, is enough to exhaust the patience even of a scientist.
 
5 J. E. Markee, "Menstruation in intraocular endometrial transplants
in the Rhesus monkey." Carnegie Institution of Washington, Publication
No. 518 {^Contributions to Embryology, vol. 28), pp. 219-308, 1940.
 
{ 151 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
The grafts survive and grow. They respond to estrogenic
hormone, injected under the skin, by swelling and growing
just as if they were still part of the uterus. If the ovaries
are removed, the grafts undergo castrate atrophy. Most
astonishing of all, when menstruation occurs in the uterus,
it occurs at the same time in the eye-graft, runs the same
course, and ceases at the same time. The menstrual hemorrhage which occurs in the eye, stains and clouds the aqueous
humor for a few days but soon clears away.
 
Markee was able to watch the process through the microscope, using low to moderate magnification, from 12 to 150
times. What he saw has helped us greatly to understand the
nature of the menstrual breakdown, although (as we shall
see) there is much still to be learned. Markee tells us that
the first sign of impending menstruation in the eye-graft
is blanching of the tissues due to shutting off of the blood
flow by contraction of the coiled arteries. This does not
happen in all the arteries of the graft at one time, but in
individual arteries, so that blanched patches appear here
and there in the graft, until all the tissues ultimately experience the blanching. After a few hours this phase wears off.
Through the relaxed arteries the blood flows again with
renewed force, but the tissues of the endometrium and
especially the capillary blood vessels have sufi^ered from
the lack of blood supply. Here and there the small vessels
give way and burst, causing tiny spurts of blood into the
tissues. The little pools of blood thus produced coalesce and
drain into the anterior chamber of the eye. In the uterus
itself, similar hemorrhages are of course discharged into the
cavity of the uterus. After a few days this strange series
of events is over, and the damage is promptly repaired.
 
With Markee's direct observations to guide us, the study
of prepared specimens of the uterus is much clearer. Observations by the two methods agree perfectly, but without
observations of the eye-grafts we should probably not have
 
{ 152 }
 
 
 
THE MENSTRUAL CYCLE
 
learned the importance of the periodic shutting off of the
spiral arteries.
 
Coiled arteries of the type thus shown to be fundamentally
involved in menstruation in the monkey are also present in
the human uterus, but have never been found in non-menstruating animals. Menstruation, then, is primarily an affair
of the coiled arteries, which control the blood supply of the
inner layer of the endometrium and by their closure cause
breakdown, tissue damage, and hemorrhage (Appendix II,
note 12).
 
In view of the violent disruption that characterizes the
retrogressive phase of the cycle in women and in the other
menstruating primates, it is a matter of great theoretical
interest to know whether this stage in the non-menstruating
animals is actually as free from tissue breakdown as I have
rather summarily indicated. In other words, is menstruation
a totally peculiar affair, sharply different from what goes
on in mammals generally, or is it merely an exaggeration of
a degenerative process that is present but not extensive in
lower animals.? This question is being investigated, but the
answer cannot be given now. We need to know most of all
what goes on in the uterus at the end of the corpus luteum
phase in the New World monkeys (the capuchins, spider
monkeys, and howler monkeys), which in spite of their close
evolutionary relationship to the other primates do not
menstruate externally. Here, if anywhere, we may expect
to find transitional conditions that may help explain the
wherefore of menstruation. The evidence is not yet in, but
I may say that there are hints, apparent to the expert
microscopist, that even in the rabbit and other non-menstruating mammals the retrogressive phase has an element
of acute damage in it. These signs are, however, slight indeed
and the statement holds true that in almost all mammals,
when the corpus luteum has done its work, and the uterus
is released from its phase of progestational proliferation, it
 
{ 163 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
settles gently and inconspicuously back to the state it was
in before the follicles matured.
 
Theories about the menstrual cycle. There is no need to
discuss outmoded theories of the cycle here, except to exclude
one or two ancient fallacies that still crop up occasionally.
For example, some people still consider that menstruation is
equivalent to estrus. This is a common notion among farmers.
Because menstruation is the most prominent event in the
human cycle, and estrus the most conspicuous phenomenon
in the cycle of the barnyard animals, they are wrongly considered to be fundamentally alike. It would follow from this
that in humans the egg is shed from the ovary at the time
of menstruation, a notion which is absolutely incorrect, as
will be seen from our previous discussion. Menstruation is
the last stage, not the first, of the corpus luteum phase of
the cycle.
 
Another false view, which prevailed widely among European gynecologists from 1880 to 1910, asserted that there
is no chronological relation whatever between ovulation and
menstruation. The egg may be shed at any stage of the cycle.
This conclusion was drawn by surgeons who knew very little
about other species, and who moreover usually saw at the
operating table not normal pelvic organs, but those of
patients with gynecological ailments, often subject to disturbances of the cycle.
 
When it began to be understood clearly that the ovary
is an organ of internal secretion, a group of first-class
German gynecologists, including especially Robert Schroeder,
Robert Meyer, and Ludwig Fraenkel (the latter two now in
exile) developed a theory which had been vaguely outlined
a generation earlier, that the corpus luteum is in some way
associated with the menstrual cycle. Gradually their views,
clarified by intensive observation of human material, arranged themselves into a theory of the cycle which was very
plausible and which has turned out to be partly correct.
 
{ 164 }
 
 
 
THE MENSTRUAL CTCLE
 
This states that menstruation is simply the downfall of the
premenstrual (progestational) endometrium, and that it
is caused by the degeneration of the corpus luteum. It will
be seen that this theory fits all that has been said about the
primate cycle thus far, and that it is compatible with our
diagram. Fig. 22. According to this theory, the endometrium
cannot menstruate unless it is first built up to the "premenstrual" state. Professor Meyer put this into an aphorism
which was much quoted by the gynecologists "Ohne Ovulation keine Menstruation" — without ovulation there can be
no menstruation.
 
This is a beautiful, clear hypothesis, and it is half true.
It is also, unfortunately, half false. The fallacy is subtle
but fundamental, and leads us headlong into a mass of unsolved problems.
 
Anovulatory cycles. The failure of the German theory of
the cycle is a matter of especial interest to me, for it was
my lot to obtain (to my great perplexity) the first undeniable
evidence against it. The story is best told as it happened.
In 1921, after several years of work on the cycle of the
domestic pig, I felt prepared to begin a study of a menstruating animal and for this purpose I chose the Rhesus monkey.
Practically nothing was known on the subject. There had
been two investigations. Walter Heape, a distinguished English biologist, had gone to India more than twenty years
before to study reproduction in Rhesus monkeys and langurs,
but illness had forced him to return to Cambridge, where
he followed and described the cycles of a few animals he had
taken home with him. M. A. Van Herwerden had studied
material of a wholly different kind. Hubrecht, the great
embryologist of Utrecht, had collected a great many reproductive tracts (uteri with ovaries) from several species of
monkeys. These had been obtained largely by Dutch colonial
officers in the East Indies. Miss Van Herwerden examined
these specimens, which were unaccompanied by life histories
 
{ 155 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
or records of menstrual cycles, because the animals had been
shot in the jungle by hunters. As regards the relation of
menstruation to ovulation in the cycle of the monkey, the
results of Heape and Van Herwerden were obscure and puzzling. Heape in his few cases observed no clear relation. Van
Herwerden actually found that in some of the Hubrecht
specimens the uterus was menstruating but there was no
corpus luteum at all in the ovaries. In other menstruating
animals a corpus luteum was present. This variability could
perhaps be reconciled with the older theories of the human
cycle, but not with the Meyer-Schroeder-Fraenkel theory.
The absence of life histories, however, cast uncertainty upon
the significance of Van Herwerden's observations. A hunter's
specimen lets us see only one instant in the life of the animal ;
who could tell the significance of these puzzling cases so
completely removed from the context of life?
 
Meanwhile the German interpretation seemed plausible
indeed. It could be matched without difficulty to all the
recently gained knowledge of the cycles of mammals. Stockard and Papanicolaou's studies of the guinea pig (1917),
those of Long and Evans on the rat (1921), which I had
been privileged to watch for four years, and my own on
the domestic pig had all emphasized the occurrence of regular
cycles of ovulation followed by the progestational phase
of the uterus. I supposed that application of the same
methods to a menstruating mammal, namely the Rhesus
monkey, would reveal a strictly parallel sequence, with menstruation as its last stage. If I kept my animals in good condition, observed their cycles with perfect vigilance, and
autopsied them at carefully chosen stages in their cycles, I
should obtain a series confirming the German theory. I
thought that 25 monkeys and three years' work would suffice
to establish the normal cycle, after which we could go on to
all sorts of experimental studies in confidence that we could
 
{ lo6 }
 
 
 
THE MENSTRUAL CYCLE
 
elucidate the normal physiology and the disorders of the
human menstrual cycle.
 
Imagine my confusion when the very first monkey we killed
disagreed completely with all we had expected. Rhesus
monkey No. 1 was in my colony more than a year. She had
12 menstrual cycles in 12 months, the last 5 of which
were respectively of 27, 29, 25, 24, 27 days, averaging 26.4
days. In the hope of recovering a young corpus luteum and
of finding an egg in the oviduct or uterus, she was killed 17
days after the onset of the last previous menstrual period
and 9 days before the expected onset of the next. To our
astonishment, neither ovary contained any sign of recent
or impending ovulation. There was no large follicle, no
recent corpus luteum, nor any older corpus luteum from the
last two or three cycles. In short, this animal was undergoing
cycles of menstruation without ovulation and therefore without corpora lutea.
 
Monkey No. 2, on the other hand, fulfilled our original
expectations. She, too, had a series of regular cycles. She
was killed 14 days after the onset of the last period and
12 days before the onset of the next expected period. The
left ovary contained a recently ruptured follicle and the
egg was in the oviduct. This, by the way, was the first egg
of any primate ever recovered from the oviduct. The case
fits the diagram perfectly.
 
To make a long story as short as possible, it turned out
that Rhesus monkeys do not ovulate in every menstrual
cycle.* When they do ovulate, the corpus luteum of course
is formed and causes progestational (premenstrual) changes
in the uterus. When the corpus luteum degenerates, typical
menstruation occurs, by breakdown of the premenstrual
endometrium. When the animal does not ovulate, then natu
6 George W. Corner, "Ovulation and menstruation in Macacus rhesus."
Carnegie Institution of Washington, Publication No. S32 {Contributions
to Embryology, vol. 15), pp. 75-101, 1923.
 
{ 157 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
rally there is no corpus luteum and therefore no premenstrual
change in the uterus. Menstruation occurs anyway, and the
breakdown takes place in an endometrium which is still in
the unaltered state. The corpus luteum is necessary for the
premenstrual state, but not necessary for the breakdown.
 
This analysis of the situation has been confirmed by
Markee through watching menstruation in endometrium
grafted in the eye. Markee tells us that when he applies the
microscope to the grafts he sees only one difference between
ovulatory and anovulatory menstruation, namely the occurrence of the progestational phase in the former and its
absence in the latter. The shutting off of the blood supply,
the subsequent reflux of blood through the coiled arteries,
the rupture of the small vessels and the hemorrhage are the
same in both instances. With all this evidence it can hardly
be doubted that anovulatory bleeding is also menstruation.
 
It is not possible to distinguish between ovulatory and
anovulatory menstruation by ordinary observation of the
living animals. The cycles are of similar length, the bleeding
is similar in appearance and duration. Recent studies by
Ines de Allende and Ephraim Shorr suggest that it may be
possible in the future to detect anovulatory cycles by studying the vaginal cells.
 
My description of menstrual cycles without ovulation was
at first rather generally mistrusted, but it has been confirmed
by everyone who has studied the Rhesus monkey.^ We know
that anovulatory cycles are likely to occur in young animals
in the first months after the establishment of menstruation,
and in fully mature females in the early fall and late spring,
that is to say at the beginning and end of the active breeding
season of the winter months. Rhesus monkeys do not menstruate regularly in summer. The anovulatory cycles tend
 
7 Carl G. Hartman, "Studies in the reproduction of the monkey,
Macacus (Pithecus) rhesus." Carnegie Institution of Washington, Publication No. 433 {Contributions to Embryology, vol. 23), pp. 1-161, 1932.
 
{ 158 }
 
 
 
THE MENSTRUAL CYCLE
 
to occur, therefore, when the reproductive tract is preparing
for its highest activity or receding from it. My papers describing the monkey cycle set off an active debate among
the gynecologists as to whether anovulatory cycles occur
in women. After much discussion and a great deal of careful
observation, it is generally agreed that anovulatory cycles
do occur, though with much less frequency than in monkeys.
They seem to be most frequent in young girls and in women
approaching the menopause.
 
There is no place for menstruation without ovulation, in
the theoretical scheme which I have called the German theory.
Therefore the savants who had formulated that theory
simply declared that anovulatory menstruation is not menstruation at all. The rest of us, however, have gone on trying
to find an explanation that fits all the facts. In this search
the new knowledge of the ovarian hormones has begun to
help us.
 
THE HORMONES AND MENSTRUATION
 
Experimental uterine bleeding. A simple experiment, made
in 1927 by Edgar Allen, opened up the whole problem of the
relation of the ovarian hormones to menstruation. Allen
found that removal of both ovaries from a mature Rhesus
monkey will usually cause within a few days a single period
of menstruation-like bleeding. Why the medical profession
had failed to discover this fact from human surgical patients
is difficult to understand. It has long been known that removal
of the ovaries abolishes the menstrual cycles, but the doctors
had missed observing the fact that one period of hemorrhage often follows the operation before the cycles cease
permanently. They seldom remove the ovaries except in the
presence of disease, when the cycles are already altered, or
for tumors which themselves produce bleeding, or as part of
a larger operative procedure which may cause surgical
hemorrhage from the uterus. Thus bleeding due purely to
 
{ 169 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
removal of the ovaries escaped notice until Edgar Allen
discovered it in monkeys.
 
As a matter of fact, an experiment like Allen's had once
been done on humans, on a large scale, and with the best
intentions in the world. Robert Battey, a surgeon of Augusta,
Georgia, in 1872 conceived the idea that neuroses and insanity in women are often concerned with the ovaries and
may be treated by removal of these organs. He was probably
led into the notion by observation of cyclic mental disturbance, paralleling the menses, insanity following child-bearing,
and other conditions in which sex and the reproductive functions were of course concerned, though in a far more complex
way than he could have imagined. Battey's radical proposal
to remove the normal ovaries was put forward just at the
time when the surgeons had gained command of the operation
of ovariotomy (as they often ungrammatically called it).
Antiseptic surgery. Lister's gift to the world, was now in
general use, and the great American ovariotomists Ephraim
McDowell, the Atlees, and their followers in Britain and
Europe had worked out the operative technique. The operation was therefore relatively safe, and no doubt the patient's
mental condition was often improved or at least subdued by
the surgical intervention, with its anesthesia and opiates,
by the rest in bed, and the nursing and general attention.
At any rate "Battey's operation" was taken up widely by a
profession thoroughly baffled by mental disease. Thousands
of women were subjected to this drastic operation, not only
in the United States, but in England, Germany and the rest
of Europe, until in good time it became obvious that the
psychiatric results did not justify it and that insanity with
cyclic or sexual symptoms cannot be pinned directly to the
ovaries. The late Dr. Edward Mulligan of Rochester, New
York, told me of an incident in the last years of Battey's
operation. Dr. Mulligan when a young surgeon studied for
a time, about 1883, at Bellevue Hospital in New York City
 
{ 160 }
 
 
 
THE MENSTRUAL CYCIiE
 
with the pathologist William H. Welch, himself a young
man on his way to the Johns Hopkins and the leadership
of the American medical profession. One morning Welch
showed his pupils a tray containing a number of normal
ovaries, removed that morning in the operating rooms, and
took the occasion to denounce the practice of Battey's
operation in words so vigorous that Dr. Mulligan still remembered them more than forty years afterward.
 
The point of all this is that removal of the normal human
ovaries was very often followed within a few days by a
period of bleeding from the uterus lasting several days. This
appears in many of the case reports in medical journals
from 1872 to 1885. The doctors did not always report all
the postoperative details, but when they did they generally
noted the hemorrhage, but never with comprehension. Thus
an important observation was missed because the observers'
minds were unprepared.
 
We must digress for a moment to mention that under the
strict corpus luteum hypothesis of menstruation (which
I have for brevity called the German theory) removal of
the corpus luteum may be expected to bring on menstruation.
This had been perceived and demonstrated at the operating
table before 1927, when Allen announced, on the basis of
his experiments on monkeys, the broader fact that removal
of both ovaries, with or without a corpus luteum, has the
same effect. It may help keep things clear, if we point out
something the reader has probably thought out already,
namely that removal of a corpus luteum produces bleeding
from a premenstrual endometrium, whereas removal of the
ovaries without a corpus luteum produces bleeding from an
unaltered endometrium, as in anovulatory menstruation.
 
Estrin-deprivation bleeding. Edgar Allen reasoned that
the effects of removal of the ovaries of his monkeys were
really due to removal of the estrogenic hormone, which had
recently been discovered, thanks so largely to his own in
{ 101 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
vestigations. He therefore took a castrated female monkey
and gave her a course of injections of estrogenic hormone.
When he discontinued the treatment, bleeding ensued. In
other experiments he removed the ovaries and immediately
began daily doses of estrogenic hormone. As long as the
hormone was given, there was no bleeding; that is to say,
the hormone was able to substitute for the ovary. When it
was discontinued, the bleeding occurred.
 
The following diagram represents graphically the experiments just described.
 
Removal of ovaries; estrin deprivaiion:
 
ovaries removgd^ ^.f^j-Zil^J^^^""^
 
INTACT ANIMAL CASTRATE ANIMAL \
 
 
 
ovAries rg-moved-^^ i^^-estrin ^iven--^
 
 
 
INTACT
 
 
 
C AST RATE \
 
 
 
Fio. 24. Illustrating the experiments of Edgar Allen, 1927, 1928. In
this and the following 3 graphs the black bars indicate uterine bleeding.
These diagrams are from an article by the author in the American
Journal of Obstetrics and Gynecology, by courtesy of the C. V. Mosby
Company.
 
On this basis Allen formulated the estrin-deprivation
hypothesis of menstruation, which suggests that natural
menstruation, like the experimental bleeding, is due to a
cyclic reduction of the amount of the estrogenic hormone
available in the body.
 
Subsequent experiments done with carefully graded doses
of the hormone, including especially those of Zuckerman, of
Oxford, have shown that not only total deprivation, but also
 
{ 162 }
 
 
 
THE MENSTRUAL CYCLE
 
mere lowering of estrogen dosage below a certain level will
produce the bleeding. The word "deprivation," as used in
this connection, is therefore to be taken in a relative sense.
 
Estrin- deprivation hijpothjesia:
 
INTACT ANH^MAL /
 
*; ^ >^
 
 
 
Teat of the hijpothesia:
 
__ est Trm_siyerv2r
INTACT ^"^ ^/__ "^ \ no bleeding
 
 
 
- ^ ^^,5 J- ^ - -^ ^ X Xr-X X X K
 
 
 
Fio. 25. In the lower figure the natural level of estrogen is shown
fluctuating cyclically, not as a proved fact, but to show how the actual
results of injecting the ovarian hormone bear on the estrin-deprivation
theory.
 
The correctness of the estrin-deprivation h3^othesis can
be tested in a very simple way. We need only choose a monkey
that is menstruating regularly, and keep up her estrogen
level by injecting the hormone, for say ten days before the
expected menstrual period. This should prevent menstruation.
I tried this in a sufficient number of monkeys, giving them
doses of estrogen I thought similar to their own natural
supply from their ovaries. Later in the experiments these
doses were increased several fold. The hormone did not stop
the next menstrual period. If the treatment was continued
into later cycles, menstruation was often delayed, perhaps
because of roundabout action through the pituitary gland.
Zondek has found that in women very large doses of estrogenic hormone disturb the menstrual cycle, owing to inhibi
{ 163 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
tion of the gonadotrophic mechanism of the pituitary. These
upsets produced with long-continued or very large doses are
however not altogether pertinent. The theory calls for relatively small fluctuations, within the body's normal range of
hormone production. On this hypothesis, however, the very
first period should be prevented, and this did not occur. If
my dosage of hormone was really physiological, as we say
(that is, something like the amount the animal herself would
produce) then the cstrin-deprivation hypothesis in its simple
original form is not adequate to explain the observed facts.
 
Progesterone and menstruation. On the other hand, administration of the corpus luteum hormone even in small
doses prevents menstruation in experimental animals, abolishing the very first menstrual period after injections are
begun (provided they are started a few days before the expected onset). Both Hisaw and I have found that experimental estrin-deprivation bleeding, produced by removal of
the ovaries or by discontinuance of a course of treatment with
estrogenic hormone, is prevented by small doses of progesterone. Smith, Engle and Shelesnyak at Columbia University
arranged an exceedingly vigorous condition of estrin deprivation. Their monkeys were first given a course of gonadotrophic hormone from the pituitary gland (see p. 141) to
stimulate the output of estrogenic hormone from the ovaries.
They were also given generous doses of estrogens for good
measure. These hormones were suddenly discontinued and at
the same time the ovaries were removed. In the face of all
these reasons for deprivation bleeding, modest doses of
progestin (crude progesterone) completely prevented hemorrhage.
 
On the other hand, progesterone deprivation, like estrin
deprivation, invariably causes menstruation-like bleeding.
This was very clearly apparent in a series of my experiments
in which progesterone was given to normally menstruating
monkeys. During the injections, menstruation ceased. When
 
{ 164 }
 
 
 
THE MENSTRUAL CYCLE
 
Progesterone preventa
eetrin-deprivaLLion bleeding:
 
ovAT?ie0 present /pros-e^lLn ^
eslriti^iven ic ^iven V
 
-^ — X X. X X
 
 
 
withcLrdLWTn. — ^ , , t ^
\ "nobleedm^
 
 
 
I NTACT CA5^RATE
 
 
 
\
 
o bleeding N \^
 
v^7^ r JS^
 
 
 
CA5TRATE V^^ >^
 
Fio. 26. The upper figure illustrates the experiments of Smith and
Engle, 1932, and Engle, Smith and Shelesnyak, 1935. The lower figure
represents the results of Hisaw, 1935, and Corner, 1938. Estrin-deprivation bleeding is postponed by progesterone; discontinuance of progesterone is then followed by bleeding.
 
the hormone was purposely stopped at a time which would
have been midway between two periods (had the latter been
occurring on their original schedule) progesterone-deprivation bleeding then occurred within a few days. The monkey
next menstruated spontaneously about 4 weeks after the
experimental period. This tells us that the monkey's timepiece mechanism accepts progesterone-deprivation bleeding
as if it were actual menstruation, and takes a fresh start
from the induced period.
 
The diagram (Fig. 26) illustrates these facts.
 
At this point Dr. Markee may be called again as a witness.
He tells us that when bleeding is produced in one of his
 
i 165 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
eye-grafts, by withdrawal of either the estrogenic hormone
or progesterone, he observes the same sequence of blanching
and hemorrhage that occurs in spontaneous menstruation.
If the monkey is given progesterone, the graft will bleed
from a "premenstrual" state; if given estrogenic hormone,
it bleeds from the interval state.
 
With this information in hand it is possible to plan an
experiment in imitation of the normal ovulatory cycle. This
is represented in the upper half of the following diagram,
Fig. 27. The underlying idea occurred to workers in the
Oxford, Harvard, and Rochester (N.Y.) laboratories at
 
Progesterone during a. courae of estrin:
 
I estrin
I 500 Inl.U.
 
cslrinl25Int.U. progesterone Im^. i ^^
 
deiilij dadlv -^
?tz"^r:2i~z?-'zr^irTi2i !
 
\
 
\ bleeding
 
CASTRATE X
 
 
 
Currenl: hijpothesis of ovulalorij incnslruation:
 
corpus luteum rclro^ressca n
-progesterone acting —^ J
X — X — X — x — X — »t — ^ — y^
 
 
 
resenrioQcL \
 
 
 
effective on
enxioimetri-u-na
 
 
 
INTACT
 
 
 
\
 
 
 
-- inetfective
 
 
 
V
 
 
 
\
 
 
 
^•-^
 
 
 
Fig. 27. The upper figure illustrates the production of bleeding after
discontinuance of a course of progesterone, in spite of continued and
more intensive estrogen treatment. The dosage shown is that of the
author's experiments (Corner, 1937, 1938) ; similar results were obtained
by Zuckerman, 1937, and by Hisaw and Greep, 1938.
 
 
 
{ 166 }
 
 
 
THE MENSTRUAL CYCLE
 
practically the same time, and gave consistent results when
tried. The dosage cited here is that of my own version of
the experiment. A castrate female monkey is given a daily
dose of estrogenic hormone, 125 international units, sufficient
to build up the endometrium to normal thickness and structure. After 10 days, a daily dose of progesterone is added
(just as would have happened had the animal developed a
corpus luteum of her own). Ten days later, at the 20th day
of the experiment, the progesterone is discontinued, but the
daily injection of estrogenic hormone is continued. In spite
of the estrogen, we find that bleeding invariably occurs in a
few days. Indeed, the dose of estrogen may be greatly increased, say to 500 international units, beginning on the
day on which the progesterone is discontinued ; but menstruation-like bleeding still occurs. Seven hundred units or more
may be necessary to prevent it, although such doses as 500
or 700 international units are of course much more than
necessary to maintain the uterus when not working against
progesterone deprivation.
 
These facts enable us to construct a relatively simple
hjrpothesis of the menstrual cycle which is really a modified
form of the estrin-deprivation hypothesis (Fig. 27, lower
part). We start by assuming that progesterone in some way
or other has the property of suppressing the menstruationpreventing power of estrogen, while itself holding off menstruation. In the normal cycle the animal does not bleed
in the first half of the cycle (follicular phase), because the
ovaries are furnishing estrogen. She will not bleed during
the second half of the cycle (corpus luteum phase) because
the corpus luteum is furnishing progesterone. By our assumption, however, the corpus luteum is suppressing the protective
effect of the estrogen; therefore when the corpus luteum
undergoes retrogression, the animal finds itself deprived of
the action of both estrogen and progesterone, and the en
{ 167 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
dometrium breaks down. Ovulatory menstruation is thus a
special case of estrin-deprivation bleeding.
 
This explanation of the normal cycle is, of course, simply
a hypothesis which has been formulated to explain our observations. Whether things happen this way in the normal
monkey or in woman remains to be proved. It is at least not
contradicted by any of the known facts, and it has the merit
of simplicity, because it calls for a cyclic variation in only
one hormone, namely progesterone. Its one unproved assumption, that progesterone somehow cuts down the action
of estrogen on the uterus, is supported by various other
evidences of a sort of antagonism between the two hormones
in some of their other activities. It has been suggested that
progesterone has the property of speeding the elimination
of estrogens from the body. If this proves correct it is all
we need to complete our hypothesis.
 
This scheme does not explain anovulatory menstruation,
for in cycles without ovulation there is, of course, no coming
and going of the corpus luteum. Anovulatory menstruation
is therefore probably due to estrin-deprivation alone. We
can imitate it perfectly in castrate animals by simply giving
a course of estrogen injections interrupted or sharply
reduced at suitable intervals. What is actually happening
in the female organism remains to be worked out. We are not
yet sure that there is an actual up-and-down of estrogen
in the body sufficient to produce deprivation bleeding. The
daily assay of estrogens in the blood is very expensive and
at present not reliable enough for our purpose. Zuckerman
has shown that when a castrate monkey is kept on a relatively small but constant daily dose of estrogen, there is a
tendency to occasional uterine bleeding which may become
fairly regular. We may conjecture, on this basis, that perhaps some sort of give-and-take relation exists between
estrogen and some other hormone, just as between estrogen
and progesterone when the corpus luteum is present, so that
 
{ 168 }
 
 
 
THE MENSTRUAL CYCLE
 
even without the corpus luteum a periodic state of estrin
deprivation occurs. Can it even be that the adrenal gland
produces something that can suppress the estrogens (we
know that a number of steroidal compounds resembling progesterone are extractable from that gland) ? The play of
hormones in anovulatory menstruation is anybody's guess,
and those of us who have worked on it can assure our colleagues, on the basis of much vain conjecture and many
futile experiments of our own, that the problem is not an
easy one. Some little fact is lurking just beyond our grasp.
 
Since the first draft of this chapter was written, Hisaw
has reported from the Harvard zoological laboratory some
experiments which show that very small doses of progesterone
given and then discontinued (1 milligram a day, for one to
five days) will set off menstruation-like bleeding in castrate
monkeys which are receiving large daily quantities of estrogenic hormone. He suggests therefore that anovulatory
menstruation may be due to progesterone deprivation; even
if there is no corpus luteum, he says, there may be a little
progesterone produced in Graafian follicles (there is, in
fact some collateral evidence for this latter part of the conjecture) and this may be enough to cause menstruation when
such a secretion of progesterone ceases. It is a plausible conjecture, and one which calls for no new factor outside the
ovary ; but it will be difficult to prove.
 
The immediate cause of the menstrual process. From the
foregoing sections it will be perfectly clear that the breakdown and hemorrhage of menstruation are consequent to the
deprivation of estrogenic hormone or progesterone. It is
also very probable, from the studies of Markee, that these
effects are initiated by constriction of the peculiar coiled
arteries of the endometrium, which produces damage to the
tissues and ultimate degeneration. But how can it be that
a temporary deprivation of one of these two particular
hormones can shut off the arteries in one particular tissue.''
 
{ 169 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
This question is now the key problem in the theory of
menstruation, and it remains unsolved. The attack upon it is
in the stage of skirmishing, in which all the possible explanations are being put forward for discussion and trial ; but up
to the present no one of them has found support by experiment. The reader may, however, be interested in the mental
processes of a group of puzzled investigators, and therefore
I list the conjectures for what they are worth. To merit
consideration at all, any explanation must fit the facts that
(a) hormone withdrawal causes uterine bleeding; (b) this
does not take place at once, but only after 3 to 8 days;
(c) the bleeding, once hormone deprivation is well under
way, cannot be postponed by renewed injections of estrogen
or progesterone; (d) it takes place in grafted bits of endometrium (in the eye or elsewhere) which have no connection with the nervous system.
 
Since all of these conjectures involve the arteries, it may
be helpful to recall the fact that the walls of an artery
contain numerous cells of involuntary muscle, laid on in
circular fashion around the inner tube (endothelium) that
conducts the blood. When these muscle fibers contract, they
squeeze down upon the blood stream like a man's fingers
abput a rubber bulb. It is thus that the blood pressure is
raised by a dose of adrenin or by a strong emotional state,
both of which cause the arterial muscle cells to contract.
Such muscular cells exist in the coiled arteries of the uterus
as in all other arteries (Appendix II, note 13).
 
Hypothesis 1. It may be that the coiled arteries are peculiarly and directly dependent upon the ovarian hormones,
in some such way (for example) as the ovary is dependent
upon the pituitary. This means that withdrawal of the
ovarian hormones would let down the condition of the
coiled arteries, causing them to contract. This hypothesis is
the simplest, calling for no other hormones or special substances, but it is exceedingly difficult to try out, for the only
 
{ 170 }
 
 
 
THE MENSTRUAL CYCLE
 
way of proving that the ovarian hormones are the sole factors
involved is to exclude all other possible factors, but when
we cut off the estrogenic hormone, how can we know we are
not thereby putting some other factor into action? If somebody could show us how to keep a coiled artery alive and
working outside the body where we could deal with it alone,
we could soon test this hypothesis, but the infant art of tissue
culture has by no means reached the point of keeping an
artery alive all by itself, and moreover these arteries are
so tiny that they would have to be handled under the microscope — a truly difficult project!
 
Hypothesis 2. This admits the possibility, mentioned
above, that withdrawal of estrogen permits something else
to go into action. We know that even in the non-menstruating
animals, withdrawal of the ovarian hormone causes a certain
amount of deterioration of some of the cells of the surface
epithelium and of the glands of the uterus. Under the microscope we see fragmentation of the nuclei and the accumulation of protoplasmic debris in the cell bodies. Is it possible
that some chemical substance produced in the course of
cellular breakdown (as histamine, for instance, is produced
in burned tissues) diffuses through the endometrium to the
arteries and causes them to contract? This hypothesis has
interested me very much and I have made many experiments
to test it, but always with negative results.
 
Hypothesis S. Another conjecture, a variation upon the
foregoing, is that the uterine coiled arteries are sensitive,
when not protected by the ovarian hormones, to some substance that is normally present in the blood stream. We must
suppose that withdrawal of the hormone allows this substance
to act upon the arteries. One of the possible constrictor substances would be pituitrin, the secretion of the posterior lobe
of the pituitary gland, a hormone which is highly potent in
promoting contraction of smooth muscle. Carl G. Hartman
tried this with negative results, and moreover P. E. Smith
 
{ 171 }
 
 
 
THE HORMONES IN HUM AN REPRODUCTION
 
obtained bleeding by estrin deprivation in monkeys from
which he had removed the whole pituitary gland. Adrenin
has been thought of, but Edgar Allen succeeded in producing
estrin-deprivation bleeding in monkeys from which the adrenal
glands had been removed. This experiment is not quite conclusive, for monkeys may possibly have other sources of adrenin
beside the adrenal gland. Up to the present, at least, this
hypothesis has yielded no valuable clues.
 
Hypothesis 4. George Van S. Smith and 0. W. Smith have
suggested that the bleeding of menstruation is caused by
conversion of estrogenic hormone into a non-estrogenic byproduct which is toxic to the endometrium. This hypothesis
could perhaps explain ovulatory cycles, but it cannot be fitted
very well to simple estrin-deprivation bleeding; in any case
it will be acceptable only when somebody comes forward with
chemical derivatives of the estrogenic hormones that are
especially toxic to the endometrium (Appendix II, note 14).
 
These are the most plausible current guesses about the immediate cause of uterine bleeding after hormone deprivation.
None of them has been proved or even rendered likely, by
experiment. It is indeed vexatious that we cannot clear up
this important problem.
 
The modern concept of the cycle. By way of summary, let
us now set forth a concise description of the primate cycle
as revealed by recent research. What follows will, I think, be
accepted by most of the American investigators, and also the
British, although a die-hard English gynecologist a few years
ago dubbed it "the American theory."
 
We begin by suggesting that there is a basic tendency to
cyclical function of the ovaries, and that this is produced by
a sort of reciprocal "push-pull" reaction between the pituitary and the ovarian hormones, as explained in full earlier
in this chapter. In most cycles of fully mature human females,
the pituitary gonadotropic hormones cause the ripening of
 
( 172 }
 
 
 
THE MENSTRUAL CYCLE
 
a Graafian follicle, the discharge of its egg, and the formation
of a corpus luteum. This in turn sets up the progestational
or "premenstrual" state of the endometrium. When the corpus
luteum degenerates, menstruation ensues because of the withdrawal of progesterone. In some cycles, however, especially
in young girls and in women approaching the menopause, a
follicle does not ripen in the ovary, but after about the same
interval as in an ovulatory cycle, namely 4 weeks, some process not yet understood leads to reduced action of estrogenic
hormone, and bleeding ensues which we call anovulatory menstruation.
 
This view of the cycle requires, of course, much more investigation before we shall be able to understand the whole
process; I have already pointed out the larger gaps in our
knowledge. It certainly represents a great advance toward
the truth; and what is indeed important, it gives us a far
clearer and more hopeful viewpoint about the disorders of
menstruation than do older concepts of the cycle. Since menstrual bleeding is caused by fluctuation in levels of the ovarian
hormones, it follows that noncyclic, pathological bleeding,
such as occurs in excessive and irregular periods may also be
caused by abnormalities in amount proportion, or kind of
these hormones. We must consider that there are not two
sharply distinct kinds of functional bleeding, one being normal menstruation and the other abnormal hemorrhage. On
the contrary, the modern hypothesis tells us that we must
expect a series of types of hemorrhage ranging from normal
menstruation through every grade of disturbance to the most
severe disorder of the cycle. Gynecologists are already beginning to study and treat these distressing and difficult conditions in the light of this concept, and we may well hope
these same hormones that control the normal cycle will help
us to control its aberrations and at last to banish the specter
of uterine hemorrhagic disease.
 
{ 173 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
THE UNKNOWN SIGNIFICANCE OF MENSTRUATION
 
In all this discussion of the nature and the course of menstruation, we have had nothing to say about the significance
and possible usefulness of the periodic breakdown and hemorrhage. The human mind has an intractable desire that natural
phenomena shall be useful. We are not comfortable in the
presence of useless or undirected activity. Menstruation in
particular ought to have a practical reason for its occurrence, for otherwise it seems a totally wasteful, destructive,
and vexatious business. Up to the present, however, no one
has been able to demonstrate such a meaning. There are in
fact only two guesses that are even worth talking about.
 
The late Walter Heape of Cambridge, England, one of the
pioneers in the study of the reproductive cycle, proposed in
1900 that menstruation is the same thing as a period of
bleeding that occurs in female dogs when they are going into
heat, i.e. in the week preceding ovulation. A somewhat similar
proestrous bleeding occurs in cows, particularly in heifers.
Such bleeding is easily explained, for it is clearly due to
engorgement of the blood vessels produced by a strong action
of the estrogenic hormone. Under the microscope it does not
resemble menstruation ; the blood oozes from superficial blood
vessels and there is little or no breakdown of the tissues. When
Heape wrote, nothing was known of the time of ovulation in
the primate cycle, nor of the premenstrual endometrium and
its dependence upon the corpus luteum. In the primates, on
his theory, ovulation would be expected to occur during menstruation, or immediately after the flow, just as in the bitch
and cow ovulation occurs about the end of the proestrous
bleeding. Since we know now that ovulation takes place a
week to ten days after the cessation of menstruation, we can
reconcile Heape's theory with the facts only by supposing
that in the menstruating primates there is first proestrous
bleeding, then a delay unknown in the other animals, and
 
{ lU }
 
 
 
THE MENSTRUAL CYCLE
 
finally ovulation. This theory, and one or two ingenious variations upon the same theme by later English writers, F. H. A.
Marshall and Zuckerman, all seem too complex to be probable,
and moreover they suffer from a very serious objection.
Unlike the menstruation-like bleeding, which can be produced
in monkeys and women by withdrawing estrogenic hormone,
the proestrous bleeding of dogs is produced by building up
the level of estrogenic hormone, as was shown by R. K. Meyer
and Seiichi Saiki in our Rochester laboratory in 1931.
 
A few years ago, Carl G. Hartman discovered that in
Rhesus monkeys there is almost always a slight bleeding from
the uterus about the time of ovulation. This does not show
externally and is discernible only by applying the microscope
to washings of the vagina. Sections of the uterus made at
this time reveal that a few red blood cells are escaping from
superficial capillary blood vessels of the endometrium, which
are engorged by the action of the estrogenic hormone. In the
laboratories we call this slight bleeding "Hartman's sign"
and take it as evidence that there is a ripe follicle in the ovary.
This is the actual equivalent of Heape's proestrous bleeding.
It has since been found to occur in women, though probably
not as regularly as in monkeys. These observations prove
clearly that menstruation is something else than proestrous
bleeding.
 
Hartman has proposed another explanation for menstruation. He points to the fact that in many mammals, at the
time of implantation of the embryo, the uterine secretion contains red blood cells. He tells us also that in many viviparous
animals lower than the mammals, for example certain salamanders and fish, in which the embryo depends upon the
maternal tissues for nourishment, bleeding in one form or
another usually occurs into the brood chamber. Hartman
compares menstruation to bleeding of this kind and conjectures that it is simply a means of getting the vitally useful
blood pigment, hemoglobin, into the region where the early
 
{ 176 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
embryo is to reside. We have to suppose that if in any given
cycle an egg is fertilized, the premenstrual changes go to the
very verge of menstruation, letting a little blood out of the
vessels into the tissues to enrich the implantation site for the
embryo. Since, however, a "missed period" is the first sign of
beginning pregnancy, we must also suppose that attachment
of the embryo then stops the process before external hemorrhage occurs, and even before there is any significant breakdown of the endometrium. If there is no embryo, the breakdown goes all the way. This is a very interesting conjecture,
for it assigns a necessary and worthy function to the strange
flux of menstruation. Careful study, however, of the uterine
lining of the monkey just before and during implantation
of the embryo, and of the very few human specimens during
early implantation that are as yet available, does not support this hypothesis, for they do not show beginning hemorrhage in the endometrium. We know that many other
mammals succeed in implanting their embryos without any
such provision of free blood or hemoglobin in the endometrium; and we know also that sometimes in women and
often in Rhesus monkeys menstruation occurs in anovulatory
cycles, when there can be no embryos to profit by it. This
hints that perhaps the process of menstruation evolved
without reference to the embryo.
 
Menstruation, then, is still a paradox and a puzzle — a
normal function that displays itself by destruction of tissues ;
a phenomenon seemingly useless and even retrogressive, that
exists only in the higher animals ; an unexplained turmoil in
the otherwise serenely coordinated process of uterine function.
 
 
 
{ 176 }
 
 
 
ENDOCRINE ARITHMETIC
 
 
 
"/ often say that when you can measure what you are speaking
about and express it in numbers you know something about it;
but when you cannot measure it, when you cannot express it in
numbers, your knowledge is of a meagre and unsatisfactory kind:
it may be the beginning of knowledge, but you have scarcely, in
your thoughts, advanced to the stage of science." — Lord Kelvin,
in Popular Lectures and Addresses, lecture on Electrical Units
of Measurement, 1883.
 
 
 
CHAPTER VII
 
ENDOCRINE ARITHMETIC
 
HOW much of a given hormone is found in the body
at one time? How much is produced in a day? How
much is found in the gland at one time ? What is the
output of a single cell? These are questions to which we must
have an answer if we want to understand the glands of internal
secretion and use our knowledge for the benefit of mankind.
Certainly every merchant must have this kind of information
about his stock in trade, and the manufacturer about his
materials and his product. The science of endocrinology is,
however, a long way from any such basis for calculation.
How can we measure the output of a factory (i.e. an endocrine
gland) when we do not know exactly what raw materials it
uses, how it makes the product, or what becomes of the product when it is used? In the case of most of these chemical
factories we do not even know the capacity of the manufacturing plant. The insulin factory, for example, consists of
many thousand bits of tissue, the pancreatic islets, irregular
in size and shape, scattered through the pancreas. In the
pituitary, although the gland is measurable as a whole, we do
not know what particular cells are associated with the various
hormones made in the gland, nor even indeed just how many
hormones it produces. So it goes throughout this puzzling
system of glands. We are dealing at present largely with
unmeasurable organs and with incalculable processes. We are
able only to appreciate some of the end results, not the fundamental steps. To measure and calculate what is going on
within the glands and thus to understand the chemical reactions and strike the balance of input and outgo — that task
lies ahead.
 
{ 179 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
RATE OF SECRETION OF THE CORPUS LUTEUM
HORMONE
 
It happens that of all the endocrine glands, the corpus
luteum is the one with which we can go farthest at present
toward calculating the answers to the questions with which
this chapter opens. The amount of glandular tissue can be
ascertained, for it occurs in discrete masses of more or less
spherical form and is composed of cells which can be measured
and even counted with a fair degree of accuracy. The chemical
structure and molecular weight of the hormone are fully
known, and the dose necessary to produce certain definite
effects is known. With these data at hand, let us take pencil
and paper and see how far we can get.
 
The following calculations are of course approximate, not
precise. They represent a preliminary exploration in a brand
new field of study. There are unavoidable flaws in our procedure. In our arithmetical operations, for instance, we shall
have to combine figures obtained from observations on rabbits with others learned from swine, thus violating one of the
primary-grade rules of arithmetic, picturesquely stated long
ago by one of my teachers, "You can't add cows and horses."
Some other uncertainties will appear as we go along. If our
results come out anywhere between 50 per cent and 200 per
cent of the true figures we shall be doing very well for a start.
Physicians who have to decide on the dosage of ovarian hormones for their patients will be glad to have even that; and
as for my lay readers, they may at least fmd this chapter
amusing. At any rate, when I presented some of these calculations at the Cold Spring Harbor Symposium on Quantitative
Biology in 1937, that earnest little assembly of research men
surprised itself — and me — by being very much amused, partly
perhaps because it really was funny to see a medical man so
gaily slip the leash and wander down a strange pathway, and
partly because of the incongruity between our simple experi
{ 180 }
 
 
 
ENDOCRINE ARITHMETIC
 
ments on rabbits and sows, and the final emergence into pure
theory in terms of molecules by the billion. Toward the end of
my discourse, however, the hearers settled down and discussed
the calculation quite seriously. Our chairman, in fact, sat up
all the next night figuring on a furtiier stage of the investigation, and in the morning, weary but still enthusiastic, brought
me several more pages of arithmetic. What follows here is the
substance of that presentation, revised in consideration of
some facts contributed in discussion by members of the symposium, and corrected also in the light of subsequent knowledge.
 
1. How much progesterone is produced daily by a given
amount of corpus luteum tissue? We begin by considering the
fundamental property of the corpus luteum, namely, to produce progestational proliferation of the lining of the uterus
(Chapter V, page 107 and Plate XVII, B), This has been
studied chiefly in the rabbit, in which species it shows up with
especial clearness. In a rabbit there are, of course, several
corpora lutea at a time. By cutting down their number by surgical operation on the ovaries under anesthesia, it is possible
to ascertain the minimum number of corpora lutea necessary
to produce full progestational proliferation as in figure D
of Plate XVIII.
 
(a) A young Frenchman, Joublot, the first to try such an
experiment (1927), found that two corpora lutea were sufficient, but one was insufficient. I tried it also, and found that
one corpus was sufficient, but half a corpus insufficient. Lucien
Brouha, then in Belgium (1934), found one or two corpora
lutea necessary. In our calculations we shall take the average
of these three results and start with the assumption that in
the rabbit one corpus luteum produces just sufficient progesterone to cause typical eff'ects upon the lining of the uterus.
 
(b) To produce the same effect with progesterone, giving
one injection per day, requires about 0.2 milligrams daily.
Dr. Pincus reports that by giving the hormone in two injec
{ 181 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
tions, the dail}' dose can be brought down to about 0.13 mg.
Let us take this lower figure as the basis for subsequent calculations. It may help to visualize the quantities we are discussing if we remind ourselves again that an ordinary postage
stamp weighs 60 milligrams.
 
From (a) and (b) we may conclude that one corpus luteum
produces about 0.13 mg. of progesterone daily. Here we are
making another assumption, namely that the progesterone
we administer in oily solution is utilized by the rabbit as
efficiently as she can utilize the progesterone she makes in her
own ovaries. This is really not impossible, for only very small
amounts of oil are used and they are slowly but completely
absorbed. This point will be discussed again later when we
attempt to calculate the rate of output of estrogenic hormone.
 
Our calculation can be checked roughly by considering
another action of progesterone, namely the maintenance of
pregnancy in the rabbit. This requires more of the hormone.
Brouha found that to preserve pregnancy to the 8th day, the
rabbit must have three or more corpora lutea (instead of
merely the one corpus luteum required to produce typical
changes in the uterus). If we want to maintain pregnancy
with progesterone after removal of the ovaries, we must also
increase the dose something like 3 times or more. Willard
Allen found 0.5 to 1.0 mg. of progesterone daily to be the
necessary dose. In this sort of experiment we find therefore
that one corpus luteum provides the equivalent of 0.16 to 0.33
mg. of progesterone daily, a figure in crude agreement, at
least, with that of 0.13 mg. arrived at previously.
 
The volume of tissue in a rabbit's corpus luteum is approximately 3.25 cubic millimeters. Dividing this into the daily
output of 0.13 mg., we get the answer to question 1: One
milligram of rahhifs corpus luteum produces about O.O4
milligram of progesterone daily,
 
{ 182 }
 
 
 
ENDOCRINE ARITHMETIC
 
2. How much progesterone is made daily in the ovaries of
one rabbit? Although the number of eggs shed by a rabbit at
one time, and hence the number of corpora lutea in one crop,
varies from 1 to 18, the number occurring most frequently
(modal number) is 8. Eight corpora lutea multiplied by 3.25
(the volume of one corpus luteum in cubic millimeters) and
then by 0.04 (the output of progesterone, in milligrams, by
one milligram of corpus luteum) gives the answer to question
2: The modal daily output of progesterone by the ovaries of
one rabbit is about 1.04 milligrams^ and the range is from
0.13 mg. when only one corpus luteum is present, to 2.3 mg.
with the maximum number of corpora lutea, namely 18.
 
3. How much progesterone is produced daily by the ovaries
of a sow? This is important to know because the sow is the
source of most of the natural progesterone that has been
extracted and the only animal in which we know the amount
that is present in the ovaries at any one time. The volume of
one corpus luteum of the sow is approximately 625 cu. mm.,
the equivalent of 160 rabbit corpora lutea. Assuming that
the corpora lutea of the two species are equally efficient,
volume for volume, and therefore that the amount of progesterone produced in each is directly proportional to the
amount of glandular tissue (an assumption for which at
present there is no evidence) then 1 corpus luteum of the
sow would produce 21 mg. of progesterone daily.
 
In a sow possessing the modal number of corpora lutea,
which is 10 in that species, the total daily output of progesterone would be 210 mg. per day. The range would be from
21 mg. when one corpus luteum is present to 525 mg. with the
maximum recorded number of corpora lutea in the sow,
namely 25. This result seems improbably high, but since we
have no present means of improving it, let us use it tentatively
in answering the next question.
 
4. How does the daily output compare with the amount
present in the ovaries at any one moment? All the corpora
 
( 183 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
lutea in the ovaries of one sow, when the modal number is
present, weigh about 5 grams. By direct extraction the yield
of crude progestin is equivalent to 0.05 mg. of progesterone
per gram of raw tissue. Therefore one sow having 10 corpora
lutea has about 0.25 mg. progesterone in the ovaries at the
moment of killing. If the total output per day, estimated in
section 3 above as 210 mg., is anywhere near correct, this
means that the amount present in the ovaries at any one
moment is less than 2 minutes* supply. This is a very important fact, for it points to a very high rate of "turnover" of
secretion in the gland. We must think of the corpus luteum
as making the hormone quite rapidly, working up only a
Httle at a time but putting it through very quickly.
 
5. What is the daily output of the human corpus luteum?
The volume of secretory tissue in the human corpus luteum
is very difficult to measure, since the gland has a folded wall
about a large cavity filled with connective tissue, like the
monkey's corpus luteum shown in Plate IX, A. Estimates
which I have made by two rough methods give 450 to 500
cu. mm. as the volume of secretory tissue in one corpus luteum.
This is 150 times the volume of the rabbit's corpus luteum;
and assuming once more that the human corpus luteum produces progesterone at the same rate as the rabbit's, volume
for volume, then the daily output of the human corpus luteum
may be estimated as about 20 milligrams per day.
 
This calculated result seems rather high when compared
with a few estimates obtained in other ways. For example,
Kaulfmann in 1935 reported producing a progestational endometrium in a human patient with 50 rabbit units in 15 days.
These were presumably Clauberg units, of approximately 0.4
mg. each, making the dose about 1.3 mg. daily. Assuming that
this is somewhere near the minimum effective dose, and allowing for a ratio of about 1 :4, as in the rabbit (section 1 above)
between the minimum daily dose for progestational proliferation and the amount necessary to carry out the real task of
 
{ 1S4 }
 
 
 
ENDOCRINE ARITHMETIC
 
the corpus luteum, namely maintenance of pregnancy, then
the human corpus luteum would be expected to produce about
5 mg. daily. Wiesbader, Smith and Engle of Columbia University Medical School (1936) found that a certain effect of
the removal of the human corpus luteum (bleeding from the
uterus) cannot be prevented by substituting 0.5 mg. daily of
progesterone by injection, but can be prevented by 5 mg.
This suggests that 5 mg. is a quantity sufficient to produce
one of the known effects of the corpus luteum, though not
necessarily the full effects.
 
Another way of getting at this figure is through the fact
that in human females, used-up progesterone leaves the body
through the kidneys as sodium pregnanediol glycuronidate,
as explained in Chapter V, page 120. Venning and Browne,
who discovered this fact, found that if they administered a
given quantity of progesterone, they could recover about half
of it in the urine as the excretion product. When they collected
all the pregnanediol excreted by a patient in a whole menstrual cycle, they found that the total recoverable amount
was normally about 60 mg. This would mean about 120 mg.
of progesterone actually produced. Since the corpus luteum
is probably actively functional during about 10 days of each
cycle, we arrive at an estimate of 12 mg. of progesterone produced daily. Another research group, Pratt and Stover of
the Henry Ford Hospital, Detroit, obtained considerably
smaller values, for their patients yielded only 2 to 3 mg. of
pregnanediol daily, which we may consider to represent at the
most 6 mg. of progesterone. It is known, however, that the
chemical recovery of pregnanediol and estimations of corpus
luteum activity based upon this method are subject to numerous errors not fully understood. It is perhaps all we
should ask for, that the various estimates and calculations
we have made and cited fall within limits as close as 5 and 20
milligrams per day (Appendix II, note 15).
 
Physicians who have used progesterone for disturbances
 
{ 186 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
of menstruation and for threatened abortion have seldom
administered more than 2 mg. per day. If (as seems credible)
beneficial results have been obtained with this and even smaller
dosage, we must suppose that clinical benefit may require only
the redressing of a slightly disordered balance. Our calculations make it clear, however, that larger doses, of the order
of 5 mg. or more, will have to be given thorough trial before
the medical possibilities of this hormone are fully understood.
 
6. What is the progesterone output of a single cell? Returning to the rabbit's corpus luteum, it is possible to calculate approximately the output of a single cell.
 
The averages of a number of measurements of the diameters
of individual corpus luteum cells were 0.028 x 0.028 x 0.036
mm., giving for the cell a calculated volume of 0.000015 cu.
mm. Dividing this into the volume of the whole corpus luteum
we get 217,000, and making due allowance for space occupied
by the blood vessels we arrive at an estimate of 180,000
endocrine cells in one corpus luteum of the rabbit.
 
Since 180,000 cells produce 0.13 mg. progesterone per day,
the daily output of otie cell is about 0.0000007 mg.
 
The figure at first sight seems very small, but when the
number of molecules is considered the resultant expression
looks like the astronomer's rather than the biologist's quantities. We get the number of molecules made by a single cell,
by the following calculation. We ascertain the molecular
weight of progesterone by adding the atomic weights of the
elements it is made of, namely 21 atoms of carbon, 30 of
hydrogen, and 2 of oxygen. The sum is 314. This is the relative weight in comparison with the atomic weight of oxygen
taken as 16. Applying Avogadro's law we know that 6 x 10^'
molecules^ weigh 314 grams. Dividing the latter by the former
 
1 In dealing with very large numbers and very small decimal fractions
it is convenient to avoid writing dozens of ciphers by using exponents.
Thus 100 is 102 and .01 is 10-2. 600 is 6 x 102. The figure cited above,
6 X 1028, when written in full is 6 followed by 23 zeros, or six hundred
thousand billion billions.
 
{ 186 }
 
 
 
ENDOCRINE ARITHMETIC
 
figure, the actual weight of one molecule is 5.2 x 10"" gram.
Dividing this weight into the weight of the daily output of
one cell, we find that one cell produces about 1.3 x lO"-^ or
1,300,000,000,000 molecules, i.e. more than a thousand billion
molecules of secretion produced in one day by one cell.
 
For comparison, it may be noted that in one cubic centimeter (about 1/3 of a thimbleful) of air there are about 10"
molecules.
 
What has just been presented is to the best of my knowledge
the first attempt to calculate the actual output of a single
secretory cell in any organ. It is, of course, no more than a
first approximation to the truth. Yet such conjectures as
this, improved and extended beyond the present powers of
science, are going to lead us some day to the innermost secrets
of cellular life. Perhaps the reader begins to be confused by
all this reckoning of enormous numbers of very small things.
Perhaps, on the other hand, he has acquired an awesome sense
of the complexity of the cells, each one of them an island universe, a frail microscopic enclosure within which arise whirling billions of molecules, themselves in turn complex frameworks of latticed atoms. Upon the correct behavior of these
fantastic congeries of particles in the corpus luteum each
one of us depended for life itself when we were embryos ; so
did all our mammalian ancestors and so will our descendants
forever.
 
QUANTITATIVE ASPECTS OF THE RECEPTOR ORGAN
We can get a further glimpse of the workings of the corpus
luteum by doing a little figuring about the receptor organ,
that is to say the uterus, which receives the progesterone and
is affected by it.
 
As we have seen (Chapter V) the corpus luteum acts upon
the epithelial cells which cover the inner surface of the uterus
and dip down to form the uterine glands. It is the growth and
multiplication of these cells which constitute the progesta
{ 187 )
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
tional proliferation by which the early embryos are nourished
and implanted.
 
From a count of the epithelial cells in sections of the uterus,
I estimate that a rabbit's uterus contains (in the two horns)
about 100,000,000 epithelial cells. This means that each of
the 180,000 epithelial cells in a corpus luteum can affect
about 500 epithelial cells. The corpus luteum cells are, however, about 25 to 50 times as large (in volume) as the epithelial cells, and therefore each of the former takes care of
about 10 to 20 times its volume of the latter at the start of
progestational proliferation. The disproportion is not quite
so great if we calculate on the basis of the amount of corpus
luteum tissue to maintain pregnancy, not merely to induce
progestational proliferation. On this basis one corpus luteum
cell controls at first about 3 to 5 times its volume of epithelial
cells. By the time the effect is complete, the number of epithelial cells has increased a great deal, and thereafter the
corpus luteum cell must maintain more of them. This means
that small amounts of progesterone stir up a proportionately
large effect in the uterus. That sort of trigger-like action
("You push the button, we do the rest") is characteristic of
the internal secretions. It is necessary to suppose that some
sort of chemical reaction between the hormone and something
in the cells of the uterus starts a chain of secondary reactions
which profoundly change the physiology of the uterine lining.
We might have a better idea of what actually happens if we
could know how much progesterone actually reaches each
epithelial cell; but this cannot be calculated, because we do
not know what proportion of the hormone is diverted to other
receptors (the uterine muscle, the mammary gland cells, and
possibly other tissues). If all of it went to the epithelial cells
of the uterus, each such cell would receive daily about 1.3 x
10"* milligrams. This is almost 10^^ molecules. The actual
share received must be considerably smaller.
 
{ 1S8 }
 
 
 
ENDOCRINE ARITHMETIC
 
THE RATE OF SECRETION OF ESTROGENIC
HORMONE
 
It is not possible at present to estimate the rate of secretion
of estrogenic hormone with anything like the fullness and
probability with which such an estimate could be made regarding the corpus luteum. As pointed out in Chapter III,
the cells which produce the estrogenic hormone are probably
scattered throughout the ovary in the walls of small and large
follicles. The number and the total volume of these cells is
obviously not subject to computation, and therefore the best
we can do is to estimate the activity of the ovaries as a whole.
I shall give here a summary of such an estimation which was
published recently in more technical form elsewhere. As in
the case of the corpus luteum, we get our answer by finding
out how much of the hormone we need to administer in order
to restore one or another of the functional effects of the
ovaries after they have been removed.
 
How much estrogen is required daily by the monkey? As
described in Chapter VI, removal of the ovaries of the Rhesus
monkey causes menstruation-like bleeding from the uterus due
to removal of the source of estrogenic hormone. If we take
out the ovaries and then administer estrogenic hormone, we
can try various doses and discover how much we have to give
to prevent bleeding. This amount will represent the replacement of the hormone formerly produced by the ovaries when
they were present. In my notebooks there are records of twelve
experiments of this kind which are suitable for our present
consideration. In each of them the animals received 125 international units of estrone daily, beginning the day the ovaries
were removed. Of these, 4 bled from the uterus beginning on
various days from the 3d to the 14th after the operation, in
spite of the treatment with estrone. Seven did not bleed at all
during the 15 days of the experiment. One, which received a
larger dose of estrone, namely 500 international units, showed
 
{ lli9 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
a few red blood cells from time to time, beginning on the 3d
day, but no external bleeding. The experiment shows that 125
international units of estrone will substitute in many cases,
but not in all, for the natural product of the animal's own
ovaries, as tested by the prevention of postcastration bleeding. A somewhat larger dose would obviously be required to
prevent such bleeding in every case.
 
A variation of this experiment is to give castrated female
monkeys large doses of estrogenic hormone and then drop the
dosage until bleeding sets in. A number of such experiments
were reported by S. Zuckerman of Oxford, England, in 1936.
This investigator found that whenever he reduced the daily
dose from several hundred or several thousand international
units to any amount below 200 international units, estrindeprivation bleeding occurred thereafter. With more than 200
international units daily no bleeding occurred.
 
These observations suggest that the output of estrogenic
hormone from the normal ovaries, which is of course sufficient
to prevent estrin-deprivation bleeding, may be about 150 or
200 international units.
 
A third means of estimating the probable amount of estrogenic hormone produced by the monkey is provided by the
fact that the so-called sex skin (the red swollen areas of the
rump and thighs) is under the control of the hormone. Removal of the ovaries leads to shrinkage and pallor of the sex
skin, whereas administration of an estrogen in sufficient
amount will within a few days restore the color of this region.
One of my animals, a young adult, had its ovaries removed at
a time when its sex skin was in exceedingly florid condition.
The whole area over the rump, the back of the thighs, and the
ventral side of the base of the tail was swollen, thrown into
distinct ridges and deep red in color. After the operation, but
on the same day, the color and swelling were slightly reduced,
owing no doubt to the stress of the operation. One hundred
twenty-five international units of estrone was given daily
 
{ 190 }
 
 
 
ENDOCRINE ARITHMETIC
 
beginning on the day of operation. A slight but definite
decrease in the color of the sex skin took place during the
next 10 days. The swelling of this region diminished also,
although not to the same extent as the color, and on the 10th
day, in spite of the administration of estrone, external vaginal
bleeding began.
 
From the facts that the condition of the sex skin retrogressed very slowly and external bleeding did not begin until
the 10th day, that is to say later than if the animal had been
given no estrogen at all, it seems that the dose of 125 international units daily was almost but not quite sufficient to
maintain the animal in the same condition as before removal
of the ovaries. We may estimate therefore that 150 or 200
international units would have been required to substitute
completely for the ovaries.
 
Another method of arriving at the desired information
depends upon the fact that effective action of progesterone
upon the endometrium to produce the progestational ("premenstrual") condition in castrated female monkeys requires
that an estrogenic hormone be administered in conjunction
with the hormone of the corpus luteum. Engle of Columbia
University (1937) stated that a satisfactory combination
for the castrated Rhesus monkey is 30 AUen-Doisy rat units of
estrone (this is approximately 150 international units) daily
with 0.5 Corner- Allen unit of progesterone (approximately
0.5 milligram). Hisaw and Greep (1938) gave a similar figure,
i.e. about 150 international units of estrogen with 0.5 mg. of
progesterone. These experiments are subject to the difficulty
that they involve varying the dosage of two hormones simultaneously. The animals used by Hisaw and Greep were, moreover, relatively young, and the progestational changes involved were not as elaborate as the natural progestational
state. The result fits however those obtained above in giving
150 international units of estrone as somewhat less than an
 
{ 191 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
adequate substitute for what the animal's own ovaries produce.
 
Probable daily output of estrogenic hormone by the monkey. By all these means of estimation we arrive at the result
that the probable daily output of estrogenic hormone by the
young adult Rhesus monkey is equivalent to somewhat more
than 150 international units and may be set tentatively at the
equivalent of 200 international units of estrone. This is a
minimum figure; the true amount may be greater, but can
hardly be smaller.
 
This estimate is based necessarily on the assumption that
an ovarian hormone injected once daily in oil solution is
utilized by the body as efficiently as hormone produced in the
animal's own ovaries. There is at present no way of ascertaining how nearly this is true, but in any case, the slow absorption of an oily solution must afford a fairly good imitation of
natural processes, and we may recall that my estimate of the
rate of secretion of progesterone, which involved the same
assumption, turned out to be near the truth, when checked by
the recovery of the excretion product, pregnanediol.
 
Administration of estrogenic hormone in pellets. In recent
years many experimental workers have been administering
estrogenic hormones by compressing them into small hard
pellets which are buried under the skin. This method has the
advantage that the hormone is absorbed continuously from
the surface of the pellet, whereas when given by injection the
rate of absorption fluctuates, being high just after an injection and lower as more and more of the injected dose is absorbed. For this reason a given effect is obtained from a
smaller daily dose when absorbed from a pellet than when
injected. Pellets will probably be used in human cases in which
long continued action is required, not only because of the
continuous absorption, but also because insertion of the pellet,
which can be done through a hollow needle, avoids repeated
hypodermic punctures.
 
{ 192 }
 
 
 
ENDOCRINE ARITHMETIC
 
It becomes important for our present calculations to kjiow
just how much more effective this method is, dose for dose,
than injections, because our estimate of the daily need for
estrogenic hormone is based on comparison with injected
doses. At first sight the results obtained by pellets seem to be
achieved by very small doses indeed, and it is generally taken
for granted that the method is much more effective than injection. Very little, however, is known about the exact comparison by actual experiment. Carl G. Hartman has reported, for
instance, that the sex skin of a Rhesus monkey was kept red
and swollen for 4 months with a single 3-milligram pellet of
estrone. This seems small, but assuming that the pellet was
entirely used up, this gives a daily dose of 0.025 mg. or 250
international units (3 mg. divided by 120 days). Hartman's
monkey thus actually received a larger daily dose than is
called for on the basis of our estimate, namely 200 international units.
 
Deanesly and Parkes of London, who introduced the pellet
method, cite an experiment with one of the male hormones
which indicates that the dose by pellet is about one-half that
by injection. I have heard of experiments with another male
hormone in which the ratio was 2 to 3. If any such proportion
as these is true of estrone, then our calculated daily output of
estrogen by the monkey is roughly one-third to one-half too
large.
 
But here again we are guessing. What evidence is there
that absorption from a pellet is really comparable to the
natural absorption of the animal's own hormone from the
ovarian cells? Nobody knows the answer to this. It might
even be true that the pellets yield their substance to the blood
stream more easily than do the cells of endocrine glands, in
which the hormone is made and stored within the cellular substance. The big molecules of the hormone have to make their
way through the outer layers of the cell, not merely drop off
the surface of a pellet.
 
{ 193 )
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
In short, it would be premature to let the pellet method outweigh, in these very crude calculations, the results from injections, about which at present wc know very much more;
and therefore I propose to maintain for the present the estimate arrived at above, namely that a female Rhesus monkey
produces from her two ovaries estrogenic hormone equivalent
to about 200 international units of estrone daily.
 
If this were actually estrone, the daily output would weigh
0.02 milligram.
 
Application of these calculations to the human female.
Can we apply this estimate to the human female? A woman
weighs on the average 15 times as much as a monkey. Two
hundred international units x 15 gives 3,000 international
units as the daily output of the woman's ovaries. Various
medical observations which have been published might be
analyzed to give us some sort of check on the estimate. My
friend, W. M. Allen, for example, informs me that in his
treatment of women whose ovaries had been removed previously he could induce menstruation-like bleeding with estrogenic hormone equivalent to about 4,200 international units
of estrone daily. This figure, which is the most pertinent I
can find, is roughly 50 per cent higher than my calculation
from the monkey experiments, but we have no way of telling
how closely this amount compares with that needed by a
normal woman. Perhaps what Allen was trying to do required more, perhaps less, than the normal output.
 
Unfortunately we cannot get help in this problem by measuring the estrogen discharged in the urine, because we do not
know just what relationship exists between the hormone which
is at work in the body and that which is excreted. The number of milligrams of estriol and similar substances recovered
from the urine does not tell us how much of the ovarian
hormone was made and used in the body (Appendix II, note
16).
 
This chapter has contained, after all, a good deal of valiant
 
{ 194 }
 
 
 
ENDOCRINE ARITHMETIC
 
shooting in the dark. Our conclusions and estimates are sure
to be better in time to come. Meanwhile the reader will perceive that after the excitement and drama of the pioneer
phase of research on the ovarian hormones, we are in for a
lot of tedious, unspectacular measurement and computation,
until the reactions of these substances in the body are quantitatively known as well as the chemist knows the reactions
in his flasks. Then, as Lord Kelvin said, we shall really understand our subject.
 
 
 
{ 196 }
 
 
 
THE HORMONES IN PREGNANCY
 
 
 
*Long was I hugg'd close — long and long.
Immense have been the preparations for me.
Faithful and friendly the arms that have help'd me.
Cycles ferried my cradle, rowing and rowing like friendly
 
boatmen.
For room to me stars kept aside in their own rings.
They sent influences to look after what was to hold me.
Before I was born out of my mother generations guided me.
My embryo has never been torpid, nothing could overlay it.'
— ^Walt Whitman, Song of Myself.
 
 
 
CHAPTER VIII
THE HORMONES IN PREGNANCY
 
THE maintenance of pregnancy is a truly complex
afFair. A living creature is growing at a tremendous
rate inside a hollow chamber, the uterus. This organ
must at first tolerate, even support the newcomer. It must
grow in size and strength so that its enterprising tenant may
not overwhelm it (Fig. 28). All the other muscle-walled
organs of the body are built to keep things moving — the
heart, the intestines, the bladder for example — and so, ultimately, is the uterus. For nine months, however, it must be
kept in check and not allowed to expel the infant prematurely.
Then all of a sudden its energies are released and it is called
upon to deliver its contents into the world, through the narrow bony canal of the pelvis, with sufficient force and speed
on one hand, and sufficient gentleness on the other, to avoid
wearing out the mother or crushing the baby. To use a current expression of bewilderment, figure out all that if you
can ! Nature, indeed, has figured it out reasonably well ; but
when the physiologist attempts to discern the factors of this
multifarious process and to see how they are set in motion,
timed, and controlled, he finds he has yet a long research
ahead of him.
 
In this book we can do no more than sketch the problems
involved. In outline, what has to be worked out is the growth
and function of a muscular organ, controlled in part by
the nervous system, in part by hormones. The latter are those
which come from the ovary, the pituitary and the adrenal,
together with the output of a new source, peculiar to pregnancy, the placenta.
 
THE PLACENTA
 
Once the embryo is safely lodged in the uterus and has
begun to grow, a new era of hormone activity begins. The
 
{ 199 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
 
 
 
Fig. 28. Enlargement of the human uterus during pregnancy. At v,
virginal uterus; the large hatched area is the pregnant uterus, at full
term, drawn to same scale, approximately % natural size. Adapted from
a figure by Stieve.
 
task of the ovary is not yet over, but its functions are in large
part to be taken up, reinforced, and even superseded by a new
organ of internal secretion, the placenta. The human placenta
is an object of considerable size, as shown in the fine old
engraving from Casserius (Plate XX). When fully developed
it is about 18 centimeters (7.5 inches) in diameter, and weighs
500 grams (a little more than one pound) on the average.
When in place in the uterus, its structure is like nothing else
so much as the matted roots of a tree planted in a tub. The
roots simulate the villi of the placenta, which carry within
their slender strands the finest branches of the blood vessels
coming from the infant in the umbilical cord. Through these
delicate vessels the blood of the infant circulates in a constant
and rapid stream. The tub in which we imagine the tree
planted simulates the pool which the embryo has excavated
for itself in the wall of the mother's uterus (Fig. 14, p. 58).
 
{ 200 }
 
 
 
THE HORMONES IN PREGNANCY
 
Through this pool the mother's blood slowly flows, out from
the arteries that supply the region and back into the veins,
bathing the rootlike villi of the placenta. From the mother's
blood to the blood of the embryo, oxygen and dissolved foodstuffs filter through the covering cells of the villi and through
the thin walls of the blood vessels that run along within them,
just as nutritive substances pass into the roots of a plant
from the moist soil in which they grow. The infant sends back
carbon dioxide, urea, and other wastes from its tissues, to be
filtered out through the placental vessels into the mother's
blood, which carries away these wastes to be disposed of with
the products of her own metabolism.
 
The covering cells of the villi are called upon, however, not
only to take part in the process of filtering foodstuffs inward
and waste products out, but also to produce a whole series of
endocrine substances. This important fact is unfortunately
masked by a great deal of confusion in our present knowledge.
The placenta differs greatly in different species, not only in
its structure but also in its endocrine activities. Statements
which are true of one species may not apply at all in others.
For this reason our discussion will be limited to the human
species (except as specifically stated) and even then we shall
be restrained by a certain amount of uncertainty. To begin
with, the placenta begins very early in pregnancy to elaborate
a hormone of its own, having profound gonadotrophic properties (that is, power to stimulate activity of the ovary and
the testes) much like that of the pituitary gonadotrophic
hormones.^ This activity begins, indeed, before we can properly speak of the placenta, for the hormone in question is
made by the cells (i.e. the trophoblast) covering the early
villous processes that surround the embryo, as soon as they
 
1 For the sake of clearness, it seems best to refer to the gonadotrophic
material in the singular, i.e. "a hormone," but actually it seems to be a
hormone complex comprising two substances, one of which tends to
stimulate growth of the follicles, the other to convert the follicles into
corpora lutea (Appendix II, note 11).
 
{ 201 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
begin to grow. Knowledge of this subject goes back to 1928,
when Aschheim and Zondek, then of Berlin, found that during
pregnancy the human urine contains something that has a
powerfully stimulating effect on the ovaries of young mice and
rats. This provided the basis for the now famous AschheimZondek test for pregnancy. The urine of a pregnant woman,
injected into an infantile mouse or rat, produces prompt and
characteristic signs of activity in the ovarian follicles. An
even quicker test for pregnancy is provided by a modification
of this procedure, introduced by Maurice Friedman, an American investigator. In the Friedman test the urine, either raw
or partially purified by precipitation with alcohol, is injected
into the ear vein of a rabbit. If the patient is pregnant, the
rabbit ovulates about 10 hours after the injection. This hormone test for pregnancy is (in both variations) probably
more nearly infallible than any other biological test used by
physicians, for when properly performed it is accurate in
better than 98 per cent of all cases.
 
The gonadotrophic hormone complex of the urine can also
be extracted from the placenta and in all probability is made
there. George O. Gey, a tissue culture expert of Baltimore,
recently showed that placental tissue growing in his test tubes |
was able to produce a gonadotrophic substance. Chemically
the urinary gonadotrophic material is protein, like the gonadotrophic hormone that is produced in the pituitary gland,
and indeed it is so much like the latter that it was for a time
considered to be identical with it, but clear differences between
the two substances have been observed, as evidenced by the details of their effects on animals of various species. The placental gonadotrophic hormone complex appears in the urine in
the first month of pregnancy, in sufficient amount to give a
positive Aschheim-Zondek or Friedman test. It is present
throughout pregnancy, but reaches its greatest amount in the
second month and falls off rapidly thereafter. In the Rhesus
monkey it is found only between the 18th and the 25 th day. In
 
{ 202 )
 
 
 
THE HORMONES IN PREGNANCY
 
the blood of the pregnant mare there is a gonadotrophic hormone which also has a stimulating effect on the ovaries of test
animals, such as rats, differing considerably, however, in detail. This does not get into the urine in significant amounts,
which means that it must be different chemically from the
human hormone of similar action.
 
We do not know why these substances can be found in some
species of animals and not in others, nor do we know what
function they perform in pregnancy. The whole series of
pituitary and pituitary-like hormones has been extremely
difficult to investigate chemically because the substances are
proteins and they defy purification. The ovaries of the rat
and the rabbit can distinguish them better than the chemist.
For the present we must content ourselves with being grateful
for the pregnancy test and await the day when these troublesome substances yield themselves to chemical isolation.
 
As mentioned previously (Chapter IV) the urine of pregnant women contains relatively large amounts of estrogenic
substances, which increase as pregnancy advances and disappear after parturition. These substances have been found
in the urine of several other species during pregnancy. The
human placenta also contains large amounts of estrogenic
hormones, chiefly estriol, and is almost certainly the source
of those which appear in the urine. As mentioned in Chapter
IV, when the ovaries are removed during pregnancy, estrogens continue to be excreted in the urine, a fact which proves
that some other source exists, and this can hardly be anything
else than the placenta. A similar situation, produced experimentally in the monkey, has been studied very carefully and
reported by R. L. Dorfman and Gertrude Van Wagenen of
Yale Medical School.
 
There are several possible ways in which the production of
estrogens by the placenta may be useful. It has been suggested
that these hormones are needed, in larger amounts than the
ovaries can provide (a) to promote the growth of the uterus
 
{ 203 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
which occurs during pregnancy; (b) to cause growth of the
mammary glands to get them ready for the production of
milk; (c) to set up contractions of the uterus when the time
comes for parturition ; (d) to cause persistence of the corpus
luteum. These possibilities will be discussed again later in
this chapter.
 
As regards progesterone in the placenta, it has already been
pointed out that in some animals the corpora lutea are indispensable until the end of pregnancy. In the rat and the
cow, for example, the ovaries cannot be removed at any time
without causing loss of the embryos, and the corpora lutea
appear to be functional until almost the end of gestation. In
the human species, on the other hand, the ovaries can be
removed without affecting the survival and birth of the infant,
as early as the third month of pregnancy. After such an
operation pregnanediol has been found in the urine, an indication that progesterone has continued to be produced somewhere. Naturally the placenta has been suspected, and assays
have yielded small amounts of progesterone or a substance of
closely similar kind.
 
ACTION OF THE HORMONES IN PREGNANCY
 
We can do hardly more here than sketch what is known
about the multifarious interactions of the hormones in pregnancy. Readers who wish to follow the subject in detail may
consult the excellent book on this subject by my colleague
S. R. M. Reynolds.^ In the first place, the two ovarian hormones contribute to the growth of the uterus. Growth of the
muscular wall is known to involve (as one might well expect)
first an increase of the number of the muscle cells, and then an
increase of the size of the individual cells. In the human uterus
the measurements of the German histologist Stieve indicate
that the muscle cells are 17 to 40 times larger at the end of
 
2 Physiology of the Uterus, with Clinical Correlations, by Samuel R. M.
Reynolds, New York, 1939.
 
{ 204. }
 
 
 
THE HORMONES IN PREGNANCY
 
pregnancy than in the empty uterus. Other elements of the
uterine wall, namely the connective tissue, blood vessels, and
nerves, also increase in amount. In this process the estrogenic
hormone contributes its general growth-promoting effect,
which it exerts by augmenting the blood flow through the
tissues of the uterus. Under its influence there is some increase
in number of the uterine cells. Progesterone in turn causes a
decided wave of cell division in the muscle, and then within a
few days at the beginning of pregnancy there is a large increase in the number of muscle cells. Subsequent growth of
the individual cells, and consequently of the whole wall of the
uterus, comes about as the result of stretching by the growing
embryo. As the uterus is distended it grows in thickness and
strength; if this were not so, the infant would soon rupture
the walls that confine it. Everyone is, of course, familiar with
the fact that working a muscle makes it grow, and this is no
less true of the involuntary muscles of the internal organs
than of the skeletal muscle; but like most other familiar
responses of the body, we often take it for granted without
realizing how little we know how it comes about. Why the
uterine muscle grows when that organ is distended is a large
question of general physiology, beyond the scope of this book.
Reynolds has shown that if he distends the rabbit's uterus
by introducing pellets of wax, it will grow in thickness just as
it does in pregnancy. By this means he has been able to test
the eff*ects of the ovarian hormones upon the growth-response
to distention, and has found (among many other interesting
facts) that treatment with estrogenic hormone cuts down this
response. This hormone, then, which at first helps start the
growth of the pregnant uterus, afterward helps to control it.
In human pregnancy we know there is plenty of estrogen
available in the later months; in all probability this serves
to keep the growth of the uterus from going too far. With
this hint that the interplay of the hormones is indeed complex,
 
{ 205 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
we had better leave the subject to the specialists for further
study.
 
Finally the time comes when gestation can go on no longer.
The uterus, overburdened by its rapidly growing tenant, must
deliver itself. Degenerative changes begin in the placenta, the
nourishment of the infant is thereby impaired, and the uterus
commences its efforts to expel the child. This it accomplishes
by means of strong contractions, efficiently timed and coordinated so that the infant is pushed toward the outlet of the
uterus. The uterine orifice, and afterward the vaginal canal,
are stretched open to allow passage of the infant, while the
rest of the uterus contracts to provide the necessary force.
There is no simple explanation of the onset of labor. Many
physicians and biologists have tried to discover some simple
reason why at a particular time — 9 months in the human, 2
years in the elephant, 21 days in the mouse, or whenever,
according to the species, the fated hour arrives — the act of
parturition begins. It has been thought, for example, that the
uterus is at last simply stretched too far and is thereby irritated into contracting again; or that the breakdown of the
placenta constitutes a stimulus to the uterine muscle ; or that
some chemical substance from elsewhere in the body sets the
muscle into action. When it was discovered that estrogenic
hormones stimulate the involuntary muscle of the uterus, and
that progesterone tends to relax it, an attractive theory of
the cause of labor at once suggested itself. We need only
suppose that when the end of gestation draws near, the production of progesterone goes down, and estrogenic hormone
is thereby allowed to build up contractions of the uterine
muscle. This hypothesis is however much too simple, as
Reynolds points out in the book cited above. For one thing,
the contractions of the uterus in labor are very different in
their timing and coordination from those of the nonpregnant
uterus. The fact is that the uterus at the end of pregnancy is
operated by a very elaborately organized set of adjustments.
 
{ 206 }
 
 
 
THE HORMONES IN PREGNANCY
 
The proportion of the infant to the space it occupies; the
strength of the uterine wall and the pressure it exerts upon its
contents; the rate of blood flow through the uterus; the
sensitivity of its muscle and nerves ; the balance of the hormones that affect it; the nutrition of the infant and the
placenta — all these factors (and others beside them, for all
we know) are balanced one against the other and when the
crisis comes they are all involved at once. The physiologist
who looks for one specific cause of the onset of labor is up
against the same kind of problem as the economist who tries
to find one single cause for a stock market crash or to pin
down a nationwide problem of unemployment to one specific
factor. When dealing with such complex affairs as those of
a nation or a pregnancy the investigator cannot isolate one
factor at a time and study it singly. He has to unravel a
whole system of balanced forces. In the problem we are considering, the hormones are certainly to be numbered among
the most important factors, but it is scarcely safe at present
to say more,
 
LACTATION
 
When the mother's body has completed its provision of
shelter and nourishment for the child by means of the hormones and has seen him safely into the world, it has yet
another service to render on his behalf — namely that the
breast for which he will so promptly cry is ready to supply
him with milk.
 
The recent discovery of a specific hormone for lactation,
in the pituitary gland, was a great surprise. It involved a
simple little piece of scientific logic which the reader may
enjoy after the preceding complexities of this chapter. We
had better clear the way for this story, however, by recalling
to mind the earlier history of the mammary gland. When a
girl or a young animal reaches sexual maturity, the mammary
glands are brought from the immature state to the adult con
{ 207 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
dition, by action of the estrogenic hormone. Nothing is more
striking than to watch the growth of the mammary glands in
a young animal receiving estrogen. Each gland is a system of
branching channels lined by cells derived from the outer layer
of the skin (epidermis). Long before birth these ducts begin
to grow from the nipples and to spread out around them in
a little circle under the skin. At first the channels are few and
short, and only slightly branched (Fig. 29, A). Under the
action of the estrogenic hormone they branch extensively and
spread to adult dimensions (as indicated in the diagram, Fig.
29, B). In the girl at puberty this is, of course, a gradual
change, but in an experimental animal under hormone treatment it can be produced quite rapidly. The nipples quadruple
in size in a few days, and the ducts push outward in a widening circle. In pregnancy a much greater development occurs.
The branches of the duct system develop extensive terminal
twigs ending in secretory alveoli (Fig. 29, C, B). These become more numerous as pregnancy advances. Finally, globules
of milk-fat accumulate in the cells of the alveoli (Fig. 29, E).
The actual flow of milk in quantity does not begin, however,
until after parturition.
 
From the time it was first conjectured that the corpus
luteum is a gland of internal secretion, until quite recently, it
was supposed that this particular endocrine organ is responsible for the growth of the mammary gland in pregnancy and
the secretion of milk. On the face of it, there could hardly be
a more plausible conjecture, for the growth of the mammary
gland closely follows the appearance of the corpus luteum,
and is so obviously a part of the general preparation for the
infant that it seems very logically to go with the other functions that the ovary exerts during pregnancy.
 
If this is true, however, why does not the corpus luteum
produce mammary growth and even lactation not only in
pregnancy but in each ovarian cycle.? To this query A. S.
Parkes of London in 1929 offered the tentative reply that
 
{ ^08 )
 
 
 
THE HORMONES IN PREGNANCY
 
 
 
 
Fig. 29. Diagrams illustrating the development of the mammary gland
as seen in laboratory animals. A, mammary gland of immature animal,
consisting of simple ducts radiating from the nipple. B, small area of A
enlarged to show adult virginal gland. The action of estrogenic hormone
has produced extensive growth and branching of the ducts. C, small part
of B enlarged again to show the effect of pregnancy; there has been a
great development of duct twigs with terminal alveoli. D, terminal alveoli
enlarged to show their cell-structure. E, secretion of milk globules by the
cells of the alveoli. Based on a figure by C. W. Turner In Sex and
Internal Secretions.
 
 
 
perhaps in the ordinary cycle, in which the corpus luteum
lasts but two weeks, there is not time to build up the mammary
gland sufficiently. He therefore ingeniously proposed to apply
the discovery, then quite new, that the corpora lutea can be
made to persist for weeks by injection of anterior pituitary
extract. He tried this experiment in rabbits, by mating them
to males rendered infertile by having their seminal ducts
 
{ 209 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
blocked, so that these females ovulated but did not become
pregnant. The corpora lutea, which under these circumstances
would normally degenerate after about 14 days, were made to
persist by the pituitary hormones. The expectations of the
experimenter were brilliantly fulfilled by the occurrence of
mammary growth and lactation. When the report of these
experiments reached the United States, we had in our University of Rochester laboratory a fair amount of the then
new corpus luteum hormone in crude form (progestin) and
took the obvious step of trying to produce mammary growth
and lactation with the progestin alone. To my surprise we got
no lactation and no marked growth of the mammary gland.
From this failure, however, an important deduction could be
made. Parkes had subjected his rabbits to the action of two
hormones (pituitary and corpus luteum) ; I had given only
the latter. He obtained lactation, I did not. Subtracting my
procedure from his, it looked as if the anterior pituitary hormone was the only necessary factor. We made up a flask of
pituitary extract from sheep and injected it into six adult
castrated virgin female rabbits. In 3 days milk began to drip
from their nipples ; in 10 days the mammary glands had thickened and spread all over the chest and belly as in advanced
pregnancy and when we milked them the milk spurted across
the room.
 
I thought at first that this discovery of the lactogenic
potency of the anterior lobe of the pituitary was completely
new, but study of the scientific journals revealed that a few
months previously two Alsatians, Strieker and Grueter,
working in Strasbourg in the laboratory of Paul Bouin, had
done exactly the same experiment with the same result. By
what process of logic they were led to try it was not narrated
in their report.
 
The extracts were very crude and we set out to purify
them. One of the large drug houses provided more extract by
the quart and one of their research staff started to work out
 
i 210 }
 
 
 
THE HORMONES IN PREGNANCY
 
the chemical separations, but be and I found only that we
were dealing with a protein, after which we simply got lost in
this most difficult field of biological chemistry. Meanwhile my
genial and versatile friend Oscar Riddle of the Carnegie Institution (Department of Genetics, at Cold Spring Harbor),
ably assisted by his colleague R. W. Bates, applied his allround knowledge of tissue chemistry to the task and succeeded in purifying the hormone to a considerable degree. He
called it prolactin. The complete chemical isolation and chemical identification of this important substance is now a problem for the most advanced special experts in the chemistry of
proteins (Appendix H, note 17).
 
There is a queer sequel of this discovery of prolactin, which
opens a vista of the long past origin of the hormones in evolutionary history. This story has to do with pigeons' milk.
Not that pigeons have mammary glands ; but females of the
genus actually secrete into their crops a kind of milky secretion which they regurgitate and feed to their nestlings. This
crop-milk is produced by special glands in the lining of the
crop. Dr. Riddle knows all about pigeons ; he has been studying their physiology for years and had a fine collection of
them at Cold Spring Harbor. Impressed by the parallelism
between the formation of crop-milk and mammalian lactation,
he administered his extract of beef pituitaries to some of his
female pigeons and got proliferation of the crop glands just
as if they were mammary glands. This reaction is so easy to
produce that it is now the standard test for prolactin. The
strangest part is, however, yet to be told. The eggs of the
amphibians (frogs, toads, and salamanders for example) are
laid in the water and the embryos have the benefit neither of
nest and crop-milk nor of uterus and mammary gland. When
the eggs are shed by the mother, however, they are protected
by an envelope of jelly, laid on in the mother's oviduct. An
Argentine physician, already mentioned in this work. Dr.
In^s de Allende of Cordoba, has discovered that a hormone
 
{ sii }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
like that found in extracts of beef pituitary glands is responsible for the secretion of the protective jelly of the eggs of
toads. She elicited this function by inserting pieces of toad
or beef pituitary gland under the skin of her toads, thus increasing the available amount of pituitary hormones; and
in a few cases she could even elicit it by injecting Riddle's
prolactin.
 
Here, then, are three particular means of provision for the
newborn infant, occurring in three widely different branches
of the animal kingdom, and adapted to offspring living under
very dissimilar circumstances, yet all these secretions are controlled by the pituitary gland and can be induced by extracts
of beef pituitaries. The embryologist perceives a further
remarkable feature of this story. The mammary gland, he
knows, is derived from the outer of the three fundamental
tissue layers of the embryo, the ectoderm'^ the crop glands
of the pigeon are derived from the inner layer, the endoderm ;
and the secretory lining of the toad's oviduct is derived from
the middle layer, the mesoderm. These three tissues from which
the pituitary gland elicits reactions of such similar usefulness, are about as widely different in their position in the
body, and in their embryological history, as they can possibly
be, but when in the evolution of toad, bird, and mammal there
was need to call upon them to foster the fledglings of their
kind, the pituitary gland took control in each case.
 
Has the corpus luteum, then, no role whatever in the processes leading to lactation, and can the pituitary extracts induce lactation in a mammary gland prepared only by estrogenic hormone.'* My rabbits seemed to indicate that this is
true, but Strieker and Grueter declared that their pituitary
extracts were not successful unless there had been corpora
lutea in the ovaries at some time during recent months ; in
other words, the pituitary lactogenic hormone appeared able
only to jact upon a mammary gland sensitized by progesterone. This difference in the findings led to a great deal of
 
{ 212 }
 
 
 
THE HORMONES IN PREGNANCY
 
subsequent work by various investigators, well summarized by
C. W. Turner of Missouri, himself one of the leaders in this
work, in Sex and Internal Secretions} It now appears that
the second of the three more or less distinct stages of growth
and function of the mammary gland, already referred to and
illustrated (Fig. 29), involves somewhat different responses
to the hormones in different species. The first stage, that of
preliminary growth of the duct system to the adult virginal
state, occurs under the influence of estrogenic hormone as
already described. In the second stage, the ends of the ducts
proliferate and branch into numerous terminal alveoli. This
stage in many animals requires the action of progesterone ; in
a few species (of which the guinea pig is an example) progesterone is not needed at all and the proliferation can be
completely induced by the estrogens ; in some other species
growth of the alveoli is at least facilitated or speeded up by
progesterone, though not actually dependent upon that hormone. Judging from various observations which have been
reported on monkeys, the primate mammary gland is among
this intermediate group. Whether this is also true of the
human we do not know at present. The third stage, that of
secretion of milk, is brought about by the lactogenic hormone of the pituitary. It is a striking evidence of the potency
of these hormones to induce lactation that the rudimentary
mammary glands of male animals can readily be made to
lactate by a suitable course of treatment with the estrogenprolactin or estrin-progesterone-prolactin sequence.
 
We have yet to discover how the pituitary gland is stimulated to exert its lactogenic effect during pregnancy. The
reason the flow of milk does not begin until just after parturition, and then begins suddenly, is that lactation is inhibited
by the estrogenic hormone of the placenta. Once the placenta
is out of the way, the flow of milk is released.
 
8 Sex and Internal Secretions, edited by Edgar Allen, Baltimore, 2d
ed., 1939; Chapter XI, The Mammary Glands, by C. W. Turner.
 
{ 213 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
The induction of lactation in pregnancy is thus another
example of those remarkable integrative linkages among the
various parts of the reproductive system by means of hormones, by which shelter, warmth, and nourishment are provided for the mammalian egg while it is incubated within the
body and at the breast of its mother. By such extraordinary
means as this have the children of men, latest of a long series
of creatures to haunt the earth, been protected from isolation
and danger in their earliest days, and given time to grow for
nine months before being exposed to the rigors of the outer
world. This privilege of uterogestation, which would be impossible without the ovarian and placental hormones, gives
an incalculable advantage to mankind and the other mammals
in the struggle for superiority in the animal kingdom.
 
 
 
i
 
 
 
{ IBU)
 
 
 
THE MALE HORMONE
 
 
 
'She \^Nature'\ spawneth men as mallows fresh,
Hero and maiden, flesh of her flesh;
She drugs her water and her wheat
With the flavors she finds meet.
And gives them what to drink and eat;
And having thus their bread and growth.
They do her bidding, nothing loath."
 
— Ralph Waldo Emerson, Nature II.
 
 
 
CHAPTER IX
 
THE MALE HORMONE
 
THE male sex glands (testes) of man and the other
mammals, like the ovaries, perform a double task.
They exist primarily, of course, to produce the male
germ cells. In primitive aquatic animals this is all they need
to do. The Hydra, for example, shown in Plate II, C, in the
act of discharging its sperm cells directly into the v/ater, has
fulfilled its reproductive task for the season, and its empty
testes are of no more consequence than a spent skyrocket. In
mammals, however, things are not so simple. There are other
needs that can be fulfilled only by the coordination of various
parts of the body by means of a hormone. Not only must the
sperm cells be formed and ripened ; they must also be stored
until they are needed in mating. What is more, they must be
stored in a most particular way, immersed in a watery environment, for the mammals have never fully shaken off their
ancient adaptation to the sea. They spend their lives on land,
but when the time comes to reproduce their kind, their spawning requires salt water — not indeed the actual sea, but the
internal fluids of the generative organs. The egg ripens in the
fluid of the Graafian follicle. The sperm cells accomplish their
tortuous journey to the Qgg by swimming, and the offspring
of all the mammals spend the long term of gestation in a submarine environment. You and I cannot remember our ancestral life in the water, nor the nine months we ourselves lived
beneath the chorio-amniotic sea, but our tissues recall it ; the
skin, the kidneys and the adrenal glands working to hold
sufficient water and just enough salt, the testes providing
through their accessory organs those fluids in which the sperm
cells may be effectually launched upon the sea of life.
 
In another way also the endocrine function of the testis
becomes necessary. The higher animals lead complicated lives.
 
{ 217 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
They wage a varied battle for existence and are swayed by
many circumstances. Perpetuation of the race amid such distractions requires especially active maintenance of sexual
vigor and the urge to mate. This too becomes a function of
the testis as an organ of generation.
 
THE MALE REPRODUCTIVE ORGANS
 
The testis. To follow the story in detail we must first review
the anatomy of the testis and the associated male organs of
reproduction. The diagram (Fig. 30) will serve to orient us.
The two testes lie in their pouch of skin (scrotum) . They are
objects of ovoid shape, about the size of walnuts, that is to
say 4.5 x 3 centimeters (2x1% inches) in diameter. Within
these small rounded bodies the business of sperm cell production is carried on inside an extraordinary system of tubular
canals. The testis, in fact, consists essentially of many hundred small tubules, called seminiferous tubules, each about 30
to 70 centimeters (1 to 2 feet) in length and about as large
in diameter as a strand of sewing silk. These tubules are coiled
very tightly in the small space available, and thus when we
look through the microscope at a section of the testis, we see
countless sections of the individual tubules, cut in every possible direction (Plate XXIII, A). How they actually run,
and how they are connected, was for a long time one of the
most difficult problems of microscopic anatomy. We should
get a similar picture if we took a thoroughly tangled ball of
twine and cut a section through it with a sharp knife. Nobody
could possibly tell from such a cut whether the ball of twine
contained one long piece of twine, or several shorter ones, or
how they were joined together. Likewise a section of the testis
cannot tell us anything about the course of the seminiferous
tubules. For a century microscopists applied their various
technical tricks to this problem, including the making of magnified models from serial sections, but with only imperfect success, owing to the difficulty and laboriousness of following
 
{ 218 }
 
 
 
 
1.#
 
 
 
 
 
 
 
 
 
 
^.•v:^v^£^:-^'*3^
 
 
 
Plate XXIII. ^, portion of human testis and epididymis, magnified 10 times.
The large circles and loops at the right are sections of the coiled tube of the
epididymis; the smaller tubules filling the left two-thirds of the picture are the
seminiferous tubules of the testis. B, area of the same testis magnified 200 times,
showing 5 clumps of interstitial cells between the tubules. Photographs from preparation lent by Joseph Gillman through I. Gersh.
 
 
 
■ V t-i .IS' ©■_•■ "!¥ -r -Jin,'
 
 
 
t
 
 
 
\
 
 
 
 
 
 
 
 
 
'^â– ^.,>
 
 
 
 
 
 
 
 
 
^^ 4, V-' ..-:> ^^^^ '^ "^ #
 
 
 
 
 
 
 
Plate XXIV. A, portion of seminiferous tubule of rat, showing formation
sperm cells. Note the peculiar hook- or halberd-shaped heads and long tails of tl
rat's sperm cells (form of human sperm cells shown in Fig. 7). Magnified 600 time
From specimen lent by K. E. Mason. B, portion of seminifierous tubule of unde
scended (cryptorchid) testis of pig. Note that sperm cell formation is totally
absent, the tubule being lined by ill-defined cells (epithelial cells). The interstitij
cells are, however, well preserved. Magnified about 600 times.
 
 
 
THE MALE HORMONE
 
these minute and lengthy canals. Finally in 1913 the problem
was cleverly solved by the late Professor Carl Huber of the
University of Michigan, who worked out a method of soften
 
 
 
Fio. 30. The human male reproductive system. From Attaining Manhood, by George W. Corner, by courtesy of Harper and Brothers.
 
{ 219 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
ing the testis with acid and then, with incredible patience and
dexterity, dissected out complete tubules under the microscope with fine needles and mounted them, without breakage,
on glass slides. He found that they are arranged in loops or
arches, all opening into a network of channels at the hilum a
of the testis, whence they are drained off by a dozen larger |
channels into the epididymis. All these facts have been depicted in Fig. 31.
 
In cross section under high magnification (Plate XXIV,
A ) the tubules are seen to be lined by several layers of cells.
The outermost layer (i.e. that farthest from the central
channel of the tubule) is made up of large clear cells. As these
divide to form the next and succeeding layers, the cells become smaller. Finally little is left except the nucleus, and
even this becomes more compact. A long tail-like process
grows out of the rapidly shrinking cell. This figure represents
the rat's sperm cells with their hook or halberd-shaped heads.
The completed human sperm cell is shown in Fig. 7. It has
a total length, including the tail, of about 60 microns or
1/400 inch. The head is about 5 microns long by 3 wide. The
sperm cell is therefore by far the smallest cell in the body.
An idea of its relative dimensions may be gained by comparing
it with the printed period at the end of this sentence. If the
sperm heads were laid like a pavement, one layer deep, on such
a dot, it would take about 2,500 of them to cover it. About
12 eg^ cells could be placed on such an area.
 
As the sperm cells are formed, little clumps of them cling
to supporting cells in the lining of the tubules until finally
they drop off and are carried along the channel toward the
seminal ducts. In animals that breed at all seasons of the
year, for instance man, rat, rabbit and guinea pig, sperm
production goes on continuously, passing in waves along the
tubules, so that sperm cells are always available. Many
wild species, however, have distinct breeding seasons once a
year, and in these there is a cycle of testicular activity. In the seasons of inactivity spermatogenesis ceases and the
testis diminishes in size.
 
 
 
 
 
Fig. 31. Arrangement of the tubules of the testis, the epididymis, and
the seminal duct. Adapted from Spalteholz and Huber. From Attaining
Manhood, by George W. Corner, by courtesy of Harper anl Brothers.
 
 
 
The testis, like the ovary, is under control of the pituitary
gonadotrophic hormones. One of the most striking results
of the brilliant campaign of investigation of the pituitary
led by Philip E. Smith, now of Columbia University, has been
the discovery (1927) that removal of the pituitary gland
from an adult male causes degeneration of the testis, and
in an immature male prevents the development of sperm cell
formation. The implantation of bits of pituitary gland or
the injection of pituitary extracts will substitute for the
missing organ and prevent degeneration of the testis. In some
species, but not in others, success has been attained in starting sperm formation in immature animals by injecting pituitary extracts.
 
Another remarkable discovery about spermatogenesis was
announced by Carl R. Moore (University of Chicago) in
1924, namely, that the mammalian testis cannot form sperm
cells unless it is subjected to a temperature slightly lower
than that of the interior of the body.^ In its normal place
in the scrotal sac the testis is under temperature conditions
exactly suited to its function. It has long been known that
a man with undescended testicles is not fertile, and horse
breeders are well aware that the same is true of cryptorchid
stallions. They often call upon veterinary surgeons to bring
down the testes of colts by operation. Moore's investigations
have given us the reason for this sterility. In man descent
of the testes normally occurs before birth. The sex glands
are formed in the abdominal cavity near the lower pole of
the kidneys, but they gradually move downward (or as some
embryologists prefer to say, the body grows upward past the
testes) until they have fully descended and have occupied
their permanent place in the scrotum. Just why this elaborate
transfer of the testes takes place, seemingly leaving them
less protected than if they remained in the abdominal cavity,
as in lower vertebrate animals, has never been satisfactorily
explained. One can only guess that when the process of evolution of the warm-blooded condition was accomplished, Nature
discovered (so to speak) that after all the testes could not
stand the temperature at which she had stabilized the mammals, and had to get them to a cooler place; but any such
conjecture seems to put Nature (or whatever you choose
to call the forces that guide evolution) in a position like
that of tariff legislators, chess players and others who find
that one change in a complicated situation may set off unexpected changes elsewhere. At any rate, descent of the
testes is a deep-seated phenomenon that has become essential
to fertility. The inside of the scrotum is several degrees
cooler than the abdominal cavity, because the scrotal sac
has thin walls and no insulating layer of subcutaneous fat,
but numerous sweat glands by which it loses heat. Moore
found that if he put the testis of a guinea pig or other animal
back in the abdominal cavity (preserving its blood supply)
and stitched it there, the seminiferous tubules became disorganized within a week, but recovered if he brought them
down again before the damage had become permanent. He
took also a fertile ram and wrapped its scrotum in woolen
coverings so that the testes were brought to the temperature
of the rest of the body. This too caused cessation of sperm
production. Actual direct heating of the testis has a similar
effect. A single exposure of the guinea pig's testis for 15
minutes to a temperature 6 degrees above that of the interior
of the body causes degeneration of the seminiferous tubules.
It is known that in man high fevers are followed by temporary
loss of spermatozoa.
 
 
1 For a full account of this subject, see Sex and Internal Secretions,
edited by Edgar Allen, 2d ed., Baltimore, 1939; Chapter VII, "Biology
of the Testes," by Carl R. Moore.
 
 
 
 
 
Descent of the testis into the scrotum is part of the general pattern of the development of the sex gland and is
therefore subject to control by the pituitary and pituitarylike hormones. It has been known for about 10 years that
gonadotropic hormones from pregnancy urine can be used
for the treatment of non-descent of the testis in boys. It does
not always succeed, for adhesions and other obstacles may  interfere; therefore the treatment must be used only in selected cases after thorough study. When the hormone fails,
surgical methods are usually still available.
 
Interstitial cells. In the angular spaces between the tubules
the microscope reveals little clumps of relatively large cells
not in any way connected with the sperm-forming cells
(Plate XXIII, B), Although there are only a few cells at
any one point, there are so many clumps that the total mass
of the interstitial cells adds up to a significant proportion
of the whole testis. Some writers call the totality of these
cells "the interstitial gland." There is an ample network of
capillary blood vessels among these cell clumps. The arrangement is obviously like that seen in the glands of internal
secretion; and it is in fact very probable that this is the
source of the testicular hormone. We cannot however be
sure that the hormone is not made by the cells of the seminiferous tubules, as will be discussed later.
 
The genital duct system. When the sperm cells have reached
completion in the testis, they are perfectly formed but inactive. Freed from their parent cells, they are swept passively
along the tubules into the larger ducts that drain the tubule
system. If the sperm cells were discharged from the body in
this nonmotile state they could not fulfill their task of reaching and fertilizing the egg cell. They require a further period
of ripening and conditioning until they become fully motile
and potent. Furthermore the seminal fluid in which they are
to be carried must be made and added to them, bringing suitable substances for their nourishment and stimulation.
 
These needs are served by a complex system of ducts and
accessory glandular structures. The dozen or more ducts
that leave the testis all drain into a single tube about 7
meters (21 feet) long, which is tightly coiled, as shown in
Fig. 31, into a dense mass, the epididymis, which lies upon
the testis. This coiled duct is lined by special secretory cells
and is believed to function as a storage place for sperm cells, which take many days to be carried through its whole length.
During this journey they have time to mature. If one examines under the microscope sperm cells taken from the
epididymis of a freshly killed animal, they are found to be
in active motion, whereas those taken from the testis are
motionless. There has been a good deal of discussion, not
yet settled, as to whether the activation of the sperm cells
is brought about by stimulatory substances secreted by the
cells lining the tube of the epididymis, or merely by the
process of maturing. Regardless of this question, it is at
least certain that the epididymis is a favorable place for the
sperm cells, for when experimenters have tied off its tube
in two places, leaving sperm cells trapped between the ligatures, the cells have been found to remain active for two weeks
or more.
 
Emerging from its coiling in the epididymis, the seminal
canal becomes less tortuous and finally runs directly upward
under the skin toward the groin, as shown in Fig. 30. This
part of the system is called the seminal duct or vas deferens.
The two ducts (one from each testis), pass over the front
of the pelvic bones to enter the interior of the pelvis. Proceeding down the side and rear of the pelvis the two ducts
approach each other under the urinary bladder. Before
they unite each of them gives rise to a small saccular offshoot or branch, the seminal vesicle. These vesicles are clubshaped hollow structures, really side branches of the seminal
duct. They are each about 10 centimeters (4 inches) long,
but folded to half that length as they lie in place. They
are glands of external secretion, producing in their cavities
a clear gelatinous substance which becomes part of the
seminal fluid. There is an old notion, hardly yet cleared out
of the medical textbooks, that the seminal vesicles are reservoirs for sperm cells, but the fact is that sperm cells are not
normally found in them.
 
 
 
The whole course of each seminal duct from epididymis to
their junction, is about 30 centimeters (1 foot) long. As
shown in Fig. 30, the two ducts unite just below the bladder
and enter the urinary channel, the urethra^ just after it
makes its exit from the urinary bladder. The combined seminal and urinary channel then passes through the prostate
gland and enters the penis.
 
The prostate gland. To most people the name of the prostate gland probably conveys no clear impression, but only
a vague and slightly ominous suggestion of something one
hardly speaks of unless it makes trouble. Years ago Mr.
Henry Mencken, when a columnist on the Baltimore Sun^
wrote an amusing article on the relative respectability of
the human organs. The heart and lungs, he said, are perfectly respectable, the liver not quite, the spleen dubious
and the kidneys definitely vulgar. In those days the prostate
gland was so far below the standard of respectability that
it could not even have been mentioned in the newspaper.
Possibly the fact that its prosaic name, from the Greek
prostates ("standing before" the urinary bladder), is often
confused with the word "prostrate" adds to its flavor of
indignity.
 
This unjustly disparaged organ is actually a gland of
external secretion. It consists of 15 to 30 branched tubular
glands, imbedded in connective tissue and muscle, forming a
round mass 20 grams (2/3 ounce) in weight and almost
completely surrounding the urethra just below the urinary
bladder. The branching tubules of the prostate gland deliver
a special secretion to the spermatic fluid, about which we
know very little except that it is favorable to the activity
and function of the sperm cells.
 
The various portions of the duct system and accessory
glands are connected through the autonomic nerves so that
all of them contribute to the seminal fluid when it is ejaculated
at the climax of sexual excitement.
 
 
The prostate gland is one of those organs which carry on
their useful functions in complete silence, never making known
their presence or their action as long as they are in good
working order ; but when something goes wrong with one of
them it suddenly becomes the focal point of the universe for
the sufferer. Its bad reputation as a source of trouble in
elderly men is due to the fact that for some obscure reason,
probably of endocrine nature, the gland tends to enlarge in
men past 50. Situated as it is around the urinary channel
(see Fig. 80), and enveloped in a heavy capsule, which prevents it from swelling outward, any marked enlargement of
the prostate inevitably blocks the outflow of urine, with serious consequences. The hope that prostatic enlargement may
(when we know enough about it) be brought under control by
treatment with hormones, lies temptingly before the investigators and may some day be realized.
 
Secondary sex characters. Before we can discuss the hormone of the testis we must take account of certain other
matters that form part of the pattern of sex. Primarily a
male animal differs from the female, or a man from a woman,
because the one has in all his cells the chromosomes for
maleness, the other the chromosomes for femaleness. One
therefore develops testes, the other ovaries. The sex glands
then begin, even in the early embryo, to call forth the secondary sex characters of their respective sexes. When the
individual reaches the age of puberty these characters become
prominent. In most mammals the males are larger, and possess
heavier, rougher skeletons and stronger muscles. The shape
of the pelvis, and to a lesser extent that of the skull and the
other bones, is different in the two sexes. In humans the
anatomy of the larynx is different and therefore the voice
becomes either male or female. The distribution and growth
of the hair are different. One sex has well developed mammary
glands, the other only rudiments.
 
In the various divisions of the animal kingdom there is a
vast array of secondary sex differences. The tail of the peacock, the antlers of the stag, the beard and the smell of the
billy goat, are evidences of what Nature can do in this way.
The subject would fill a large book.^ Perhaps the most familiar
of all, the comb of Chanticleer, has been seized upon by the
experimenters (as we shall see) and has been made to tell us,
more than any other one sign, just how the hormones control
the secondary sex characters.
 
THE HORMONE OF THE TESTIS
 
People have known since prehistoric times that castration
of men and domestic animals suppresses the development of
secondary sexual characters and causes atrophy of the
accessory male sex organs, such as the seminal vesicles and
prostate gland. The gelding of stallions, the castration of
male calves to make steers, of cockerels to produce capons,
and even of boys for the production of eunuchs, has long been
practiced. If anyone asked how the testis can control the size
and form of the skeleton, the distribution of hair, or the tone
of the voice, the explanation was vaguely to the effect that
some sort of "sympathy" existed between the parts of the
body, with the implication that the nervous system is the connecting agent. In 1849, however, Arnold Adolph Berthold, a
physician and zoologist of Gottingen, proved once for all
that the influence of the testis is carried by something that
travels in the circulating blood. Berthold's little contribution
(it is only four pages long) belongs to the fundamental
classics of endocrinology.' He tells us that on August 2, 1848,
he castrated 6 cockerels, 2 to 3 months old. Their combs,
wattles and spurs were not yet developed. From two of them
the testes were completely removed. These became typical
 
2 See many, chapters of Edgar Allen, Sex and Internal Secretions.
8 A. A. Berthold, "Transplantation der Hoden," Archiv fur Anatomie,
Physiologie, und Wissenschaftliche Medizin, 1849 (Appendix II, note 18).
 
{
 
 
 
THE MALE HORMONE
 
capons, fat, docile, without cocks' combs, wattles and spurs,
unable to crow. In the case of two others, Berthold removed
both testes but put one of them back, dropping it among the
intestines. Anatomical examination months later showed that
the reimplanted testes had become attached to the intestines
and had acquired a good blood supply, so that the testicular
tissue flourished in its new site. Both these cockerels became
typical cocks ; they grew combs and wattles, crowed, fought
their rivals, and, as Berthold delicately observes, "showed the
customary attention to the hens." One of these was later
opened surgically, the implanted testis was removed, and the
comb and wattles cut off. The head furnishings did not regenerate, and the bird, now fully castrated, reverted to the status
of a capon. The other two each had one testis removed, then
Berthold exchanged the remaining testes, giving each bird
the other's sex gland, which he implanted on the intestine.
These also became typical cocks. This beautiful experiment
showed that the testis by no means depends upon specific
nerves to maintain its control of the secondary sex characters,
but works through the blood.
 
A long story could be told of all the efforts that were made
to follow up this discovery, and there would be many divagations to relate. There was, for example, the episode of
Charles-Edward Brown-Sequard, a brilliant, restless FrancoIrish- American (181T-1894!), who made two incursions into
the field of the internal secretions. In 1856 he was the first to
remove the adrenal glands from animals and to observe the
fatal disorder thus produced, like an exaggerated Addison's
disease. In 1889, when he was seventy-two years old, he began
to dose himself with extracts of dogs' testicles. He was feeling
the debility of age, and hoped to rejuvenate himself. BrownSequard had been a good scientist and it is almost incredible
that he could have hoped to do critical experiments with himself as the only guinea pig, prejudiced by all his hopes and
fears for his own health. He thought that after the injections
 
{ 229 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
he felt much stronger and more alert, and reported his experience with pathetic enthusiasm and intimate personal detail
before the medical societies of Paris and in the journals. The
medical profession was on the whole incredulous and Paris
made a good deal of fun of him. We know now that the extract
could have had little or none of the genuine testis hormone in
it. It was made by putting mashed-up testes in water and
filtering the mixture. We are now well aware also that when a
man grows old he ages all over, not only in his testicles.
Nevertheless the idea of administering gland extracts had its
up-to-date appeal in those days of the earliest discoveries
about the endocrine organs. German biochemists had recently
isolated from animal testes a peculiar nitrogenous substance
called "spermine." Various people leaped to the conclusion
that this might be the active substance in Brown-Sequard's
extracts. Spermine was therefore put on the market under the
auspices of the chemist Poehl, and thus became (to the best
of my knowledge) the first endocrine product to be commercialized. Thus Brown-Sequard's notoriety was probably responsible, more than anything else, for the exploitation of
endocrine preparations in the drug trade ahead of scientific
knowledge. Since then, barrelfuls of extracts and millions of
tablets have been fed and injected into human patients, with
uncritical optimism, before the chemists and physiologists
could learn the facts. The benefits of endocrine research on
the reproductive glands have almost been stifled by this
exploitation. Even today the practicing physician finds it
difficult to distinguish what is sound and practical amid the
flood of well advertised endocrine drugs.
 
There have been premature efforts also to apply Berthold's
experiment of transplantation of the testis to the rejuvenation of senile men. The most widely publicized of these was
that of the Franco-Russian surgeon Serge Voronoff, who was
busy from about 1912 to 1925 implanting monkey testes into
human patients. The American journalists of those days
 
{ 230 }
 
 
 
THE MALE HORMONE
 
could not refer to the testicles by name in the newspapers, and
introduced the expression "monkey glands," which became a
byword and finally a joke. Some of the patients reported
hopeful results. The grafts may indeed have yielded a little
of their hormone to the body before they disintegrated and
disappeared. More often, no doubt, the benefit was entirely
psychic. It is now clearly established that tissues from one
species of mammal cannot grow in another species, and indeed
it is practically impossible to secure a permanent transplant
from one human to another. Grafting of the testis has therefore not been adopted as a sound procedure.
 
While we are on the subject of rejuvenation, we may as
well mention the Steinach operation. Eugen Steinach of
Vienna, a scientist of good reputation, came forward about
1920 with a proposal based on two premises. The first of
these, which has even yet not been proved, was that the testis
hormone is made entirely by the interstitial cells. (The question will be discussed more fully below.) The second premise
has since been proved incorrect; it was that if the seminal
duct is tied off, the seminiferous tubules will degenerate leaving more room for the interstitial cells, and these will increase
in number and presumably make more hormone. Steinach
believed that such a ligation of the seminal ducts of man
(vasectomy) would restore vitality of body and of sexual
function to elderly men. He brought forward apparently
strong evidence from animal experiments to support the
idea. The operation made a strong appeal to men who were
yearning to regain their lost youth. It has been tried widely,
but the medical profession remains unconvinced, and the
scientific basis for it as outlined above has been disproved.
 
Meanwhile, through all this period of sensationalism and
premature publicity, the slow implacable attack upon the
problem by inconspicuous investigators has gone forward to
notable success. The important thing in endocrine research is
 
{ 231 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
to find a test for whatever hormone one suspects to exist —
some sharp-cut characteristic effect that is lost when the
gland is removed and that can be restored by giving back the
gland in implants or in extracts. At each step of our story in
this book such a method has been the key to success. The
vaginal smear test for the estrogens, the rabbit uterus test
for progesterone, promptly made possible the purification of
these substances. If the test is quick and cheap, the results
will come that much faster. Berthold's experiment with the
cockerels provided an ideal method of testing for a hormone
of the male sex gland. Success came to those who followed his
lead, putting aside premature efforts to work with slowly
growing mammals or to rejuvenate old men. Between 1907
and 1927 two or three European investigators reported that
they had extracts of the testis which induced growth of the
head furnishings of cocks. None of these experiments, however, was fully convincing. Meanwhile the estrogenic hormones were isolated and discovered to be soluble in fat solvents. In 1927 a graduate student in biochemistry under
Professor F. C. Koch at the University of Chicago, L. C.
McGee (now a physician in Elkins, West Virginia) applied
the new methods of extraction to the tissues of the bull's testis
and promptly secured a relatively pure extract that was
capable of producing rapid growth of capons' combs (Fig.
32). This lead was followed up by a group of workers in
biochemistry and zoology in the University of Chicago,
including McGee, F. C. Koch, C. R. Moore, L. V. Domm, and
Mary Juhn, and by various workers abroad. The successive
steps in the purification and identification of the male or
androgenic hormones were much like those in the isolation of
the estrogenic substances. In 1929, S. Loewe and S. E. Voss
of Dorpat (Estonia) and also Casimir Funk and B. Harrow
of New York found androgenic substances in human urine
from males. The indefatigable Butenandt and his aides then
 
{ 232 }
 
 
 
THE MALE HORMONE
 
 
 
 
 
Fig. 32. The effect of testis hormone on the rooster's comb, a, untreated
castrated cockerel. 6, castrated cockerel after 11 days' treatment with
testis extract. Drawn from photograph by Freud and coworkers.
 
isolated, completely purified and identified two of these compounds, called respectively androsterone and dehydroandrosterone, in 1931-1932. L. Ruzicka and his colleagues at
Basel made them synthetically in 1934. The next year David,
Dingemanse, Freud and Laqueur of Amsterdam succeeded
in the difficult task of purifying the hormone from extracts
of the testis itself, and found the substance called testosterone, which differs slightly in its chemical constitution from
the androsterone found in urine. The groups of workers led
by Butenandt and Ruzicka immediately synthesized this hormone as well. Now that such substances could be made in the
test tube as well as in the testis, and (as we shall see) began
to be found in other tissues also, the adjective "male" as
applied to them gave place to the more apt word "androgenic," meaning "promoting masculinity"; the latter word
defines the effects without implying any particular place of
origin and can therefore be used of such substances when, for
example, they turn up in female urine, in the cortex of the
adrenal gland, or in a chemist's flask.
 
Chemistry of the androgenic hormones. These substances
belong to the same family of chemical substances as the estro
 
 
{
 
 
 
}
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
genie hormones and progesterone. Testosterone has the following structure :
 
CH3 ^OH
 
 
 
 
TESTOSTERONE
 
 
 
Androsterone, prepared from human male urine, has this
formula :
 
 
 
 
ANDROSTERONE
 
 
 
A statement of the relation of these particular sterols to
simpler chemical substances will be found in Appendix I.
 
At the present time at least thirty-five substances of similar composition are known which have androgenic effects.
Some of these have been found in the adrenal gland, or in the
urine under special circumstances, but most of them are
artificial products of the chemical laboratory. A list of them
is given by Koch.* The male hormone which is actually at
work in the body is probably testosterone itself or a closely
similar substance. The reason a definite statement cannot be
made on this point is that we are not sure that the chemical
procedures necessary to extract and concentrate the hormone
do not change it chemically. When testosterone is administered to a castrated animal, it is transformed in the body and
is excreted by the kidney as androsterone. Since androsterone
occurs in the urine of normal men, this is presumptive evi
* Edgar Allen, op, cit.. Chapter XII, "The Biochemistry of Androgens,"
by F. C. Koch.
 
 
 
THE MALE HORMONE
 
dence that testosterone, or something very much like it, is in
circulation in the body.
 
Just what cells in the testis are responsible for producing
the hormone is an interesting and debatable question. There
are two possibilities, the interstitial cells on one hand, and
the spermatogenic cells of the tubules on the other. Let us
examine the evidence. In the first place the interstitial cells
look like endocrine tissue, since they are large cells provided
with a rich circulation of blood but obviously not producing
an external secretion, for they are not arranged in channels
and ducts. Years ago, moreover, Bouin and Ancel called
attention to evidence favoring the interstitial cells as the
source of the hormone. When the testes fail to descend and
therefore do not form sperm cells, the cells lining the tubules
are reduced to an inactive state (Plate XXIV, B). They
assume a vague, nondescript form as if they were merely
surviving without any function. The interstitial cells however
remain in place, they look normal, and indeed have even been
thought to increase in amount. Although the cryptorchid
animal or man bearing such sex glands is sterile, he develops
male secondary sexual characters and male sex psychology.
With the spermatogenic cells seemingly inactive (as judged
by appearances under the microscope) but the interstitial
cells in good condition, it is difficult to avoid the assumption
that the latter are making the sex hormone. When bits of the
testis are grafted successfully into a castrated animal the
same cellular state develops in the grafts, and the animal
likewise develops male qualities. It was formerly thought that
tying off the seminal ducts produced the same effect. The
Steinach operation described above was based upon this whole
set of considerations. It is now known, however, that blocking
the ducts and thus damming up the semen does not stop
spermatogenesis. It is also known that cryptorchid (undescended) testes with inactive sperm cell formation do not
 
{ 235 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
produce more hormone but considerably less. In short, the
two functions of the testis, spermatogenesis and hormone production, run parallel to a certain extent. For this reason some
of the soundest of the investigators are not willing to point
to one or the other of the constituent tissues of the testis and
saj^ "here is the sole source of the hormone." The tubule cells,
even if they are inactive in producing sperm cells, may for all
we know still be taking part in making the hormone ; or perhaps the two kinds of cells work together. If a time ever comes
when the hormone can be recognized in the tissues in very
small amounts, say by some sort of super-spectrograph or
X-ray analysis, such as the modern magicians of the physics
laboratories are using in their easier problems of test tube
chemistry, then perhaps we can answer such questions as
these.
 
There is no sharp division between the estrogens, the androgens, and the progestins. Several of these substances give
both estrogenic and androgenic effects, and a few have been
found even to affect the uterine lining like progesterone,
though only in very large doses.
 
The androgens are usually assayed by testing their effect
upon the growth of the comb of the capon. The League of
Nations Committee on Standardization of Drugs set up in
1935 an international standard of potency, specified as the
equivalent of 0.1 milligram of crystalline androsterone. This
is approximately the daily dose required to give a measurable
response in a capon's comb in 5 days.
 
The androgenic hormones are usually injected in oil solution. In recent years the method of implanting pellets under
the skin has begun to be tried. The hormones are also effective
when applied in suitable ointments. Growth of the cock's
comb can be elicited by applying hormone-containing ointments directly to the comb itself (Appendix II, note 19).
 
Effects and medical use of the androgenic hormones. The
 
{ 236 }
 
 
 
THE MALE HORMONE
 
effects of the androgenic hormones, as C. R. Moore" neatly
puts it, are measured by the difference between a castrated
and a normal man. These substances substitute completely, in
animal experiments, for the normal internal secretion of the
testis. They counteract castrate atrophy of the seminal
vesicles and prostate gland ; when given to immature animals
they stimulate precocious growth of the accessory sex organs,
and they induce sex activity and mating in castrated and
immature males. A castrated male, skillfully treated with
potent hormones, will resemble a normal animal of his species
in all respects except that he will be infertile because he is
producing no germ cells.
 
These effects have been tested quite thoroughly in an experimental way upon human patients who lack the testis hormone.
In these men and boys, as in laboratory animals, the injected
hormones bring out all the known responses which the bodily
tissues normally make to the natural hormones of the testis.
It should be recalled here that the symptoms of deprivation
of testis hormone may be due to defects in either one of two
glands. The testes may themselves be missing or deficient, or
the pituitary gland may be furnishing an inadequate supply
of gonadotropic hormone (see Chapter VI). In the latter
case the testis will not be functional and the patient will show
symptoms of testis hormone deficiency exactly as if the testis
itself were the seat of the difficulty. At some time in the future,
when endocrine treatment has reached a higher state of perfection, it may become possible to treat the pituitary cases
with pituitary hormones, reserving the androgenic hormones
for cases of deficiency of the testis itself. At present, however,
the distinction is more or less academic. In either case the
physician finds himself confronted with signs of male hormone
deficiency, and the question of immediate importance is how
 
8C. R. Moore, "Physiology of the Testis," in Glandular Phytiology
and Therapy , 2d ed., Chicago, 1942.
 
{ 237 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
far he can hope to help the patient by treatment with androgenic hormones.
 
I write about this subject of the medical use of the androgenic hormones with hesitation, because it is difficult on one
hand to avoid raising false hopes without on the other hand
underrating the progress that has been made and the future
possibilities in this field. To make the problem clearer, let us
consider a specific case.® Here is a boy in his middle 'teens who
is not exhibiting the usual signs of sexual maturation. We
know that if the deficiency persists he will grow to be a
eunuchoid man. He will have underdeveloped genital organs,
a delicate skin, the childhood type of hair distribution, a highpitched voice; possibly also he will be overfat and he may
suffer from muscular and circulatory difficulties causing easy
fatigability and inability to do hard muscular work. Another
important feature of his general immaturity will show itself
in the long bones of the skeleton. The growth zones (epiphyseal junctions) will not close up at the usual time (18 to
20 years), but will go on growing, so that he will develop the
long delicate bones of the eunuch and will thus display his
defect in the entire configuration of his body. Although the
deficiency has nothing to do with intelligence or fundamental
character, he is very likely, as he grows up, to suffer from
psychological damage due to a sense of defectiveness and of
difference from other men.
 
If this boy could be treated as simply as a guinea pig is
treated in the laboratory, we could control all these visible
defects by administration of androgenic hormone. The treatment is fairly expensive and must be kept up by frequent
injections or inunctions. Administration by pellets buried in
the tissues may in time become practical, but is hardly yet
ready for use. We are, moreover, not yet free from insecurity
about possible danger from long continued administration of
 
ej. B. Hamilton, "Testicular Dysfunction," in Glandular Physiology
and Therapy, 2d ed., Chicago, 1942.
 
 
 
THE MALE HORMONE
 
the sex hormones through damage to the tissues of various
organs. Finally, whatever improvement is gained by treatment
will wear off fairly rapidly if the drug is discontinued. In one
feature only, so far as known, the improvement is permanent;
that is in the skeleton, for the growth of the long bones will be
permanently stopped by closure of the epiphyseal junctions.
Even this requires care and forethought, for if the treatment
is begun too early, the epiphyses may be closed prematurely
and growth stopped before the boy reaches full stature.
 
I have no doubt said enough to make it clear that the use of
androgenic hormones to correct testicular hormone deficiency
is very decidedly still in the stage of exploration, and that
every case so treated is an experiment. This does not mean
that the attempt should not be made by properly trained
physicians and scientists who are in a position both to guard
the welfare of the patient and to study the results with rigid
scientific standards for future guidance. We have, of course,
been considering an extreme case, one in which there is permanent total deficiency. The androgenic hormones are certainly going to be useful in many disturbances of less intensity
and as collateral treatment. To make up for partial deficiencies, to tide over the acute deprivation which follows surgical
removal of the testicles, to supplement the treatment in various cases of sexual disability and impotence — for such purposes the androgenic substances will no doubt be helpful in
competent medical hands.
 
At any rate, the contemplation of these distressing deficiencies of the sex hormones must have impressed the reader
anew with the thought that the normal processes of reproduction involve a remarkable series of linkages and coordinations within the body. It is indeed a subtle and potent chemistry by which the reproductive glands create the egg and the
sperm cell and surround them with all that is needful of nourishment and protection to carry them through their critical
journey from conception to birth. In this book we have traced
 
{ 239 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
the main outlines of these complex physiological patterns.
We have seen the great advance of knowledge that has taken
place in less than fifty years, by the efforts of faithful laborious men who worked in peace and quiet, giving their lives to
the understanding and improvement of life. When I wrote
these closing words, the guns were sounding all over the world.
The scientists were dropping their instruments, or turning
them perforce to the uses of death and wastage. But life goes
on nevertheless, and the problems of life will be studied until
the day comes we all dream of, when mankind may everjrwhere
seek the truth undaunted by fear of war and oppression. In
that day we shall gather the fruits of our labor. The childless
wife, the ailing girl, the boy deprived of his birthright of sex
by some failure of Nature's process, will call and not in vain
for the help that science can bring them, and man shall understand at last the miracle of his birth.
 
 
 
==APPENDIX I==
 
MORE ABOUT THE CHEMICAL STRUCTURE
OF THE SEX GLAND HORMONES
 
WHEN discussing the chemistry of the ovarian
and testicular hormones, in Chapters IV, V, and
IX, I tried first to make their general nature as
clear as possible to readers who have not studied chemistry
at all, and then I gave the structural formulas for the benefit
of those who are familiar with organic chemistry. Most of my
readers, however, probably belong to a middle category. They
have studied the elements of chemistry in a college course that
included a few weeks on the compounds of carbon, so that
they can comprehend an organic formula, at least of the more
familiar sort, especially if written out in full and its significant features are explained. They are on the other hand
hardly prepared to grasp at once the full meaning of one of
these complex and unfamiliar hormones or to perceive its
relation to the simpler substances chiefly dealt with in college
chemistry. For the guidance of such readers I propose to
write the formulas of the more important sex gland hormones
as clearly as possible and to explain their nature exactly as
I had to have them explained to me when I found that nowadays even an anatomist must struggle with chemistry.^ I
assume that the reader recalls that the valence of carbon is
4, of hydrogen and the hydroxyl group (OH) is 1, and of
oxygen 2:
 
I
 
C — H — OH 0=
 
 
 
1 In preparing this discussion, I have drawn freely upon the standard
textbooks of organic and biological chemistry. See also The Chemistry
of Natural Products Related to Phenanthrene, by L. F. Fieser, New
York, 1936; Sterols and Related Compounds, by E. Friedmann, Cambridge, England, 1937; and The Chemistry of the Sterids, by Harry
Sobotka, Baltimore, 1938.
 
{ 243 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
and that he comprehends the general significance of simple
formulas such as that of ethyl alcohol and benzene :
 
 
 
H
 
 
 
I I
 
 
 
C C — OH
 
 
 
HC
 
 
 
HC
 
 
 
^
 
 
 
^.
 
 
 
 
 
 
H H
 
ETHYL ALCOHOL
 
 
 
BENZENE
 
 
 
The basic hydrocarbon of the sex gland hormones. All the
naturally occurring sex gland hormones can be understood in
relation to certain basic hydrocarbons. One of these, called
estrane, has the following structure:
 
 
 
CH2
 
 
 
 
CH2
 
 
 
HpC
 
 
 
H2C
 
 
 
ESTRANE
 
For the sake of convenience we number the carbon atoms
arbitrarily, as shown in the diagram. We can save time and
trouble henceforth by omitting the obvious CH's, as follows :
 
 
 
}
 
 
 
 
ESTRANE
 
This means the same as the complete formula above. Whenever, in formulas cited hereafter, a linkage point is written
without indication of the elements, it means a carbon atom
with enough hydrogen atoms to fill up its quota of 4 valences.
Unsaturated carbon atoms will be indicated by double bonds.
 
The relation of estrane to simpler organic compounds.
Those substances derived from estrane which are of interest
to us as hormones belong to a group of compounds called
sterols, which have already been characterized briefly in
Chapter IV. The relation of the sterols to more familiar substances can be explained as follows :
 
Three benzene rings condensed in line form the substance
anthracene :
 
 
 
 
ANTHRACENE
 
 
 
In a slightly different arrangement, exactly the same atoms
constitute phenanthrene :
 
{ ^i5 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
 
 
 
PHENANTHRENE
 
With one more ring, this time of 6 carbons instead of 6, we get
cyclo-penteno-phenanthrene :
 
 
 
 
CYCLOPENTENOPHENANTHRENE
 
 
 
This structure of 4 rings, two upstairs and two downstairs,
has a great significance to the chemist and physiologist, for
it is the basis of many important substances in the body.
When the rings are unsaturated at various linkages and provided with various side groups and side chains, an enormous
series of compounds occurs, which are known as steroids.
These include the sterols (one of which, cholesterol, is a widespread constituent of the animal body), the bile acids, and
the sex gland hormones. The unravelling of their constitution
has been one of the great feats of modern organic chemistry,
and it is now being followed up by the rapid production of
 
{ 246 }
 
 
 
APPENDIX I
 
scores and hundreds of new synthetic compounds of similar
constitution.
 
To proceed from cyclopentenophenanthrene to estrane, the
hydrocarbon first mentioned above, let us imagine the former
compound completely saturated with hydrogen and a methyl
group (CH3) attached to the carbon atom which we have
numbered 13:
 
 
 
 
ESTRANE
If the first ring is unsaturated, we have estratriene :
 
 
 
 
ESTRATRIENE
 
The estrogenic hormones. At last we have arrived at an
actual hormone, for the best-known of all the estrogenic substances, estrone^ is like estratriene except that it has a hy
{ 247 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
droxyl group at carbon 3, and an atom of oxygen at carbon
17; in other words it is 3-hjdroxy, 17-keto estratriene (for
clearness, the formula is written in full as well as in the usual
simplified form) :
 
 
 
 
HO-C^^/C^^^CH^
 
 
 
ESTRONE
 
 
 
 
ESTRONE
 
 
 
As explained in Chapter IV, a large series of naturally
occurring estrogens is known. All these are closely related to
estrone. Among the representative estrogens are the following:
 
Estradiol, the hormone which probably exists in the greatest amount in the body, has a hydroxyl group at position 17
instead of the doubly-linked (ketonic) oxygen:
 
{ 248 }
 
 
 
APPENDIX I
 
 
 
CH3 ^OH
 
 
 
 
ESTRADIOL
Estriolf which occurs abundantly in the human placenta, is
 
 
 
CH3 ^OH
 
 
 
 
ESTRIOL
 
Equilenin, isolated from mare's urine, belongs to a group
of estrogenic substances which have unsaturated carbon
atoms in the second ring as well as the first :
 
 
 
CH3 ^0
 
 
 
 
EQUILENiN
{ U9 }
 
 
 
THE HORMONES IN HUMAN REPRODUCTION
 
With the foregoing explanation the reader, if he is stiU
curious about these relationships and wishes to follow out such
problems as the synthesis of estrone, is now in a position to
study a more technical discussion of the chemistry of the
estrogenic hormones such as E. A. Doisy gives in Sex and
Internal Secretions,*
 
The androgenic hormones. These may be understood by
reference to their basic hydrocarbon, androstane, which differs from estrane by having a second methyl group, attached
 
to carbon 10:
 
CH.
 
 
 
 
ANDROSTANE
 
 
 
Androsterone, referred to in Chapter IX, as the hormone of
male type first isolated from human urine, is 3-hydroxy, 17keto androstane: ^^
 
o =0
 
 
 
 
ANDROSTERONE
 
2 Sex and Internal Secretions, edited by Edgar Allen, 2d edition,
Baltimore, Williams and Wilkins, 1939. Chapter XIII, "Biochemistry of
the Estrogenic Compounds," by E. A. Doisy.
 
{ 250 }
 
 
 
APPENDIX I
 
 
 
Testosterone, the male hormone obtained directly from the
testis, has a double bond in the first ring :
 
 
 
CH,
 
 
 
oy
 
 
 
 
TESTOSTERONE
 
A large number of substances having androgenic potency,
and the steps by which they have been prepared synthetically,
are discussed by F. C. Koch in Sex and Internal Secretions.
Progesterone. The corpus luteum hormone can best be understood by comparison with its basic hydrocarbon, which is
called pregnane. This has the two methyl groups already seen
in androstane, and also an ethyl group (CH2 . CH3) as a side
chain on carbon 17. (The two ethylic carbons are numbered
20 and 21, those of the methyl groups being 18 and 19.)
 
CH,
 
 
 
CH2
 
 
 
 
PREGNANE
{ '^61 }
 
 
 
Progesterone, as will be seen from the following formula, has
 
a double bond in the first ring, and two atoms of oxygen at
 
positions 3 and 20 respectively. It is therefore 3, 20 diketo
pregnene :
 
CH3
 
 
 
0<^
 
 
 
 
PROGESTERONE
 
Its excretion product in the human body, pregnanediol, can
be derived from this formula by the addition of 6 atoms of
hydrogen; that is, the 2 ketonic atoms are replaced by
hydroxyl groups, the extra bonds at these points being satisfied by one hydrogen each, and the two unsaturated carbons
are saturated:
 
CH,
 
 
 
CHOH
 
 
 
 
PREGNANEDIOL
{ 252 }
 
 
The preparation of progesterone from pregnanediol and
from stigmasterol (a natural vegetable sterol) and other
chemical matters of interest concerning progesterone and its
related substances are fully discussed by W. M. Allen in
Sex and Internal Secretions.
 
As explained in Chapter V, when pregnanediol leaves the
body in the urine, it does so in combination with glycuronic
acid and with sodium. The resultant compound, sodium pregnanediol glycuronidate, has the following structure :
 
 
 
CH3 H\
 
 
 
 
u
 
H H H
 
C — C — C — C— COONa
 
OHO
 
H H
 
 
 
SODIUM PREGNANEDIOL GLYCURONIDATE
 
 
==APPENDIX II==
Note 1 (Preface, page x, line 30). Bibliographic referCTices. Full bibliographies covering practically the whole field of this book will be found in :
 
Sex and Internal Secretions, edited by Edgar Allen, 2d
 
edition, Baltimore, 1939. Glandular Physiology and Therapy , 2d edition, Chicago,
 
1942. Biological Actions of Sex Hormones, by Harold Burrows, Cambridge, England, 1945. Endocrinologie de la Gestation, by Robert Courrier,
 
Paris, 1945. Patterns of Mammalian Reproduction, by S. A. Asdell, Ithaca, N.Y., 1946.
 
Note 2 (page 64, line 32). The Atlantic palolo. An interesting account of the swarming of an Atlantic species closely related to the oft-cited palolo of the Pacific Ocean, has recently been published by L. B. Clark and W. N. Hess, "Swarming of the Atlantic Palolo W6rm," Carnegie Institution of Washington^ Publication d'^l).. Papers from the Tortugas Laboratories, vol. xxxiii, 1943.
 
Note 3 (page 96, line 24). Action of the sex-gland hormones on the embryonic sex organs. Since the preparation of these lectures, there has been a considerable clarification of our knowledge of the action of the estrogens and of the male hormones (androgens) upon the growth of the accessory sex organs of the embryo and in particular upon their differentiation into male and female types.
 
Stating the fundamentals of the problem briefly, the original determination of the sex of an individual mammalian animal is made at the time of fertilization of the Qgg, by a mechanism which operates through the chromosomes of the ^gg- and sperm-nucleus. No visible difference between the sexes appears however until the embryo reaches an age (in the human species, about six weeks after fertilization) when the sex glands begin to show the characteristics of the ovary or testis respectively. The accessory sex organs, when they first develop, are capable of being directed toward the pattern of either sex. All the necessary rudimentary tissues for the development of both the male and the female sex organs are present in every embryo, regardless of the sex of the individual as determined by fertilization. About the 9th week of embryonic life (in humans) the sex-pattern of the accessory organs begins to be distinguishable, and after that the male organs (epididymis, vas deferens, prostate, seminal vesicles), and the female organs (uterus, vagina) begin to be recognizable to the embryologist, according to the sex of the individual.
 
Experiments on a number of species of laboratory animals, done at these early stages, reveal that before the definite characteristics of the accessory organs of the two sexes appear, and to a gradually diminishing degree thereafter, their differentiation may be modified and controlled by treatment with estrogens and androgens. For example, an embryonic animal which is genetically a male (as determined at the time of fertilization) may be made by suitable doses of estrogenic hormone to develop accessory sex organs of female type. Reversal in the opposite direction may be accomplished by subjecting a genetic female to treatment with androgenic hormone. The hormone administered by the experimenter thus overrides and contradicts the influences which normally control the sex-pattern of the accessory organs.
 
Such experiments were first done on the relatively accessible embryos of aquatic animals, especially the amphibians. The extensive literature which has grown up on this subject is well reviewed in Sex and Internal Secretions, Baltimore, 1939. Experimentation on mammals has been more difficult because of the inaccessibility of the embryos in the uterus. R. K. Burns, Carl Moore and others have cleverly taken advantage of the peculiar reproductive processes of the opossum. This creature, the only marsupial dwelling north of Mexico, gives birth to its young at the extraordinary age of 13 days after ovulation ; that is to say, the embryos leave the uterus at that time and migrate to the brood pouch on the lower belly of the mother, where each embryo firmly grasps a nipple with its mouth and goes on growing and developing for many weeks. At the time of transfer to the pouch, the young are so embryonic that the accessory sex organs, including even the external genitals, are in the indifferent stage. The sex cannot be clearly determined by inspection until ten days after birth, when the scrotum of the male and the pouch of the female are definitely recognizable.
 
Once in the pouch, the young are accessible to the experimenter, who needs only to anesthetize the mother to get at them and inject them with micro-doses of the hormones. As in the salamanders and other lower vertebrates, so also in the opossum it has been possible to reverse the sex pattern of the accessory organs and to make genetic males acquire the structure of females, and vice versa. The gonads (testis or ovary) remain unchanged in their sex- affinity. In higher mammals, such as the rat, mouse, and guinea pig, in which the young are carried in the uterus until birth, very similar results have been obtained by the expedient of giving relatively enormous doses of the hormones to the mother during pregnancy. For detailed reviews of this subject the reader is referred to articles by R. K. Burns, "Hormones and the Growth of the Parts of the Urinogenital Apparatus in Mammalian Embryos," Cold Spring Harbor Symposia on Quantitative Biology, X, 1942 ; and C. R. Moore, "Gonad Hormones and Sex Differentiation," American Naturalist, 78, 1944.
 
These experiments teach us that the hormones of the kind produced by the adult sex glands can be used in the laboratory to induce differentiation of the originally indifferent accessory sex organs into structures typical of the male and female respectively. The experiments obviously do not tell us whether the substances that are produced in the embryonic gonads, acting under natural conditions to induce the development of the sex organs, are themselves hormones of the steroid estrogen-androgen types which are effective in adult physiology. For all we know at present, the embryonic hormones may be chemically like or unlike the known estrogens and androgens. This query has implications too large for further discussion here, leading us into the whole question of the nature of the embryonic inductor substances and their relation to growth-inducing and morphogenetic hormones. (For a brief elementary statement of the theory of embryonic inductors or "organizers," see G. W. Corner, Ourselves UnborUf New Haven, 194«4, pages 103-106; for a detailed discussion, see Joseph Needham, Biochemistry and Morphogenesis ^ Cambridge, England, 1946.)
 
^^ParadoxicaV^ effects. It has frequently been observed, in experiments with the sex-gland hormones upon embryonic tissues, that higher dosages of the androgenic substances may induce female rudiments to accelerate development in the female direction, and there is evidence that estrogenic substances may sometimes act similarly upon male structures. The studies of Burns (see the article cited above) have shown that these so-called "paradoxical" effects occur in his embryonic opossums only when the dosage of the hormones is relatively high. By reducing the dose of the male hormone Burns was able to limit its stimulative effects to male structures only, all the female structures being unaffected. We may suppose therefore that the action of these hormones upon embryonic rudiments is fundamentally sex-specific, and that the "paradoxical" effects reported by various authors for a number of animals are the result, in some way, of excessive doses.
 
Note 4 (page 111, line 33). Is the corpus luteum necessary for segmentation of the egg and for implantation of the embryo? Nothing has turned up, since the first edition of this book was published, to cast any doubt upon the conclusion that the hormonal action of the corpus luteum is necessary for the survival of the early embryo in the uterus before its' attachment, and for its implantation in the endometrium. A number of considerations make it necessary, however, to restate the matter somewhat differently. In a recent striking investigation M. N. Runner of the Jackson Memorial Laboratory at Bar Harbor (Anatomical Record, 98, 1947, p. 1) removed fertilized eggs of the guinea pig from the oviducts and placed them in the anterior chamber of the eye, where they could be observed with a microscope through the clear cornea. It has been known for some time that the fertilized mammalian egg can go on segmenting and reach the blastocyst stage outside the mother, in tissue-culture dishes. The motion pictures of W. H. Lewis (see page 56 and Plate XI) were made from eggs cultured in that way. The anterior chamber of the eye is well-known to be a favorable place for the growth of transplanted tissues, for the aqueous humor is an excellent physiological salt solution, and a good bloodsupply is readily available for tissues that become attached to the iris (cf. Markee's grafts of endometrium, page 150). Runner found that when placed in the eye, the fertilized eggs of the guinea pig would continue dividing, would proceed to the blastocyst stage and become implanted, or at least begin to implant upon the iris. All these phenomena of embryonic growth were found, moreover, to occur even though the ovaries were removed or the eggs placed in the eye-chamber of another animal which had not ovulated and therefore had no corpora lutea. Indeed, the eyes of male mice proved to be as favorable for growth of embryos as those of females.
 
Some years ago J. S. Nicholas of Yale University operated upon rats in such a way that the fertilized eggs passed out of the oviduct into the abdominal cavity. Among a large number of animals thus prepared there were a few cases in which the embryos thus misplaced grew, attached themselves to the mesenteries or elsewhere on the peritoneal lining of the abdominal cavity, and lived out the full term of gestation.
 
The distinguished French biologist Robert Courrier in his Endocrinologie de la Gestation (Paris, 1945) reports a curious observation upon a rabbit in which, on the 19th day of pregnancy, one embryo was caused by surgical means to escape from the uterus into the abdominal cavity, where it attached itself to the peritoneum. Two other embryos were allowed to remain in the uterus. The ovaries were removed at this same operation. At the end of the usual term of gestation, the fetus in the abdominal cavity was alive, whereas those left in the uterus had died as a result of the loss of the ovaries. Evidently the corpora lutea are essential for the welfare of the embryos only if the latter are in the uterus.
 
We must assume from such experiments that the early mammalian embryo has a strong inherent vitality which will enable it to grow wherever it has the necessary warmth, a supply of oxygen and nutritive materials, and a generally suitable chemico-physical environment. Since, on the other hand, as experiments have proved, the early embryo cannot survive in the uterus except under the influence of progestational changes induced by the corpus luteum, it follows that the uterus, when not so prepared, is actually an unfavorable place for the early embryo as compared with the anterior chamber of the eye, the peritoneal cavity, or even a tissue-culture slide.
 
This seemingly paradoxical situation is made intelligible by thinking of the evolutionary background of mammalian reproduction. It is characteristic of eggs and early embryos of lower animals that they are prepared to develop without shelter and nutriment from the mother. When the mammals evolved the phenomenon of utero-gestation, the chosen place of shelter, the uterus, was developed from part of the oviduct, a channel that had for its purpose the efficient transportation and discharge of the eggs, not their retention and maintenance. To fit it for gestational functions, the endocrine mechanism of the corpus luteum was evolved. In the light of this thought it is not surprising that the uterine chamber is actually a less favorable place for early embryos than, say, the anterior chamber of the eye, except when the hormones of the ovary act upon it and change it into a place of superior efficiency for its new function.
 
Note 5 (page 118, line 11). Progestin by mouth. The progesterone-like substance that can be administered orally is called pregneninolone (preg-nene-in-ol-one) or ethinyl testosterone. Its chemical structure is
 
 
PREGNENINOLONE
 
Note 6 (page 122, line 6). Excretion products of progesterone. The statement in the text is not quite correct. Marker, Wittle, and Lawson have found pregnanediol in the urine of pregnant cows and mares, in concentrations not greatly different from those in human pregnancy urine. They found, strangely, that the urine of bulls contains about twice as much pregnanediol as human pregnancy urine. It unfortunately remains true that the end-products of progesterone metabolism have not been identified in the common laboratory animals.
 
Note 7 (page 126, line 2). /« the corpus luteum necessary throughout pregnancy? Experiments on the Rhesus monkey by C. G. Hartman and G. W. Corner, which were under way when the first edition of this book was published, have been completed (Anatomical Record, vol. 98, August 1947). They prove that the corpus luteum of pregnancy, and probably the whole of the ovarian tissue, can in this species be removed as early as the 25th day of pregnancy without disturbing gestation.
 
Note 8 (page 132, line 11). Clinical use of progesterone and pregneninolone. Five years after these pages on the practical use of progesterone were first written, they may be reprinted with little or no modification. The same hopes, the same successes, the same cautions, still stand. Some progress has been made in selecting cases suitable for progesterone therapy, thanks to the use of pregnanediol excretion as a test of the need for progesterone. In the large university hospitals, where there are laboratories in the women's clinics equipped for the assay, only those cases of habitual abortion and of menorrhagia that show a low excretion of pregnanediol are treated with progesterone or pregneninolone. In these selected cases, naturally, the percentage of favorable results is higher than when all cases of a given disease are treated on a hit-ormiss basis.
 
Sterility, when there is similar evidence that a low progesterone level is involved, is to be added to the list of pathological conditions in which progestin therapy is now being tried.
 
Note 9 (page 135, line 24). Menstruation in lower primates. Evidence has accumulated that something like menstruation, in an elementary form at least, occurs in the New World monkeys. In several vspecies of howler, spider and capuchin monkeys there is periodic shedding of small amounts of blood into the tissue of the lining of the uterus. A few red blood cells escape into the genital canal and can be detected in washings made by injecting salt solution into the vagina, removing it again and examining it under the microscope. There is not enough blood lost to show externally.
 
A process apparently resembling menstruation in the elephant shrew of South Africa has recently been described by Van der Horst and Gillman. The species in question belongs to a family of animals which has been assigned by some naturalists to insectivores and by others to the primates.
 
In summary, it begins to appear that menstruation is not sharply limited to the higher primates, but that on the contrary it exists in a rudimentary form in other families of primates and primate-like animals. (See S. A. Asdell, Patterns of Mammalian Reproduction, Ithaca, N.Y., 194!6.)
 
Note 10 (page 137, line 26). Menstrual cycles in infrahuman primates. Thanks largely to the work of Zuckerman and Gillman, the cycles of two species of baboon have now been studied in numbers large enough to warrant comparison with other primates. The cycles are longer than those of the human species and the Rhesus monkey, averaging about 33 to 36 days, modal length, in various groups of animals. (The subject of menstrual cycles in primates is thoroughly reviewed in S. A. Asdell, Patterns of Mammalian Reproduction, Ithaca, N.Y., 1946.)
 
Note 11 (page 141, line 33, and page 201, footnote). The gonadotropic substances of the pituitary gland and the placenta. When this book was first written, it was thought best in the interest of clarity not to refer in detail to the moot question of the existence of two or more gonadotrophic substances. The problem is still not settled, but it has become somewhat better defined, and for the sake of readers who wish to proceed from the very general account given here, to the more technical literature, the following outline is now supplied.
 
The prime fact is that the pituitary gland, the placentas of certain species, the urine of pregnant females of certain species, and the blood serum of the mare, all contain hormonal substances that stimulate the growth and differentiation of the ovaries and testes of animals into which they are injected. The precise nature of the effects of these hormones differs considerably, however, according to the particular source of the hormone and also according to the species of animal receiving the injections and the dosage. Under these varying circumstances, the constituent tissues of the ovary, for example, respond differently. Sometimes the follicles merely grow larger or even become cystic or atretic ; in other experiments they are caused to form corpora lutea. In the testis likewise, there may be stimulation on one hand of the spermatogenic tubules, on the other hand of the interstitial cells (see Chapter IX). Workers using the ovaries of various species as test objects have found first that as their efforts to purify the gonadotrophic substances advanced, they seemed more and more clearly able to achieve at least partial separation of the two effects just mentioned; that is to say some of the partially purified preparations tended to produce only follicle stimulation, others only to cause luteinization. Separation of the two effects, perhaps even better than can be attained as yet in the chemist's flasks, is observed as a result of biological processes. To mention one example, urine of women after the menopause, or after removal of the ovaries, contains a substance presumably produced by the pituitary gland that has almost pure follicle-stimulating properties. The hypothesis has therefore sprung up that the pituitary gland produces two distinct hormones, usually denoted respectively by the initial letters FSH for "folliclestimulating hormone," and LH for "luteinizing hormone." There is ample evidence that the gonadotrophic substances are of protein nature, and this is sufficient explanation of the fact that as yet, in spite of immense effort, no one has obtained preparations which solely give one or the other effect upon test-animals. The question therefore remains unsettled whether there are two hormones, chemically separable, or one which acts differently under different circumstances; but the hypothesis that there are two has been generally accepted as a working basis for further chemical research and for speculation about the part played by the pituitary gland in the menstrual cycle and in pregnancy.
 
In the human species, the urine acquires during pregnancy a gonadotrophic potency which appears to depend upon a mixture of properties resembling those of FSH and LH. The same is true for limited periods in the pregnancy of chimpanzees and Rhesus monkeys. Whether the substances producing these effects ("Prolan A" and "Prolan B" respectively) are chemically and biologically identical with FSH and LH, has been debated, and this question, like many others relating to the gonadotrophic hormones, awaits the final purification and identification of the substances. The prolan-complex is undoubtedly produced by the tissues of the placenta.
 
The blood serum of pregnant mares contains a gonadotrophic substance, believed to be produced by the placenta, which because of some chemical peculiarity does not get into the urine. This substance, known as equine gonadotrophin or PMS (for pregnant mare serum), acts upon test-animals as if it were a mixture of an FSH-like hormone with a small proportion of LH-like material. The serum of pregnant mares has been much used as a source of gonadotrophic hormones by experimenters and drug manufacturers.
 
A good review of this subject, bringing it up to 1945, will be found in Burrows, Biological Actions of the Sex Hormones, 1945.
 
Note 12 (page 153, line 9). The coiled arteries. New questions about the theory of menstruation, and particularly about the. role of the coiled arteries, that have arisen since the first writing of this book, are fully discussed in Note 13. At this point, however, it will be well to modify the assumption that the coiling of the arteries is essential to menstruation. In a pending article, a fellow-worker of the author, Dr. Irwin H. Kaiser, shows that the corresponding arteries in certain New World monkeys that undergo at least a rudimentary type of menstruation, are not coiled. Some, moreover, of the current hypotheses about the structure and function of the arteries in women and in Rhesus monkeys, to be mentioned in Note 13, do not depend upon the coiling.
 
The reader should therefore substitute for the statement in our text that "menstruation is primarily an affair of the coiled arteries" the more cautious and less specific thought that menstruation is primarily dependent upon special peculiarities of the arterial circulation of the endometrium, meanwhile keeping his mind open until this fascinating problem is further elucidated.
 
Note 13 (page 170, line 21). Current thought about the mechanism of menstruation. The hypotheses set forth in the original edition of this book may still be read profitably, except that the reader should substitute the term "endometrial arteries" for "coiled arteries" because (as explained in Note 12) there is evidence that the coiling is not per se essential to the menstrual process. The whole subject of the cause of menstruation has been actively revived in 1946-194!'7, largely as the result of studies made in Copenhagen by a group of anatomists and pathologists who did not let the German occupation stop their research.
 
Most of the thinking still involves the idea that the periodic menstrual flow results from some peculiarity or other of the endometrial arteries which makes them dependent upon hormonal support. As already mentioned, a view now somewhat in disfavor held that it is the coiling of these arteries which renders them sensitive to fluctuation of the ovarian hormones. It was conjectured that as the endometrium grows thicker in each cycle under the influence of estrogen, the coiling becomes more intense until the flow of arterial blood is impeded, the capillary circulation is impaired, ischaemia of the endometrium results and is followed by menstrual breakdown. As a variant of this idea, it has been thought that a drop in estrogen occurring toward the end of the cycle causes involution of the endometrium, with a reduction of its thickness and consequent tighter coiling of the arteries. This was supposed to cause damage to the tissues and consequently to bring on menstrual bleeding.
 
Another totally different supposition is now put forward by the Danish investigators Schlegel, Dalgaard, and Okkels (see, for instance, J. V. Schlegel, "Arteriovenous Anastomoses in the Endometrium in Man," Acta Anatomica, vol. 1, 1945-46). These workers, using very careful methods of injecting the uterine blood vessels, have shown almost beyond any doubt that in the human endometrium there are frequent direct connections (anastomoses) between the terminal arterioles and the venous spaces from which the uterine veins take origin. Some of the blood flowing through the lining of th^ uterus follows the pathway usual in other organs and tissues, through the capillary blood vessels, thus serving the ordinary metabolic functions of the blood. Some of the blood, however (according to these investigators) passes directly through a shunt, as it were, into the veins. Schlegel off^ers a theory of menstruation based on this finding. He conjectures that as the endometrium grows thicker in each cycle under the influence of estrogen, the number of short circuits between the arterial and venous systems increases. The increasing proportion of blood thus shunted must be compensated for by an increased flow through the capillaries also. Such a flow, it is well known, is eff'ected by the estrogenic hormone. The time comes, however, it is thought, when the estrogenic stimulus is not able to produce further capillary flow whereas the shunts still divert much of the blood. The tissues nourished by capillary blood suffer injury and menstruation is thus initiated.
 
A variation of this hypothesis, suggested by Professor Okkels, involves also a vasoconstrictor substance (cf. Hypothesis 3, page 171).
 
American workers of the Bartelmez-Daron school, who have not observed arteriovenous anastomoses in their material, obtained chiefly from monkeys and prepared with great care though by methods differing from those of the Danish investigators, are naturally doubtful of hypotheses that depend upon the arteriovenous shunts.
 
Other possible mechanisms that have been hinted at, but not as yet supported by thorough anatomical demonstration, depend upon supposed peculiarities of the walls of the endometrial arteries, which are indeed somewhat different in microscopic structure from those of other organs. It is thought, at least vaguely, that their general structure requires in some way the support of estrogenic hormones, or that there are special points or regions on the arteries which are sensitive to hormone fluctuations and thus serve as sphincters to shut off arterial flow.
 
Enough has been said to show that while the relation of the uterine arteries to the menstrual process is still unsolved, the question is being actively studied and we may hope for better knowledge by the next time this book requires revision.
 
Note 14 (page 172, line 17) . Toxin theory of menstruation. O. W. Smith and George Van S, Smith have modified their conjectures about the cause of the menstrual breakdown of the endometrium. As explained in an article in Clinical Endocrinology^ 1946, vol. 6, they suggest that catabolic changes of the endometrium resulting from reduction of estrogen at the end of the cycle cause the formation of a toxic substance which damages the finer blood vessels and thus brings on the menstrual necrosis and hemorrhage.
 
Note 15 (page 185, line 34). Amount of progesterone secreted daily in the human. It is now known that by no means half the progesterone that gets into the blood is excreted in the urine as pregnanediol. If a measured amount of progesterone is administered by injection, only about 10 to 15% of it appears as pregnanediol. On the basis of such results G. Van S. Smith and O. W. Smith, Seeger-Jones and Te Linde, and others now estimate that the corpus luteum secretes about 50 milligrams of progesterone per day at the peak of its cyclic activity.
 
Note 16 (page 194, line 33). Amount of estrogen produced daily in the human. G. Van S. Smith, O. W. Smith, and Sara Schiller, American Journal of Obstetrics and Gynecology, vol. 44, pp. 605-615, 1943, published an estimate based admittedly on a number of unproved assumptions concerning the metabolism of the estrogens. Their result, 0.08 to 0.70 milligrams, averaging 0.33 mg., is not far from that reached by my totally different method of estimation ; my figure, expressed as estrone, is equivalent to 0.30 milligrams.
 
Note 17 (page 211, line 12). The isolation and identification of prolactin. Two months after these Vanuxem lectures were delivered. White, Bonsnes, and Long of Yale University announced success in the isolation from beef pituitary glands of a crystalline substance of high lactogenic activity. The hormone is a protein of high molecular weight (32,000 or more). Readers with a knowledge of biochemistry will be interested in their account of their own work and that of Lyons and other investigators upon which their efforts were partly based. {Journal of Biological Chemistry, vol. 143, 1942, pp. 447-464).
 
Note 18 (page 228, last line of footnote). Berthold's article. A translation of the original paper into English, by D. P. Quiring, was printed in the Bulletin of the History of Medicine, Baltimore, vol. xvi, 1944, pp. 399-401.
 
Note 19 (page 236, line 33). Oral androgen. Androgenic hormones that can be taken by mouth in tablet form have been prepared by chemical synthesis and are on the market.


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Corner GW. The Hormones in Human Reproduction. (1942) Princeton University Press.

   Hormones in Human Reproduction (1942): 1 Higher Animals | 2 Human Egg and Organs | 3 Ovary as Timepiece | 4 Hormone of Preparation and Maturity | 5 Hormone for Gestation | 6 Menstrual Cycle | 7 Endocrine Arithmetic | 8 Hormones in Pregnancy | 9 Male Hormone | Appendices
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This historic 1942 textbook by Corner describes endocrine changes during pregnancy.



Modern Notes: Reproductive Cycles

Menstrual Cycle Links: Introduction | menstrual histology | ovary | corpus luteum | oocyte | uterus | Uterine Gland | estrous cycle | pregnancy test
Historic Embryology - Menstrual 
1839 Corpus Luteum Structure | 1851 Corpus Luteum | 1933 Pap Smear | 1937 Corpus Luteum Hormone | 1942 Human Reproduction Hormones | 1951 Corpus Luteum | 1969 Ultrastructure of Development and Regression | 1969 Ultrastructure during Pregnancy


Endocrine Links: Introduction | BGD Lecture | Science Lecture | Lecture Movie | pineal | hypothalamus‎ | pituitary | thyroid | parathyroid | thymus | pancreas | adrenal | endocrine gonad‎ | endocrine placenta | other tissues | Stage 22 | endocrine abnormalities | Hormones | Category:Endocrine
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1903 Islets of Langerhans | 1903 Pig Adrenal | 1904 interstitial Cells | 1908 Pancreas Different Species | 1908 Pituitary | 1908 Pituitary histology | 1911 Rathke's pouch | 1912 Suprarenal Bodies | 1914 Suprarenal Organs | 1915 Pharynx | 1916 Thyroid | 1918 Rabbit Hypophysis | 1920 Adrenal | 1935 Mammalian Hypophysis | 1926 Human Hypophysis | 1927 Adrenal | 1927 Hypophyseal fossa | 1930 Adrenal | 1932 Pineal Gland and Cysts | 1935 Hypophysis | 1935 Pineal | 1937 Pineal | 1935 Parathyroid | 1940 Adrenal | 1941 Thyroid | 1950 Thyroid Parathyroid Thymus | 1957 Adrenal
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The Hormones in Human Reproduction

George Corner (1889 - 1981)

Corner GW. The Hormones in Human Reproduction. (1942) Princeton University Press.


by George W. Corner


Published By Princeton University Press


To the young physicians and biologists, Fellows of various foundations and scientific societies, who came from other lands to study with the author of this book problems common to all humanity Sidney Arthur Asdell, Cambridge, England Seitchi Saiki, Tokyo, Japan Eduardo Burster Montero, Santiago, Chile Friedrich Hoffmann, Dusseldorf, Germany Graham Weddell, London, England Ines Lopez Colombo de Allende, Cordoba, Argentina Luis Vargas Fernandez, Santiago, Chile Washington Buno, Montevideo, Uruguay

WE TOOK counsel TOGETHER AND WALKED IN THE WAY OF TRUTH AS FRIENDS


Copyright 1942, 1947 by Princeton University Press


GEORGE W. CORNER was born in Baltimore and studied at The Johns Hopkins University and its medical school. He holds honorary degrees from the Catholic University of Chile, the University of Rochester, Boston University, Tulane, Temple, Oxford and the University of Chicago. Now professor emeritus of embryology at Johns Hopkins, Dr. Corner has also taught at the University of California, Rochester and Oxford, and has held chairs both at the Carnegie Institute and at the Rockefeller Institute. He is an honorary member and fellow of many American and foreign societies in the fields of anatomy and embryology and is the author of numerous books in those fields, as well as in medical history. He lives in Philadelphia where he is the Executive Officer of the Amepican Philosophical Society.


Preface

This book represents, with considerable additions, the substance of the Vanuxem Lectures, given at Princeton University in February 1942. The invitation to be Vanuxem Lecturer carried with it the expressed wish of the Committee that I should discuss the hormones of the reproductive system for the benefit of a general audience, assuming on the part of my hearers no familiarity with biology. This imposed no easy task, for it called upon me to describe some of the most intricate and elaborate mechanisms of the body, to listeners who perhaps had never seen the organs and tissues in which these activities take place. The structure of the living cells and the manner in which they are put together to form the organs are matters not merely so unfamiliar, but actually even so daunting to most people, as to create serious difficulties for the biologist and physician who tries to explain his work. For the first time in my life I could have wished I were an astronomer or physicist, for the heavenly spheres, their orbits and attractions, and even such matters as warps in space and corpuscles of light can be described to a certain extent in terms of the workshop and the household; but how can we explain the marvels of the human egg or the action of an estrogenic hormone without a background of cellular biology.'* My only recourse has been to begin at the very beginning, to devote as many as three chapters to general preparation for actual discussion of the hormones, and at every step to explain and illustrate the underlying anatomy and physiology as clearly as possible. This is, to the best of my knowledge, the first time an American university has devoted one of the great endowed lectureships to the subject of human reproduction. A few years ago it might even have been impossible to break through the old conventions that hampered free public discussion of this subject. We have a tradition that sex and reproduction must be attended by privacy, dignity and romance. It is a good tradition, provided we add a fourth attribute, namely understanding; for otherwise the fundamental life activities concerned in sex may become involved in fears, inhibitions and blind taboos. I emphasize the importance — nay even the necessity — of instruction and understanding in matters of sex, in case there are still among my readers some who are troubled by our free discussion of intimate functions, and especially in case it seems to them that the dignity and the romance of life are threatened by frank acceptance of the animal nature of mankind or by our use of other creatures to explain human affairs. There is of course no denying that man is an animal, and since human physiology cannot always be subjected to direct experiment (particularly in this field of investigation), we must study the lower animals not only for their own intrinsic interest but also in order to understand ourselves. It is equally true that man is more than an animal. The ape, the tiger, and the worm mate and reproduce their kind, and so do human beings, but only man tries to understand what he is doing and why he does it. In such understanding and in right living based upon knowledge lies our best hope of attaining dignity, honor and beauty in the physical life of mankind.


A book of this kind rests upon the laborious work of many scientific^ investigators. The author, in drawing freely upon the writings of his colleagues, has endeavored to acknowledge their contributions as fully as possible, by mention in the text, footnotes and legends. References however are necessarily limited; readers who wish to consult the original literature will find full bibliographies in Appendix II, note

1. Many fellow workers who have generously permitted the use of illustrations, as indicated in text and legends, deserve especial thanks.


The quotation at the head of Chapter I is from Two Lives, by William EUery Leonard, copyright 1922, 1925, by permission of the Viking Press, Inc., New York. The quotation from C. Day Lewis's translation of Virgil's Georgics, in a footnote to Chapter III, is used by permission of Jonathan Cape, Limited, London and Toronto.

The author's wife, Betsy Copping Corner, and his son, Dr. George W. Corner, Jr., have given unfailing encouragement and have been patient and thoughtful critics. Mr. Arthur G. Rever has been good enough to read the manuscript and has made useful suggestions.

The author's researches upon the menstrual cycle of monkeys, cited in this book, were aided by grants to the University of Rochester by the Rockefeller Foundation and the John and Mary R. Markle Foundation.

GEORGE W. CORNER

Carnegie Institution of Washington Department of Embryology, Baltimore

Contents

Preface

List of Plates

List of Text Figures

Chapter I. The Place Of The Higher Animals, and of Mankind in Particular, in the General Scheme of Animal

Simple division into parts a frequent mode of reproduction in lower animals; necessity of egg and sperm cells in higher and more complicated creatures ; the participation of two individuals, male and female, essential to the process in all higher animals ; in mammals, including mankind, the fertilized egg sheltered and nourished within the mother's body; correlation of the various organs of the reproductive system to this end by action of chemical substances (hormones) made in the sex glands.


Chapter II. The Human Egg And The Organs That Make And Care For It

The egg a cell growing in a cavity (follicle) in the ovary; its progress, after discharge from the ovary, via the oviduct to the uterus ; its implantation in the uterus, if fertilized by a sperm cell ; division into many cells and development into an embryo ; nourishment from the mother's blood during growth in the uterus, through an organ of attachment, the placenta.


Chapter III. The Ovary as Timepiece

Development of the eggs of mammals to maturity at regular intervals; occurrence, in most mammals, of a phase of sexual responsiveness (estrus) at the time of ripening of the eggs ; resultant mating, and fertilization of the eggs ; the reproductive cycle constituted by recurrence of these events; peculiar modification of the cycle in the human race, apes and higher monkeys, characterized by monthly disturbance in the uterus resulting in menstruation.

Chapter IV. The Hormone of Preparation and Maturity

Production by the ovaries of a remarkable substance, the estrogenic hormone ; its property of causing the other organs of the reproductive tract (oviducts, uterus, vagina, mammary glands) to grow to adult size, and of maintaining them in the adult state.

Chapter V. A Hormone for Gestation

Conversion of the ovarian follicle, after discharge of the egg, into a temporary gland of internal secretion, the corpus luteum; production by this gland of a hormone called progesterone, which acts upon the uterus in such a way as to insure attachment and nourishment of the early embryo.

Chapter VI. The Menstrual Cycle

Menstruation a peculiar phenomenon limited to a few species of higher animals ; its period (in humans) about four weeks, but not perfectly regular. Digression about the cycle in general, showing that it is probably due to interaction between the ovaries and the pituitary gland. Menstruation a periodic breakdown of the uterine lining (endometrium) when the corpus luteum retrogresses. Occurrence, however, of anovulatory cycles, without a corpus luteum, and without "premenstrual" changes. Explanation of the bleeding as due to shutting oflf of the coiled arteries of the endometrium caused by deprivation of estrogenic hormone or of progesterone; bleeding due to progesterone deprivation believed to be a special case of estrin-deprivation bleeding. Theory of the menstrual cycle based on these ideas. The significance of menstruation unknown.

Chapter VII. Endocrine Arithmetic

Calculation of the quantities of the two hormones produced in the ovaries and the rate at which they are secreted; in the case of the corpus luteum, discussion of such questions as the amount of hormone made by a single cell, the amount made by the whole gland in one day, and divers other matters of interest concerning the quantitative aspect of ovarian function.

Chapter VIII. The Hormones In Pregnancy

The maintenance of pregnancy a complex affair, dependent partly on the hormones. The placenta as a source of gonadotrophic and estrogenic hormones ; progesterone also apparently made by the human placenta. Lactation induced by a special hormone of the pituitary gland.

Chapter IX. The Male Hormone

The testis constructed of tubules in which the sperm cells are made; the interstitial cells. The seminal ducts, seminal vesicles, and prostate gland under control of the testis through its hormone. Secondary sex characters described and shown to be controlled by the testis. Chemistry and effects of the androgenic hormones.


Appendices

List of Plates

Plate Facing Page

I. Reproduction by budding, in hydra

II. Sexual reproduction in hydra

III. Fertilization and division of the egg of the sea urchin, as seen in sections

IV. Development of the sea urchin's egg, from living specimens

V. The human ovaries, oviducts, and uterus

VI. Regner de Graaf's original picture of the graafian follicle, 1672

VII. The primate ovary and egg

VIII. GROWTH OF THE FOLLICLE IN THE RAT

IX. THE CORPUS LUTEUM

X. THE OVIDUCT ( FALLOPIAN TUBe) AND THE TRANSPORT OF THE EGG

XI. DIVISION OF THE RABBIt's EGG, FROM LIVING SPECIMENS

XII. IMPLANTATION OF THE EMBRYO IN THE RHESUS MONKEY AND IN MAN

XIII. THE VAGINAL CYCLE IN THE RAT

XIV. CASTRATE ATROPHY

XV. THE EFFECT OF ESTROGENIC HORMONE ON THE VAGINA

XVI. THE EFFECT OF ESTROGENIC HORMONE ON THE UTERUS

XVII. PROGESTATIONAL PROLIFERATION OF THE UTERUS

XVIII. THE EFFECT OF PROGESTERONE ON THE UTERUS AND EMBRYOS OF THE RABBIT

XIX. X-RAY PHOTOGRAPH OF THE HUMAN SKULL, SHOWING LOCATION OF THE PITUITARY GLAND

XX. HUMAN INFANT AT BIRTH, WITH PLACENTA

XXI. THE UTERUS OF THE RHESUS MONKEY AT SUCCESSIVE STAGES OF THE CYCLE

XXII. The uterus of the rhesus monkey during menstruation

XXIII. Structure of the testis

XXIV. Sperm cell formation ; the cryptorchid testis

List of Text Figures

1. Reproduction by lengthwise fission 4

2. Reproduction by budding 5

3. Reproduction by spore formation 6

4. Reproduction by transverse fission 6

5. Reproduction by eggs and sperm cells, in Hydra 7

6. Conjugation of a one-celled animal 13

7. Sperm cells of various animals 15

8. The human female reproductive tract 86

9. The corpus luteum 42

10. Form of the uterus in various animals 49

11. Diagram of the human female reproductive tract 50

12. The lining of the uterus (endometrium) 53

13. Diagram of a uterine gland 55

14. Implantation of the embryo in rabbit and man 58

15. Diagram of the reproductive cycle of the sow 67

16. Diagram of the menstrual cycle and the cycle in general 70

17. Apparatus for studying the activity of uterine muscle 122

18. Effect of progesterone on the rabbit's uterus 125

19. Diagram of the reproductive cycle of mammals 140

20. Form and location of the pituitary gland 142

21. Diagram of the hormone-alternation theory of the cycle 143

22. Diagram of the menstrual cycle 147

23. The arteries of the endometrium 150

24. Diagram, the effect of estrin deprivation 162

25. The estrin-deprivation hypothesis 163

26. Diagram, effect of progesterone on estrin-depriva tion bleeding 165

27. Hypothetical explanation of the ovulatory cycle 166

28. Growth of the human uterus in pregnancy 200

29. Development of the mammary gland 209

50. The human male reproductive tract 219

51. Structure of the testis and epididymis 221

52. Effect of testis hormone on the cock's comb 2S3


   Hormones in Human Reproduction (1942): 1 Higher Animals | 2 Human Egg and Organs | 3 Ovary as Timepiece | 4 Hormone of Preparation and Maturity | 5 Hormone for Gestation | 6 Menstrual Cycle | 7 Endocrine Arithmetic | 8 Hormones in Pregnancy | 9 Male Hormone | Appendices
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