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Young WC. Sex and internal secretions Vol. I. (1961) 3rd Eda. Williams and Wilkins. Baltimore.

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Internet Archive

Sex and Internal Secretions

Third Edition


A. Albert David W. Bishop Kichard J. Blandau K. K. Burns A. T. Cowie John W. Everett S. J. 1 olley Thomas II. Forbes J. W. (iowen

Koy O. Greep A. M. Guhl Joan G. Hampson John L. JIampson Frederick L. llisaw Frederick L. llisaw, Jr. James II. Leathem Daniel S. Lehrman Margaret Mead John W. Money

Helen Padykula

Dorothy Price

Herbert D. Purves

Ari van J'ienhoven

Claude A. Villee

H. (iuN Williams- Ashman

(ieorge B. Wislocki

William C. Young

M. X. Zarrow

Baltimore 1961



Edited by William C. Young, Ph.D.

Professor of Anatomy, University of Kansas, Lawrence

Foreword by George W. Corner, M.D., D.Sc.

Director Emeritus, Department of Embryology, Carnegie Institution of Washington

The Williams & Wllkins Co.

Publication was supported in part by Public Health Service Research Grant M-464S from the National Institute of Mental Health, Public Health Service.

The Williams & Wilkins Company

Made in the United States of America

Library of Congress Catalog Card Number 60-12279

To the Memory of Robert Mearns Yerkes


Foreword. George W. Corner

Edgar Allen. William C. Young

Preface to Third Edition

Preface to First Edition

section a

Biologic Basis of Sex

1. Cytologic and Genetic Basis of Sex. /. W. Gowen 3

2. Role of Hormones in the Differentiation of Sex. R. K. Burns 76

section b

The Hypophysis and the Gonadotrophic Hormones in Relation to Reproduction

3. Morphology of the Hypophysis Related to Its Function. Herbert D. Purves

4. Physiology of the Anterior Hypophysis in Relation to Reproduction. Roy b. Greep

section c

Physiology of the Gonads and Accessory Organs

5. The Mammalian Testis. .4 . Albert

6. The Accessory Reproductive Glands of Mammals. Dorothy Price and H. Guy Williams- Ashman

7. The Mammalian Ovary. William C. Young

8. The Mammalian Female Reproductive Cycle and Its Controlling Mechanisms. John W. Everett

9. Action of Estrogen and Progesterone on the Reproductive Tract of Lower Primates. Frederick L. Hisaw and Frederick L. Hisaw, Jr 556

10. The Mammary Gland and Lactation. A. T. Cowie and S. J. Folley 590

11. Some Problems of the IMetabolism and Mechanism of Action of Steroid Sex Hor mones. Claude A . Villee 643

12. Nutritional Effects on Endocrine Secretions. James H. Leathern 666

Volume II

section d

Biology of Sperm and Ova, Fertilization, Implantation, the Placenta, and Pregnancy

13. Biology of Spermatozoa. David W. Bishop

14. Biology of Eggs and Implantation. Richard J. Blandau.

15. Histocliemistry and Electron Microscopy of the Placenta. George B. Wislocki and Helen Padykida

16. Gestation. M. X. Zarroiv

section e

Physiology of Reproduction in Submammalian Vertebrates

17. Endocrinology of Reproduction in Cold-blooded Vertebrates. Thomas R. Forbes

18. Endocrinology of Reproduction in Birds. Ari van Tienhoven

section f

Hormonal Regulation of Reproductive Behavior

19. The Hormones and Mating Behavior. William C. Young

20. Gonadal Hormones and Social Behavior in Infrahuman Vertebrates. .4. AI. Guhl

21. Gonadal Hormones and Parental Behavior in Birds and Infrahuman Mammals. Daniel S. Lchrman

22. Sex Hormones and Other Variables in Human Eroticism. John W. Money

23. The Ontogenesis of Sexual Behavior in J\Ian. John L. Hampson and Joan G. Hampson

24. Cultural Determinants of Sexual Behavior. Margaret Mead



George W. Corner, M.D., D.Sc.

Director Emeritus, Department Of Embryology, Carnegie Institution Of Washington

Publication of the third edition of Sex and Internal Secretions signalizes the accomplishment of about a half century's intensive work by investigators of many countries, among whom those of the United States have been notably active. Any such burst of discovery as this rests, of course, upon a long preceding period of more gradual progress. Taking as landmarks Regner de Graaf's recognition that the "female testis" of mammals is an egg-producing organ comparable to the ovaries of birds (1672) and Leeuwenhoek's description of the spermatozoa (1674), we can trace the continuous development of knowledge about the reproductive system down to our own times. Discovery of the actual mammalian ovum by Karl Ernst von Baer in 1827 accelerated the progress of research on the origin of the germ cells, the de^'elopment and discharge of the Graafian follicle, transport and fertilization of the ovum, and implantation and development of the embryo. Such studies inevitably drew attention to the cyclic aspects of reproductive function, particularly from students of animal breeding and from faunal naturalists, who acquired a great deal of information about the estrous cycles of wild as well as domestic animals and those of the laboratory. The work of the English leaders in this kind of investigation, Walter Heape and F. H. A. Marshall, reached fruition in the latter's well known "Physiology of Reproduction," published in 1910. At this same period (1890-1910) gynecologists, especially in Germany and Austria, were putting their specialty on a scientific basis. Becoming aware of the current advances in knowledge of embryology and the biology of reproduction of mammals in general, they were seeking similar clues to the explanation of the human menstrual cycle, ostensibly so different from the estrous cycle of domestic animals. European workers, notably Hitsch

mann and Adler, Robert Schroedcr, and Robert Meyer, from about 1900 to the beginning of the first World War, put together from operating-room material a histologic description of the human cycle that became more and more clear as the embryologists related it to their understanding of the general mammalian cycle. The young sciences of psychology, psychiatry and anthropology also joined the concerted attack upon the problems of sex and reproduction. Since about 1870 European psychiatrists, led by such men as von Krafft-Ebing and Forel, had been studying sex psychology, with the aim of understanding behavior of a kind that was considered abnormal or conducive to social difficulties such as those created by prostitution and homosexuality. The way was thus opened for psychology to investigate the biologic basis of normal sex behavior. European and American anthropologists had begun to document and analyze the sex attitudes of primitive races and distant nations, and even of their own peoples. Nor must we forget the influence of the Women's Rights movement, with its fight against all forms of bondage of women and its emphasis on standards of sex behavior equally applicable to both sexes. All these new sciences and new social movements called for better understanding of basic sex physiology, which only biologists could provide.

Thus at the beginning of the 20th century and during the next decades investigation in this field became more intense. Naturalists, animal breeders, histologists, embryologists and gynecologists gradually came to understand each other's problems, and began a period of rapid advance not yet ended nor even slowed down, in which scarcely a year has passed without major contributions.

American zoologists were already prepared by their embryologic studies to take part in this exploration, and the rapid devc^lopment of medical research in the United States in the early part of the 20th century provided speciahsts in human embryology, pathologists, physiologists, and biochemists who were ready to join the biologists in such investigations. When in 1922 the National Research Council was called upon by influential groups centered in the American Social Hygiene Association, to bring together existing knowledge and to promote research upon human sex behavior and reproduction, our nation already possessed a corps of competent investigators who rallied to the call of Robert M. Yerkes and Frank R. Lillie, forming the Committee for Research in Problems of Sex. This Committee, with financial support from the Rockefeller Foundation, successfully undertook to encourage research on a wide range of problems of sex physiology and behavior.

The younger readers of this book will hardly be a])le to appreciate the full significance of such an alliance between biologists, psychologists, and physicians on one hand, and social philanthropists on the other. It represented a major break from the so-called Victorian attitude which in the English-speaking countries had long impeded scientific and sociologic investigation of sexual matters and had placed taboos on open consideration of human mating and childbearing as if these essential activities were intrinsically indecent. To investigate such matters, even in the laboratory with rats and rabbits, required of American scientists, including some of the contributors to the first edition of Sex and Internal Secretions, a certain degree of moral stamina. A member of the Yerkes Committee once heard himself introduced by a fellow scientist to a new ac(}uaintance as one of the men who had "made sex respectabl(\" Ccrlaiiily the prestige of lh<^ Committee and the successes of American in\'(>stigators working with and without its assistance helped to bring about a more I'ealistic attitude toward sex research, although reactions from some ciuarters to such important recent work as that of the late Alfred C. Kins(\v show that the battle is even yet not fully won.

Ten years after its formation tiie Committee for Research in Problems of Sex, proud of the achievements it had helped to foster, sponsored the first edition of Sex and Internal Secretions. The information thus brought together in 1932 came largely from research in genetics, cytology, embryology, and endocrinology, almost exclusively utilizing morphologic methods of study. In contrast to the present situation as reflected in the third edition, biochemistrv of the sex glands was still in an elementary stage, having barely achieved the preliminary chemical identification of the ovarian, placental, and testicular hormones; and the psychology of sex behavior was only beginning to develop its experimental methods. The sum total was, however, a deeply impressive record of progress that drew many new workers into this fi(^ld of research.

It would be difficult to ascribe priority in this achievement to any one of the biologic disciplines. Genetics and cytology had provided one of the major clues by C. E. jMcClung's discovery in 1902 of the significance of the accessory chromosome, and his brilliant conjecture that this minute fragment of protoplasm is related to the determination of sex. Coming just before an outburst of discoveries concerning the chromosomal mechanism of heredity, based largely on the fruit fly Drosophila, the concept of genetic determination of sex gave rise to an immense amount of investigation and theorizing about the way in which a developing individual is caused to become either male or female. Three decades after the publication of McClung's hypothesis, enough information on this (luestion was in hand to fill two ci'owded chapters in the first edition of Si.r and I idcriud Secretions.

The contribution of cmbryolog}' to our sul)ject goes back to the ISth and 19th centuries and in particulai' to the (h^scription of the early stages of (lc\('loi)nient of the internal reproductive system, with which the names of Kaspar Fried rich Wolff' and Johannes Aliiller are ind(>libly associated. In this field, too, a period of activity investigation began early in the 20tli century, with the aid of improxcd methods of microtomy and the apj^lication of pr(H'is(> histoloiiic staininti to eiubi'vonic tissues. The development of the gonads and the metamorphosis of the Wolffian and Miillerian ducts into the secondary internal reproductive organs was rapidly worked out in animals of every vertebrate order, by an army of in\'estigators too numerous to mention in a short resume. The story of the first appearance of primordial germ cells and their migration through the tissues of the embryo to the newly forming gonads, adumbrated in the 1880's by the work of Semon, was confirmed and extended to several species of mammals. If in these latter creatures and in the human species, th(> complete line of descent from the fertilized ovum to the first appearance of the germ cells is till not as clear as in many lower forms, enough at least was discovered within a few decades to indicate an essential similarity in the history of the germ cells in all vertebrates.

To the embryologists of Europe and America w^e owe in large part also the successful analysis of the mammalian reproductive cycle that has been achieved during this half century. In order to procure mammalian embryos of known age the time of ovulation and fertilization had to be related to the outward manifestations of the estrous cycle. Comparati^'e description of the cycles of the various mammals for this purpose was climaxed by the discovery, or rather rediscovery and practical application of cyclic changes in the vaginal epithelium by C. R. Stockard and G. X. Papanicolaou. The vaginal smear method, thus introduced to the experimental laboratories, made possible a wide range of investigations on the physiology and biochemistry of the cycle and the ovarian hormones. As apphed to the white rat by Herbert M. Evans and J. A. Long it became a basic tool in such studies.

Another influence which also greatly forwarded investigation of the ovarian cycle has already been mentioned. This was the efTort of the gynecologists and especially gynecologic pathologists to interpret cychc events in the human ovary and uterus. One of the most notable American discoveries, that of the influence of the corpus luteum in decidua formation by Leo Loeb, stemmed from his familiarity with the German studies on the human cvcle. Much of our knowledge of the corpus luteum and its hormone, progesterone, was in fact won by investigators who approached the problem through gynecology.

Had it not b(>en for the first World War, moreover, European gynecologic experimenters might have attained clear knowledge of the estrogenic hormones, for even before 1900 Emil Knauer and Josef Halban of Vienna had demonstrated in a preliminary w^ay the endocrine dominance of the ovaries over the uterus, and by 1913 various investigators, notably Henri Iscovesco of Paris and Otfried Fellner of Vienna, had prepared crude extracts which we now know contained estrogens. It remained, however, for the American zoologist-anatomist Edgar Allen and his biochemical colleague E. A. Doisy, e(iuipped with the vaginal smear method of testing ovarian hormone action, to isolate an estrogen from the fluid of the Graafian follicles, thus starting an era of ovarian endocrinology which has ultimately resulted in clear definition and discrimination of estrogens and progestins and their respective effects upon the uterus and other organs of the reproductive system. Applying this new knowledge to the complexities of the human reproductive cycle, the zoologists, embryologists, gynecologists and endocrinologists, among them several distinguished contributors to the first edition of this work, have combined forces to work out a clear account of the endocrine basis of menstruation and the implantation of the primate embryo.

The parallel story of the hormones of the testis can be read in the successive editions of Sex and Internal Secretions. Berthold's proof, published in 1849, that in fowls the testis presides over the development of the cock's comb, wattles, and spurs ultimately led to the isolation of the first known androgen in F. C. Koch's laboratory at Chicago, and thence to the development of a great body of knowledge about androgenic steroids.

The more complex history of the hormones of the hypophysis, becoming somewhat clearer in each successive edition of this work, well illustrates a main theme of this introductory essay, namely the dependence of scientific advance upon the intermingling of ideas from various fields. It is not merely by chance that among the American workers on the hypophysis two names stand out, those of a surgeon, Harvey Gushing, and a zoologist-anatomist, Philip E. Smith.

The central achievement of this half century of intensive work can be summarized in one sentence. It was, first, recognition, description and explication of the reproductive cycle of mammals and man; and, second, identification of the chemical substances that serve to integrate the cycle and preside over gestation. Those who took part in these investigations recognized, of course, that in due time their work must be extended in two directions, downward to the domain of molecular chemistry and ultimately of ionic physics in order to understand the basic nature of hormone action, and upward to the field of animal and human behavior, where sex gland hormones join with other forms of bodily and mental integration in directing the life and behavior of the organism.

Once the histologists and embryologists had identified the sex gland hormones it was inevitable that further investigation of these remarkable substances should be taken over by biochemists, as can be seen from the successive editions of this book. The chief unsolved problems now demanding attention relate largely to the sites of action of the hormones and the precise molecular effects which they exert upon their target organs. Recent indications that estrogens take part in hydrogen transfer in the citric phase of carbohydrate metabolism, and that progesterone affects uterine muscle cells by altering their permeability to potassium ions, show clearly that there is hope of understanding th(^ action at molecular level of these remarkably specific and powerful substances, which were bai'ely beginning to be known when the first edition of this book appeared in 1932.

As the investigators of the future leai'n exactly where the sex gland hormones exert their chemical action, and just what they do to the fundamental elements of th(> cells of their target organs, we may confidently expect ever-increasing knowledge even of the most complex sexual and reproductive activities. Running over the chapter headings of this third edition of Sex and Internal Secretions, we see indeed that almost every author concerns himself with one or another aspect of sex and reproduction in the light of what is already known about endocrine regulation. Chapter after chapter deals with cyclic events determined by sex gland hormones. Phenomena which in the first edition could be explained only suppositionally on a hormonal basis, for example the "free martin" state in domestic cattle, and menstruation in primates, are now much better understood. Others which seemed hardly within the scope of endocrinology are now seen to be in some degree influenced by hormone action, and thus to call for discrimination between endocrine effects and other types of regulation such as gene action and control through the nervous system. The experimental embryologists, for example, seek to understand the respective effects of genes and hormones in determining the development of the internal accessory sex organs; students of animal psychology likewise are beginning to discriminate between the action of hormones and neuro-psychologic factors in determining the patterns of sex behavior.

Among the subjects discussed in this book, only psychiatry and anthropology are as yet not greatly influenced by our recently acquired stores of endocrinologic information. The complex, high-level patterns of human thought and behavior with which these sciences deal are presumably far less subject to chemical regulation than to the integrative control of the nervous system as it affects learning, memory, and racial tradition. Yet when we consider the extent to which daily life and ethnic customs are bound up with the sexual and reproductive activities of mankind, we are prepared to find this edition of Sex and Internal Secretions not only advancing greatly beyond its predec(>ss()rs in the study of animal behavioi-, but also looking forward, through exploi'niory chaptcn-s on psychiatric and anthi'opologic asix'cts of liuninn s(\\ Ix^liavior, to a time when we shall more fully understand the interrelations of all the controlling factors even of these most complex activities, upon which the continuation and renewal of life depend.



Soon after his untimely death, February 3, 1943, many of the important details of Edgar Allen's life were recorded by colleagues who were close to him. Separated from these memorials, however, was Sex and Internal Secretions, understandably the most permanent and tangible memorial. It is appropriate, therefore, that in this long-delayed third edition, much of the material in those records of his life should be combined with the review of the field in which his substantive contributions and directive thought were so important. With the permission of Doctors George W. Corner and William U. Gardner, portions of their biographical sketches have been used here. A few minor errors have been corrected and supplementary information has been added when it was felt that the picture of Edgar Allen would thereby be enlarged and sharpened. For much of the latter, indebtedness is expressed to Doctor Charles H. Danforth, a long-time friend and senior colleague at Washington University, and to Doctor J. Walter Wilson, with Allen as a graduate student at Brown University.

Doctor Allen ("Ed" to his many friends, and "The Skipper" in his department at Yale) was born at Canyon City, Colorado, May 2, 1892. He was the son of a physician about whom little seems to be known. The Allen family moved to Providence when he was very young. His early training was obtained in the public schools of Providence and at Brown University. Immediately after his graduation in 1915 he started graduate study in biology. This was interrupted two years later by World War I, but was sufficient to fulfill the not too rigorous requirements for a master of arts degree. His record during this period does not seem to have been impressive and nothing that has been learned about it foreshadowed his later distinguished accomplishments. However, one hitherto unrecorded experience mentioned on one occasion to the present biographer, may have had unusual significance in the years that followed. Doctor Albert Davis Mead, to whom editions 1 and 2 were inscribed, was Professor of Biology and instructor in the course in vertebrate embryology. At that time and for many years later the uteri, tubes, and ovaries of pregnant sows were collected from the local slaughterhouse and dissected by the class. Allen, probably as an assistant in the course, visited the slaughterhouse where his attention was attracted by the numerous large follicles in most of the ovaries. The curiosity thus engendered seems to have been the extent of his interest in reproductive physiology while he was at Brown, but it could have been instrumental in directing his attention to the ovary a few years later in St. Louis, and it could have prepared him to seek the sow's ovaries as a source of follicular fluid when he was desirous of obtaining large quantities of it for his first tests on spayed mice.

In May, 1917, he volunteered for service in the Brown University Ambulance Unit. Later he transferred to a mobile unit of the Sanitary Corps with which he served in France. When he was discharged in February, 1919, he held a commission as second lieutenant.

Before leaving for France in 1918 he married Marian Pfeiffer, a fellow student enrolled in Pembroke College, the Women's College in Brown University. Throughout the balance of his life she was his devoted companion. She too died as a relatively young woman and did not long survive him. • There are two daughters. For a man in his position, he lived modestly. It is easy to imagine that he valued the warmth and affection of his family and friends and his boat abo\T other luxuries he might have had.

When he returned to civilian life he had no permanent position in sight, but he must have sought the help of Mead, for during the summer of 1919 he was an investigator in the laboratory of the U. S. Fish Commission at Woods Hole. Doctor H. C. Bumpus, an older colleague of Mead's, had been Director of the Biological Laboratory in the Fish Commission at Woods Hole and summer appointments, paying two or three himdred dollars, were a source of help to the graduate students at Brown in that period. The summer seems to have been important, not because of any research Allen did, but because it was then that Charles Danforth, who was at Cold Spring Harbor for the summer and had heard Doctor FL E. Walter speak highly of Allen, wrote him and called his attention to the instructorship then open in Washington University School of Medicine. Danforth suggested that Allen communicate with Doctor Robert J. Terry, head of anatomy in that institution. He must have done so promptly and been accepted, with the understanding that graduate study would hv continued. Danforth's recollection of his first sight of Allen is repeated:

"When I returned to St. Louis in the fall and went up to the anatomy department I saw a man in the hall whose white liair and impressive bearing led me to suspect that he was probably a distinguished alumnus returning for a visit. I soon learned, however, that this was Mr. Allen, who had been appointed instructor in anatomy and was already installed in an office on the third floor."

Little time seems to have been lost in starting his work for the Ph.D., although the circumstances under which the choice of a problem was made ar(^ somewhat ohscuiv. Doctor H. H. Willier who met Allen for- the first time that sunnner (probably on "stony beach") does not remembeithat he mentioned any special interest in the physiology of sex and reproduction. Danforth, who saw nuich of him from this time on, l;elie\-(>s that two cii'cunistaiices may lia\-e licen important. His oflice was on the floor with that of Doctoi' Locb, always a stimulating p(M-soii, and in the animal quarters above was a colony of mice which had been developed for use in what was perhaps the first course in embryology to be based exclusively on mammalian material — gametogenesis, follicular growth, ovulation, fertilization, cleavage, etc. He probably discussed problems with Loeb and he must have read the recent paper of Stockard and Papanicolaou in which changes in the vaginal epithelium in the guinea pig were correlated with the o^'arian cycle. Whether he was sensitive to the generally increasing interest in reproductive phenomena or was influenced more by the fact that the mouse had been inadequately studied and was right at hand and ready is not known. The latter possibility would have been consistent with his temperament and the way he worked. On the other hand, the fact that the first of the three "purposes" stated in his thesis was "to make possible a more efficient mating for the collection of embryological material" may indicate that the larger importance of what he was about to start was not yet apparent to him.

With the double responsibility of teaching and doing the research for a thesis, he must have worked incredibly long hours. But the rewards were great. The observations recorded in his thesis, "The oestrous cycle in the mouse," ignited the fire that was to burn and to be spread during the remaining years of his life, and to eradicate fore\'er the diffidence which characterized him during his earlier graduate years at Brown. Briefly, he observed that large follicles were present in the proestrous and cstrous stages of the cycle, but that ovulation had occurred by the time of the metestrum. Regressive changes were noted in the uterus and these were analogized with menstruation in lower primates and the human female. The reference on page 111 to Hobin.son's belief that a secretion tVoni the follicle causes estrous changes rcxcals how close he was to the hypothesis that was to rccciNc gencn-al acc(>ptance only a few years latci'. It is clear, how(>\-ei', that he was not rcad^' for this simple and direct conclusion. Instead, he started by rejecting the suggestion that 1 h(^ growth stimulus to the genital tract comes from the corpus hiteum and then, after noting that "the follicles are the only remaining ovarian possibility," continued, "the presence of maturing ova in large follicles is the cause of the prooestrum and oestrus" and "the renewal of the ova at ovulation (or their atresia if this fails to occur) is the primary cause of the degenerative changes of the metoestrum."

Except for the addition of the active role of the estrogenic substances contained in the follicular fluid, demonstrated by himself and Edward A. Doisy less than two years later, the pattern of Allen's thought for the next 20 years was contained in his thesis — the cyclic origin of ova from the germinal epithelium, the primacy of the ovum, the growth effects of estrogens, the consequences of their withdrawal, a discounting (the word used in his thesis) of the importance of the hormone of the corpus luteum in the regulation of reproductive phenomena.

Rarely has so much of the important conceptualization of a pre-eminent scientist been "roughed in" in his thesis. Also of interest is the place of the thesis in the history of American anatomy. It was written at a time when the emphasis was shifting from structural anatomy to functional anatomy. Rightly or wrongly, there were then, as there are now, those who feel that this trend could go too far. Allen seems to have been caught in this controversy. At all events, he must have felt compelled to enlist the help of friends at Brown, for it was the men there with their orientation toward biology who seem to ha^'e been less concerned with the amenities of the time and to have recommended that he be awarded the Ph.D. The omission of any acknowledgment to indi\4duals or to institutions could have been an understandable oversight in his haste to test the action of follicular fluid on the vaginal epithelium of the mouse, or it could have been a device for avoiding any embarrassment. It is a coincidence that 15 years later in an office at Brown when a younger colleague was threatening to look into the problem of the hormonal control of mating behavior, Allen asked in his characteristically friendly way and also somewhat paternally, ". . . why don't you return to your woi-k on the epididymis?"

With hurdles of the thesis and its publication iK^iind him, and the conviction that the follicular fluid contains the substance he was seeking, he must have thought of injecting follicular fluid from the large follicles of the sow (he had seen them at Brown) into ovariectomized mice and examining the vaginas for the sequence of changes he had described in intact mice. It is clear that the idea was not suggested to him by anything he read. As he often said jocularly, we did the work first and looked up the literature later. The published statement to this effect (J. Biol. Chem., 61: 711-727, 1924) was somewhat qualified but almost as direct, ". . .we paid but little attention to the papers of the various workers who have claimed to have demonstrated active preparations until after our own first definitely positive results were obtained." An unconventional approach, but excuseable perhaps when the hunch is as "logical" as it was to Allen.

By the early spring of 1923 he had made promising preliminary tests and a few days before Charles Danforth left Palo Alto for the Anatomists' meetings in Chicago, he received an exultant telegram saying that he (Allen) had succeeded in inducing estrus in a spayed mouse by injecting follicular fluid. Others had come close to the discovery, but the reason they failed was that no one had had a clear-cut practical test. Danforth is the authority for saying that the ideas back of all this were Allen's, but in order to obtain a purified product of the active hormone in the liquor folliculi he was using, he enlisted the cooperation of Edward A. Doisy whose laboratory was in an adjoining building. Time has made it clear that Doisy was undoubtedly the most capable collaborator Allen could have found anywhere for this kind of research.

A side of Allen that ingratiated him to all was seen at the time of the first announcement of the discovery of the action of follicular fluid on the vagina and is quoted from Danforth's letter to the present biographer :

"On my way to the 1923 meeting of Anatomists I went around by St. Louis and had dinner that night at the Allen home. In the evening Doisy, Allen, and I had a long and animated discussion over how their findings should be reported. Allen, sanguine and ebullient, was all for announcing them immediately at the Anatomists' meeting, even though there w^as no place for such an announcement on the program. Doisy, no less convinced of the importance of the findings, so far as they went, but temperamentally careful and thorough, thought any announcement should be withheld till more extensive data could be presented. Allen did not weaken, and when he was called upon at the meetings to present his paper, "Ovogenesis during sexual maturity," whic-h had been duly submitted and published in the abstracts, he by-passed that paper with only a few remarks and used the available time to tell about the effects of follicular hormone on spayed mice. I think this oral report was the first public announcement, the first published one being the AUen-Doisy paper in the Journal of the American Medical Association, September, 1923." Danforth's letter continues:

"When the report was presented, I think it was received on the whole with reservation if not outright skepticism, particularly since no abstract had been published and the topic was unannounced and unexpected. George Corner said later that was true in his case. Someone else who was there told me of his own skepticism and said that he thought Allen, relatively unknown and with an unconventional idea, was regarded as something of an 'upstart.' Stockard is said to have made some very caustic comments, which I don't recall. Herbert M. Evans seems to have been among the few who immediately sensed the significance of the paper. He and 1 returned to California on the same train and over and over he kept saying, 'I think Edgar (he sometimes called him Ezra) Allen has something,' or words to that effect."

Cooperation with Doisy continued in a skillful chemical analysis which soon made possible the isolation and chemical identification of the estrogenic hormones. It is unlikely that this stage of the investigation would have been greatly prolonged had Allen adhered to a 9 to 5 o'clock schedule or a 40-hour wTek, but it is apparent from a letter he wTote to Doctor Carl G. Hartman that the discovery of the Allen-Doisy test for estrogens might ha\'e been delayed had he not made a midnight trip to the laboratory. According to Hartman, "It was Saturday night and Ed and his wife had been at the theatre. Would he or would he not make a midnight visit to the animal colony at the University in St. Louis and examine the castrated mice which had been receiving Doisy's extracts? He did and much to his delight found cornificd cells in the vaginal smears, which might not have been there if he had waited till Monday morning I"

Beyond this point, most of what happened has been recorded by the earlier biographers. In 1923, and almost certainly before the importance of his work was fully appreciated, Allen was appointed Chairman of the Department of Anatomy in the then 2-year University of Missouri School of Medicine. He was made Associate Dean of the School of Medicine in 1929 and Dean the following year. He was happy at Columbia, "things have worked out so nicely here. . . ," he wrote Danforth, and later he began to think he "was planted definitely in Missouri." But April 1, 1933, he wrote, "Dean Winternitz visited Columbia day before yesterday and asked me to go on to Yale ..." as Professor of Anatomy and Chairman of the Department of Anatomy in \hc ^'ale University School of McHlicine.

The unusual extent to which his reseai'ch and lh(> i-esearch he super\is('(l in his department were suggested by his thesis has been indicated. We find, theictoic, investigations pertaining to the problem of oxogenesis. At a time when it was generally assumed that the female mammal possesses a full quota of ova when she is born, he demonstrated that new ova arise after birth and even after sexual maturity.

As Doctor WilHam U. Gardner, a former student and his successor at Yale, has written, his early conviction that the ovum is "the dynamic center of the folHcle" persisted throughout his life; he left two partially completed manuscripts dealing in part with the subject. Less than a year before he died he wrote to Danforth, "I still think of the ovum as a dynamic center for mitosis and there is no reason why the fertilized ovum shouldn't be." Gardner is of the opinion that Allen's interest in ova prompted the collaboration with Doctors J. P. Pratt, Q. J. Newell and L. J. Bland that resulted in securing in 1930 the first human ova from the oviduct, and in providing evidence bearing on the time of ovulation in the human female.

Overshadowing these studies of the ova were, of course, Allen's many investigations on the relationship of the ovarian estrogenic hormones to the growth of tissues. His demonstration that removal of the ovaries of the rhesus monkey under appropriate circumstances is followed by a uterine bleeding, indistinguishable from that of normal menstruation, led to the formulation of his estrogen-deprivation theory of menstruation. Although challenged and shown to be in need of modification, his statement of this theory stimulated many studies of that phenomenon which is still not understood.

After moving to Yale, he became increasingly involved in investigations of the influence of steroid hormones on carcinogenesis, especially the relationship of estrogens to malignant transformation of the uterine cervix. His interest in the growthstimulating capacity of the ovarian hormones was fiu'ther indicated by his use of the mitosis-stimulating and mitosis-arresting drug, colchicine, in studies on the genital tissues.

During the relatively short span of his professional life, he and his collaborators published more than 140 original investigations. Of these, most were under joint authorship. This is explained by the fact that he rarely worked alonc^ on a scientific problem. This may have been just as well, for his excitement and enthusiasm reached their peak in team work. In all such relationships, but especially when younger colleagues were involved, he gave full support and generous credit. He would have been proud of the large number of th(^ latter who have since worked their way to important posts in anatomy. Were he alive, he probably would still be prodding them to look into this or that problem.

Although the number of articles and reviews of which Allen was author or coauthor was relatively large, it was small compared with the many which can be attributed to the encouragement and enthusiasm he inspired among his students and associates, and to the many more which his work inspired in other laboratories throughout the world. In this sense, rather than in the strictest sense of the word, he was a foremost anatomist.

At the height of his career, he undertook the editing of the first edition of Sex and Internal Secretions. The editorship of the second edition was shared with Doctors Danforth and Doisy. The former was undoubtedly over-modest in recalling the parts of the co-editors in the undertaking, but his statement is ciuoted for the information it contains.

"I had helped a little with the first edition, especially with Bridges' chapter (Bridges being in Russia at the time), and in the second edition took I'esponsibility for Section A, as Doisy did for his group of chapters. I read the entire book in manuscript or in proof (mostly both) as I think Doisy did also, but neither of us, I feel sure, thought of ourselves as co-editors. On Jan. 4, 1939 Allen wrote, T have asked the publishers to make the book, Allen, Danforth and Doisy; as it has been team work all through.' My own reaction, and probably Doisy's is expressed in my reply of January 9, 'Instead of writing a long personal letter in reply to yours of January 4 I am going to send a short note by air mail protesting against your suggestion in the last paragraph. It would be quite unjust and misleading for you to put Doisy's and my names in any sense coordinate with yours. . . . And to put our names in any Vnit the most subordinate position would he to give credit that is not due.' "

Allen's services were not unrecognized. Three of the universities with which he was associated, Vale, Brown, and Washington University, awarded him honorary degrees. Had he lived a few months longer, he would have received an honorary doctor of law from the University of IVIissouri. In 1987 he was awarded the Legion of Honor in l-*aris where he was guest of the Fondation Singer-Polignac at a colloquium on the sexual hormones. In 1941 he was honored by the Royal College of Physicians of London when they conferred upon him the Baly Medal for researches on the female sex hormones. In the last year of his life he was president of the two national societies most closely representative of his field of work, the Association for the Study of Internal Secretions (now the Endocrine Society) and the American Association of Anatomists.

As Corner, Danforth and Stone wrote in their memorial for the American Association of Anatomists, "Allen was a striking figure personally, for his broad shoulders, ruddy face and snow-white hair made him conspicuous in any group. He made friends (luickly and was always the first to encoiu'age and to admire good work by others. His boyish frankness and his good will contributed more perhaps than any other factor to the effective cordiality which has prevailed among the American workers in the physiology of reproduction." The writer of this skc^tch recalls that in any meeting Allen was always one of the first to rise to the floor with a (juestion or lo mak(> a constructive' coniineul .

The Viest of the spirit of I he man that we can preserve is containe'd in \\\o form of his own words, written inforinall>- to his fri(Mid, ( harles Danfoith, with whom he coi'responded so fre(iuentl>' and xoluminously. A numbei- have been selected for the side of him thev will recall, the enthusiasm and imagination that enabled him to do the amount and quality of work he did.

November 6, 1935: "We just had a keen thing happen here. Dr. George AI. Smith returned from Europe with information about a drug which prevents mitotic figures from completing division. . . . Combining this with theelin stimulation. . . ." Alay 23, year not stated: "Have been working since early morning on the slides from the monkey experiments. They are a corking good lot of evidence and I am in one of those elated, trembly, inspired sort of heavens to which new ideas always bring a fellow. If you were in reach, you would have been dragged over precipitately to my scope, or interrupted to talk things over a dozen times. ... As it is, I must run my ideas through a slow movie instead of talking you to death. . . . Growth in the vaginal wall is almost unbelievable. Growth in the cervical glands is more so. They grow so darned much that the cervix looks like a tumor and the cervical canal becomes a tortuous thing like the lower Mississippi." A lot of histological detail, then: "the tubes are a knockout . . . this would seem to make ciliation a growth phase of the nonciliated cells and full ciliation dependent on presence of the hormone. The mammary gland whole moimts are wonders. I am so elated as to be almost damned crazy. Am sure I'd crack one of your ribs if I could get at you." Then, "Yesterday a letter from the National Research Council giving me $800 more for monkeys. . . . Ain't it just too lucky to l)eli(n-e. . . ." And (inallw in closing one of his letters: "Well you darned tool, Allen, it will take him 10 miiuitcs to read your letter now, aren't you e\('i' going to stop writing?"

About 10 years belore Allen died he sulTered a >r\r]v coi'onaiy attack, whil(> waiting foi' a train in the ,Jackson\ille, I'lorida, Lnion Station, lie lo\-ed swinuning as well as sailing and, after a sti'enuous and fatiguingxisit with Doctoi' IJobei't M. Verkes in the heat at Orange Park, had taken time for a long swim in the breakers at Jacksonville Beach. Miraculously he reached New Haven and recovered sufficiently to return to his work. Nothing would have kept him from it. When war was declared in 1941 he was tired, but he insisted on joining the Coast Guard Auxilliary for a weekly tour of duty on Long Island Sound, as opera

tions officer of a flotilla. It was during one of their patrols that he died of coronary occlusion. There was much that was fitting to such an end of his active life. No tribute could have been more appropriate than that phrased by Gardner in th(^ Edgar Allen Memorial Number of the ^'ale Journal of Biology and Medicine, "The 'Skipper' left with 'all sails filled.' "

Preface To The Third Edition

The impact of the first two editions of Sex and Internal Secretions can never be measured, but it must be near the front for books of its kind. Few books seem to have served their purpose better and few, 20 to 25 years after their appearance, seem to be valued as greatly by those who are fortunate to possess copies. It was to be expected, therefore, that pressure would be brought to bear for the preparation of a third edition. Whether the Publisher's attempts to find an editor miscarried because of the character of the new order ushered in by World War II, or because discretion was considered the better part of valor may never be known. The odds favored the latter explanation because there was no direction in which a successor to Edgar Allen, Edward A. Doisy and Charles H. Danforth could go except down. Nevertheless, there were reasons for accepting the challenge and attempting to do for the present generation of reproductive physiologists what Allen, Danforth and Doisy and their many colleagues did for theirs. Most of the problems to which they addressed themselves had not been solved, although the need for answers was as urgent as ever, and perhaps more so. The definition of these problems had become obscured, partly by the addition of many contradictory and confusing data to the literature relating to them, and partly by the rising tide of interest in other glands of internal secretion, notably the thyroid and adrenal. Finally, new technologies had pervaded the field and there were many new data and concepts to be evaluated and Avoven into the fabric Allen and his contemporaries had created.

In the preparation of the third edition little of the first two editions was to be retained except the title. Sex and Internal Secretions, and the ideals by which the authors of these editions must have been guided. Within a framework of careful scholarship, these were seen to be a resume of the solid facts that had been learned from test and retest, broadly critical discussions, enumeration of the important unsolved problems, and the preparation of lists of references complete enough for the guidance of any seeker of information, whether his interest was in the extension of basic studies or the application to clinical and agricultural problems. Adherence to these ideals has not been easy. Even if ample allowance is made for editorial ineptitude, the period 1958 to 1961 is different from 1932 and 1939. Reviews and symposia are more numerous and many are in a style that is alien to the traditions of Sex and Internal Secretions. There are demands on the time of many of us which, 20 years ago, were reserved for only a few, and the volume of published reports has long since outstripped oiu- capacity properly to encompass them.

Despite the difficulties and misgivings, an effort has been made to step into the void created by the lapse of the old Sex and Internal Secretions. Both similarities and differences will be noted. Relatively more space has been given over to the role of the gonadal hormones in the control of reproductive behavior, and relatively less to the biochemical problems of hormone synthesis, utifization, and metabolism. This "slighting" of the biochemical side, if it is to be so considered, does not reflect any lack of appreciation of the key position occupied by this discipline. It is explained, rather, by the opinion of the biochemists who were consulted that another review, just at this time, would be anticlimactic to a number of the excellent reviews which have recently been published. The chapter by Dr. Villee, therefore, is, in his words, a presentation of the general picture without being an exhaustive citation of the tremendous body of relevant literature.

The suggestion made above that some of the shortcomings in this third edition are a reflection of changes in our habits of working is not to be taken as an attempt to excuse any errors that properly belong on the editor's doorstep. He has learned as he has gone along, but finds himself reacting very much as he usually does at the end of a lecture — if it were to be given again, parts of it would be done differently. To the contributors, there is a feeling of the deepest gratitude for the time and thought they have given to the preparation of their chapters. The editor is indebted, too, to the National Institute of Mental Health, National Institutes of Health, for a research grant, M-4648, which has taken care of a number of the costs of publication. Justification for this action is believed to have been given by the expansion of the section on the gonadal regulation of reproductive behavior. This development, in turn, would have pleased Robert M. Yerkes. He was sensitive to the need for truly scientific studies of sexual behavior, the mechanisms which participate in its expression, in the determination of its character, in its regulation, and in its development. But he was equally aware of the importance of investigations that are purely physiologic, biochemical, and morphologic, and in a quiet but effective way did much to encourage many that are recorded in the first two as well as in the present edition of this book.

Preface To First Edition

It is the purpose of this book to survey the most important recent researches in problems of sex, especially those concerned with internal secretions, in order that concepts already established by experimental evidence may be clearly stated and made readily available. While general principles can in many cases be stated concisely, the recent data have accumulated so rapidly that there has not yet been time for retesting and evaluating much of the evidence. This may account in some chapters for emphasis upon certain work with which contributors may have had personal contacts. Furthermore, sex and reproduction show such wide ranges of variation in both the structures and functions involved that major differences, even among species of higher mammals, make generalizations both difficult and dangerous. This whole field has recently undergone such rapid growth that many new ciuestions have arisen to challenge the investigator's curiosity. An attempt will be made to indicate productive approaches to some of these unsolved or only partially solved problems.

This book is intended for the reader with a moderate biological background, to whom the less involved technical terminology may not prove a serious handicap. It is not our intent that it should be a "popular book on sex." Instead, it is designed for those interested in the progress of research in problems of sex, and those who may be already engaged in investigations thereon or casting about for promising problems for investigation. Physicians who are interested in fundamentals will find much valuable recent material. In suppljnng a biological foundation for education in matters of sex, it should also attract the interest of serious students of sex function in man.

Specialization in research has reached the point where any detailed authoritative survey requires a group effort. Conseciuently, the editoi attempted to gather together a group of investigators whose work has established them in their respective fields.

Each contributor has develop(>d his chapter in his own way and assumes full responsibility for the content of his section, including his discussion of the work of othei' investigators.

Since it was inevitable that considerable correspondence would be involved, introducing the time-transport factor, choice of the group was restricted to American investigators. Several prominent workers in this field, whom we would have desired as co-authors, have necessarily been omitted because of absence abroad or press of other work.

As the Foreword indicates, this project saw its inception in a proposal by Dr. E. V. Cowdry, then Chairman of the Medical Division of the National Research Council, to the Committee for Research in the Problems of Sex. In the publication of many of the contributors to this book, acknowledgment will be found to this Committee for support of investigations. In a sense the book will serve as a summary of some of the work accomplished under grants from this Committee. Obviously, however, it was not desirable to limit choice of contributors to investigators who had received grants from the Committee, and that consideration has not determined their choice. Instead, it is probable that the Committee in the first place chose to make grants to these men because of the promise of their work shown by their previous investigations.

The editor wishes to acknowledge the support of the Committee for Research in Problems of Sex, which has made provision for the editorial expenses involved in the preparation of the manuscript. He also wishes to commend the cooperation between investigators who, even though they may be competitors in the same field, have collaborated so well. The cooperation has been completely free from the secretive reserve sometimes encountered among investigators who may be leaders in their particular fields. The editor wishes further to acknowl

edge the assistance and friendly interest of Dr E. V. Cowdry, not only during the initial phases of this project, but throughout its progress and consummation. Dr. F. R. Lillie has counselled wisely in regard to titles and content of some of the sections. Valuable counsel and encouragement has also been received from several of the contributors. The editor also wishes to commend the contributors for their team-work ni eliminating or reducing overlaps between sections which is so necessary in the unification of interlocking material from closely related subjects.

Edgar Allen

University of Missouri School of Medicine Columbia, Missouri May, 1932.

Cite this page: Hill, M.A. (2021, June 22) Embryology Book - Sex and internal secretions (1961). Retrieved from

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