0013.7227/92/1312-0543$03.00/0 Endocrinology Copyright ia 1992 by The Endocrine

The Concept

Vol. 131, No. 2 in U.S.A.

I%nted

Society

of Negative

Feedback-Moore

I met Drs. Carl R. Moore and Dorothy Price when I began my Ph.D. work under Dr. Moore in 1948 at the University of Chicago. Carl Moore was chairman of the zoology department at that time. He did not have a personal secretary and his office was always open to anyone knocking on his door. To the knock he would answer in his big voice, “Come In.” He was a tall, blond, outgoing man who sat behind his large roll-top desk. There was a microscopeon a table behind him and a typewriter on a table next to the desk. The room was blue with pipe smoke. Dorothy Price was rather slender with graying hair and at that time she was an assistant professor. Dorothy was well liked by the graduate students, especially those with whom she taught in the laboratories of the division of biological sciencessequence. She obviously had the students’ interests at heart. For most of their research lives these two people had been trying to determine the mechanisms involved in sex differentiation in mammals. The driving force for Moore was the description by Frank Lillie of the freemartin. The freemartin is the intersex female cotwin of male-female twinning in cattle. (Freemartins may also occur in such twinning in other two-toed ungulates.) Lillie’s hypothesis was that the male cotwin produced a hormone from the testis which inhibited the development of the reproductive tract of the female cotwin. Moore began a seriesof experiments to understand the processesof sex development after finishing his doctoral thesison fertilization and parthenogenesisof seaurchin eggs. The freemartin hypothesis of Lillie had led others to the idea that the female sex hormones had antagonistic effects on male reproductive tracts and testesand that male hormones had antagonistic effects on ovaries and uteri. In the absence of pure steroid hormones this idea was very popular, especially in Europe. To get pure preparations of androgens, Carl Moore and his research assistant,Dorothy Price, were working on a mammalian assay for androgens with F. C. Koch and his associatesin the biochemistry department. They hoped to use the pure androgens to help understand the freemartin. The study of the freemartin was postponed by the hypotheses about sex hormone antagonism. Moore was very skeptical about male and female hormone antagonism. He designed experiments to determine the effects of the male and female hormones on both sexesof rats. The hormones injected were impure extracts: bull testis extract for androgen, estrin from human placentae (prepared by Gustavson and D/Armour) for estrogen, and pregnancy urine and pituitary implants for gonadotropins. Young adult and mature adult Received February 25, 1992. “Remembrance” articles discuss people and events as remembered the author. The opinion(s) expressed are solely those of the writer do not reflect the view of the Journal of The Endocrine Society.

by and

and Price

rats, both normal and castrate, were used. (Most of the initial experiments were on males with some observations on females.). The effects of the injections were: 1) estrin did not cause a change in the accessory glands of castrate rats, nor did testisextract change the uterus of spayed rats; 2) injection of estrin in normal malescaused a reduction of testis weight and also decreased the weight of the accessory glands; 3) injection of testis extract in normal females caused cessation of estrous cycles; 4) injection of testis extract in malescaused cessationof spermatogenesisand decreasedtestis weight, but the accessoryglands remained enlarged; and 5) injection of estrin in females enlarged the uterus, but the animals stopped cycling. Injection of each preparation with gonadotropic substanceseither completely or partially reversed the effects of the steroid hormone treatments. Both investigators were very puzzled by the results, but the answer was supplied by Dorothy Price, who realized that the steroid extracts were inhibiting the secretion of the gonadotropic stimulating hormones from the pituitary. In their papers (1, 2), Moore and Price concluded “a substancethe hypophysis could not supply” was absent when the steroid extracts were used, and this substance was supplied when the gonadotropic preparations were injected into rats treated with the steroid extracts. Moore presented the work in a paper in London in 1930, and both authors quickly published the results in a short paper (1) and a long one later (2). Thus, by 1932 the major hypothesis and its evidence had been presented. It was not modified during their lifetimes by either Carl Moore or Dorothy Price because,except for a few additional studies on females by Moore’s students, they did little further work on the negative feedback theory. Moore and Price felt that they could explain cycling in female rats and testicular responsesin male rats on the basis of their hypothesis. They knew that light could trigger gonadal activity in some annually breeding mammalsand birds and felt that the cessationof breeding activity in these species was due to the feedback of the gonadal steroid hormones. However, Moore remained interested in species that bred annually. He found negative feedback a possibleexplanation for the cessation of breeding activity in annual breeding mammals that were not light sensitive (13-lined ground squirrels and prairie dogs) but felt that the long quiescence of the reproductive system made negative feedback a difficult explanation for these species. Moore and Price were familiar with the work of Perry McCullagh (3), in which he hypothesized a nonsteroidal feedback mechanism to the pituitary. Moore tried some experiments but could get a clear-cut effect that he could ascribe to inhibin. Real evidence became available after new techniques of tissueculture of granulosa cells were developed (4). McCullagh was a secretary of the American Association for the Study of Internal Secretions (now The Endocrine

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REMEMBRANCE

Society) in 1938 and president of The Endocrine Society in 1958. I talked to him once about a Cleveland Sigma Xi event over the telephone, and he was surprised that anyone remembered either him or his work on inhibin. Although Moore and Price did know about inhibin they did not know the work of Holweg and Junkmann (5) in Germany. Price later said it was a more limited and less international climate for science at that time and, of course, there was a worldwide depression. The real understanding of the research of Holweg and Junkmann came with the publication by Harris in 1955 of “The neural control of the pituitary gland” (6). Carl Moore was raised in the Missouri Ozarks and loved the outdoors. He was a fly fisherman and had a summer home on Elk Lake in Michigan, where he had a shed he used for his microscopic studies. His reputation was firmly established before the negative feedback theory was published. He had already shown that scrota of mammals maintained testicular temperatures below body temperatures and thereby prevented heat damage to spermatogenic tubules. His experiments included wrapping the scrota of rams in flannel pajamas made by his wife (the rams grazed on Chicago’s Midway) and heating only part of the scrotum of guinea pigs to 37 C. In 1950, he received an award from the American Urological Association in recognition of his studies of cryptorchidism and the function of the scrotum. After the publication of the negative feedback papers Moore returned to his first love, the analysis of the factors involved in sexual differentiation in the embryo with sidetracks to other problems in reproduction (e.g. effects of high altitude, role of the ovarian germinal epithelium). One of these side-tracks involved him in a court case in 1938. His students had found that estrogens (they used face creams) were absorbed through the skin of rodents and that they had systemic effects on uterine and mammary growth even in male guinea pigs. This work was first reported in JAMA, and that journal’s editor, Morris Fishbein, wrote an editorial about the uncontrolled use of steroids by the cosmetic industry. About 24 h after this editorial was printed, the AMA, Fishbein, Moore, and the graduate students were all sued by the cosmetic industry. The suit ended in a draw because no human studies were done, even though steroid activity was expressedin terms of rat assaysas claimed by the defense. The estrogenic face creams remained on the market. By the late ‘1930s Moore was using the oppossum for his studies because it was born before the gonads and reproductive ducts had differentiated and the young could be castrated in the pouch with less damage than treating the fetuses of pregnant rats. Moore’s work brought Dr. Alfred Jost (seeRef. 7) to Chicago in 1949 to present his experiments on rabbit embryos. Moore was very pleased with Jost’swork and was able to get him to visit the class on the Biology of Sex to explain his experiments. In 1950 Moore went to Paris and reported on his oppossum studies at a colloquium. This was his last major conference, as illness was beginning to take its toll. Moore was president of the American Association for the Study of Internal Secretions from 1944-1946 during World War II and in 1955 was awarded the first Endocrine Society

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Medal and Certificate of Award. He was a member of the National Academy of Science and active in the National ResearchCouncil asa member of the Committee for Research on the Problems of Sex, the Committee on Human Reproduction, and the Committee on Growth. He supported strongly the research of Kinsey on male and female reproductive behavior against the attacks of clergymen and others. He believed that research alone would lead to the understanding of the biological and psychological aspectsof sexual activity. Carl Moore died of cancer in the fall of 1955 at the age of 63. He had been chairman of zoology at Chicago since 1934. Moore was devoted to teaching and considered it a proper obligation and privilege to be able to teach students. The different research projects and the numerous awards presented to Moore have been described by Price (8). Dorothy Price was raised in Illinois. She started her graduate work in 1922 at Chicago, but family finances forced her to seek employment. She was a first a research assistantfor Lillie and later a research associatefor Moore. She finished her doctoral work in 1935 on the development of the prostate and its responses to androgens (9). She used the newly isolated androgens from Koch’s laboratory for someof these studies. She was hired as an assistant professor by the zoology department in the 1947. She was, I believe, the only woman on a natural science faculty of any major research university at that time. After her doctoral studies, Dorothy Price also turned to the study of sex differentiation. Her approach was to use organ culture of embryonic male and female reproductive tracts with and without their associated gonads or with gonads of the opposite sex. She published numerous papers on the results of these studies with Drs. Evelina Ortiz and Johanna Zaaijer in what she described as a “long-term, long-distance collaboration between Chicago, Leiden, and Puerto Rico.” She was promoted regularly and was a full professor well before she retired in 1967. Dorothy Price remained a lively and interesting person devoted to her scienceeven after her retirement. She continued her studies using organ culture and wrote some historical discussionson the development of sex. She was appointed the Boerhaave Professor (an honorary visiting chair) at the University of Leiden in 1967 and was awarded their Medal for Distinguished Service that year as well. In later years, Dorothy described her role in the negative feedback hypothesis and how she thought that they had backed into the hypothesis in the processof studying sex hormone antagonism. She also discussedlater developments with reference to the original hypothesis (10). We should remember that although our present knowledge is more complete, her insight gave the right explanation to the results obtained in 1930. Dorothy continued to work in Leiden after her retirement but also often came back to Chicago. In November 1980, I received notice from Drs. Ortiz and Zaaijer of Dorothy Price’s death in Leiden on November 17. Women in endocrinology should consider Dorothy Price an appropriate ancestral role model becauseshe brought talent, insight, patient experimentation, and steadfast courage to the science that interested her, in spite of the tremendous odds against the progressof women in science, even at so enlightened an institution as the

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REMEMBRANCE Universitv, of Chicago.

Darhl Foreman Department of Biology CaseWestern Reserve University References

Moore CR, Price D 1930 The question of sex hormone antagonism. Proc Sot Exp Biol Med 28:38-40 Moore CR, Price D 1932 Gonad hormone functions and the reciprocal influence between gonads and hypophysis with its bearing on the problem of sex hormone antagonism. Am J Anat 50:13-67 McCullagh PR 1932 Dual endocrine activity of the testes. Science 76:19-20 Schwartz NB 1991 Why I was told not to study inhibin and what I

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did about it. Endocrinology 129:1690-1691 5. Holweg W, Junkmann K 1932 Die hormonal-nervose Regulierung der Funkion des Hypophysenborderlappens. Klin Wochenschr 11:321-323 6. Harris GW 1955 Neural control of the pituitary gland. Monographs of the Physiological Society. No. 3. Edward Arnold Ltd, London 7. Unite de Recherches sur 1’Endocrinoloeie du Develooement INSERM 1991 Rememberance of Dr. ifred Jost. Endocrinology 129~2274-2276 8. Price D 1974 Carl Richard Moore. Biographical memoirs. Proc Nat1 Acad Sci USA 45:385-412 9. Price D 1936 Normal development of the prostate and seminal vesicles of the rat with a study of experimental postnatal modifications. Am J Anat 60:79-126 10. Price D 1975 Feedback control of gonadal and hypophysial hormones. Evolution of the concept. In: Meites J, Donovan BT, McCann SM, (eds) Pioneers in Neuroendocrinology

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The concept of negative feedback--Moore and Price.

0013.7227/92/1312-0543$03.00/0 Endocrinology Copyright ia 1992 by The Endocrine The Concept Vol. 131, No. 2 in U.S.A. I%nted Society of Negative...
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