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In the 1993 Volume of Remembrances of The Endocrine Society, there were many references to LH and FSH, but there is mere mention of the contributions of Frederick Hisaw to the stimulation of ovulation, an essential finding in the field of reproductive endocrinology. Dr. Hisaw also discovered and named the corpus luteum hormone, relaxin. He and a number of his colleagues made a significant contribution to endocrinology, in the course of their research. This review is a documentation of their contributions (1, 2, 3).
Born in 1891, Frederick Hisaw was raised and educated in Missouri. He obtained a bachelors degree, and in 1916 a M.S. degree at the University of Missouri. Dr. Hisaw subsequently joined the faculty of the University of Mississippi, but after 1 yr enlisted in the military for World War I. On his release from military service in 1919, he joined the faculty of Kansas State Agricultural College as a junior member of the faculty. He was subsequently promoted to Assistant Professor of Zoology. Dr. Hisaw studied in the summers at the University of Wisconsin, until he was awarded his Ph.D. in 1924, at which time he was invited by the University of Wisconsin to join the faculty as Assistant Professor of Zoology. By 1929, he was promoted to Professor of Zoology. In 1935, Dr. Hisaw accepted the invitation to the Professorship of Zoology at Harvard University and the responsibility for teaching the course in biology. In 1953, he was appointed to an endowed chair, The Fisher Professorship of Natural History.
By way of his interest in a local pest animal, the pocket gopher, he observed that in some of the gophers there was fusion of the pelvis on the ventral side of the animal, and in others there was a palpable opening, presumably due to the resorption of the symphysis pubis. This situation was found to occur only in sexually mature females. He later switched his studies to the guinea pig, which had a softening and broadening of the pelvic ligament in the female at the time of delivery, thereby enlarging the pelvic orifice and facilitating delivery of the offspring. Over the years, working with many of his fellows and associatesAlexander Albert, E. H. Frieden, W. L. Money, R. V. Talmage, and M. X. ZarrowDr. Hisaw learned that the hormone he was seeking was derived from a hitherto undiscovered hormone of the corpus luteum, which he called relaxin. It was later learned that it was a polypeptide.
In the period 19251930, Dr. Hisaws research was shared with many notable co-workers, namely R. K. Meyer, H. L. Fevold, C. K. Weichert, and S. L. Leonard. Dr. Hisaw learned from S. Ascheim and B. Zondek, world renowned reproductive endocrinologists, that a pituitary extract could cause ovarian enlargement and luteinization in immature female rats. They said it had two fractions, which they called Prolan A and Prolan B. Dr. Hisaw and his chemist associate, Fevold, separated these two fractions, which became known as FSH and LH. By elucidating their effect on the ovary, Hisaw explained the mechanism of ovulation and, ultimately, of menstruation.
In 1929, Dr. Hisaw and his associates foresaw the feedback mechanism between the pituitary and peripheral endocrine glands. They observed that giving estrogen to immature female rats inhibited the normal growth of the ovaries. In addition, the pituitary glands of estrogen-treated rats, when implanted into immature female rats, had a much lower capacity to induce ovarian enlargement than if they had not been pretreated with estrogen (i.e. suppressed). Sam Leonard, one of Dr. Hisaws graduate students, was honored to be permitted to present the report of this work at the annual meeting of the American Association for the Advancement of Science in 1930. This was an indication of Dr. Hisaws humility and his relationship to his associates.
From the early 1930s until his retirement, Dr. Hisaw continued to investigate the pituitary gonadotropic effect on the ovaries with his associates, Mark Foster, Roy Greep, Arthur Hellbaum, and Roy Hertz, in addition to those previously mentioned. While at the University of Wisconsin, Dr. Hisaw taught and was associated with other scientists who were to become renowned in their own right and fathered large families of scientists of great renown. These scientists included H. M. Goodman, F. L. Hisaw, Jr., and Robert Kroc.
When Dr. Hisaw transferred from the University of Wisconsin to Harvard, Roy Greep followed. At Harvard, they were joined by an additional group of fellows and Ph.D. students; among them were Alexander Albert, Edwin B. Astwood, W. L. Money, and Hilton Salhanick.
For the year 19491950, Dr. Hisaw was appointed to the Vice Presidency of The Endocrine Society, and in 1956 he was awarded the Medal of The Endocrine Society, which was the highest award of The Society at that time. In 1952, he was awarded The Gold Medal of The American Gynecological Society, which was its most prestigious award.
In addition to the academic recognition of Dr. Hisaws achievements, the world-renowned scientific accomplishments of his trainees and associates and their disciples are further compliments to his scientific greatness.
Dr. Roy Hertz
Another product of the midwest, Roy Hertz was born in Cleveland, Ohio, in 1909. Dr. Hertz obtained his A.B., Ph.D., and M.D. degrees and later, an honorary Sc.D. at the University of Wisconsin. While working as a graduate student under Dr. Hisaw, he began research on the gonadotropins. His doctoral thesis described the first induction of ovulation by the sequential administration of FSH and LH. In December 1941, after completing his internship and acquiring a MPH, he began to work under Dr. W. H. Sebrell in the Division of Physiology at the National Institutes of Health (NIH). After 4 yr, he was appointed head of the Endocrinology Branch of the National Cancer Institute, a scientific team that subsequently produced five presidents of The Endocrine Society. Concurrently, he was an Assistant Clinical Professor of Medicine at The George Washington University School of Medicine. In 1971, he retired from the NIH and moved to The Rockefeller University in New York. Here, he continued his work in the field of reproductive endocrinology and added to his previous contributions in the field of anovulatory physiology. After 5 yr at Rockefeller Institute, he returned to George Washington University as Research Professor of Pharmacology, Obstetrics, and Gynecology. Five years later, Lynn Loriaux lured him back to NIH as Scientist Emeritus for life.
Among Dr. Hertzs earliest observations was the discovery that in the genital tract of chicks on synthetic diets, supplemented by nutritional trace factors, estrogen failed to induce growth. However, the addition of small amounts of dried yeast or liver corrected this problem. By the process of elimination, he found that the addition of biotin corrected this deficiency. From this, he concluded that if vitamins were so essential to reproductive tissue growth, maybe their antagonists would inhibit not only normal growth, but also the growth of hormone-dependent tumors. This stimulated him to study the effect of folic acid antagonists on breast and prostate tumors. From these studies, he turned to trophoblastic tumors, in which he had developed an interest while working with Dr. Hisaw. Because they were hormone-producing tumors, he thought that folic acid antagonists might be effective in their treatment. He undertook a study and found that methotrexate was a very effective therapeutic agent for this condition. Using the disappearance of bioassayable human chorionic gonadotropin from the urine to monitor tumor response, Dr. Hertz and his associates showed that the intermittent administration of large doses of methotrexate over a 5-d period was an effective treatment. The latter contribution was made by Dr. C. H. Li. As a result of this discovery, choriocarcinoma, a condition that formerly was almost a 100% fatal malignant disease, is now curable in over 90% of cases. This was the first cancer to be cured by chemotherapy. For this work, Dr. Hertz was elected to the National Academy of Science.
Dr. Hertzs most recent interest has been on the treatment of AIDS in females, with the ultimate intention of preventing its transmission to their offspring. Because of the limited transmission of AIDS from mother to fetus, he recommended the treatment of women with the hormones of pregnancy then to give them choriocarcinoma, because of the ease with which the malignancy can be treated. This, hopefully, would decrease the transmission of AIDS from mothers to offspring to an even greater extent. In the summer of 1999, he was invited to present these theories to the Ninth World Conference on Gestational Trophoblastic Diseases.
Dr. Hertz had many young scientists under his tutelage, many of whom have become deans or chairmen of departments around the country, including Wayne Bardin, Mort Lipsett, George Gey, Lynn Loriaux, Donald Goldtsein, Ron Patillo, Monte Greer, James Pittman, Charles Hammond, Saul Rosen, Peter Kohler, Griff Ross, John Lewis, William Tullner, and Bert OMalley.
Dr. Hertz was Vice President of The Endocrine Society in 19601961 and recipient of The Fred Conrad Koch Award, the most prestigious award of the Society, in 1996 (Friedman, A., personal interview).
Dr. Roy Greep
Roy Greep grew up on a Kansas farm and left school early, because he felt it was more fun to herd cattle, hunt, trap, and participate in other outdoor activities. After 3 yr, however, the local high school principal, who was aware of Greeps academic potential, convinced him to go back to school. Greep matriculated at the Kansas State Agricultural College, where he immediately distinguished himself as a student and was given a teaching assistantship. In his senior year, he was invited to participate in a research project on the isolation of sex hormones from the urine of cows. This project was unsuccessful. Because Dr. Hisaw had failed in this same research attempt, he became interested in Greep and, in 1930, invited him to become a graduate student in his laboratory at the University of Wisconsin, where his research was in the field of gonadotropins. While performing this research in 1935, Greep earned his Ph.D. at the University of Wisconsin. When, in 1935, Dr. Hisaw was invited to Harvard as Professor of Zoology, he invited Dr. Greep to accompany him.
While in Wisconsin, with the aid of his wife, Dr. Greep taught himself to perform hypophysectomies on rats, which enabled Dr. Hisaw and his staff to establish the existence of the two gonadotropic hormones.
Another of Dr. Greeps outstanding achievements was the observation that transplantation of pituitary tissue to the sella turcica of hypophysectomized rats facilitated growth and reproduction, whereas transplanting the pituitary tissue elsewhere in the body was ineffective. This ultimately led to the realization that the hypothalamus, not the pituitary, is probably the master gland. In association with Helen Deane, he performed significant experiments on the effect of hypophysectomy on the adrenal cortex and proved the independence of the zona glomerulosa from the pituitary.
His other valuable nonscientific accomplishment was the resurrection of the journal Endocrinology, which had slipped to a 9- to 12-month delay between submission and publication of manuscripts. In his home, with the aid of his wife, both unpaid, he edited and managed the journal for 10 yr. Lastly, he was the first and only Dean of the Harvard School of Dental Medicine without a dental degree.
Dr. Greep was President of The Endocrine Society from 19651966 and was awarded the Fred Conrad Koch Award of the Society in 1971 and The Robert H. Williams Award in 1978.
The Roy Greep Award of The Endocrine Society has been established by his peers in his honor. He was one of the founders of the Laurentian Hormone Conference and for 13 yr, editor of its proceedings, Recent Progress in Hormone Research (4).
Dr. Edwin B. (Ted) Astwood
Dr. Astwood was another of Dr. Hisaws trainees, a research fellow who was world-renowned for his research and the clinical application of the use of the antithyroid drugs.
Ted Astwood was born and raised in Bermuda and was graduated from McGill University School of Medicine in 1934. He interned for 1 yr at The Royal Victoria Hospital in Montreal, then went to the Johns Hopkins Hospital in Baltimore as a research fellow under Dr. Charles F. Geschickter. His early investigations were in the field of reproductive endocrinology. In 1937, he became a Rockefeller Fellow at Harvard, where he continued his investigations in the field of female reproductive hormones with Drs. Hisaw and Greep. After achieving his Ph.D. in 1939, Dr. Astwood returned to Johns Hopkins Hospital in the Department of Obstetrics for 1 yr, then returned to Harvard as Assistant Professor of Pharmacology and Associate in Medicine at Peter Bent Brigham Hospital. In 1945, he moved to Tufts School of Medicine and The New England Center Hospital, where he remained Head of the Department of Endocrinology and Endocrine Research until his retirement.
Dr. Astwoods investigations into the field of antithyroid drugs, their therapeutic application, thyroid physiology, the early use of radioactive iodine, purification of ACTH, and the isolation of other peptide hormones earned worldwide recognition. The antithyroid drugs on which he worked are in daily use to this day.
Among his fellows are many world-renowned endocrinologists, such as Maurice Raben and Gerald Aurbach, as well as some of the more renowned thyroid researchers in North America. They are John Beck, Henry Friesen, Joe Glennon, Monte Greer, Jerome Hershman, Charles Hollenberg, J. Maxwell McKenzie, Ira Pastan, Clark Sawin, David Solomon, and Willard P. Vander Laan.
Dr. Astwood was President of The Endocrine Society from 19611962. He was awarded the Ernst Oppenheimer Award of The Society in 1944, the Fred Conrad Koch Award in 1967, and the Robert H. Williams Leadership Award in 1975. The Edwin B. Astwood Award of The Endocrine Society has been established in recognition of his accomplishments (5, 6).
Dr. Alexander Albert (Abramowitz)
Alexander Albert was born in upstate New York, early in the 20th century. He did very well in school and strove to get top grades, because there was no other way he could afford to go to college. He applied and was accepted for a Hudson Valley Fellowship to St. Stephens College. The college was later incorporated into Columbia University, but subsequently spun off as Bard College. Dr. Albert was influenced to go to Harvard College by Prof. George Parker, a zoologist. He subsequently was awarded M.S. and Ph.D. degrees under Dr. Hisaw. While working for his graduate degrees, Dr. Albert was sent to Bermuda on a summer fellowship. During this period he learned to hypophysectomize a fundulus that caused degeneration of the gonads. He also developed a technique for the extraction and purification of relaxin from sow ovaries. Both of these interests evolved from his association with Dr. Hisaw and his research endeavors.
In 1943, Dr. Albert was graduated from Harvard University School of Medicine, and in 1946, he was invited to the Mayo Clinic as a Research Endocrinologist. He also established and directed their research laboratories. Dr. Albert worked extensively in the field of thyroid physiology, the development of exophthalmos in the fundulus, and various aspects of the function and inactivation of TSH.
Dr. Albert was President of The Endocrine Society from 19701971 and was awarded The Fred Conrad Koch Award of The Society in 1974 (Sawin, C. T., personal interview).
Dr. Robert Kroc
Robert Kroc was born in Illinois in 1907 and remained there until going to Oberlin College, where he received his bachelors and M.S. degrees. Although it was never published, his thesis was on basal metabolism in college students. Subsequently, he matriculated at the University of Wisconsin, where he was awarded a Ph.D. in zoology and physiology under Dr. Hisaw.
During that time, Dr. Kroc took a course in medical physiology and Hisaws course in endocrinology. On receiving his doctorate, he was invited to the University of Indiana, where he rose to Assistant Professor of Zoology. His field of research involved the relationship of the adrenal cortex to the ovary. He remained there from 19321944. While in Indiana, he befriended a biochemist through whom he met a drug company research investigator. Dr. Kroc invited the guest to give a lecture at the University of Indiana; as a result, the guest invited Dr. Kroc to come to New York and work for him. Originally, his association was with The Maltine Company, which became The Chilcott Laboratories and subsequently the Warner-Lambert Corporation. At Warner-Lambert, Dr. Kroc worked on the synthesis of thromboplastin and performed some thyroid research, including studies on antithyroid drugs and investigations into the biochemistry and physiology of relaxin. While working at Warner-Lambert, he produced 21 research articles on relaxin, which obviously stemmed from his association with Dr. Hisaw. He remained there from 19441969. From l9501969, he was Director of Physiology Research.
On his retirement from Warner-Lambert, Dr. Kroc was persuaded by his brother, the head of the McDonalds hamburger empire, to become President of the Kroc Charitable Foundation. During the next 15 yr, under his administration, the foundation sponsored over l00 conferences and contributed over $50 million to medical research, with a generous share going to various facets of endocrinology (Vander Laan, W. P., personal interview).
Dr. Samuel Leonard
Dr. Leonard is a nonagenarian and probably the oldest living disciple of Dr. Hisaw, having been born in New Jersey in 1905. He obtained his undergraduate degree at The Rutgers Agricultural College, then his M.S. and Ph.D. degrees at the University of Wisconsin. He was accepted as a research assistant to Dr. Hisaw. In his laboratory, Dr. Leonard was introduced to the field of reproductive endocrinology. His first full-time job was as a National Research Council Fellow in the field of endocrinology under Dr. P. E. Smith at Columbia University College of Physicians and Surgeons. While in Dr. Smiths laboratory, Dr. Leonard conducted research that was a continuum of his work on the effects of pituitary gonadotropins under Dr. Hisaw. Subsequently, Dr. Hisaw helped him obtain an Assistant Professorship in Biology at Union College in Schenectady, New York. Dr. Leonard then made a critical move to Cornell University, where he received an Associate Professorship with tenure. In 1950, he was promoted to a full Professorship, from which he retired a few years ago.
Throughout his academic career, Dr. Leonard pursued his research in reproductive endocrinology and pituitary gonadal relationships. In addition to his specific studies on reproductive physiology, Dr. Leonard studied various aspects of phosphorylase activity in skeletal muscle and rat uterus and the specific effects of hormones on phosphorylase activity on the musculoskeletal system of mice. He also did some investigations on the effects of other agents and hormones on the function and effectiveness of gonadotropic hormones (Friedman, A., personal communication and correspondence).
Among his more successful associates were Ernst Knobil, W. R. Hazard, Rafael Kurzrok, P. E. Smith, Preston Perlman, Bob Foote, and Bill Hansel.
Why were these scientists singled out and why did they warrant so much attention? Although the portion of their careers that was devoted to reproductive endocrinology varied, each had devoted some of his career to reproductive endocrinology. This most probably was attributable to their training and association with Dr. Hisaw. In the cases of Drs. Astwood, Albert, and Kroc, it occurred in the early phases of their careers, whereas Drs. Hertz, Greep, and Leonard devoted their lives to this branch of endocrinology. This influence has been observed in many trainees of famous scientists.
Acknowledgments
I express my appreciation to Susan Koppi and Dr. Clark Sawin for editorial assistance in the preparation of the manuscript, to Dr. Sawin for permitting me to use the transcript of his interview with Dr. Alexander Albert, and to Dr. Vander Laan for his transcript of his interview with Dr. Robert Kroc.
Received September 16, 2002.
Accepted November 13, 2002.
References
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