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Perspective: Reproductive Endocrinology and Human Health in the 20th Century—A Personal Retrospective

Department of Neurobiology and Physiology Northwestern University Evanston, Illinois 60208

Address all correspondence and requests for reprints to: Dr. Neena B. Schwartz, Northwestern University, Department of Neurobiology and Physiology, 1853 North Campus Drive, Evanston, Illinois 60208. E-mail: n-schwartz{at}northwestern.edu

	Introduction

Top Introduction First in order of... The next most important... My third selection is... Fourth, I would vote... A fifth application of... References

 
In a moment of weakness and grandiosity I accepted the request from the editors of Endocrinology to write a historical perspective of the contributions of reproductive biology and endocrinology to human health during the last century. Marshall’s comparative textbook Physiology of Reproduction, published in 1910, did not mention the anterior pituitary gland or the brain at all (1)! Even a superficial review of the spectacular growth of reproductive endocrinology over the past 100 yr would more than fill a whole issue of our journal. Nevertheless, I thought it possible to select a few highlights in terms of their overall impact on human health. Here are my "top five" picks ¹.

	First in order of importance has to be the pill

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Early in the 20th century endocrinologists became certain that the gonads secreted "sex" hormones that were responsible for maintaining the accessory sex organs and the phenotypically differentiated secondary sex characteristics (1). A major advance occurred when Philip Smith succeeded in performing hypophysectomies on rats and guinea pigs in the late 1920s (2, 3). The gonads regressed after the surgery, and he subsequently showed that pituitary implants restored ovarian follicle growth and uterine growth. He had established the important cascade of signals from pituitary to gonad to accessory tissue.

A theory of "sex hormone antagonism" surfaced with demonstrations that implanting a testis into a female could interfere with ovarian morphology and visa versa. Steinach (4) had proposed that the female and male sex hormones were directly antagonistic to each other and to the heterologous gonad. Carl Moore and Dorothy Price, working at the University of Chicago, showed experimentally that this was not true, and in so doing closed the loop between the pituitary and gonads (5, 6). From their elaborate and painstaking experiments on rats they formulated four basic principles: "(a) gonadal hormones stimulate homologous reproductive accessories but are without effect upon heterologous accessories; (b) secretions produced by the hypophysis stimulate the gonads to function both in germ cell and in hormone secretion; (c) gonadal hormones have no direct effect on the gonads of either the same, or the opposite sex; (d) gonadal hormones, of either sex, exert a depressing effect upon the hypophysis which results in a diminished amount of sex stimulating factor available to the organism." They summarized their observations as follows: "We conclude that a large number of reproductive phenomena, gonadal and reproductive accessory behaviors, can be interpreted logically upon a basis of hypophyseal-gonadal interrelationships. Gonads function only when they are forcibly stimulated by ... hypophyseal activity. Hypophyseal activity, on the other hand, is to some extent controlled by gonadal secretions ... " (5).

Once the concept of negative feedback of estrogens and progestins on the pituitary was formulated and it was noted that ovulation did not occur during pregnancy, the science was in place to suggest that ovulation could be blocked in females by means of ovarian steroid hormone administration. The demonstration of negative feedback of steroids on the hypothalamic-hypophyseal axis led directly to the development and testing of the oral contraceptives for women, undoubtedly the most far reaching and universal consequence of research in reproductive endocrinology on human reproductive health. The story has been told many times of how Margaret Sanger, a leader in the Women’s Movement in the first half of the century, with Katherine McCormick, heir to the International Harvester fortune, asked Gregory Pincus at the Worcester Foundation in 1955 to help develop a pill that could provide an individual woman a choice to reproduce or not and would help foster population control (see Refs. 7, 8, 9). Pincus focused pragmatically on the development of an oral contraceptive and accomplished his goal. He died prematurely in 1967. I was honored in 1968 to be asked to present the first Gregory Pincus Memorial Lecture (10) at the Laurentian Hormone Conference, which he founded, and which published Recent Progress in Hormone Research from 1947–1999. Many of endocrinology’s "firsts" were presented at that conference.

The background on the pharmaceutical industry entry into the field has been told by Djerassi (11), Edgren (12), and Hansel (13). After 40 yr, the pill remains the only widely used, effective, and relatively safe contraceptive for women. Today over 100 million women worldwide use the pill as a reversible oral contraceptive. Long-acting implantable or injectable progestogenic steroids are very effective but have not been popular in the U.S. (14). Overpopulation has put a strain on water and food supplies worldwide (15), and at the moment oral contraceptives are the only widely available means of birth control. The search for a male contraceptive has never been as vigorous as the attention paid to female contraception. The same principle of using steroid suppression of the pituitary has recently been applied to this goal using transdermal patches or injection of androgens that induce a reduction in spermatogenesis while maintaining sexual potency (16).

	The next most important application of basic endocrine biology is the technique of RIA

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First used for the measurement of hormone levels, the technique is now used for measuring many other substances, providing a reliable, valid, and most important, more sensitive substitute for bioassays. I can still remember the grueling days of using the ovarian ascorbic acid bioassay to measure the amount of LH in the pituitaries of rats. After a full day’s autopsying of 50 prepuberal rats that had been primed with PMSG, injecting homogenized pituitary extracts into their tail veins and then removing the ovaries for ascorbic acid determinations, my technicians and I were exhausted. All we had to show for the hard day’s labor were six estimates of pituitary LH content and six 95% confidence limits! Unless you have done such laborious bioassays you cannot know what it means to set up a 1,000-tube assay for serum LH and have the LH in ng/ml of each sample within a day or so.

Rosalyn Yalow (17) has told the story of how RIA came into being, and a recent biography about her tells that story and more (18). RIA has permitted complete hormonal profiles for patients throughout a 24-h day, or through a 28-day menstrual cycle. The principle of RIA has made it possible for couples to test for pregnancy privately at home within several weeks of insemination. Measurement of circulating prostate-specific antigen (19) has proven to be an excellent early marker for prostate cancer. Because of the exquisite sensitivity of the RIA method, frequent blood samples are possible, leading to the discovery of the pulsatility of LH, and thus to the pulsatility of GnRH (20). Recognition of pulsatility, in turn, led to deeper understanding of the transduction of GnRH and other releasing hormone signals on the gonadotropes, and a recognition that frequency of GnRH pulses is part of the signal differentiating LH and FSH secretion (21).

	My third selection is the concept of regulation of the secretions of the anterior pituitary by neurohormones

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Because it was apparent that sexual behavior was dependent, at least in animals, on gonadal hormones, it was accepted early in the century that the brain must be a target for estrogens and androgens (22). It was not recognized until the 1930s that the brain was, in turn, a major regulator of the anterior pituitary. Roy Greep told this story in detail from a 1961 perspective (22). The effects of environmental clues like light-dark ratio and seasonal changes on reproduction in animals including primates were already known when Goeffrey Harris in Cambridge, England (23) showed, in 1937, that electrical stimulation in the hypothalamus of the rabbit could cause ovulation. A neural pathway between the hypothalamus and anterior pituitary, resembling the situation in the posterior pituitary, was first postulated and then refuted. The portal system between the brain and pituitary finally became the focus of research and was shown to be the connecting path between the hypothalamus and the anterior pituitary gland.

The race was on to isolate and identify the various hypothalamic releasing factors. Papers by Guillemin (24), Schally (25, 26), and McCann (27) presented at the Laurentian Hormone Conference in the 1960s depict the early attempts to isolate TRF, CRF, and GnRH. Science journalist Nicolas Wade has told the story in The Nobel Duel (28), a book well worth reading. Success in identifying GnRH (26) led to a broad spectrum of analogs (29) that are useful for treating prostate cancer (30), hypothalamic hypopituitarism (31), and precocious puberty (32). Understanding of the participation of synaptic neurotransmitters in regulating brain releasing factor secretion has also contributed to our ability to treat indirectly some hypothalamic disease with CNS acting drugs. Bromoergotryptine, an agonist of dopamine that inhibits PRL secretion, is useful in treating hyperprolactinemia that accompanies some pituitary tumors (33).

Perhaps the most important result of identifying the brain’s control of the anterior pituitary is the concept that affects, emotions, stresses and environmental inputs can alter hormonal secretion. Women’s so-called "hormonal imbalances" are often interpreted to act unfavorably on their emotional and intellectual performance, and men’s "testosterone poisoning" is judged to render them aggressive and unfit for parenting. It is comforting to this endocrinologist to know that our brains are as much in charge of our hormones as our hormones control our brains.

	Fourth, I would vote for the identification of hormone receptors, particularly steroid receptors

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Endocrinologists began to turn to the issue of hormone mechanism of action on cells in the 1950s. Because hormones circulated to all cells it became obvious that cells that were "targets" for a given hormone differed from nontarget cells. Experimentally, labeled estrogens were first shown by Jensen and also Gorski to be bound to the uterus (34, 35, 36). While there was initially disagreement about whether specific steroid hormone receptors were in the cytoplasm or in the nucleus, it became obvious that the steroid-receptor complex acted within the nucleus on parts of DNA and led to transcription of specific mRNA and subsequently proteins (37).

The steroid receptors turned out to be a broad family of proteins with a hormone (ligand) binding domain and a DNA binding domain, which bound to specific nucleotide sequences (37). Other domains within the receptors are responsible for controlling transcription. Steroid analogs were developed principally in the laboratories of the pharmaceutical industry, both for the purpose of improving efficacy and lowering required doses, as well, perhaps, for the accrual of patents. Tamoxifen, a competitive inhibitor of estradiol, has proven to be a very effective treatment against recurrence of breast cancer in estrogen-dependent cancers (38). As a direct outgrowth of tamoxifen use, with concern about its possibly adverse effects on bone and uterus, a new group of estrogen analogs—SERMs—is currently being tested (39). These are "designer estrogens" that may serve as ligands in some target tissues but not in others, because of differences in receptor structure from target to target or differences in local tissue cofactors.

The use of estradiol for hormone replacement therapy in postmenopausal women has been received by many women as a boon, while there has also been opposition to the principle that menopause is a "disease" that requires treatment (9, 40). There seems little doubt that estradiol can help prevent osteoporosis, an idea that was strengthened when it was shown that males who lacked estrogen receptors also suffered from osteoporosis (41).

Much in the news recently, RU486 is a competitive inhibitor of progesterone on its receptor. RU486 was recommended as a "contragestive" by Beaulieu (42) and has been widely tested and used in Europe. It provides a relatively safe noninvasive early abortion by antagonizing luteal progesterone on uterine receptors. The progesterone antagonist may also be useful in treating breast cancer (43). The drug recently won FDA approval for use in the first trimester of pregnancy with a prostaglandin in the USA. The same groups that have opposed other kinds of abortions have opposed RU486.

	A fifth application of basic endocrinology to human reproductive health is the discovery of contaminating "endocrine disrupters" in the environment, which are detrimental to animal reproductive health and most likely to human health as well

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Rachel Carson’s "Silent Spring" (44, 45) sounded the first warning when birds began disappearing from Long Island after crop spraying with DDT. We now know that many pesticides can act as estrogens after they are broken down in the environment (46). Even very small amounts of methoxychlor residue, for example, when ingested by pregnant mice alter the behavior of the male pups (47). The controversy over possibly declining sperm counts in humans has cited environmental estrogens as a possible cause. The possible "organizing" effects of endocrine disruptions on human infants in vitro, as well as on other species in the wild, evokes a nightmarish possibility. A spin-off from the "brain regulates the pituitary story" was the "testosterone organizes the brain story." Pfeiffer (48) and subsequently Barraclough (49) showed that testosterone given to rat pups postnatally masculinized females so that estradiol could no longer elicit an LH surge (positive feedback); conversely, postnatal castration of male pups rendered them capable of showing an estrogen-induced LH surge as adults, which normal male rodents do not show. Interestingly, testosterone needed to be aromatized to estrogen locally in order for this to occur (50). These observations and others led to the idea that once testosterone acted on the developing brain, certain physiological responses and behaviors were locked in or "organized" regardless of the genetic or phenotypic sex (49). Estrogen has recently also been proposed to have important effects on sexual differentiation of the brain (51, 52). If it is true that prenatal or postnatal hormones permanently hard-wire circuitry in the brain of humans as well, this discovery is obviously of extreme importance in behavior as a Nature vs. Nurture issue. Fausto-Sterling, a biologist and feminist, has commented brilliantly on the implications of these observations in humans (40).

There are many other discoveries in addition to the five mentioned above that have affected reproductive health in individual humans. While important to them and their families, they do not have the potential at present to affect the sheer numbers of people influenced by the five discoveries mentioned above. The isolation and purification of the gonadotropic hormones (53) makes it possible to induce ovulation in women for the purpose of artificial insemination or in vitro fertilization. In fact, the assisted reproduction industry owes its existence to reproductive endocrinology, as well as to other areas of basic reproductive biology. But it remains to be seen how these techniques will advantage the public health broadly.

The application of molecular techniques to reproductive biology and medicine has led to many discoveries that have revealed intracellular complexities of hormone and receptor actions on cell function. The number of pathways used by hormone membrane receptors to signal ligand binding to the cell nucleus keeps growing—each is a potential site of adverse mutation and pharmacological intervention (54). The discovery of transcription factors, repressors, and cofactors involved in steroid-receptor interaction with DNA, enhances the possible sites of genetic defects in steroid actions. Mutations in peptide hormones as well as in their receptors can cause defects of loss of function as well as persistence of function (55). Knockouts of progesterone (56) and estradiol (57) receptors have revealed some unexpected effects in male mice. Inhibition of inhibin subunit genes leads to gonadal tumors in male and female mice (58). These very recent discoveries are exciting. Time will tell how broadly they will impact on human reproductive health in the 21^st century.

Reproductive endocrinology was born early in the 20^th century and has progressed unbelievably to the present, both as a basic science and in translation to human reproductive health. Adele Clarke, a medical sociologist, has written about the social and cultural milieu in which reproduction became a "discipline" (9). She discusses the reasons why the topic of reproduction has sometimes been seen as "illegitimate": 1) it is associated with sexuality and reproduction and therefore is stigmatized along with this "taboo" subject; 2) it has been associated with controversial social movements such as contraception, abortion, infertility services, and fetal research; 3) it has been associated with "clinical quackery"—the monkey gland affair and others; and 4) it has been associated with "brave new worlds" threatening the so-called "natural" order of life. Reproductive science does not exist in a vacuum and has been controversial from its beginning. Our field has witnessed a number of public and political controversies in the past year: RU486, cloning, stem cell research, fetal research, surrogate mothering, late-pregnancy abortion. Because we live and work in this social milieu, it behooves us to understand these broad cultural and political contexts and the controversies that surround our science.

	Footnotes

 
¹ In the interest of restricting the number of references, I have cited mostly reviews, rather than original research articles. I have also cited some remembrances and biographies to enhance a feeling for the participants in this abbreviated history.

Received February 27, 2001.

	References

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