The History of Estrogen Therapy.

INTRODUCTION: Menopausal hormone therapy (MHT) has proven an effective treatment for the amelioration of symptoms of menopause. The idea that a substance was the missing factor in a woman's body after menopause dates to the 1800s, when cow ovarian tissue was injected into German women in a successful attempt to reverse the sexual symptoms of menopause. The early 1900s saw the rise of commercialized menopause "treatments" that ranged in substance and even theoretical efficacy. The role of estrogen was first accurately described in Guinea pigs in 1917 by Dr. Papanicolaou. AIM: To tell the detailed history of how estrogen was discovered and the controversy surrounding MHT. METHODS: A literature search was conducted using PubMed to identify relevant studies and historical documents regarding the history of estrogen therapy. RESULTS: The history of estrogen supplementation and its controversies are interesting stories and relevant to today's ongoing investigation into hormone replacement. CONCLUSION: The controversy of MHT remained until the first randomized trials examining MHT in the early 1990s that suggested MHT is cardioprotective in postmenopausal women, although this conclusion was contradicted in subsequent trials. In the present day, MHT is approved only for short-term use for the symptomatic treatment of menopause. Kohn GE, Rodriguez KM, Hotaling J, et al. The History of Estrogen Therapy. Sex Med Rev 2019;7:416-421.

History of Estrogen: Its Purification, Structure, Synthesis, Biologic Actions, and Clinical Implications.

This mini-review summarizes key points from the Clark Sawin Memorial Lecture on the History of Estrogen delivered at Endo 2018 and focuses on the rationales and motivation leading to various discoveries and their clinical applications. During the classical period of antiquity, incisive clinical observations uncovered important findings; however, extensive anatomical dissections to solidify proof were generally lacking. Initiation of the experimental approach followed later, influenced by Claude Bernard's treatise "An Introduction to the Study of Experimental Medicine." With this approach, investigators began to explore the function of the ovaries and their "internal secretions" and, after intensive investigations for several years, purified various estrogens. Clinical therapies for hot flashes, osteoporosis, and dysmenorrhea were quickly developed and, later, methods of hormonal contraception. Sophisticated biochemical methods revealed the mechanisms of estrogen synthesis through the enzyme aromatase and, after discovery of the estrogen receptors, their specific biologic actions. Molecular techniques facilitated understanding of the specific transcriptional and translational events requiring estrogen. This body of knowledge led to methods to prevent and treat hormone-dependent neoplasms as well as a variety of other estrogen-related conditions. More recently, the role of estrogen in men was uncovered by prismatic examples of estrogen deficiency in male patients and by knockout of the estrogen receptor and aromatase in animals. As studies became more extensive, the effects of estrogen on nearly every organ were described. We conclude that the history of estrogen illustrates the role of intellectual reasoning, motivation, and serendipity in advancing knowledge about this important sex steroid.

8th Pieter van Keep Memorial Lecture. Estrogen and bone: have we completed a full circle?

Estrogen therapy was considered first-line therapy for the prevention and treatment of postmenopausal osteoporosis in 1984. Evidence from a large, randomized clinical trial in 2002 proved the efficacy of estrogen in the prevention of all types of osteoporosis-related fractures. Ironically, estrogen was relegated to second-line therapy, based on perceived safety concerns. The historical background to these decisions is presented. It is argued that this decision is not a reasonable reflection of the available evidence, especially in comparison to other available drugs.

What the future holds for women after menopause: where we have been, where we are, and where we want to go.

With an increasing world population of postmenopausal women, providers of health care need to focus on improving the quality of life as well as the longevity of women. This review emphasizes the importance of health care for postmenopausal women, particularly the role of menopausal hormonal therapy (MHT), from the perspective of where we have been, where we are now, and where we can expect to be in the future. Use of MHT increased dramatically in the 1980s and then fell very abruptly in the early 2000s with the publications of various randomized hormonal trials, including the Women's Health Initiative (WHI). The recent publications from the WHI with 13 years of follow-up are different from the initial reports and do not show an increase in cardiovascular risk in any age group (with the exception of venous thrombosis). Breast cancer risk increased marginally with estrogen/progestogen therapy, related to duration of use, but with estrogen-alone therapy, breast cancer risk decreased significantly, as did mortality. For younger women receiving estrogen alone, there is great consistency between all randomized trials, including the WHI and observational data showing a coronary benefit and a decrease in all-cause mortality. Recent data also confirm the 'timing hypothesis', suggesting that younger women benefit from MHT, while older women do not exhibit this effect. In the future, we will have many more genetic and molecular tools to guide therapy and risk assessment, as we move into an era of personalized medicine. An important opportunity presents at the onset of menopause to prevent diseases which usually occur some 10 years later. Part of this preventative strategy may involve MHT.

The history of hormone therapy use and recent controversy related to heart disease and breast cancer arising from prevention trial outcomes.

The reasons for hormone therapy use have changed dramatically over time from being very popular for the purpose of preserving youth in women to menopause-related symptom management, disease prevention, and now back to menopause-related symptom management. Over time, several important risks associated with the use of hormone therapy have become evident, causing dramatic reductions in the use of hormone therapy for periods of time following identification of these risks. Most recently, randomized controlled prevention trials that evaluated hormone therapy for the purpose of reducing or preventing coronary heart disease among women have found that hormone therapy is associated with increased rather than decreased risks for coronary heart disease. The most recent of these trials again identified increased risks for breast cancer associated with estrogen plus progestogen therapy. The evolving evidence base from these randomized controlled prevention trials is complicated and in some cases contradictory. Specifically, the data suggest that the timing of when hormone therapy is initiated once a woman is postmenopausal may influence her risk for developing heart disease and breast cancer. In this article, contradictory evidence is carefully sifted so risks and benefits can be weighed by clinicians when partnering with women to individualize decisions about using hormone therapy.

The incidence of breast cancer and changes in the use of hormone replacement therapy: a review of the evidence.

Even though a link between hormone replacement therapy (HRT) and breast cancer has been well documented in the epidemiological literature since the 1980s, it was not until publication of the results of the Women's Health Initiative (WHI) study in 2002 and the Million Women Study in 2003 that women and doctors started reconsidering the use of HRT and sales of HRT started to drop. This paper evaluates the impact of the publication of these two landmark studies on the expected and observed changes in the incidence of breast cancer. Between 2001-2002 and 2005-2006, sharp and significant reductions in the incidence of breast cancer of up to 22% were reported in many US and European populations, temporally consistent with the drop in usage of HRT. Declines in the rates of breast cancer were strongest for 50-60-year-old women (those most likely to be current users of HRT), affected mainly ER+ and PR+ cancers (those most strongly associated with HRT use), and were largest among women with the highest pre-decline prevalence of HRT use and the sharpest decline in its use. A considerable amount of scientific evidence supports the hypothesis that the decline in the incidence of breast cancer is in large part attributable to the sudden drop in HRT use following publication of the WHI and Million Women studies. Nevertheless, the problem of how to advise women contemplating HRT use today remains. Medical relief will remain necessary for many women with menopausal complaints, and so new therapeutic options need to be explored.

Prophylactic oophorectomy: a historical perspective.

Removal of a woman's ovaries (known as bilateral oophorectomy, ovariectomy or, historically, ovariotomy) is undertaken in a number of countries. An estimated 19,000 women aged <60 years had a bilateral prophylactic oophorectomy in the UK in 2003, either as a planned response to an increased specific genetic risk of ovarian or breast cancer or, more frequently, as a prophylactic measure to prevent ovarian cancer. Despite its popularity, however, a full evaluation of the risks, costs and benefits of prophylactic oophorectomy in the absence of genetic markers and at the time of hysterectomy has not yet been undertaken. This paper seeks to provide a historical perspective on current practice by outlining approaches to the ovary in Britain from the 19th century onwards. Historically, ovarian removal has raised many questions about the costs and benefits of surgery. The aim of this article is to highlight the issues, and in so doing, to contribute to a more informed assessment of current practice.

[Historical perspective of hormone replacement therapy]. / Historique du traitement hormonal substitutif de la ménopause.

Clinical manifestations of menopause are partly related to estrogen deficiency. Estrogen replacement was long believed to reverse not only climacteric symptoms but also other chronic conditions associated with menopause such as osteoporosis, cognitive disorders or cardiovascular risk. However, it rapidly became obvious that hormone replacement therapy (HRT) was also associated with an increased risk of breast cancer and venous thrombo-embolic events. Until the end of the 1990's, based on cohort studies, HRT was thought to prevent cardiovascular complications of atherosclerosis. Risk/benefit ratio was thus considered as in favor of HRT, explaining its very wide prescription, after specific contra-indications have been ruled out. In 1998, the publication of HERS, the first randomized controlled study evaluating the effects of HRT in secondary cardiovascular prevention, allowed the scientific community to be conscious of the fact that HRT, not only did not prevent cardiovascular risk but also, probably, aggravated it. In 2002, the premature interruption of WHI study, by confirming that this was also true for primary prevention, has profoundly altered the common beliefs about HRT. Indeed, if HRT was associated with an increased cardiovascular risk, the benefits/risks ratio became unfavorable. Since that time, less women are treated and some of them have stopped their HRT. Recent recommendations have been published about indications of HRT, mainly based on the presence of climacteric symptoms. The potential interest of transdermic route for administration of estrogens needs to be confirmed. The potential deleterious effect of progestins needs to be explored. The difficult story of HRT had, at least, the merit to show, one more time, that in medicine, scientific evidence is always better than beliefs.

Estrogens and progestins: background and history, trends in use, and guidelines and regimens approved by the US Food and Drug Administration.

The US Food and Drug Administration (FDA) approved marketing of diethylstilbestrol in 1941 and conjugated equine estrogens (CEE) in 1942 for treatment of menopausal symptoms. Estrogen sales doubled and tripled in the mid-1960s to mid-1970s, until 1975, when reports of increased endometrial cancer in estrogen users resulted in a dramatic decline. Estrogen use increased again, with evidence of protective effects of progestins on estrogen-induced endometrial changes, combined with a 1982 report that Premarin (conjugated estrogen tablets; Wyeth Pharmaceuticals, Philadelphia, PA) retained bone mass and a 1984 National Institutes of Health (NIH) Consensus Conference on Osteoporosis statement that estrogens were the most effective means for preventing bone loss. Despite conflicting reports in 1985 regarding the relation between estrogens and coronary heart disease (CHD), many published observations of reduced CHD risk in estrogen users--reinforced by clinical trial findings in 1995 of favorable lipoprotein changes in women assigned to CEE with or without a progestin--promoted increased use through the 1990s. By 2001, approximately 15 million US women were using estrogen therapy, with or without progestins. The 2002 Women's Health Initiative (WHI) report of greater harm than benefit of combined CEE plus a progestin resulted in a precipitous decrease in estrogen and progestin use and a serious reevaluation of menopausal hormone therapy, as well as increased interest in alternative approaches to managing menopausal symptoms, including use of "bioidentical" hormones. FDA guidelines regarding treatment indications for vasomotor symptoms, vaginal atrophy, and osteoporosis prevention have resulted in approval of several estrogen (and progestin) formulations, doses, and routes of administration, thereby providing many options for women who seek conventional therapy.

Tools for making correct decisions regarding hormone therapy. part I: background and drugs.

OBJECTIVE: To review existing scientific data related to the biology of estrogen in the aging process of women, and to understand the pharmacology, physiology, and diversity of sex hormones. DESIGN: A MEDLINE computer search was performed to identify relevant articles. RESULT(S): Estrogen and progesterone have been prescribed for postmenopausal women over the last 60 years. Various formulations have had divergent properties, which are related to dissimilarities in the molecule structure, metabolism, plasma carrier, distribution, receptor binding, and the specific localizations of the different receptors in the various organs. CONCLUSION(S): Extensive data are available on the various characteristics of sex-hormone formulations, which are related to clinical consequences. The drugs and means of application have resulted in fundamental differences in activity, such as variance between oral and transdermal applications resulting in different forms of liver involvement. This information could assist in understanding why certain formulations may either prove harmful or beneficial to specific women.

"What do these women want?": Feminist responses to Feminine Forever, 1963-1980.

In 1963, Brooklyn gynecologist Robert A. Wilson and his wife, Thelma, published a paper in the Journal of the American Geriatrics Society arguing that untreated menopause robbed women of their femininity and ruined the quality of their lives. In 1966 Robert Wilson published a best-selling book, Feminine Forever, in which he maintained that menopause was an estrogen-deficiency disease that should be treated with estrogen replacement therapy to prevent the otherwise inevitable "living decay." This paper explores the issues raised by the convergence of Wilson's campaign and the emergence of the women's movement. Between 1963 and 1980, feminists did not respond with one voice to Wilson's ideas: at first, some embraced them as a boon for aging women, while others resisted regarding female aging as pathological. In 1975, studies linking ERT and endometrial cancer challenged the wisdom of routine hormone therapy; this shifted the tenor of the feminist discussion, but it did not create a consensus about the meaning of menopause or its treatment. Nevertheless, the feminist discussion of menopause revealed a larger women's health agenda-namely, the unyielding belief that women should retain control of their bodies and participate fully in the decision-making efforts regarding their health. By controlling their bodies, all women, whether feminist or not, could ultimately control their lives.

Hormones and the health of women: past, present, and future. Keynote address.

The past and possible future roles for hormone use to prevent or encourage pregnancy and to manage or prevent menopause are considered. Beginning in the 1880s, gonadal extracts were used for 50 years to improve health and vigor; evidence for the benefit of these extracts was lacking. Oral contraceptives revolutionized women's lives in the 1960s but had side effects unsuspected until after marketing. Hormone replacement therapy, used for 50 years without large clinical trials of disease outcomes, now proves to have rather similar side effects. Physicians and politicians played interesting roles in their initial distrust and later embrace of hormones. Future uses of sex hormones are likely to be viewed as overmedicalization initially, and time will tell whether these uses are healthy or merely controversial.

Perspective on women's health: editors' 1997-1998 year in review.

Heart disease, breast cancer, and hormone therapy were top clinical concerns in women's health in 1997. One of the major reports on heart disease confirmed that women are no different from men in terms of early infarct-related artery patency rates, reocclusion after thrombolytic therapy, and ventricular functional response to injury/reperfusion; nevertheless, women have 3 times the mortality of men in the first 30 days after an acute myocardial infarction. Research brought only modest gains in the understanding of breast cancer etiology in 1997, but engendered major debate on whether women younger than 50 years should have mammograms every 1 to 2 years. A National Institutes of Health consensus conference said no, but the National Cancer Institute's National Cancer Advisory Board said yes. Evidence of estrogen benefits and risks mounted: One report added to the data suggesting that estrogen may retard age-related memory loss, while another study reported that the risk of breast cancer significantly increased with long-term use of estrogens. The interest in selective estrogen receptor modulators (SERMs), also called "designer estrogens," grew. Efforts to develop pharmacologic treatment for obesity suffered a setback in 1997 when a team reported that 1 in 3 patients who used d-fenfluramine developed abnormal valvular thickening, with the most severe cases needing valve replacement. One of the most promising events in colorectal cancer, the third most common cancer in women, was the set of screening guidelines issued by the Agency for Health Care Policy and Research. The year ended with major ethical debates about multiple gestation and cloning.

Overview of estrogen replacement therapy: a historical perspective.

In the last 30 years, we have made enormous advances in understanding how estrogen works in multiple physiologic systems and how much it affects the health of aging women. We have also made major improvements in how we prescribe estrogen. As clinicians, we are obliged to provide our patients with acceptable, tolerable, safe therapy which can be continued long enough to provide clinically significant health benefits. Determining optimal long-term hormone replacement therapy is therefore the challenge for the 21st century.