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 METHODS: A literature search was conducted using PubMed to identify relevant studies and historical documents regarding the history of estrogen therapy.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.

Celebrating 75 years of oestradiol.

Oestrogens exert important effects on the reproductive as well as many other organ systems in both men and women. The history of the discovery of oestrogens, the mechanisms of their synthesis, and their therapeutic applications are very important components of the fabric of endocrinology. These aspects provide the rationale for highlighting several key components of this story. Two investigators, Edward Doisy and Alfred Butenandt, purified and crystalized oestrone nearly simultaneously in 1929, and Doisy later discovered oestriol and oestradiol. Butenandt won the Nobel Prize for this work and Doisy's had to await his purification of vitamin K. Early investigators quickly recognized that oestrogens must be synthesized from androgens and later investigators called this process aromatization. The aromatase enzyme was then characterized, its mechanism determined, and its structure identified after successful crystallization. With the development of knock-out methodology, the precise effects of oestrogen in males and females were defined and clinical syndromes of deficiency and excess described. Their discovery ultimately led to the development of oral contraceptives, treatment of menopausal symptoms, therapies for breast cancer, and induction of fertility, among others. The history of the use of oestrogens for postmenopausal women to relieve symptoms has been characterized by cyclic periods of enthusiasm and concern. The individuals involved in these studies, the innovative thinking required, and the detailed understanding made possible by evolving biologic and molecular techniques provide many lessons for current endocrinologists.

[Naming and classification of steroids and human stress ulcers. Articles of historic significance published by Hans Selye 70 years ago]. / A szteroidok elnevezése, felosztása és az emberi stresszfekélyek. Selye János 70 éve megjelent történelmi jelentoségu cikkei.

The name of Hans Selye is mostly known worldwide as the discoverer of stress reaction. Yet, he made numerous other seminal and clinically relevant discoveries. Namely, since he had a focused research on steroid hormones originating from the adrenal cortex that play a crucial role in stress response, he was the first who introduced about 70 years ago the first classification of steroids that is still valid nowadays. This is based on three objective facts: (a) the names of steroid groups are identical with their organ of origin (e.g., corticoids from the adrenal cortex, testoids/androgens from the testis); (b) chemical structures of the steroids are identical within a group (e.g., all corticoids have pregnane nucleus with 21 carbon atoms); and (c) the biological effects are homogenous within a group (e.g., all glucocorticoids exert catabolic effect, while androgens are anabolic). It should be emphasized that Selye also discovered in animal models the pro-inflammmatory effect of mineralocorticoids and the anti-inflammatory properties of glucocorticoids, about 8-10 years before Nobel Prize was awarded to a physician for the first clinical use of adrenocorticotrop hormone and cortisone. Last, but not least, Selye was the first who recognized about 70 years ago the occurence of stress ulcers in humans, based on clinical reports on the huge increase in the number of perforated gastric anti-duodenal ulcers during bombings of London in World War II. The subsequent ulcer research by Selye`s former students and their contemporaries resulted in the recognition of anti-duodenal ulcer effect of dopamine, and the central gastroprotective actions of thyreotrop releasing hormone and endogenous opioids. Thus, Hans Selye made much more contributions to medical science and clinical practice than 'just' the discoverer of biologic stress response.

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.

History of oral contraception.

On the 50th birthday of the pill, it is appropriate to recall the milestones which have led to its development and evolution during the last five decades. The main contraceptive effect of the pill being inhibition of ovulation, it may be called a small miracle that this drug was developed long before the complex regulation of ovulation and the menstrual cycle was elucidated. Another stumbling block on its way was the hostile climate with regard to contraception that prevailed at the time. Animal experiments on the effect of sex steroids on ovulation, and the synthesis of sex steroids and orally active analogues were the necessary preliminaries. We owe the development of oral contraceptives to a handful of persons: two determined feminists, Margaret Sanger and Katherine McCormick; a biologist, Gregory Pincus; and a gynaecologist, John Rock. Soon after the introduction of the first pills, some nasty and life-threatening side effects emerged, which were due to the high doses of sex steroids. This led to the development of new preparations with reduced oestrogen content, progestins with more specific action, and alternative administration routes. Almost every decade we have witnessed a breakthrough in oral contraception. Social and moral objections to birth control have gradually disappeared and, notwithstanding some pill scares, oral contraceptives are now one of the most used methods of contraception. Finally, all's well that ends well: recent reports have substantiated the multiple noncontraceptive health benefits paving the way for a bright future for this 50-year-old product.

Estrogen action: a historic perspective on the implications of considering alternative approaches.

In the 50 years since the initial reports of a cognate estrogen receptor (ER), much has been learned about the diverse effects and mechanisms of estrogens, such as 17beta-estradiol (E(2)). This expert narrative review briefly summarizes perspectives and/or recent work of the authors, who have been addressing different aspects of estrogen action, but take a common approach of using alternative considerations to gain insight into mechanisms with clinical relevance, and inform future studies, regarding estrogen action. Their "Top Ten" favorite alternatives that are discussed herein are as follows. 1 - E(2) has actions by binding to a receptor that do not require its enzymatic conversion. 2 - Using a different strategy for antibody binding could make the estrogen receptor (ER) more discernible. 3 - Blocking ERs, rather than E(2) production, may be a useful strategy for breast cancer therapy. 4 - Secretion of alpha-fetoprotein (AFP), rather than only levels of E(2) and/or progesterone, may influence breast cancer risk. 5 - A peptide derived from the active site of AFP can produce the same benefits of the entire endogenous protein in endocrine cancers. 6 - Differential distribution of ER subtypes in the body and brain may underlie specific effects of estrogens. 7 - ERbeta may be sufficient for the trophic effects of estrogen in the brain, and ERalpha may be the primary target of trophic effects in the body. 8 - ERbeta may play a role in the trophic effects of androgens, and may also be relevant in the periphery. 9 - Downstream of E(2)'s effects at ERbeta, there may be consequences for biosynthesis of progestogens and/or androgens. 10 - Changes in histones and/or other factors, which may be downstream of ERbeta, potentially underlie the divergent effects of E(2) in the brain and peripheral tissues.

A century of deciphering the control mechanisms of sex steroid action in breast and prostate cancer: the origins of targeted therapy and chemoprevention.

The origins of the story to decipher the mechanisms that control the growth of sex hormone-dependent cancers started more than 100 years ago. Clinical observations of the apparently random responsiveness of breast cancer to endocrine ablation (hormonal withdrawal) provoked scientific inquiries in the laboratory that resulted in the development of effective strategies for targeting therapy to the estrogen receptor (ER; or androgen receptor in the case of prostate cancer), the development of antihormonal treatments that dramatically enhanced patient survival, and the first successful testing of agents to reduce the risk of developing any cancer. Most importantly, elucidating the receptor-mediated mechanisms of sex steroid-dependent growth and the clinical success of antihormones has had broad implication in medicinal chemistry with the synthesis of new selective hormone receptor modulators for numerous clinical applications. Indeed, the successful translational research on the ER was the catalyst for the current strategy for developing targeted therapies to the tumor and the start of "individualized medicine." During the past 50 years, ideas about the value of antihormones translated effectively from the laboratory to improve clinical care, improve national survival rates, and significantly reduced the burden of cancer.

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.

"Doctor, are you trying to kill me?": ambivalence about the patient package insert for estrogen.

In 1976, the U.S. Food and Drug Administration proposed new requirements for patient labeling for estrogens prescribed for menopausal and postmenopausal women. This paper explores the variety of responses to this proposal from women and their husbands, feminist and consumer activists, physicians, pharmacists, and pharmaceutical manufacturers, as represented in letters written to the FDA. The drug industry and the medical profession opposed patient labeling on the grounds of cost and a resentment of governmental intrusion. Feminists and consumer advocates were in favor of the idea, but the response from current estrogen users was mixed: most women wished to be better informed, but many expressed concern that estrogen would be removed from the market. This ambivalence suggests unresolved tensions regarding conceptions of female aging, the medical management of menopause and aging, informed consent in medicine, and governmental regulation of medical practice. The debate thus represents an important moment in the history of women's health care.