The History of Testosterone and the Evolution of its Therapeutic Potential.

INTRODUCTION: Testosterone therapy has been controversial since its synthesis in the 1930s to the present day. Testosterone's history provides depth and context for current controversies. AIM: To review the history of testosterone therapy from its initial synthesis in the 1930s to the modern day. METHODS: Expert review of the literature. MAIN OUTCOME MEASURES: Impactful events in the history of testosterone. RESULTS: By the 1940s there was already a fascinating literature that described the many symptomatic benefits of testosterone therapy that are recognized today. Numerous early reports suggested testosterone therapy improved angina pectoris and peripheral vascular disease. The assertion by Huggins and Hodges (Cancer Res 1941;1:293-297) in 1941 that testosterone activated prostate cancer (PCa) cast a pall for the next 70 years. The introduction of the radioimmunoassay in the 1970s shifted the diagnosis of testosterone deficiency from signs and symptoms to an undue emphasis on blood test results. The fear of PCa was the primary obstacle to the adoption of testosterone therapy for decades. Prescription rates increased as accumulated evidence showed testosterone therapy was not associated with increased PCa risks. The observation that androgenic stimulation of PCa reaches a maximum at relatively low testosterone concentrations-the saturation model-provided the theoretical framework for understanding the relation between androgens and PCa and led to multiple case series documenting reassuring results of testosterone therapy in men with PCa. Recent concerns regarding cardiovascular risks also have diminished because new evidence suggests testosterone therapy might actually be cardioprotective. In 2016 the Testosterone Trials provided high-quality evidence of multiple benefits of testosterone therapy, nearly all of which had been recognized by clinicians by 1940. CONCLUSIONS: If the past has any lessons for the future, it is likely that research will continue to demonstrate health benefits of testosterone therapy, while it remains one of the most controversial topics in medicine. Morgentaler A, Traish A. The History of Testosterone and the Evolution of its Therapeutic Potential. Sex Med Rev 2020;8:286-296.

History and epidemiology of anabolic androgens in athletes and non-athletes.

The use of androgens, frequently referred to as anabolic-androgenic steroids (AAS), has grown into a worldwide substance abuse problem over the last several decades. Testosterone was isolated in the 1930s, and numerous synthetic androgens were quickly developed thereafter. Athletes soon discovered the dramatic anabolic effects of these hormones, and AAS spread rapidly through elite athletics and bodybuilding from the 1950s through the 1970s. However it was not until the 1980s that widespread AAS use emerged from the elite athletic world and into the general population. Today, the great majority of AAS users are not competitive athletes, but instead are typically young to middle-aged men who use these drugs primarily for personal appearance. AAS abuse has now become particularly prevalent in regions such as Scandinavia, the United States, Brazil, and British Commonwealth countries, but remains rare in countries such as China, Korea, and Japan - a pattern that reflects cultural differences in attitudes towards male muscularity.

[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.

Molecular mechanisms of androgen action--a historical perspective.

Androgens and the androgen receptor (AR) are indispensable for expression of the male phenotype. The two most important androgens are testosterone and 5α-dihydrotestosterone. The elucidation of the mechanism of androgen action has a long history starting in the 19th century with the classical experiments by Brown-Séquard. In the 1960s the steroid hormone receptor concept was established and the AR was identified as a protein entity with a high affinity and specificity for testosterone and 5α-dihydrotestosterone. In addition, the enzyme 5α-reductase type 2 was discovered and found to catalyze the conversion of testosterone to the more active metabolite 5α-dihydrotestosterone. In the second half of the 1980s, the cDNA cloning of all steroid hormone receptors, including that of the AR, has been another milestone in the whole field of steroid hormone action. Despite two different ligands (testosterone and 5α-dihydrotestosterone), only one AR cDNA has been identified and cloned. The AR (NR3C4) is a ligand-dependent transcription factor and belongs to the family of nuclear hormone receptors which has 48 members in human. The current model for androgen action involves a multistep mechanism. Studies have provided insight into AR association with co-regulators involved in transcription initiation and on intramolecular interactions of the AR protein during activation. Knowledge about androgen action in the normal physiology and in disease states has increased tremendously after cloning of the AR cDNA. Several diseases, such as androgen insensitivity syndrome (AIS), prostate cancer and spinal bulbar muscular atrophy (SBMA), have been shown to be associated with alterations in AR function due to mutations in the AR gene or dysregulation of androgen signalling. A historical overview of androgen action and salient features of AR function in normal and disease states are provided herein.

[Men in a critical age: Kurt Mendel and the controversy over the male climacterium]. / Männer im kritischen Alter : Kurt Mendel und die Kontroverse über das männliche Klimakterium.

Since the 1990s, with concepts like the male climacterium, andropause or PADAM, the idea of a"change of life" in men has gone through a spectacular reinvention. Recent research has focused upon the ways when, how and why these concepts emerged, thus taking cultural and historical approaches into account. This paper contributes to the growing corpus of such works. It sheds new light on the early decades of the twentieth century - a period that was decisive in establishing the modern, endocrinological understanding of the climacteric period as a result of hormonal deficiencies. Concurrently, this period saw several initiatives to conceptualize the male climacterium as a new and important diagnostic entity for health problems of men in their middle and later life. In Germany, the most important advocate was the Berlin neurologist Kurt Mendel, who published an influential article in 1910 entitled "The Change of Life in Men (Climacterium virile)". Mendel's concept evoked considerable interest and was much debated across medical disciplines, including neurology, psychiatry, sexology, endocrinology and urology. This article revisits and reassesses Mendel's concept of the male climacterium, discusses its specific status and significance, and places it within the historical context. Furthermore this, the paper argues that a historical approach is indispensable for a more nuanced understanding of the current arguments given to legitimize (or delegitimize) the status of a climacteric period in men.

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.

The history of the development of anabolic-androgenic steroids.

The history of anabolic-androgenic steroids (AASs) is an interesting tale that has its roots in ancient "endocrinology." More than 6000 years ago, farmers noted enhanced domestication of animals after castration. The development of AASs, and, later, their artificial synthesis, have remained a hot topic in scientific research and pharmaceuticals. Over the years, AASs have been used as a proposed treatment for a wide variety of ailments, despite deleterious side effects. Unfortunately, they have been, and still are, abused by body builders, athletes, and teens.

A double life: academic physician and androgen physiologist.

My work in physiology was designed to investigate the process of androgen action within target cells and to use this information to provide insight into the clinical disorders of androgen action. The discovery that the circulating male androgen testosterone is 5alpha-reduced to a more potent hormone, dihydrotestosterone, in target tissues and that dihydrotestosterone and testosterone work by binding to the same androgen receptor protein has provided insight into the inherited syndromes of androgen resistance that impair the formation of the male urogenital tract during embryogenesis and into the role of continued dihydrotestosterone formation in the pathogenesis of prostatic hyperplasia in dogs and men.

Hormonal doping and androgenization of athletes: a secret program of the German Democratic Republic government.

Several classified documents saved after the collapse of the German Democratic Republic (GDR) in 1990 describe the promotion by the government of the use of drugs, notably androgenic steroids, in high-performance sports (doping). Top-secret doctoral theses, scientific reports, progress reports of grants, proceedings from symposia of experts, and reports of physicians and scientists who served as unofficial collaborators for the Ministry for State Security ("Stasi") reveal that from 1966 on, hundreds of physicians and scientists, including top-ranking professors, performed doping research and administered prescription drugs as well as unapproved experimental drug preparations. Several thousand athletes were treated with androgens every year, including minors of each sex. Special emphasis was placed on administering androgens to women and adolescent girls because this practice proved to be particularly effective for sports performance. Damaging side effects were recorded, some of which required surgical or medical intervention. In addition, several prominent scientists and sports physicians of the GDR contributed to the development of methods of drug administration that would evade detection by international doping controls.

Androgenic--anabolic steroids and body dysmorphia in young men.

There has recently been increasing attention focused on the use of androgenic-anabolic steroids (AAS). Some research has suggested that a disturbance in body image in males leads to AAS use. At present, the available literature is sparse and there is little/no discussion on the causal factors for their use. This review gives a historical account of the development and the changing patterns of AAS use. Both the physical and psychological side-effects are presented. The available evidence and theories for external/social and internal, psychological, and developmental influences are discussed in relation to AAS use. The current trends for the treatment of AAS abusers are also presented. Recommendations regarding further research are made in the conclusions.