Endocrinology's early historians (1889-1914) and the forgotten prehistory of testosterone.

INTRODUCTION: An often-retold historical outline of endocrinology was established over a century ago. An exhaustive history of sexual physiology remains forthcoming, however. OBJECTIVES: To explore and contextualize the remarkable medical-historical and medical-anthropologic frenzy triggered by Brown-Séquard's 1889 self-injections with testicular juice, which ultimately settled down into an early history of endocrinology. METHODS: Pertinent primary sources were selected from a broader study, primarily between 1889 and 1914, as well as selected older texts identified and unidentified by these sources. RESULTS: Endocrinology's early historians in a short space of time moved from the history of testicular opotherapy to that of glandular typology and physiology and to increasingly encompassing medical-historical accounts of internal secretion as an epochal idea. Early historians nominated "precursors" to Brown-Séquard but underestimated physiologic continuities-specifically, early modern protoendocrinologic notions concerning semen as a "recrement," notions still recited by Brown-Séquard and early Brown-Séquardists as well their detractors. Brown-Séquard himself worked through this old (recremental) concept of semen between 1889 and 1892 but was later identified with it, by among others Ancel and Bouin. CONCLUSION: Western sexual physiology is a medical palimpsest, the undertexts of which remain to be studied in detail.

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.

ENDOCRINE HISTORY: The history of discovery, synthesis and development of testosterone for clinical use.

As the most important male hormone, testosterone has an impact on almost all organs and body functions. The biological effects of testosterone and the testes have been known since antiquity, long before testosterone was identified as the active agent. Practical applications of this knowledge were castration of males to produce obedient servants, for punishment, for preservation of the prepubertal soprano voice and even for treatment of diseases. Testes were used in organotherapy and transplanted as treatment for symptoms of hypogonadism on a large scale, although these practices had only placebo effects. In reaction to such malpractice in the first half of the 20th century science and the young pharmaceutical industry initiated the search for the male hormone. After several detours together with their teams in 1935, Ernst Laqueur (Amsterdam) isolated and Adolf Butenandt (Gdansk) as well as Leopold Ruzicka (Zürich) synthesized testosterone. Since then testosterone has been available for clinical use. However, when given orally, testosterone is inactivated in the liver, so that parenteral forms of administration or modifications of the molecule had to be found. Over 85 years the testosterone preparations have been slowly improved so that now physiological serum levels can be achieved.

From bench to bedside: bipolar androgen therapy in a pilot clinical study.

Prostate cancer remains a leading cause of cancer death in Europe and the United States and is an emerging problem in Asia despite significant improvements in available treatments over the last few decades. Androgen deprivation therapy (ADT) has been the core treatment of advance-staged disease since the discovery of prostate cancer's androgen dependence in 1941 by Huggins et al. [1] Options for initial medical treatment include gonadotropin-releasing hormone analogues such as leuprolide (LHRH agonist) and degarelix (LHRH antagonist) and androgen receptor (AR) binding agents such as bicalutamide. Although most patients will initially respond to either surgical or medical castration, there is almost always progression to castration-resistant prostate cancer (CRPC) necessitating treatment with more novel agents. [2] However, even drugs such as abiraterone and enzalutamide, two next-generation agents used commonly in metastatic CRPC, have failed to demonstrate persistent efficacy in most patients. [3] ,[4].

The long and tortuous history of the discovery of testosterone and its clinical application.

INTRODUCTION: The testis importance in homeostasis was recognized for millennia, but a consistent interest in exploring their endocrine function only goes back to about a century. AIM: The aim of this study is to provide a succinct perspective of the events leading to the discovery of testosterone, the mind-boggling early attempts at therapy and today's situation. METHOD: The literature was reviewed with searches in OvidSP Medline, PubMed, and Google Scholar under the headings of testosterone/androgens history. Due to the explosion of reports between the late 19th and early 20th centuries, a manual review of the collection of the period's journals at the university's library was performed. Pertinent books were consulted for specific biographical details. RESULTS: There is a robust body of literature dealing with testicular function for the period starting in the late 1800s. It is illustrative to learn the painful efforts of many well-intentioned and honest scientists with more conviction and determination than knowledge. Among them, unfortunately, a number of charlatans and profiteers tainted the concept of hypogonadism and its treatment with repercussions lasting until this day. The discovery and synthesis of testosterone represent the effort of brilliant minds (two Nobel Prizes) in various countries and frequently working for the pharmaceutical industry. Shortly after testosterone became available, controversy arose about its application, use, abuse, and potential detrimental effects. Over the decades, the hullabaloo about hypogonadism and its treatment has focused on a variety of issues ranging from absurd efficacy claims to solid studies and from doubts of its existence to convincing proof of a detrimental age-associated deficit in testosterone production. CONCLUSIONS: The history of testosterone discovery, synthesis, and introduction into the therapeutic armamentarium is an outstanding example of human curiosity, ingenuity, greed, and skepticism. Despite the vast progress in the field, many issues remain unresolved, but thoughtful science augurs well for its future.

A brief history of rejuvenation operations.

PURPOSE: We discuss the place in history of operative procedures for hormonal rejuvenation. MATERIALS AND METHODS: The scientific and historical literature was reviewed. RESULTS: In the early 20th century, building on the earlier work of Berthold and Brown-Séquard, Eugen Steinach developed a combination of vasectomy and vasoligature that became known as the Steinach operation. This procedure, along with testicular implantation popularized by Serge Voronoff, was an attempt to rejuvenate older and fatigued men around the world. The early experiments and results of Steinach, Voronoff and their followers were plagued by secrecy, subjectivity and sensationalism in an effort to produce the most scientific data. These rejuvenists used their results to outcompete one another. Ultimately the lack of verifiable outcome data and the chemical isolation of the "internal secretion" (testosterone) ended this era in surgery. CONCLUSIONS: Always a work in progress, the practice of medicine has been guided by human curiosity with trial, error and success. History records aberrant paths along the way and the rejuvenation movement was one such journey. While superseded by later knowledge, the efforts of the rejuvenists comprise an interesting chapter in the development of urology, endocrinology and transplant surgery.

[A brief history of testosterone]. / Eine kurze Geschichte des Testosterons.

The history of testosterone is closely connected with the application of aphrodisiacs, research on sexual differentiation, and several therapies for rejuvenation around the year 1900. Chemical isolation and synthesis of androgens was achieved between 1931 and 1935 and only since then has clinically effective substitution therapy with testosterone for hypogonadism been available.

Guilt by association: a historical perspective on Huggins, testosterone therapy, and prostate cancer.

INTRODUCTION: A long-standing belief is that higher testosterone (T) will increase the risk of prostate cancer (PCa), yet recent studies do not support this view. AIM: To identify the key historical and scientific events leading to the establishment and persistence of the belief in a T-dependent model of PCa growth, despite evidence to the contrary. METHODS: Review of key historical scientific articles regarding T and PCa. RESULTS: The T-dependent model of PCa growth arose from the work of Huggins and coworkers, who in 1941 demonstrated dramatic responses to castration among men with advanced PCa. These authors and others also reported a rapid clinical progression with T administration. This led to the concept that T was like "food for a hungry tumor" for men with PCa. Fowler and Whitmore recognized in 1981 that the negative effect of T administration did not occur unless men had been previously castrated. However, this critical observation was either forgotten or dismissed amid major changes in PCa diagnosis and management during the 1980s. More recent studies have failed to provide clinical evidence supporting the belief that higher T represents a risk for PCa. Factors contributing to the persistence of the T-dependent model included dramatic effects of castration, continued use of androgen deprivation for treatment of PCa, an influential spokesperson (Huggins), groupthink (failure to acknowledge evidence inconsistent with the prevalent ideology), and an imprecise formulation of the model ("more T, more cancer growth"), making refutation difficult. CONCLUSIONS: The fear that higher T will increase PCa growth stems from a theory of T-dependent PCa growth that originated with observations in a special population (castrated men) that is not particularly relevant to T therapy in hypogonadal men. The negative view of T with regard to PCa should be recognized for what it is--guilt by association.

The medicalisation of male menopause in America.

The topic of male menopause occupied space on the medical radar screen from the late 1930s through the mid-1950s, then virtually disappeared for the next four decades, until the late 1990s. By contrast, articles on this subject appeared in American popular magazines and newspapers at a consistent, if low-level, rate throughout the same period. This essay describes how the male menopause became medicalised, not by the driving forces of academic researchers and influential clinicians, but instead by a model perpetuated by lay people and medical popularisers. A medicalised conceptualisation of the body and the life-cycle had become widespread by the second half of the twentieth century, as Americans grew accustomed to regarding their lives through the lens of medicine. People came to expect medicine to provide a cure for any ailment; in the wake of the development of the so-called wonder drugs, no affliction seemed beyond medical and pharmaceutical intervention. A medicalised model had also been effectively produced for understanding and treating the menopause in women; a parallel, if not identical, stage in the life-course of men seemed reasonable. This framework, rather than persuasive evidence from the research laboratory or clinic, helped to medicalise male menopause and provided the basis for its eventual pharmaceuticalisation at the end of the twentieth century.

The endocrine pharmacology of testosterone therapy in men.

The review starts off by outlining the history of the discovery of the male sex hormone testosterone and the historical background to the various, often dubious, approaches to the treatment of age-related endocrine disorders in older men. A discussion of congenital androgen deficiency in young men is followed by methods of diagnosing hypogonadism in older men. Among therapeutic options, the alternatives to direct testosterone replacement are discussed, although none of them have proved to be particularly successful in clinical practice. For testosterone replacement itself, various routes of administration and pharmaceutical formulations are now available, facilitating good monitoring and individualized therapy.

Brown-Séquard revisited: a lesson from history on the placebo effect of androgen treatment.

BACKGROUND: In 1889, Brown-Séquard, aged 72, reported dramatic rejuvenating effects after self-administering testicular extracts of dogs and guinea-pigs. His report resulted in widespread use of testicular extracts throughout Europe and North America for several decades. More recently, the male ageing process has been attributed to partial androgen deficiency, or "andropause", and testosterone treatment is claimed to improve well-being in middle-aged and elderly men. DESIGN: We prepared extracts from five dog testes using Brown-Séquard's methods and assayed testosterone concentrations. RESULTS: Testosterone concentrations were four orders of magnitude less than that required for a biological effect. CONCLUSIONS: Our study illustrates the marked placebo response that can be evoked by androgen treatment. It cautions against the empirical use of testosterone treatment for older men, unless a diagnosis of hypogonadism has been substantiated.