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

Nieschlag, Eberhard; Nieschlag, Susan

doi:10.1530/eje-19-0071

Cited by 90 publications

(44 citation statements)

References 58 publications

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“…However, the active agent responsible for virility—that is testosterone—has only been identified quite recently. Nevertheless, on the assumption that the testes contain the ingredients required for manhood, organotherapy with animal testes and testis transplantation have been used over centuries in different medical cultures for treatment of symptoms of hypogonadism, for example in Greco‐Roman, Arabic, Chinese, Voodoo, and modern medicine (for historic details see Nieschlag & Nieschlag 2019). Moreover, ever since antiquity rejuvenation and eternal youth continue to be a much‐desired wish.…”

Section: Historical Perspectivementioning

confidence: 99%

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Late‐onset hypogonadism: a concept comes of age

Nieschlag

2019

Andrology

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The term Late‐onset hypogonadism (LOH) was coined in 2002 and defined as a disease entity in the ISA, ISSAM, EAU, EAA and ASA endorsed Recommendations for Investigation, Treatment and Monitoring of LOH (2005 and 2008) as ‘a clinical and biochemical syndrome associated with advancing age, characterized by symptoms and a deficiency in serum testosterone (T)’. LOH was classified as a combined primary and secondary hypogonadism since the endocrine capacity of the testes and the pituitary are impaired. Symptoms of LOH include loss of libido, erectile dysfunction, loss of muscle mass, increased body fat, anemia, osteoporosis, depressed mood, decreased vitality, sweating, and hot flushes. Since these symptoms may also have origins other than LOH, exclusion of other disease entities and subnormal serum T levels are considered prerequisites for the diagnosis and possible treatment of LOH. However, during following years these guidelines were often neglected and, especially in the USA, indiscriminate prescribing of T was widely practised so that the US FDA warned against such irresponsible behavior. In Europe, T prescribing remained largely restricted to LOH as defined above. Nevertheless, a discussion started whether LOH really exists or is only a consequence of age‐related comorbidities. Numerous studies have helped to clarify the situation, in particular, the European Male Aging Study (EMAS) and the US‐initiated 7 T trials. Consequently, the newest US Endocrine Society Practice Guideline on T treatment (2018) includes advanced age as a cause of organic hypogonadism and recommends that ‘in men >65 years who have symptoms or conditions suggestive of T deficiency … and consistently and unequivocally low morning T concentrations we suggest that clinicians offer T therapy on an individualised basis after explicit discussion of the potential risks and benefits’. Thus, the concept of LOH as conceived two decades ago has weathered criticism and survived the times.

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Section: Historical Perspectivementioning

confidence: 99%

“…Moreover, both in the USA and Europe at the beginning of the 20th century, and as a direct translation of Berthold’s and his followers’ animal experiments, surgeons began transplanting human as well as animal testes to patients for treatment of hypogonadism and for rejuvenation (for details see Nieschlag & Nieschlag 2019).…”

Section: Historical Perspectivementioning

confidence: 99%

Late‐onset hypogonadism: a concept comes of age

Nieschlag

2019

Andrology

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“… 1 For simplicity, only baseline and day 365 data shown. Biomarkers also assessed on days 90 and 180. 2 Analysis after excluding all values >10 mg/l.…”

Section: Resultsmentioning

confidence: 99%

“…Historically, efforts to administer oral T have taken two primary paths: alkylation of T at the C-17 position to create T analogs that are resistant to first-pass hepatic metabolism (exemplified by methyltestosterone); 2 or fatty-acid esterification of T to create a T-ester (exemplified by TU) that is absorbed via the intestinal lymphatic system thus bypassing the portal circulation. 3 Oral methyltestosterone, originally discovered and used clinically in the mid-1930s, 1 is the only oral TRT ever approved for use in the US, but has been associated with serious hepatotoxicity such as cholestasis, peliosis hepatis, and hepatic adenocarcinoma 4–6 and therefore is not recommended for clinical management of male hypogonadism. Conversely, while oral TU has not been associated with liver toxicity, an early oral TU formulation approved for use in many countries but never in the US (Andriol®) was highly influenced by dietary fat, thus leading to significant intra- and inter-patient variability in T response and questionable clinical utility.…”

Section: Introductionmentioning

confidence: 99%

A new oral testosterone undecanoate therapy comes of age for the treatment of hypogonadal men

Swerdloff

Dudley

2020

Therapeutic Advances in Urology

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Background: A novel formulation of oral testosterone undecanoate (TU) was studied in a long- and short-term phase III trial to evaluate safety and efficacy. Methods: Hypogonadal men (age 18–65 years; two morning serum testosterone (T) <300 ng/dl with signs/symptoms) were recruited into a 365 day (trial I) or 105 day (trial II), randomized, multicenter trial. Patients were randomized 1:1 to oral TU ( n = 161) or T-gel ( n = 160) in trial I, and 3:1 to oral TU, twice daily (BID) JATENZO® ( n = 166) or a topical T product [Axiron® ( n = 56)] in trial II. Dose adjustments were based on average T concentrations ( Cavg). Efficacy was assessed based on T levels, body composition and bone density. Safety was assessed by standard clinical measures. Results: Oral TU efficacy (% of patients with eugonadal T Cavg) was 84% (serum Cavg = 628 ± 343 ng/dl) and 87% (serum T equivalent Cavg ≈ 489 ± 155 ng/dl) in trials I and II, respectively. Oral TU significantly ( p <0.0001) improved all Psychosexual Daily Questionnaire parameters in trials I and II. In trial I, lean mass increased 3.2 ± 2.7 kg and fat decreased by 2.4 ± 3.6 kg (both p <0.0001) and bone density improved in hip (+0.012 ± 0.0225 g/cm2) and spine (+0.018 ± 0.0422 g/cm2) after 365 days (both p <0.0001). Oral TU-associated adverse effects were consistent with other T-replacement therapies but oral TU patients experienced a greater number of mild gastrointestinal adverse effects. Oral TU subjects in both studies exhibited an increase in mean systolic blood pressure of about 3–5 mmHg. Oral TU was not associated with liver toxicity nor did it cause an elevation in high-sensitivity C-reactive protein or lipoprotein-associated phospholipase A2 (cardiovascular safety biomarkers) after 365 days of therapy. Conclusion: A new oral TU formulation was safe and effective and represents a significant therapeutic advance for the treatment of appropriate hypogonadal men.

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“…Testosterone. Following the scientific saga initiated in the late 19th century by Brown-Séquard in France and resumed by a few European scientists and pharmaceutic companies at the beginning of the 20th century, which led Ružička and Butenandt to be awarded the Nobel prize, testosterone has been available for androgenic therapy since 1935 (Nieschlag & Nieschlag, 2019). Different pharmaceutical formulations of testosterone exist, which are administered by various routes.…”

Section: Formulations Used For Androgen Therapymentioning

confidence: 99%

Androgen Treatment in Adolescent Males With Hypogonadism

Rey

Grinspon

2020

Am J Mens Health

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During adolescence, androgens are responsible for the development of secondary sexual characteristics, pubertal growth, and the anabolic effects on bone and muscle mass. Testosterone is the most abundant testicular androgen, but some effects are mediated by its conversion to the more potent androgen dihydrotestosterone (DHT) or to estradiol. Androgen deficiency, requiring replacement therapy, may occur due to a primary testicular failure or secondary to a hypothalamic–pituitary disorder. A very frequent condition characterized by a late activation of the gonadal axis that may also need androgen treatment is constitutional delay of puberty. Of the several testosterone or DHT formulations commercially available, very few are employed, and none is marketed for its use in adolescents. The most frequently used androgen therapy is based on the intramuscular administration of testosterone enanthate or cypionate every 3 to 4 weeks, with initially low doses. These are progressively increased during several months or years, in order to mimic the physiology of puberty, until adult doses are attained. Scarce experience exists with oral or transdermal formulations. Preparations containing DHT, which are not widely available, are preferred in specific conditions. Oxandrolone, a non-aromatizable drug with higher anabolic than androgenic effects, has been used in adolescents with preserved testosterone production, like Klinefelter syndrome, with positive effects on cardiometabolic health and visual, motor, and psychosocial functions. The usual protocols applied for androgen therapy in boys and adolescents are discussed.

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

Cited by 90 publications

References 58 publications

Late‐onset hypogonadism: a concept comes of age

Late‐onset hypogonadism: a concept comes of age

A new oral testosterone undecanoate therapy comes of age for the treatment of hypogonadal men

Androgen Treatment in Adolescent Males With Hypogonadism

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