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The medicalization of testosterone: reinventing the elixir of life (2022)
Thiago Gagliano‑Jucá · Mauricio Alvarez · Shehzad Basaria
Abstract
The pursuit of longevity, which during the Renaissance era was limited to longing for miraculous ways of rejuvenation, such as bathing in the fountain of youth, took a scientific turn in 1889 with the publication of Brown-Sequard’s self-experiments with an extract of animal testes, which apparently improved his vitality, physical strength, and cognition. This extract, marketed then as the "Elixir of Life", was sold for decades throughout Europe and North America. However, recent replication of Brown-Sequard’s experiments demonstrated that such an extract only contains homeopathic concentrations of testosterone that are insufficient to exert any biological effect. Thus, the birth of Andrology began with a placebo effect. Over the past few decades, the quest for compounds that might lead to rejuvenation has regained traction, with testosterone being at the forefront. Though clinical practice guidelines advocate testosterone therapy in men with organic hypogonadism—the only indication approved by the Food and Drug Administration—testosterone continues to be marketed as a wonder drug with rejuvenating effects on sexual function, vitality, and a host of other unproven benefits. Additionally, the epidemic of obesity and diabetes, conditions associated with low testosterone, has further brought testosterone into the limelight. Although the number of testosterone prescriptions written has increased several-fold in the past two decades, carefully conducted randomized trials suggest modest benefits of testosterone therapy. At the same time, safety concerns, particularly in older men, remain valid.
1 Introduction
Throughout history, humanity has searched for ways of rejuvenation and to extend healthy lifespan. While in the 1500 s, imagery of magical places, such as the Fountain of Youth (Fig. 1), kept the dreams of achieving eternal youth alive, the late 1800s saw the dawn of the scientific quest for antiaging products, especially after the widely publicized report of Brown-Sequard’s experiments [1]. In his report published in the Lancet in 1889, the 72-year-old physician-scientist described the effects of subcutaneous self-administration over two weeks of an aqueous extract derived from the testicles of dogs and guinea pigs. He reported significant improvements in his strength, endurance, and cognition. The presumed benefits of Brown-Séquard’s "Elixir of Life" were widely advertised throughout Europe and North America, where this magic potion was commercially sold for decades (Fig. 2). Brown-Séquard’s experiments even provided an impetus for “organotherapy”; a ‘science’ of therapy with extracts derived from various animal organs, which were used to treat several diseases and to counter the effects of aging [2]. Though the ‘science of organotherapy’ led to successful treatment of hypothyroidism (with thyroid extracts), diabetes (with pancreatic extracts), and dwarfism (with pituitary extracts), this was not the case with sex steroids. Indeed, recent replication of Brown-Séquard’s published methods demonstrated that his ‘elixir’ likely contained 112 ng/mL (388 nmol/L) of unesterified testosterone, which is equivalent to the administration of 186 ng/day [3]. This is in stark contrast to the testicular secretion of ~ 6 mg/day of testosterone by healthy adult men [4]. Indeed, the Endocrine Society’s clinical practice guidelines on male hypogonadism recommend treatment with 5–10 mg of testosterone daily [5]. In addition to the homeopathic concentrations of testosterone in Brown Sequard’s magic potion, the half-life of unesterified testosterone is only limited to ~ 30 min [6]. Thus, the birth of Andrology started with a placebo effect.
2 Anabolic androgenic steroids: use, misuse, and abuse
As this paper focuses on the medicalization of testosterone, we will first highlight various terms that have been associated with the use of testosterone (and other androgens) to provide some context on how the commercialization of testosterone has impacted its use in various segments of the population.
Use The use of Anabolic Androgenic Steroids (AAS) implies taking prescription androgens (mainly testosterone) for medical conditions. An example is the treatment of hypogonadal men with organic disease of the hypothalamus, the pituitary, or the testes. Testosterone therapy, at a physiologic dose, is indicated to induce or maintain secondary sexual characteristics. This is the only indication currently approved by the Food and Drug Administration (FDA). Additionally, clinical practice guidelines on male hypogonadism also advocate the use of testosterone therapy in men with organic (classic) androgen deficiency.
Misuse The misuse constitutes systematic prescribing of AAS for unproven medical indications in men who do not have organic androgen deficiency. This includes prescribing androgens to primarily treat obesity, diabetes, impaired cognition, male infertility or to reverse aging.
Abuse The abuse of AAS constitutes their use for nonmedical purposes. In this context, androgens are often used in supraphysiologic doses to either achieve performance enhancement (competitive sports) or image enhancement. For these purposes, AAS are usually procured illicitly from compounding pharmacies, fitness centers, or even veterinary clinics.
3 Promotion of ‘ideal male body’ image by the media
4 Influence of advertising on testosterone prescriptions
5 Age‑related low testosterone: is it a big public health problem?
6 Large market, modest benefits
7 New trends and the risk of testosterone misuse
8 Safety concerns
The reason behind these conflicting data is likely the fact that no published randomized trial was adequately powered to assess cardiovascular events. In addition to the advisory and updated testosterone labeling, the FDA also issued guidance “… requiring manufacturers of approved testosterone products to conduct a well-designed clinical trial to more clearly address the question of whether an increased risk of heart attack or stroke exists among users of these products”. The Testosterone Replacement Therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men (TRAVERSE) study was designed in response to this FDA guidance to determine the effects of testosterone treatment on the incidence of major adverse CV events (MACE) in middle-aged and older men with hypogonadism with or at high risk for CV disease. The TRAVERSE trial is currently ongoing [71], and will randomize ~ 6,000 men aged 45–80 years with serum total testosterone levels <300 ng/dL (10.4 nmol/L) and at high risk of cardiovascular disease (primary prevention) or with a known history of cardiovascular disease (secondary prevention), to receive testosterone gel or placebo gel for 5 years. The trial will also evaluate the impact of testosterone treatment on the incidence of high-grade prostate cancer [71]. Until the results of the TRAVERSE trial become available, risks of the cardiovascular and prostate disease remain unclear and require an open discussion with patients before testosterone therapy is started.
9 Conclusion
In a society that is constantly in the quest for the fountain of youth, testosterone has found its spot on the center stage. In addition to the increase in longevity (and the resulting interest in age-related low testosterone), which has substantially increased the market for testosterone products, the prevalence of obesity and diabetes has also increased to epidemic proportions. This, together with the promotion of hypermuscular male body image, has created a perfect storm that has escalated both misuse and abuse of testosterone. In older men, the benefits of testosterone therapy are modest while safety issues remain unresolved. Though there will always be room for more rigorously conducted studies to assess the benefits and risks of testosterone therapy, there is a greater need to educate the general public regarding the benefits and potential harm of testosterone treatment and to highlight the fact that testosterone is a medicine that is indicated in men with organic androgen deficiency, and that it is NOT an Elixir of Life.
Thiago Gagliano‑Jucá · Mauricio Alvarez · Shehzad Basaria
Abstract
The pursuit of longevity, which during the Renaissance era was limited to longing for miraculous ways of rejuvenation, such as bathing in the fountain of youth, took a scientific turn in 1889 with the publication of Brown-Sequard’s self-experiments with an extract of animal testes, which apparently improved his vitality, physical strength, and cognition. This extract, marketed then as the "Elixir of Life", was sold for decades throughout Europe and North America. However, recent replication of Brown-Sequard’s experiments demonstrated that such an extract only contains homeopathic concentrations of testosterone that are insufficient to exert any biological effect. Thus, the birth of Andrology began with a placebo effect. Over the past few decades, the quest for compounds that might lead to rejuvenation has regained traction, with testosterone being at the forefront. Though clinical practice guidelines advocate testosterone therapy in men with organic hypogonadism—the only indication approved by the Food and Drug Administration—testosterone continues to be marketed as a wonder drug with rejuvenating effects on sexual function, vitality, and a host of other unproven benefits. Additionally, the epidemic of obesity and diabetes, conditions associated with low testosterone, has further brought testosterone into the limelight. Although the number of testosterone prescriptions written has increased several-fold in the past two decades, carefully conducted randomized trials suggest modest benefits of testosterone therapy. At the same time, safety concerns, particularly in older men, remain valid.
1 Introduction
Throughout history, humanity has searched for ways of rejuvenation and to extend healthy lifespan. While in the 1500 s, imagery of magical places, such as the Fountain of Youth (Fig. 1), kept the dreams of achieving eternal youth alive, the late 1800s saw the dawn of the scientific quest for antiaging products, especially after the widely publicized report of Brown-Sequard’s experiments [1]. In his report published in the Lancet in 1889, the 72-year-old physician-scientist described the effects of subcutaneous self-administration over two weeks of an aqueous extract derived from the testicles of dogs and guinea pigs. He reported significant improvements in his strength, endurance, and cognition. The presumed benefits of Brown-Séquard’s "Elixir of Life" were widely advertised throughout Europe and North America, where this magic potion was commercially sold for decades (Fig. 2). Brown-Séquard’s experiments even provided an impetus for “organotherapy”; a ‘science’ of therapy with extracts derived from various animal organs, which were used to treat several diseases and to counter the effects of aging [2]. Though the ‘science of organotherapy’ led to successful treatment of hypothyroidism (with thyroid extracts), diabetes (with pancreatic extracts), and dwarfism (with pituitary extracts), this was not the case with sex steroids. Indeed, recent replication of Brown-Séquard’s published methods demonstrated that his ‘elixir’ likely contained 112 ng/mL (388 nmol/L) of unesterified testosterone, which is equivalent to the administration of 186 ng/day [3]. This is in stark contrast to the testicular secretion of ~ 6 mg/day of testosterone by healthy adult men [4]. Indeed, the Endocrine Society’s clinical practice guidelines on male hypogonadism recommend treatment with 5–10 mg of testosterone daily [5]. In addition to the homeopathic concentrations of testosterone in Brown Sequard’s magic potion, the half-life of unesterified testosterone is only limited to ~ 30 min [6]. Thus, the birth of Andrology started with a placebo effect.
2 Anabolic androgenic steroids: use, misuse, and abuse
As this paper focuses on the medicalization of testosterone, we will first highlight various terms that have been associated with the use of testosterone (and other androgens) to provide some context on how the commercialization of testosterone has impacted its use in various segments of the population.
Use The use of Anabolic Androgenic Steroids (AAS) implies taking prescription androgens (mainly testosterone) for medical conditions. An example is the treatment of hypogonadal men with organic disease of the hypothalamus, the pituitary, or the testes. Testosterone therapy, at a physiologic dose, is indicated to induce or maintain secondary sexual characteristics. This is the only indication currently approved by the Food and Drug Administration (FDA). Additionally, clinical practice guidelines on male hypogonadism also advocate the use of testosterone therapy in men with organic (classic) androgen deficiency.
Misuse The misuse constitutes systematic prescribing of AAS for unproven medical indications in men who do not have organic androgen deficiency. This includes prescribing androgens to primarily treat obesity, diabetes, impaired cognition, male infertility or to reverse aging.
Abuse The abuse of AAS constitutes their use for nonmedical purposes. In this context, androgens are often used in supraphysiologic doses to either achieve performance enhancement (competitive sports) or image enhancement. For these purposes, AAS are usually procured illicitly from compounding pharmacies, fitness centers, or even veterinary clinics.
3 Promotion of ‘ideal male body’ image by the media
4 Influence of advertising on testosterone prescriptions
5 Age‑related low testosterone: is it a big public health problem?
6 Large market, modest benefits
7 New trends and the risk of testosterone misuse
8 Safety concerns
The reason behind these conflicting data is likely the fact that no published randomized trial was adequately powered to assess cardiovascular events. In addition to the advisory and updated testosterone labeling, the FDA also issued guidance “… requiring manufacturers of approved testosterone products to conduct a well-designed clinical trial to more clearly address the question of whether an increased risk of heart attack or stroke exists among users of these products”. The Testosterone Replacement Therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men (TRAVERSE) study was designed in response to this FDA guidance to determine the effects of testosterone treatment on the incidence of major adverse CV events (MACE) in middle-aged and older men with hypogonadism with or at high risk for CV disease. The TRAVERSE trial is currently ongoing [71], and will randomize ~ 6,000 men aged 45–80 years with serum total testosterone levels <300 ng/dL (10.4 nmol/L) and at high risk of cardiovascular disease (primary prevention) or with a known history of cardiovascular disease (secondary prevention), to receive testosterone gel or placebo gel for 5 years. The trial will also evaluate the impact of testosterone treatment on the incidence of high-grade prostate cancer [71]. Until the results of the TRAVERSE trial become available, risks of the cardiovascular and prostate disease remain unclear and require an open discussion with patients before testosterone therapy is started.
9 Conclusion
In a society that is constantly in the quest for the fountain of youth, testosterone has found its spot on the center stage. In addition to the increase in longevity (and the resulting interest in age-related low testosterone), which has substantially increased the market for testosterone products, the prevalence of obesity and diabetes has also increased to epidemic proportions. This, together with the promotion of hypermuscular male body image, has created a perfect storm that has escalated both misuse and abuse of testosterone. In older men, the benefits of testosterone therapy are modest while safety issues remain unresolved. Though there will always be room for more rigorously conducted studies to assess the benefits and risks of testosterone therapy, there is a greater need to educate the general public regarding the benefits and potential harm of testosterone treatment and to highlight the fact that testosterone is a medicine that is indicated in men with organic androgen deficiency, and that it is NOT an Elixir of Life.
