madman
Super Moderator
Abstract
Androgens are potent drugs requiring a prescription for valid medical indications but are misused for invalid, unproven, or off-label reasons as well as being abused without prescription for illicit nonmedical application for performance or image enhancement. Following the discovery and first clinical application of testosterone in the 1930s, commercialization of testosterone and synthetic androgens proliferated in the decades after World War II. It remains among the oldest marketed drugs in therapeutic use, yet after 8 decades of clinical use, the sole unequivocal indication for testosterone remains in replacement therapy for pathological hypogonadism, organic disorders of the male reproductive system. Nevertheless, wider claims assert unproven, unsafe, or implausible benefits for testosterone, mostly representing wishful thinking about rejuvenation. Over recent decades this created an epidemic of testosterone misuse involving prescription as a revitalizing tonic for antiageing, sexual dysfunction, and/or obesity, where efficacy and safety remain unproven and doubtful. Androgen abuse originated during the Cold War as an epidemic of androgen doping among elite athletes for performance enhancement before the 1980s when it crossed over into the general community to become an endemic variant of drug abuse in sufficiently affluent communities that support an illicit drug industry geared to bodybuilding and aiming to create a hypermasculine body physique and image. This review focuses on the misuse of testosterone, defined as prescribing without valid clinical indications, and abuse of testosterone or synthetic androgens (androgen abuse), defined as the illicit use of androgens without prescription or valid indications, typically by athletes, body-builders and others for image-oriented, cosmetic or occupational reasons.
1. Introduction
Androgens are potent pharmacological drugs requiring a legal prescription for valid medical indications, but they are also misused for invalid, unproven, and off-label medical reasons as well as abused without prescription for illicit non-medical application for performance or image enhancement. Following the discovery (1) and first clinical use of testosterone (2) in the 1930s, medical uses and commercialization of androgens proliferated in the post-World War II decades, the Golden Age of Steroid Pharmacology, overlapping with the early years of the Cold War (Figure 1). Testosterone remains among the oldest marketed drugs in therapeutic use. Yet after eight decades of clinical use, the sole unequivocal indication for testosterone remains in replacement therapy for pathological hypogonadism, organic disorders of the reproductive system (3). Yet the application of testosterone and its synthetic androgen analogs remain clouded by various wider claims asserting unproven and/or implausible benefits, often representing the wishful thinking about rejuvenation and with undefined safety risks. This review focuses on the misuses of testosterone, defined as prescribing without valid clinical indications, and abuse of testosterone or synthetic androgens (androgen abuse), defined as the illicit use of androgens without prescription for non-medical reasons, typically by athletes, bodybuilders, and others for image-oriented, cosmetic, or occupational reasons (table 1).
2. Historical background
3. Androgen Use, Misuse, and Abuse
3.1. Physiological Treatment: Testosterone Replacement Therapy for Pathologic Hypogonadism
The sole unequivocal indication for testosterone use remains as replacement therapy for organic hypogonadism due to defects in the hypothalamic-pituitary-testicular axis arising from pathological disorders. Within the framework of medicine based on the pathological basis of disease, testosterone treatment is justified when pathological disorders of the reproductive system render it incapable of maintaining androgen-sensitive tissue functions. Such defects may be due either to testicular damage disrupting Leydig cell testosterone synthesis and secretion or else to hypothalamic-pituitary disorders that reduce pituitary LH secretion, the principal drive to Leydig cell testosterone production. Testosterone is used exclusively for androgen replacement therapy as synthetic androgens lack the full spectrum of testosterone’s effects involving the amplification and diversification pathways (figure 2). Testosterone effects are mediated by not just direct testosterone effects on androgen receptors, but also via indirect effects of its bioactive metabolites, usually generated within the androgen target tissues as local paracrine mechanisms. These bioactive metabolites comprise testosterone’s amplification by 5α-reductase enzymes to the more potent, pure androgen dihydrotestosterone (DHT) and diversification by local conversion to estradiol via the enzyme aromatase (aromatization) to act on estrogen receptors. At the tissue level, androgen action is exerted by androgen binding to and activating the androgen receptor (AR) so genetic mutations impairing AR function can produce complete or partial androgen insensitivity syndromes, depending on the residual function of the mutated AR (38, 39).
3.2. Pharmacological Androgen Treatment
3.3. Androgen Dependence
3.4 Free Testosterone: Dogma and Reality
The FT hypothesis is a widely disseminated but controversial and unproven concept that may contribute to misunderstanding of testosterone use and misuse. The FT hypothesis, recently comprehensively restated (40), asserts that the non-protein bound fraction of circulating testosterone (about 2%) is the only biologically active moiety capable of entering tissues to exert androgen action. This contrasts with bound testosterone representing an inert reservoir (40, 77, 78) with most being firmly bound to SHBG (about 60%) and the remainder loosely bound to albumin and other proteins (about 38%) constituting a buffer reservoir of biologically inactive circulating testosterone.
The FT hypothesis originated from the earliest, now obsolete, 1970’s pharmacology theory of drug interactions. That focused on the mutual displacement of drugs bound to circulating proteins (79) invoking the concept of a hypothetical unbound (“free”) drug fraction (77, 78, 80, 81) but is now discarded in modern pharmacology (82) in favor of physiological mechanisms of drug interaction due to molecular receptor binding, cytochrome P450 induction/inhibition, P-glycoprotein and ion channel blockade (83). Nevertheless, the enshrining of the FT hypothesis in Endocrinology was secured by the fortuitous coincidence of the developing calculational formulae for the recently invented immunoassays in the 1970s. These focus on separating antibody-bound from unbound (“free”) fractions (84) lending plausibility to the questionable physiological extrapolation of in vitro binding equation theory. Subsequently, despite the abandonment of its pharmacological underpinnings, this simple illustrative heuristic of “free” hormones evolved into an unquestioned dogma, passing uncritically from one paper to another without ever undergoing rigorous clinical evaluation of its validity, application, and interpretation. Long now considered an unchallengeable, quasi-axiomatic panchreston (explain-all), the FT hypothesis has been widely and prominently invoked to suggest (a) wider scope for testosterone treatment in male aging because FT levels fall faster with age than accurately measured testosterone observed in population-based studies (85- 91)and (b) obesity is not a state of testosterone deficiency warranting testosterone treatment because FT is normal (92-94). A parallel argument from thyroidology raised in favor of the FT hypothesis is that thyroid function testing routinely includes measurements of “free” thyroxine (T4) and triiodothyronine (T3). Yet, the FT hypothesis lacks basis, in theory, measurement, and empirical clinical application (for details see review (95, 96)).
The FT hypothesis asserts that the small moiety of circulating testosterone not bound to any circulating protein (or loosely bound to albumin and other low-affinity binding proteins) is the most “biologically active” fraction of circulating testosterone due to its greater accessibility to tissues compared with tightly bound steroid. Yet unbound testosterone is also equally more accessible to sites of degradation, so this theory cannot explain why unbound hormones would be more rather less biologically active (95). Corollary assumptions of the FT hypothesis include that the rapid transfer of testosterone from its bound state to circulating carrier proteins moving into tissues occurs passively and identically in all capillaries. While equilibrium binding theory may be reasonably assumed for testosterone during its relatively long time in the circulation, its application is dubious to the dynamic unloading of testosterone during fleeting capillary transit, an inherent nonequilibrium state. Each assumption has been invalidated by empirical evidence (for details see review (95)). For example, rather than being biologically inert protein-bound testosterone is actively transferred to androgen-sensitive tissues (97-102) and the varying thresholds for testosterone effects in different tissues (103) makes it unlikely that the capillary transfers are identical in all tissues or if they are, they do not determine androgen action in those tissues.
Despite the misconceived and ambiguous theory, dialysis-based laboratory measurement of “free” testosterone is feasible. However, dialysis-based laboratory methods lack a certified standard, quality control, or validated reference range. They are also laborious and vulnerable to artefact so are not widely used in high throughput automated chemical pathology laboratories or, if available, costly. Instead, lab measurements are replaced by formulae based on serum testosterone and SHBG concentrations combined into equilibrium binding equations (104, 105).
However, aside from the untenable assumption of equilibrium for testosterone unloading into tissues, these formulae are inaccurate relative to laboratory measurements due to their reliance on arbitrary plug-in constants and erroneous stoichiometry for testosterone binding to SHBG (106, 107). Amusingly, to glamorize these formulae the equilibrium binding equations have been referred to as calculations by the “Law of Mass Action” (108-112), analogous to claiming to measure weight by the Law of Gravity or temperature by the First Law of Thermodynamics. Nevertheless, flawed formulae are easy to calculate and widely but uncritically used. Crucially, through its formulaic dependence on two age-dependent variables, such calculated “free” testosterone is a deterministic (inverse) function of age. Hence, introducing this calculated variable, a masked surrogate for “age”, confuses rather than clarifies any clinical evaluation androgen status, especially for older men. Direct empirical testing reveals that calculated “free” testosterone provides no clinically meaningful prognostic information beyond accurately measured serum testosterone (96). Given the unsound theoretical and empirical basis, recourse to such derived measures of circulating testosterone does not contribute to sound clinical decision-making regarding androgen status notably in male aging.
Commercial free T4 and T3 immunoassays have an established role in the diagnosis of thyroid dysfunction having overtaken measurement of total T4 and T3 apparently to account for potential changes in circulating TBG concentrations. However, like the invalid free testosterone analog assays, free thyroid hormone analog assays violate the fundamental assay criterion of comparing like with like because there is no authentic standard for either “free” measurand. Instead, these surrogate methods introduce chemically non-authentic T4 or T3 analogs into the cognate free T4 and T3 immunoassays and then rely on complex recalibration to achieve credible clinical results. Inevitably, violating basic assay theory renders analog immunoassays vulnerable to errors and artefacts (113, 114) reflected in the difficulties of establishing a consensus common reference intervals for commercial-free T4 immunoassays (115), as recognized by one of the pioneers of the “free” hormone thinking (77, 116). Fortunately, the clinical diagnosis of thyroid dysfunction relies almost exclusively on highly sensitive TSH assays. Modern TSH immunoassays feature well defined lower and upper limits of normal with the lower limit clearly distinct from zero (unlike serum LH) and all assays readily conform to a common reference interval (117). This reliance on TSH for diagnosis of thyroid dysfunction covers hyperthyroidism (suppressed TSH) and primary hypothyroidism (elevated TSH). The serum TSH assay in isolation may not provide a diagnosis of secondary hypothyroidism; however, as a late feature of panhypopituitarism, that state is usually accompanied by hypofunction in other pituitary-dependent axes (gonadal, adrenal, GH/IGF-I). Hence, the diagnosis of thyroid dysfunction is not dependent on the error-prone “free” analog T4 or T3 assays but rather on the highly sensitive TSH assay. In any case, this tangential issue provides no counterpart justification for the dubious FT hypothesis and its implementation in actual or surrogate measurements.
Nevertheless, the FT hypothesis remains controversial in retaining some support from many experienced endocrine investigators (118-123). The most concerted application of the FT hypothesis to male aging has been in the observational EMAS study which reports that calculated FT correlates with sexual (dys)function symptoms in cross-sectional and longitudinal analyses (91, 124); however, being unable to ascribe causality these observational data leave it unclear if the FT changes are cause or effect of the sexual (dys)function, especially considering the often-overlooked evidence of reverse causality in that sexual activity maintains circulating testosterone (125-129). Despite its weak theoretical rationale and limited empirical clinical evidence base, the consistent unreflective repetition of the FT hypothesis in papers as an unchallengeable dogma with a façade of biochemical sophistication fosters confirmation bias among those schooled on an unquestioned verity. For those with second-hand knowledge of endocrinology pathophysiology derived from such textbooks and reviews, the FT hypothesis creates an attractive and facile, no-cost tool to eke statistical significance.
4. Androgen Misuse
4.1. Introduction
4.2. Pharmacoepidemiology
4.3 Specific misuses of testosterone
Male infertility
Obesity
Diabetes
Osteoporosis
Depression
Drugs
4.4 Rejuvenation and the Invention of Andropause: Age-related Functional Hypogonadism
4.5 Public health and policy
4.6 Avoiding Androgen (Testosterone) Misuse
5. Androgen Abuse
5.1. Introduction
5.2. Epidemiology
5.3. Motivation and Patterns of Use
5.4. Natural History of Androgen Abuse
5.5. Medical management
5.5.1. Clinical Identification and Management
5.5.2. Harm from Androgen Abuse
5.5.3. Rehabilitation and recovery
5.6. Public health and policy
5.6.1. Performance enhancement
5.6.2. Image enhancement
Androgens are potent drugs requiring a prescription for valid medical indications but are misused for invalid, unproven, or off-label reasons as well as being abused without prescription for illicit nonmedical application for performance or image enhancement. Following the discovery and first clinical application of testosterone in the 1930s, commercialization of testosterone and synthetic androgens proliferated in the decades after World War II. It remains among the oldest marketed drugs in therapeutic use, yet after 8 decades of clinical use, the sole unequivocal indication for testosterone remains in replacement therapy for pathological hypogonadism, organic disorders of the male reproductive system. Nevertheless, wider claims assert unproven, unsafe, or implausible benefits for testosterone, mostly representing wishful thinking about rejuvenation. Over recent decades this created an epidemic of testosterone misuse involving prescription as a revitalizing tonic for antiageing, sexual dysfunction, and/or obesity, where efficacy and safety remain unproven and doubtful. Androgen abuse originated during the Cold War as an epidemic of androgen doping among elite athletes for performance enhancement before the 1980s when it crossed over into the general community to become an endemic variant of drug abuse in sufficiently affluent communities that support an illicit drug industry geared to bodybuilding and aiming to create a hypermasculine body physique and image. This review focuses on the misuse of testosterone, defined as prescribing without valid clinical indications, and abuse of testosterone or synthetic androgens (androgen abuse), defined as the illicit use of androgens without prescription or valid indications, typically by athletes, body-builders and others for image-oriented, cosmetic or occupational reasons.
1. Introduction
Androgens are potent pharmacological drugs requiring a legal prescription for valid medical indications, but they are also misused for invalid, unproven, and off-label medical reasons as well as abused without prescription for illicit non-medical application for performance or image enhancement. Following the discovery (1) and first clinical use of testosterone (2) in the 1930s, medical uses and commercialization of androgens proliferated in the post-World War II decades, the Golden Age of Steroid Pharmacology, overlapping with the early years of the Cold War (Figure 1). Testosterone remains among the oldest marketed drugs in therapeutic use. Yet after eight decades of clinical use, the sole unequivocal indication for testosterone remains in replacement therapy for pathological hypogonadism, organic disorders of the reproductive system (3). Yet the application of testosterone and its synthetic androgen analogs remain clouded by various wider claims asserting unproven and/or implausible benefits, often representing the wishful thinking about rejuvenation and with undefined safety risks. This review focuses on the misuses of testosterone, defined as prescribing without valid clinical indications, and abuse of testosterone or synthetic androgens (androgen abuse), defined as the illicit use of androgens without prescription for non-medical reasons, typically by athletes, bodybuilders, and others for image-oriented, cosmetic, or occupational reasons (table 1).
2. Historical background
3. Androgen Use, Misuse, and Abuse
3.1. Physiological Treatment: Testosterone Replacement Therapy for Pathologic Hypogonadism
The sole unequivocal indication for testosterone use remains as replacement therapy for organic hypogonadism due to defects in the hypothalamic-pituitary-testicular axis arising from pathological disorders. Within the framework of medicine based on the pathological basis of disease, testosterone treatment is justified when pathological disorders of the reproductive system render it incapable of maintaining androgen-sensitive tissue functions. Such defects may be due either to testicular damage disrupting Leydig cell testosterone synthesis and secretion or else to hypothalamic-pituitary disorders that reduce pituitary LH secretion, the principal drive to Leydig cell testosterone production. Testosterone is used exclusively for androgen replacement therapy as synthetic androgens lack the full spectrum of testosterone’s effects involving the amplification and diversification pathways (figure 2). Testosterone effects are mediated by not just direct testosterone effects on androgen receptors, but also via indirect effects of its bioactive metabolites, usually generated within the androgen target tissues as local paracrine mechanisms. These bioactive metabolites comprise testosterone’s amplification by 5α-reductase enzymes to the more potent, pure androgen dihydrotestosterone (DHT) and diversification by local conversion to estradiol via the enzyme aromatase (aromatization) to act on estrogen receptors. At the tissue level, androgen action is exerted by androgen binding to and activating the androgen receptor (AR) so genetic mutations impairing AR function can produce complete or partial androgen insensitivity syndromes, depending on the residual function of the mutated AR (38, 39).
3.2. Pharmacological Androgen Treatment
3.3. Androgen Dependence
3.4 Free Testosterone: Dogma and Reality
The FT hypothesis is a widely disseminated but controversial and unproven concept that may contribute to misunderstanding of testosterone use and misuse. The FT hypothesis, recently comprehensively restated (40), asserts that the non-protein bound fraction of circulating testosterone (about 2%) is the only biologically active moiety capable of entering tissues to exert androgen action. This contrasts with bound testosterone representing an inert reservoir (40, 77, 78) with most being firmly bound to SHBG (about 60%) and the remainder loosely bound to albumin and other proteins (about 38%) constituting a buffer reservoir of biologically inactive circulating testosterone.
The FT hypothesis originated from the earliest, now obsolete, 1970’s pharmacology theory of drug interactions. That focused on the mutual displacement of drugs bound to circulating proteins (79) invoking the concept of a hypothetical unbound (“free”) drug fraction (77, 78, 80, 81) but is now discarded in modern pharmacology (82) in favor of physiological mechanisms of drug interaction due to molecular receptor binding, cytochrome P450 induction/inhibition, P-glycoprotein and ion channel blockade (83). Nevertheless, the enshrining of the FT hypothesis in Endocrinology was secured by the fortuitous coincidence of the developing calculational formulae for the recently invented immunoassays in the 1970s. These focus on separating antibody-bound from unbound (“free”) fractions (84) lending plausibility to the questionable physiological extrapolation of in vitro binding equation theory. Subsequently, despite the abandonment of its pharmacological underpinnings, this simple illustrative heuristic of “free” hormones evolved into an unquestioned dogma, passing uncritically from one paper to another without ever undergoing rigorous clinical evaluation of its validity, application, and interpretation. Long now considered an unchallengeable, quasi-axiomatic panchreston (explain-all), the FT hypothesis has been widely and prominently invoked to suggest (a) wider scope for testosterone treatment in male aging because FT levels fall faster with age than accurately measured testosterone observed in population-based studies (85- 91)and (b) obesity is not a state of testosterone deficiency warranting testosterone treatment because FT is normal (92-94). A parallel argument from thyroidology raised in favor of the FT hypothesis is that thyroid function testing routinely includes measurements of “free” thyroxine (T4) and triiodothyronine (T3). Yet, the FT hypothesis lacks basis, in theory, measurement, and empirical clinical application (for details see review (95, 96)).
The FT hypothesis asserts that the small moiety of circulating testosterone not bound to any circulating protein (or loosely bound to albumin and other low-affinity binding proteins) is the most “biologically active” fraction of circulating testosterone due to its greater accessibility to tissues compared with tightly bound steroid. Yet unbound testosterone is also equally more accessible to sites of degradation, so this theory cannot explain why unbound hormones would be more rather less biologically active (95). Corollary assumptions of the FT hypothesis include that the rapid transfer of testosterone from its bound state to circulating carrier proteins moving into tissues occurs passively and identically in all capillaries. While equilibrium binding theory may be reasonably assumed for testosterone during its relatively long time in the circulation, its application is dubious to the dynamic unloading of testosterone during fleeting capillary transit, an inherent nonequilibrium state. Each assumption has been invalidated by empirical evidence (for details see review (95)). For example, rather than being biologically inert protein-bound testosterone is actively transferred to androgen-sensitive tissues (97-102) and the varying thresholds for testosterone effects in different tissues (103) makes it unlikely that the capillary transfers are identical in all tissues or if they are, they do not determine androgen action in those tissues.
Despite the misconceived and ambiguous theory, dialysis-based laboratory measurement of “free” testosterone is feasible. However, dialysis-based laboratory methods lack a certified standard, quality control, or validated reference range. They are also laborious and vulnerable to artefact so are not widely used in high throughput automated chemical pathology laboratories or, if available, costly. Instead, lab measurements are replaced by formulae based on serum testosterone and SHBG concentrations combined into equilibrium binding equations (104, 105).
However, aside from the untenable assumption of equilibrium for testosterone unloading into tissues, these formulae are inaccurate relative to laboratory measurements due to their reliance on arbitrary plug-in constants and erroneous stoichiometry for testosterone binding to SHBG (106, 107). Amusingly, to glamorize these formulae the equilibrium binding equations have been referred to as calculations by the “Law of Mass Action” (108-112), analogous to claiming to measure weight by the Law of Gravity or temperature by the First Law of Thermodynamics. Nevertheless, flawed formulae are easy to calculate and widely but uncritically used. Crucially, through its formulaic dependence on two age-dependent variables, such calculated “free” testosterone is a deterministic (inverse) function of age. Hence, introducing this calculated variable, a masked surrogate for “age”, confuses rather than clarifies any clinical evaluation androgen status, especially for older men. Direct empirical testing reveals that calculated “free” testosterone provides no clinically meaningful prognostic information beyond accurately measured serum testosterone (96). Given the unsound theoretical and empirical basis, recourse to such derived measures of circulating testosterone does not contribute to sound clinical decision-making regarding androgen status notably in male aging.
Commercial free T4 and T3 immunoassays have an established role in the diagnosis of thyroid dysfunction having overtaken measurement of total T4 and T3 apparently to account for potential changes in circulating TBG concentrations. However, like the invalid free testosterone analog assays, free thyroid hormone analog assays violate the fundamental assay criterion of comparing like with like because there is no authentic standard for either “free” measurand. Instead, these surrogate methods introduce chemically non-authentic T4 or T3 analogs into the cognate free T4 and T3 immunoassays and then rely on complex recalibration to achieve credible clinical results. Inevitably, violating basic assay theory renders analog immunoassays vulnerable to errors and artefacts (113, 114) reflected in the difficulties of establishing a consensus common reference intervals for commercial-free T4 immunoassays (115), as recognized by one of the pioneers of the “free” hormone thinking (77, 116). Fortunately, the clinical diagnosis of thyroid dysfunction relies almost exclusively on highly sensitive TSH assays. Modern TSH immunoassays feature well defined lower and upper limits of normal with the lower limit clearly distinct from zero (unlike serum LH) and all assays readily conform to a common reference interval (117). This reliance on TSH for diagnosis of thyroid dysfunction covers hyperthyroidism (suppressed TSH) and primary hypothyroidism (elevated TSH). The serum TSH assay in isolation may not provide a diagnosis of secondary hypothyroidism; however, as a late feature of panhypopituitarism, that state is usually accompanied by hypofunction in other pituitary-dependent axes (gonadal, adrenal, GH/IGF-I). Hence, the diagnosis of thyroid dysfunction is not dependent on the error-prone “free” analog T4 or T3 assays but rather on the highly sensitive TSH assay. In any case, this tangential issue provides no counterpart justification for the dubious FT hypothesis and its implementation in actual or surrogate measurements.
Nevertheless, the FT hypothesis remains controversial in retaining some support from many experienced endocrine investigators (118-123). The most concerted application of the FT hypothesis to male aging has been in the observational EMAS study which reports that calculated FT correlates with sexual (dys)function symptoms in cross-sectional and longitudinal analyses (91, 124); however, being unable to ascribe causality these observational data leave it unclear if the FT changes are cause or effect of the sexual (dys)function, especially considering the often-overlooked evidence of reverse causality in that sexual activity maintains circulating testosterone (125-129). Despite its weak theoretical rationale and limited empirical clinical evidence base, the consistent unreflective repetition of the FT hypothesis in papers as an unchallengeable dogma with a façade of biochemical sophistication fosters confirmation bias among those schooled on an unquestioned verity. For those with second-hand knowledge of endocrinology pathophysiology derived from such textbooks and reviews, the FT hypothesis creates an attractive and facile, no-cost tool to eke statistical significance.
4. Androgen Misuse
4.1. Introduction
4.2. Pharmacoepidemiology
4.3 Specific misuses of testosterone
Male infertility
Obesity
Diabetes
Osteoporosis
Depression
Drugs
4.4 Rejuvenation and the Invention of Andropause: Age-related Functional Hypogonadism
4.5 Public health and policy
4.6 Avoiding Androgen (Testosterone) Misuse
5. Androgen Abuse
5.1. Introduction
5.2. Epidemiology
5.3. Motivation and Patterns of Use
5.4. Natural History of Androgen Abuse
5.5. Medical management
5.5.1. Clinical Identification and Management
5.5.2. Harm from Androgen Abuse
5.5.3. Rehabilitation and recovery
5.6. Public health and policy
5.6.1. Performance enhancement
5.6.2. Image enhancement
Last edited:
