9.5.2 Androgen misuse and abuse

The Nobel prize-winning identification of testosterone as the mammalian male sex hormone in 1935 was the culmination of an ancient pursuit to learn how the testis was responsible for masculine virility and superior muscular strength. Within two years, testosterone was being used clinically, and within a decade much of the clinical pharmacology and many applications were recognised (1, 2). Given its weighty historical legacy as the archetypal virilizing substance, testosterone was soon being evaluated to boost pharmacologically the muscular size and strength of healthy men beyond physiological development. In the years following the Second World War, the pharmaceutical industry undertook an extensive quest to identify an ‘anabolic steroid’, an androgen without virilizing properties. Although this proved futile, with the search abandoned, the now meaningless term ‘anabolic steroid’, perpetuating a distinction without a difference, has persisted long beyond its scientific obsolescence largely as a journalistic device for sensationalism and demonization (3). Systematic androgen abuse first appears an epidemic, with an epicentre among Eastern European elite athletes, in the mid 1950s (4). This timing coincided with the golden age of steroid pharmacology in the postwar pharmaceutical industry boom years, which produced the oral contraceptive and synthetic glucocorticoids, and with the early years of the Cold War. This fortuitous intersection of industrial means, unscrupulous operators, and political goals shaped the emergence of systematic androgen abuse as a convenient tool by which sociopolitically dysfunctional Eastern bloc countries could gain short-cut ascendancy through symbolic victories over Western political rivals, a challenge quickly reciprocated by athletes and trainers from the advanced noncommunist countries. This bidding war escalated into national sports doping programs operated covertly by Eastern European communist governments. These organized programs of unscrupulous cheating mixed competitive fraudulence with callous ruination of their athletes’ welfare for national political goals. Of these, only the East German program, with its dire consequences for athletes’ health, has so far been fully disclosed (5). Over the next 4 decades, androgen abuse became endemic in countries where the population is sufficiently affluent to support this consumer variant of drug abuse. Once entrenched in the community, androgen abuse spreads beyond elite sports, where it remains as a low level endemic, to nonsporting users with recreational, cosmetic, and occupational motivations for body-building, such as seeking to promote a fearsome muscular image (6).

Most androgen abuse is structured according to regimens described in an underground gymnasium folklore, described and transmitted in ritualistic detail in quasiscientific publications (e.g. the Underground Steroid Handbook and replicas), and in unrestrained flamboyance on the internet. Androgens are usually taken in repeated cyclic courses of 6–12 weeks duration interrupted by periods of nonuse to recover from desensitization. Courses consist of multiple androgens used concurrently (‘stacking’) in tapering onset and offset patterns (‘pyramiding’). As each androgen is used at multiple times the recommended dose, net androgen intake may be effectively 10–100 times recommended doses. Androgen polypharmacy is also linked to abuse of other drugs as well as other risk behaviours.

Androgens are obtained mostly through leakage from the legitimate market (diversion, theft) via manufacturers, wholesalers, or retailers, but drugs are also manufactured illegally as unregistered, counterfeit or inert products. Sales are mostly through underground networks and dealers operating outlets in gyms and/or by personal contacts, with only a small proportion prescribed by compliant doctors. Policing of prohibition by urine doping tests has been effective during elite sports competitions, although the extension to unannounced out-of-competition testing is required to eliminate abuse during training periods away from competition (5). There is some early evidence from serial high school surveys that the epidemic in wider society may have peaked, (7) although it continues. The natural history of androgen abuse is not well understood but it is generally believed that most users eventually discontinue intake.

Androgen misuse is defined as the medical prescription of androgens without a valid clinical indication. Reflecting medical practices at variance with clinical best practice and evidence-based standards, androgen misuse presumably varies with the extent of continuing medical education balanced against marketing by enthusiasts in clinics and industry. However, there are few objective estimates of prevalence (8). The most prominent form of androgen misuse is the progressive increase in prescribing of testosterone as an antiageing tonic in men and women in the absence of proven safe benefit, as indicated by registration of these indications for testosterone.

Androgen abuse is the illicit use of androgens without prescription for nonmedical purposes. Accurate estimates of the prevalence and determinants of such illicit activity are difficult, due to the unreliability of uncorroborated self-report. Point estimates of prevalence have been undertaken in the captive, sentinel population of high school students. From larger surveys of high school students for self-reported androgen abuse, the prevalence of any (‘lifetime’) use is 4–5% in boys (Fig. 9.5.2.1). Usage is consistently higher in boys, and among American compared with non-American studies, and exhibits regional variability. Nevertheless, androgen abuse is still relatively uncommon in high schools compared with other drugs. Androgen abuse is much more common among elite competitive athletes, with estimates from anonymous surveys ranging from 20–50%, being highest in power sports and bodybuilding. Much lower prevalence is reported in household surveys, presumably reflecting nondisclosure of self-reported illicit activity where confidentiality and corroboration are lacking. Reported risk factors for androgen abuse include male gender, minority ethnicity, sports participation, truancy and unsupervised recreation, an unfulfilled desire to be ‘big’, steroid-using acquaintances, prior use of performance enhancers, and abuse of other drugs. Overall in the USA alone, the androgen abuse market is estimated to involve 300 000 current users, with a turnover of $500 million annually. About 1 million people have used androgens illicitly at some time.

The primary motive for androgen abuse is gaining self-valued physical or psychological benefits. The effects sought include increased muscular size, strength and endurance, a sculpted bodybuilder image, and more intensive training with less fatigue. While androgens can unambiguously rectify the symptoms of androgen deficiency, it was long believed that androgens had no objective effect in eugonadal men, with claimed benefits attributable to placebo effects of training, motivation and/or diet (9). However, a pivotal placebo-controlled, high dose study showed objective increases in muscular size and strength in healthy eugonadal men receiving supraphysiological (∼6 times replacement) testosterone doses, replicating abuse schedules. The gains in muscular size and strength were equivalent, and additive, to the effects of weight training (10), although the gains for skilled athletic performance remain less clear. The decline of elite athletic performance, particularly in female power sports, following the introduction of stringent urine drug testing for androgen doping, corroborates that androgen abuse may be effective in some circumstances (5).

Although testosterone is the only major human hormone without a naturally occurring overdosage state in men, harmful clinical effects are observed due to pharmacological suppression of the hypothalamic-pituitary-testicular axis or to toxicological effects of synthetic androgens.

The reproductive effects of exogenous androgens in men are profound but reversible. Such effects of hypothalamic-pituitary suppression of testicular function are manifest as reduced spermatogenesis, infertility, sexual dysfunction, and androgen deficiency. Recovery of testicular function after androgen abuse is usually complete. However, recovery may be slow, taking up to a year depending on the duration and intensity of the androgen abuse, and may cause transient androgen deficiency symptoms. Delayed recovery needs to be distinguished from continuation of androgen abuse by surreptitious ingestion of synthetic androgens. Treatment of this transient functional gonadotropin deficiency with human chorionic gonadotropin or antioestrogens is possible, but ultimately further delays recovery from underlying hypothalamic-pituitary suppression. In women, androgens cause acne, breast atrophy, menstrual disturbances, and infertility. These are usually reversible, but virilization (hirsutism, voice change, male pattern balding, clitoral enlargement) may be irreversible depending on the dose and duration of androgen exposure. Although nonlethal, irreversible voice change may be very disturbing in women who use their voice professionally or depend on phone contact with family and friends.

Acne and gynaecomastia are frequent side effects of androgen abuse. Androgen-induced acne in adults is typically truncal but rarely facial, the reverse of adolescent acne. Gynaecomastia may become evident during or even soon after stopping androgen abuse, but usually regresses spontaneously as testicular function recovers. Abusers with gynaecomastia, rather than stopping androgens, often seek to continue usage by adding treatment with antioestrogens, nonaromatizable androgens, human chorionic gonadotropin, or cosmetic surgery. Irreversible male pattern baldness can occur in susceptible men and women.

Androgen abuse is associated with relatively few serious or irreversible side effects. The most serious side effect, hepatotoxicity, arises exclusively from 17α-alkylated androgens, the main class of orally active synthetic androgens. The 17α-alkyl substitution facilitates oral bioavailability, but at the expense of intrinsic class-specific hepatotoxicity. The major hazards are hepatic tumours (adenoma, carcinoma, cholangiosarcoma, or angiosarcoma), peliosis hepatis, and drug hepatotoxicity (usually cholestasis). Most hepatic tumours are benign, slowly progressive, and reversible with cessation of androgen ingestion, but rare fatal cancers are reported. Peliosis hepatis, a benign pattern of focal hepatic necrosis causing vascular cysts, can result in hepatic and/or splenic enlargement and serious, even fatal, bleeding—either spontaneously or following liver biopsy. Post mortem studies show that hepatic tumours and peliosis are frequently undetected clinically during long-term therapy with oral 17α-alkylated androgens. This class of synthetic androgen, marketed prior to the 1970s, would not be considered safe for modern drug registration and is gradually being withdrawn from clinical usage. Other androgens (unmodified or esterified testosterone, nandrolone, 1-methyl androgens) are rarely associated with adverse hepatic effects.

Infections associated with androgen abuse include local sepsis at injection sites and systemic viral infection (HIV, hepatitis) from needle sharing; more fulminant systemic infections (viral, fungal, endocarditis) and local abscesses are uncommon.

Musculoskeletal injuries include tendon and ligament ruptures, and rhabdomyolysis associated with over-training. Iliopsoas hypertrophy can present as an acute abdomen, and nerve palsies can result from injection injury. In adolescents, androgen abuse may prematurely close the epiphyses and stunt final height.

Psychological disturbances associated with androgen abuse are complex to interpret, both as to their causality and mechanisms. Florid mood and/or behaviour disturbances including hypomania, aggression, depression, and sleep disturbance are reported among androgen abusers. These may be features of pre-existing psychopathology and/or confounding effects of intensive weight training that predispose to androgen abuse rather than, or in addition to, authentic drug effects. Prospective, placebo-controlled studies of androgens in healthy young men show no or minimal changes in mood or behaviour. These disparities suggest reported behavioural disturbances of androgen abusers (‘roid rage’) involves either an unusually susceptible minority and/or individuals whose recollections are coloured with exculpatory motivation (‘drug excuse’, ‘dumbbell defense’). Although observational evidence suggests psychological habituation to androgens in susceptible personalities, direct empirical testing fails to substantiate evidence for addictive properties of androgens. Androgen abuse may represent an obsessive behavioural pattern analogous to eating disorders and fanatical exercising, where distorted self-perception and dissonance between body image and reality drives an insatiable desire for continuous body shaping towards a desired goal.

The cardiovascular consequences of androgen abuse, classified into four potential mechanisms (accelerated atherogenesis, thrombosis, vasospasm, and direct cardiotoxicity), remain unclear as most evidence consists of anecdotal case reports (11). Controlled clinical studies of androgen abusers have shown minimal deleterious functional effects compared with nonuser controls. Serious cardiovascular outcomes associated with androgen abuse include cardiomyopathy, premature atherosclerosis, myocardial infarction, cardiac tamponade, cardiac failure, sudden death, thrombotic and haemorrhagic stroke, subdural hematoma, peripheral artery and venous thrombosis, and pulmonary embolism. When presenting at an unusually young age, incidental genetic or acquired (e.g. viral) heart disease need to be distinguished. In the absence of population-based studies and adequate estimates of usage, it is unclear if any cardiovascular effects of androgen abuse exceed expectations for the general population (12).

The effects of androgen abuse on the prostate have been little studied, apart from anecdotal case reports. There are no systematic population-based studies and only a single controlled study (13) so the overall risks remain ill-defined. The absence of reported deaths from premature prostate cancer among former androgen abusers, after an epidemic already lasting more than four decades, raises the possibility that no such excess will occur; however, quantitative epidemiological evidence of usage and outcomes is needed.

Uncorroborated, idiosyncratic and/or unproven associations with androgen abuse include isolated case reports of colon, Wilms and renal cancer, bleeding oesophageal varices, systemic lupus glomerulonephritis, transverse myelitis, psoriasis, and severe chickenpox. Without confirmation these are best considered coincidental. Metabolic effects including changes in insulin sensitivity, lipid profiles, and other biochemical changes associated with androgen administration are reversible.

Patients considering or admitting androgen abuse may present requesting information, prescription, or monitoring, or with side effects suspicious of unacknowledged androgen abuse. Typically they are unusually muscular men with body image dissonance. They may be preoccupied with exercising, and may exhibit telltale signs such as adult-onset truncal acne and/or gynaecomastia, or present with infertility, sexual dysfunction, or androgen deficiency. Biochemical confirmation of androgen abuse may obtained by measuring blood testosterone, SHBG, luteinizing hormone, and FSH. All recent use of exogenous androgens will depress luteinizing hormone and FSH; blood testosterone will also be decreased by synthetic androgens, and SHBG is lowered by any oral androgens or by high doses of injected androgens. Specific detection by mass spectrometry urine testing is not usually available outside accredited sports doping programs (14, 15). On the first visit of a known androgen abuser, a full history, physical examination, and investigations should be undertaken to exclude important adverse effects. While supportive counselling about the health effects of androgen abuse is warranted, prescribing androgens for abusers is inappropriate. Ongoing monitoring of abusers for medical complications lacks rational basis as it is ineffective, expensive, and colludes in perpetuating androgen abuse.

In the competitive sports, international sporting bodies have pursued the elimination of androgen abuse by programs of highly sensitive urinary drug screening (16). These were initially deployed during major competitions and, increasingly, by unannounced, out-of-competition testing. There is clear evidence that stringent testing greatly reduces abuse of known synthetic androgens and testosterone during and immediately preceding elite competition. Ultimately, random out-of-competition testing could eliminate virtually all androgens from sport, but such effective regular testing is expensive and complex to implement. In the high wealth environment of elite sports, such testing programs are susceptible to crippling either by legal manoeuvres or corruption as tax-deductible costs of business. Outside sports, the social epidemic of androgen abuse shows some early signs of abating (7), and most governments are introducing legislation to regulate the supply and use of androgens. There is a growing awareness that effective programs for nonsporting, recreational androgen abusers will require a different prevention and diversion focus from the deterrence of sports doping.

Preventing or halting androgen abuse requires an understanding of the motives for starting and continuing androgen abuse. Knowledge of these social factors, on which effective interventions must be based, is scarce. For adolescents motivated by short-term goals and protected by the aura of invincibility, or athletes motivated by a ‘win-at-all-costs’ mentality and by lucrative rewards, ‘scare tactics’ are ineffective, and more sophisticated, balanced, risk-benefit approaches are required. One educational program has proved capable of improving knowledge about androgen abuse, but was unable to deter individuals from initiating new androgen abuse effectively, (17) and further development is required. At present, largely anecdotal information suggests that the serious short-term medical dangers of androgen abuse are relatively limited considering the extent of abuse. Furthermore, androgens are not physically addictive and most abusers eventually discontinue drug use. Hence, with established androgen abuse, the most appropriate medical approach is supportive counselling and encouragement to discontinue without perpetuating abuse by prescribing androgens or perfunctory monitoring.