Steroids are a general class of agents that all have the steroid ring in common. The steroid ring is composed of three 6-carbon rings and one 5-carbon ring joined, of which cholesterol is the most basic form and, indeed, the precursor. Although the term steroid includes all agents derived from this ringed structure, this discussion includes only testosterone and the anabolic-androgenic steroids (AASs).
Testosterone is the principle hormone in humans that produces male secondary sex characteristics (androgenic) and is an important hormone in maintaining adequate nitrogen balance, thus aiding in tissue healing and the maintenance of muscle mass (anabolic). Testosterone has a dual action and can be described in terms of its androgenic and anabolic capacities.
Nevertheless, despite decades of use and tremendous advances in understanding the molecular and cellular basis of androgen action, we have far to go to achieve optimal use of testosterone. Here, an approach to this challenge in men is outlined, which involves defining and optimising appropriate clinical use, while minimising misuse and, hopefully, eliminating the abuse of testosterone.
Androgen replacement therapy
Androgen deficiency (AD), due to hypothalamus, pituitary or testis disorders of genetic or acquired aetiology, is the principal clinical indication for ART.3 Testicular testosterone production may be reduced by gonadotrophin deficiency or Leydig cell dysfunction. In ART, testosterone is used at doses designed to reproduce endogenous blood testosterone concentrations and physiological exposure of tissues to androgen. To the extent this is achieved, ART has the inbuilt safety of replicating long-term health outcomes of eugonadal men. Used in this way, testosterone can rectify all the clinical features of AD, with prominent effects of improving quality of life through enhanced energy, motivation and endurance, as well as restoring structural or functional deficits in muscle, bone, marrow and psychosexual activity.4 Specific time-limited variations of ART include treatment of delayed male puberty5 and hormonal male contraception.
Barriers to evidence
Distinguishing valid but unproven indications from unjustified or unsafe prescribing is made difficult by the formidable cost of the necessary, rigorous clinical trials geared primarily towards novel chemical entities. The post-Women’s Health Initiative era mandates that newer indications for prolonged hormonal treatment be based on adequate long-term safety, so that important but infrequent adverse effects are not overlooked. Androgens are now relatively cheap, so there is little incentive for companies to undertake the costly clinical trials required for regulatory approval of new indications. As a result, many useful clinical applications of testosterone and androgens seem condemned to dwell in the limbo of off-label use, prone to misuse and possibly doing undetected harm when used with evidence-free enthusiasm.
When circumstances foster off-label mass marketing, this lucrative option may circumvent the need for high quality but costly evidence — there remains a crucial role for vigilance by non-conflicted medical professionals.
Abuse: non-medical use
Androgen (“anabolic steroid”) abuse is the use of androgens, usually obtained illicitly and often used in massive doses, for non-medical purposes. Abusers may use any available androgens, including veterinary, illegally manufactured, stolen and counterfeit steroids, in often bizarre, high-dose regimens advocated by folkloric underground publications. An unfortunate Cold War legacy, androgen abuse originated in international elite sports that became a proxy battleground for East European countries to cheat their way to public relations victory over the West — a challenge soon reciprocated. Androgen abuse is primarily attractive in power sports where increased muscle mass leads to greater strength, roughly proportional to androgen dose even in eugonadal men, a fact long denied30 but proved by a seminal placebo-controlled study a decade ago.31
Abuse in sport
Androgen abuse in elite sports is policed by the World Anti-Doping Agency (WADA), which standardises sports doping tests internationally. The effectiveness of drug screening in competition is shown by the very low rate of positive tests (< 2% of about 170 000 tests performed by 32 laboratories in 2004) on random testing at the Olympic Games and other major international events. The most frequently detected drugs are androgens, with three (testosterone, nandrolone and stanozolol) accounting for about 80% of positive results in 2004. Testimony to the effectiveness of WADA screening to stamp out abuse of all marketed androgens are the discoveries since 2002 of three designer androgens (norbolethone,32 tetrahydrogestrinone [THG],33 and desoxymethyltestosterone [DMT]34) purpose-manufactured to evade WADA detection. These designer androgens are manufactured illegally in clandestine laboratories, with access to unpublished commercially confidential data from the 1960s allowing minor chemical modification of commercially available steroids to form potent androgens.35 Once identified, effective detection methods are added so rapidly to routine screens that there is evidence of only one (THG) ever used in competition. Although requiring continued vigilance, the opportunities for androgen abuse in competition are virtually closed for athletes. Further elimination of androgen abuse from training by random out-of-competition testing is a formidable task still to be more fully developed.
Benefits of testosterone