Pharmacology of anabolic steroids

Abstract

Athletes and bodybuilders have recognized for several decades that the use of anabolic steroids can promote muscle growth and strength but it is only relatively recently that these agents are being revisited for clinical purposes. Anabolic steroids are being considered for the treatment of cachexia associated with chronic disease states, and to address loss of muscle mass in the elderly, but nevertheless their efficacy still needs to be demonstrated in terms of improved physical function and quality of life. In sport, these agents are performance enhancers, this being particularly apparent in women, although there is a high risk of virilization despite the favourable myotrophic-androgenic dissociation that many xenobiotic steroids confer. Modulation of androgen receptor expression appears to be key to partial dissociation, with consideration of both intracellular steroid metabolism and the topology of the bound androgen receptor interacting with co-activators. An anticatabolic effect, by interfering with glucocorticoid receptor expression, remains an attractive hypothesis. Behavioural changes by non-genomic and genomic pathways probably help motivate training. Anabolic steroids continue to be the most common adverse finding in sport and, although apparently rare, designer steroids have been synthesized in an attempt to circumvent the dope test. Doping with anabolic steroids can result in damage to health, as recorded meticulously in the former German Democratic Republic. Even so, it is important not to exaggerate the medical risks associated with their administration for sporting or bodybuilding purposes but to emphasize to users that an attitude of personal invulnerability to their adverse effects is certainly misguided.

Figure 1

Testosterone can bind directly with the androgen receptor (AR). In target tissues where intracellular enzymes are present, the action of testosterone is mediated by metabolism. Testosterone is irreversibly converted by the enzyme 5α-reductase to 5α-dihydrotestosterone (DHT), which binds with greater affinity to the androgen receptor (AR), or by aromatase to oestradiol, which binds to the oestrogen receptor (ER). Testosterone and DHT can be also converted to weaker androgens (not displayed), again being dependent on whether the target tissue has the necessary enzyme activity, e.g., 3α-hydroxysteroid dehydrogenase, 17β-hydroxysteroid dehydrogenase.

Figure 2

Structural modifications to the A- and B-rings of testosterone that increase anabolic activity; substitution at C-17 confers oral or depot activity (i.m.). Figure from Kicman and Gower (2003b), a commissioned article by the Analytical Investigations Standing Committee, reproduced with permission from the Association of Clinical Biochemists.

Figure 3

Structures of anabolic–androgenic steroids with corresponding diagnostic metabolites and examples of registered trade names. Superscripts (^1–6) refer to 17β-hydroxyl-esterified preparations: ¹undecylenoate; ²acetate; ³propionate; ⁴heptanoate; ⁵decanoate; ⁶hexahydrobenzylcarbonate. Superscript⁷—see the section on ‘Designer steroids'.

Figure 4

The ‘supplements' (I) dehydroepiandrosterone (DHEA), (II) and (III) androstenedione (Δ4 and 5, versions respectively), (IV) and (V) androstenediol (Δ4 and 5 versions, respectively), (VI) 19-norandrostenedione (only Δ4 version displayed), (VII) 1-testosterone, (VIII) boldione and (IX) prostanozolol.

Figure 5

Catalytic hydrogenation of gestrinone to form tetrahydrogestrinone (THG). An example of a catalyst is palladium on carbon (Pd/C), as described in a procedure employed by Catlin et al. (2004).

Figure 6

In androgenic tissues, nandrolone (19-nortestosterone) is readily converted by the enzyme 5α-reductase into 5α-dihydro-19-nortestosterone, i.e., the double bond between C4 and C5 is reduced. This metabolite binds with weaker affinity to the androgen receptor compared with the parent steroid. Further metabolism can occur because of the high activity of the enzyme 3α-hydroxysteroid-dehydrogenase (which reduces the 3-oxo group) in androgenic tissue. In skeletal muscle, 5α-reductase activity is negligible and, therefore, the parent steroid itself binds with strong affinity to the androgen receptor. It follows that there is a favourable disassociation of the myotrophic effects from the androgenic effects of nandrolone and also that there is a greater myotrophic-to-androgenic ratio when compared with testosterone.

Figure 7

In the absence of hormone, the steroid receptor exists as an inactive oligomeric complex with the molecular chaperone heat-shock protein, Hsp90, and p23, and co-chaperones utilizing tetratricopeptide repeat (TPR) motifs. After hormone binding, the receptor–Hsp90 complex disassociates and the activated receptor is translocated into the nucleus. Activated receptors interact as homodimers with the steroid response element on the chromatin, triggering the formation of a transcription complex, a cluster of coregulators resulting in gene activation, transcription of the gene, protein translation, and a resultant alteration in cell function, growth or differentiation. This figure is redrawn in the own author's style but was based on part of the figure in the article by Weigel and Moore (2007).