Biopharmacology of Testosterone

Biopharmacology of Testosterone

Testosterone, the primary male sex hormone, is manufactured in the testes under the influence of luteinizing hormone (LH) in amounts of 2.5-11 mg/d.[4] Testosterone is produced under a negative feedback loop between the hypothalamus, the anterior pituitary, and the testes. Testosterone, dihydrotestosterone, and estrogen all act at the hypothalamus to exert negative feedback inhibition upon gonadotropin-releasing hormone (GnRH). Since GnRH stimulates follicle-stimulating hormone (FSH) and LH release in the pituitary, this negative feedback can be seen to inhibit subsequent testosterone production and effect spermatogenesis.

Testosterone activity is mediated via an androgen receptor that is present in various tissues throughout the human body. Testosterone binds to an intracellular receptor found in the cytosol of cells, forming a receptor complex that migrates into the nucleus, where it binds to specific deoxyribonucleic acid (DNA) segments. This, in turn, activates specific messenger ribonucleic acid (mRNA) to increase transcription, leading to an increased rate of protein synthesis; in the case of muscle cells, this means increased production of the proteins actin and myosin. After this process is complete, the receptor complex dissociates and is recycled along with the hormone, to repeat this process multiple times prior to metabolism.

These anabolic actions of testosterone are thought to be primarily due to testosterone acting upon the androgen receptor in anabolic-responsive tissues. Androgenic effects are likely mediated via the same androgen receptor in androgen-responsive tissues under the influence of dihydrotestosterone (DHT), which is produced by the interaction of 5-alpha reductase (5AR) with testosterone and the subsequent reduction of the C4-5 double bond. Additionally, DHT cannot undergo further reduction, nor is it a substrate for aromatase; thus, it is not converted to estrogenic metabolites. DHT has been shown to bind avidly to receptors in tissues, such as skin, scalp, and prostate, and to exert 3-4 times the androgenic effect of testosterone. Thus, the primary hormone mediating the androgenic effects of testosterone is actually the 5-alpha reduced DHT.

Other mechanisms of direct and indirect anabolic effects include anti-glucocorticoid activity mediated by displacement of glucocorticoids from their receptor,[5] increases in the creatine phosphokinase activity in skeletal muscle,[6] and increases in circulating insulinlike growth factor (IGF)–1,[7] as well as up-regulation of IGF-1 receptors.[8] These mechanisms may play a much larger role in the anabolic/anticatabolic actions of anabolic-androgenic steroids (AASs) than once thought. At physiologic testosterone levels, nearly all androgen receptors are engaged. Therefore, supraphysiologic doses of testosterone or AASs would have no increased anabolic effect in healthy athletes unless other mechanisms of action existed.

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