Should the Nonaromatizable Androgen Dihydrotestosterone Be Considered as an Alternative to Testosterone in the Treatment of the Andropause?

Extract

How does T work on target organs?

T is a remarkable hormone that has complex mechanisms of action. It may act directly on the nuclear ARs, be converted by the 5α reductase enzymes to metabolites such as 5α dihydrotestosterone (DHT) before acting on the AR, or aromatized to estrogens (E2) that act on the nuclear ERs. The steroid-steroid receptor complex induces transcriptional regulation through the steroid response elements on the promoter region of the target gene. A complex scheme of steroid-specific coactivators and corepressors modulate this transcriptional activity. In addition, T and its metabolites may act on the cell surface in a nuclear receptor-independent fashion to exert acute nongenomic actions. The multiple mechanisms by which T can act provide a high degree of tissue and cellular flexibility and an opportunity to use androgens with selective properties to exert the desired effects.

What about T treatment for the andropause?

It is now generally agreed that male aging is associated with a slow and progressive decrease in serum T concentrations (1–3). The decreases in serum T may be accompanied by a constellation of symptoms including sexual dysfunction, lack of energy, loss of muscle and bone mass, increased frailty, loss of balance, cognitive impairment, and decreased general well being—a condition termed “andropause” or “androgen deficiency of aging men” (2). Some of these clinical symptoms are relieved by replacement therapy with intramuscular T injections or transdermal T applications. Short-term studies have reported that T replacement resulted in variable improvement in sexual function, muscle and bone mass, and quality of life in older men (4–6). In a placebo-controlled randomized clinical trial, a transdermal T patch administered for 3 yr decreased body fat and increased lean body mass but failed to demonstrate significant changes in muscle strength or bone mass. This study has been criticized by some for its design limitations, including its inclusion of men with T levels within the normal range for young healthy men. Nevertheless, the authors provided further analyses demonstrating that bone mass was increased in men with the lower serum T levels and lower pretreatment bone mineral density (7, 8). Unpublished data from another 3-yr placebo-controlled study using T enanthate injections showed significant improvement in body composition and bone mineral density. In these studies, serum prostate-specific antigen (PSA) concentrations and clinical evidence of prostate disease were not different between the placebo- and T-treated groups. In aging men, the benefits of androgen replacement must be weighed against the potential risks (9). The important question of whether chronic T replacement in aging men with partial androgen deficiency will induce prostate cancer or promote conversion of histological to clinically evident prostate cancer remains unanswered. The clinical trials conducted, to date, have insufficient power to address this question.