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

Abstract

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. 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 Unpublished data from another 3-yr placebo-controlled study using T enanthate injections showed significant improvement in body composition and bone mineral density.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. The natural potent androgen DHT is a selective androgen because it cannot be aromatized to estrogens. DHT binds to ARs more avidly than T. DHT is the product of conversion from T through the 5α reductase enzymes 1 and 2. Different tissues have different amounts of these two enzymes and, thus, can create local tissue environments that are low or high in DHT concentrations. The phenotypic appearance of men with congenital 5α reductase 2 deficiency has demonstrated the critical role DHT exerts on major androgen target tissues such as the external genitalia, prostate, and skin (10–12). Men with this congenital enzyme deficiency have very small prostate glands and ambiguous external genitalia but increase muscle mass at puberty and are not osteoporotic. Because the concentrations of DHT in the prostate are higher than that of T in normal men, it is generally believed that intraprostatic DHT may be the relevant androgen for stimulating prostate gland growth and development. Recognizing that T stimulates prostate growth, congenital 5α reductase 2 deficiency results in poor prostate development, and 5α reductase inhibitors administered to adult men with benign prostatic hyperplasia reduce prostate size, one might speculate that DHT administration might be a more potent prostate-stimulating pharmacological agent than its precursor T. It would seem paradoxical, therefore, to suggest that DHT might be used as a selective androgen that might exert androgenic effects with relatively less prostate stimulation. The observations suggesting that administered DHT may be relatively prostate sparing and the possible mechanisms for such a proposal will be discussed further. Designer androgens with selective androgen receptor modulating (SARM) effects are under development. One goal of SARM development is to obtain steroidal or nonsteroidal compounds that have potent androgenic effects on muscles, bone, and probably also on the brain, but with minimal effects on the prostate and lipids. An androgen that cannot be 5α-reduced but can undergo aromat