A role for dihydrotestosterone treatment in older men?

A ndrogens play a vital role in the maintenance of health in normal men. Testosterone supports bone development and strength, provides anabolic effects for maintenance of lean muscle mass, and contributes to normal sexual function and libido. Circulating testosterone concentrations gradually decline as men age, rendering nearly 20% of men biochemically hypogonadal by age 60. Current guidelines recommend androgen replacement, when indicated, using testosterone delivery via injection or transdermally. However, due to a lack of large, long-term clinical trials, the risks of testosterone replacement are not clearly known. Exogenous testosterone can be associated with negative effects, such as polycythemia, and might be associated with prostate growth, such that it is currently contraindicated in men with prostate cancer. Testosterone is metabolized in vivo to both estradiol, via aromatization, and dihydrotestosterone (DHT) via 5a-reduction, both of which are physiologically active. In particular, due to very high concentrations in the prostate, DHT is thought to play an important, yet unclear, role in prostate health. Moreover, DHT is a more potent androgen than testosterone, and might be clinically useful in treating hypogonadism. To determine the effects and safety of exogenous DHT in older men, a group from the ANZAC Research Institute (Australia) recently published a 2year randomized, placebo-controlled trial in the Annals of Internal Medicine entitled, ‘Long-term effects of dihydrotestosterone treatment on prostate growth in healthy, middle-aged men without prostate disease’. Idan and colleagues report results from a comprehensive trial in 114 healthy, eugonadal men who received 2 years of either DHT treatment with a transdermal, pharmacologic dose of 70 mg DHT gel daily, or matching placebo gel. The primary outcome was prostate volume measured by ultrasonography, and secondary outcomes included bone mineral density, body composition, serum lipids and hormones, and quality of life questionnaires. There were no serious adverse events and a high retention rate for such a long study (71% completed all study procedures). As expected, the DHT-treated group had a 10fold increase in serum DHT levels, well above the normal range of circulating DHT, and a concomitant decrease in serum testosterone and estradiol concentrations which were all unchanged in the placebo group. In summary, they report no DHT-specific effects on prostate volume, with both the treatment and placebo groups experiencing a similar increase in prostate volume and prostate specific antigen during the study. Compared to placebo, the DHT group demonstrated a decrease in total body fat mass and in bone mineral density at the spine, but not at the hip, and increased lean body mass, serum hemoglobin and creatinine. Both groups experienced a similar rise in low-density lipoproteins and decline in high-density lipoproteins. None of the quality of life indicators differed between the treatment groups in this eugonadal cohort. DHT is a highly potent, ‘pure androgen’ which cannot be aromatized, yet the authors hypothesized that exogenous DHT would reduce prostate size due to: (i) negative feedback on gonadotropin and testosterone production; and (ii) its metabolism to 3bandrostanediol-5a which has been suggested to inhibit prostate growth. On the other hand, 5a-reducatase inhibitors which block testosterone conversion to DHT clearly decrease prostate volume, presumably by reducing serum and intraprostatic concentrations of DHT. Prior, shorter-term studies of DHT gel in hypogonadal men reported no impact on prostate volume. This study aimed to extend these findings and, if their hypothesis was correct, perhaps provide the basis for a clinical agent that could correct the signs and symptoms of hypogonadism while avoiding costly exacerbations of benign prostatic hypertrophy and prostate specific antigen elevations. The authors definitively demonstrate that high doses of exogenous DHT in healthy eugonadal men, resulting in substantial decreases in serum testosterone, do not change prostate volume or prostate specific antigen compared to placebo. Interestingly, the increase in prostate volume in both groups was remarkably high compared to prior studies. Subjects in this study had an average increase in prostate volume of nearly 30% over 2 years, compared to prior studies showing an average 10% increase in prostate volume over 2 years. The mechanism whereby DHT acts as a ‘prostate-sparing’ androgen is unknown, but may be attributable to the observation that despite substantially raising serum DHT levels, exogenous DHT does not appear to increase intraprostatic androgen concentrations in healthy men (Page ST et al., in press in Journal of Clinical Endocrinology and Metabolism). The extremely high serum levels of DHT achieved in this study lead to significant gonadotropin suppression, thereby reducing circulating testosterone levels to nearly castrate levels and reducing circulating estradiol levels by 90%. The most concerning outcome of this study is the effect of high dose DHT gel on bone mineral density. Over 2 years, the subjects receiving DHT gel had a significant, progressive decrease in bone mineral density at the lumbar spine compared to placebo, despite expected anabolic effects on lean body mass. This effect on bone mineral density is in contrast to the effects of testosterone therapy, with or without a 5a-reductase inhibitor, which increases bone mineral density at the spine and hip when given to hypogonadal men. The negative impact of DHT on bone mineral density in the spine is likely mediated by the marked reduction in serum estradiol University of Washington Medical Center, 1959 NE Pacific St, Box 357138, Seattle, WA 98195, USA Correspondence: Dr MY Roth ([email protected]) Asian Journal of Andrology (2011) 13, 199–20