Relationship Between Testosterone Levels, Insulin Sensitivity, and Mitochondrial Function in Men

Response to Pitteloud et al.

We read with interest the excellent study by Pitteloud et al. (1) demonstrating that low serum total testosterone levels are associated with an adverse metabolic profile in aging men and suggesting a novel unifying mechanism for the previously independent observations that low testosterone levels and impaired mitochondrial function promote insulin resistance in these patients. The authors concluded their report by stating that there is a need for evaluation of the potential benefits of androgen supplementation in preventing or treating the metabolic syndrome and/or type 2 diabetes in men.

While we agree with their conclusion, we would like to provide the authors with a cautionary comment regarding the means by which androgen levels should be supplemented in these patients. The most commonly used method to increase androgen levels in aging, hypogonadal men is to administer testosterone supplementation therapy (2). From a urological perspective, a major problem with the use of testosterone supplementation alone in aging men is that the exogenously administered testosterone is metabolized by 5α-reductase to dihydrotestosterone (DHT). Based on newly emerging data from the National Cancer Institute–sponsored Prostate Cancer Prevention Trial, DHT is a proven risk factor for the development of prostate cancer in aging men (3). Moreover, the use of testosterone supplementation alone in men with low serum testosterone levels has been shown to lead to an elevation in their intraprostatic DHT levels (4).

In light of the potentially serious safety concerns associated with the use of testosterone supplementation alone in aging men, we respectfully suggest that the authors consider using androgen supplement treatment strategies that avoid the potential problems associated with the 5α-reduction of testosterone to DHT. A simple, safe, and effective treatment option in this regard may be to coadminister a 5α-reductase inhibitor as adjunctive therapy with a testosterone supplement. Such an approach would prevent the DHT elevation associated with testosterone supplementation, while still allowing for testosterone to exert its beneficial metabolic and anthropometric effects. We and others have extensively studied the use of 5α-reductase inhibitors in the treatment of aging men with benign prostatic hyperplasia (5); these drugs are well tolerated and have been shown to markedly suppress the reduction of testosterone to DHT.