Treatment with a 5-alpha reductase inhibitor did not adversely affect fat-free mass in healthy men given varying doses of testosterone, a randomized trial showed.
Mean fat-free mass increased by 0.6 to 7.1 kg over 20 weeks in men taking dutasteride (Avodart) and different doses of testosterone enanthate. Men treated with placebo and testosterone gained an average of 0.8 to 8.1 kg in fat-free mass.
Muscle strength, sexual function, and prostate volume also did not differ significantly between treatment groups, as reported in the March 7 issue of the Journal of the America Medical Association.
"The finding that 5α-reduction of testosterone to DHT [dihydrotestosterone] is not obligatory for mediating its effects on outcomes that were studied in this trial has implications for therapeutic applications of androgens and 5α-reductase inhibitors," Shalender Bhasin, MD, of Boston University, and co-authors wrote. "These findings bode well for the safety of 5α-reductase inhibitors with respect to their effects on muscle."
Steroid 5α-reductase inhibitors have evolved into a principal treatment for benign prostatic hyperplasia (BPH) and androgenic alopecia, disorders that primarily affect middle-age and older men, the authors noted.
DHT is the principal metabolite of testosterone, but its role in human development remains poorly understood. Preclinical studies and clinical investigations of kindred with 5α-reductase mutations have suggested DHT has a major role in development of the prostate and phallus.
Middle-age and older men also are at risk of reduced muscle mass and sexual dysfunction, conditions that benefit from testosterone supplementation in men with low testosterone levels.
Nonsteroidal selective androgen receptor modulators (SARMs) currently in development do not undergo 5α-reduction. The safety of SARMs and 5α-reductase inhibitors is based on the assumption that DHT is not necessary for mediating androgen's effects on muscle mass, strength, and sexual function, the authors continued.
Uncertainty also surrounds the role of DHT in mediating androgen's effects on sebum production, bone markers, hematocrit, hemoglobin, and lipids in men.
To address the unresolved questions, Bhasin and colleagues performed a randomized clinical trial to determine whether 5α-reduction of testosterone to DHT is necessary to mediate the androgen's effects on fat-free mass. Secondarily, the investigators examined the role of 5α-reduction on sexual function, hematocrit, sebum production, bone markers, and lipid levels.
The study involved healthy men, ages 18 to 50, all of whom had normal testosterone levels. The men were randomized 2:1 to dutasteride or placebo plus testosterone enanthate at doses ranging from 50 to 600 mg weekly.
Because 5α-reductase inhibitors increase testosterone levels, all men received a long-acting gonadotropin-releasing hormone agonist to suppress endogenous testosterone. The graded testosterone doses resulted in different levels of circulating testosterone.
The primary endpoint was the change in fat-free mass after 20 weeks, as determined by dual-energy x-ray absorptiometry.
The final analysis included 139 men, who had a mean age of 37.6, mean body mass index of 26.3, and mean fat-free mass of 62.7 kg.
At the end of the study, the mean testosterone level exhibited similar dose-related increases (519 to 3,898 ng/dL in the dutasteride arm and 385 to 3,578 ng/dL in the placebo group. Fat-free mass increased with testosterone dose and did not differ significantly between treatment groups.
Muscle strength, as determined by leg-press and chest-press exercises, increased with testosterone dose and did not differ between treatment groups. Scores on the International Index of Erectile Function also showed no differences in any parameters of sexual function.
Prostate volume and PSA level did not correlate with testosterone dose or concentration and did not differ significantly between the placebo and dutasteride groups.
Sebum production, acne, hemoglobin, hematocrit, and bone-turnover markers also did not differ between the treatment groups.
"While our data suggest that SARMs that do not undergo 5α-reduction can exert anabolic effects on the muscle, they also indicate that such a strategy may not necessarily be effective in sparing the prostate," the authors wrote.
"Our data also predict that efficacy of 5α-reductase inhibitors may be limited in men with normal or high testosterone concentrations," they added. "Therefore, measurement of testosterone levels might be useful in identifying men less likely to respond to 5α-reductase inhibitors."
The results should reassure physicians and patients concerned about potential adverse effects of 5α-reductase inhibitors on muscle mass, said Louis Kavoussi, MD, chair of urology at North Shore-Long Island Jewish Health System in Lake Success, N.Y.
"DHT causes prostate cells to grow, and removing this from cells causes them to shrink," Kavoussi told MedPage Today in a email. "A concern has been that this form of testosterone may be important in other areas of men's health, such as muscle mass and sexual function. This study shows that muscle mass is not affected.
"Of note, 5α-reductase inhibitors will decrease the amount of ejaculate fluid and in a small percentage of men will affect sex drive. Men must note that if they have very high testosterone levels or take testosterone replacement, the 5α-reductase inhibitors will not work in shrinking the prostate," he said.
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