Testosterone With and Without a 5alpha Reductase Inhibitor on Fat-Free Mass

[Michael Scally MD]

5?-dihydrotestosterone (DHT) is a potent metabolite of testosterone; its role in postembryonic life remains poorly understood. At least 2 isoenzymes of steroid 5?-reductase convert testosterone to DHT in humans. In marsupials and possibly in humans, DHT also can be produced from other substrates via 1 or more alternate pathways. Studies of the kindred with steroid 5?-reductase 2 mutations and mice with genetic or pharmacological disruption of steroid 5?-reductase enzymes suggest that DHT serves an important role in the formation of prostate and phallus.

An improved understanding of the role of steroid 5?-reductases has important clinical implications. Pharmacological inhibitors of steroid 5?-reductases are used to treat benign prostatic hyperplasia and androgenic alopecia, disorders of middle-aged and older men, who are at risk of reduced muscle mass and sexual dysfunction. Similarly, nonsteroidal selective androgen receptor modulators (SARMs) currently in development do not undergo 5?-reduction. Therefore, the safety of 5?-reductase inhibitors and nonsteroidal SARMs is predicated upon the supposition that 5?-reduction is not essential for mediating androgen's effects on muscle mass and strength and on sexual function.

Sexual dysfunction has been reported as an adverse event in clinical trials of 5?-reductase inhibitors in men with benign prostatic hyperplasia, who have high background rates of sexual dysfunction. However, it has been debated whether sexual dysfunction in older men receiving 5?-reductase inhibitors is causally related to these drugs and whether DHT is required for optimal erectile function. Similarly, the role of DHT in mediating androgenic effects on sebum production, bone markers, and levels of hematocrit, hemoglobin, and lipids in men remains unclear.

The primary objective of this study was to determine whether 5?-reduction of testosterone to DHT is obligatory for mediating its effects on fat-free mass. Secondary objectives were to determine whether 5-? reduction of testosterone is necessary for the maintenance of androgen effects on sexual function, hematocrit, sebum production, bone markers, and lipid levels in men. Accordingly, they determined the responsiveness of these androgen-dependent outcomes in healthy men, in whom endogenous testosterone production had been suppressed by administration of a gonadotropin-releasing hormone agonist, to graded doses of testosterone in the absence and presence of dutasteride, a potent dual inhibitor of type 1 and type 2 5?-reductase isoenzymes.

Several models have been invoked to explain the role of DHT in men. A widely held view is that conversion to DHT is obligatory for mediating testosterone's effects in some tissues with high 5?-reductase activity, such as prostate and skin, but not in others, such as skeletal muscle and bone. It is possible that conversion of testosterone to DHT is not obligatory, but that it amplifies the effects of testosterone in tissues with high 5?-reductase activity such as the prostate and skin, but not in tissues with low 5?-reductase activity such as skeletal muscle and bone. A third possibility is that 5?-reduction of testosterone is not obligatory for mediating its effects in any tissue in men, but that testosterone and DHT can both exert androgenic effects in all androgen-sensitive tissues, and their relative effects in any tissue are contingent upon their relative concentrations and potency.

The finding that 5?-reduction of testosterone to DHT is not obligatory for mediating its effects on outcomes that were studied in this trial has implications for therapeutic applications of androgens and 5?-reductase inhibitors. These findings bode well for the safety of 5?-reductase inhibitors with respect to their effects on muscle. Combined administration of testosterone plus a 5?-reductase inhibitor and the use of SARMs that do not undergo 5?-reduction have been proposed as strategies for mitigating concerns about androgen's effects on the prostate. While their data suggest that SARMs that do not undergo 5?-reduction can exert anabolic effects on the muscle, they also indicate that such a strategy may not necessarily be effective in sparing the prostate, depending upon androgen dose. The prostate safety of such SARMs will need careful scrutiny. Their data also predict that efficacy of 5?-reductase inhibitors may be limited in men with normal or high testosterone concentrations; therefore, measurement of testosterone levels might be useful in identifying men less likely to respond to 5?-reductase inhibitors.


Bhasin S, Travison TG, Storer TW, et al. Effect of Testosterone Supplementation With and Without a Dual 5?-Reductase Inhibitor on Fat-Free Mass in Men With Suppressed Testosterone Production. JAMA: The Journal of the American Medical Association;307(9):931-9. Effect of Testosterone Supplementation With and Without a Dual 5?-Reductase Inhibitor on Fat-Free Mass in Men With Suppressed Testosterone Production, March 7, 2012, Bhasin et al. 307 (9): 931 — JAMA

Context Steroid 5?-reductase inhibitors are used to treat benign prostatic hyperplasia and androgenic alopecia, but the role of 5?-dihydrotestosterone (DHT) in mediating testosterone's effects on muscle, sexual function, erythropoiesis, and other androgen-dependent processes remains poorly understood.

Objective To determine whether testosterone's effects on muscle mass, strength, sexual function, hematocrit level, prostate volume, sebum production, and lipid levels are attenuated when its conversion to DHT is blocked by dutasteride (an inhibitor of 5?-reductase type 1 and 2).

Design, Setting, and Patients The 5?-Reductase Trial was a randomized controlled trial of healthy men aged 18 to 50 years comparing placebo plus testosterone enthanate with dutasteride plus testosterone enanthate from May 2005 through June 2010.

Interventions Eight treatment groups received 50, 125, 300, or 600 mg/wk of testosterone enanthate for 20 weeks plus placebo (4 groups) or 2.5 mg/d of dutasteride (4 groups).

Main Outcome Measures The primary outcome was change in fat-free mass; secondary outcomes: changes in fat mass, muscle strength, sexual function, prostate volume, sebum production, and hematocrit and lipid levels.

Results A total of 139 men were randomized; 102 completed the 20-week intervention. Men assigned to dutasteride were similar at baseline to those assigned to placebo. The mean fat-free mass gained by the dutasteride groups was 0.6 kg (95% CI, ?0.1 to 1.2 kg) when receiving 50 mg/wk of testosterone enanthate, 2.6 kg (95% CI, 0.9 to 4.3 kg) for 125 mg/wk, 5.8 kg (95% CI, 4.8 to 6.9 kg) for 300 mg/wk, and 7.1 kg (95% CI, 6.0 to 8.2 kg) for 600 mg/wk. The mean fat-free mass gained by the placebo groups was 0.8 kg (95% CI, ?0.1 to 1.7 kg) when receiving 50 mg/wk of testosterone enanthate, 3.5 kg (95% CI, 2.1 to 4.8 kg) for 125 mg/wk, 5.7 kg (95% CI, 4.8 to 6.5 kg) for 300 mg/wk, and 8.1 kg (95% CI, 6.7 to 9.5 kg) for 600 mg/wk. The dose-adjusted differences between the dutasteride and placebo groups for fat-free mass were not significant (P = .18). Changes in fat mass, muscle strength, sexual function, prostate volume, sebum production, and hematocrit and lipid levels did not differ between groups.

Conclusion Changes in fat-free mass in response to graded testosterone doses did not differ in men in whom DHT was suppressed by dutasteride from those treated with placebo, indicating that conversion of testosterone to DHT is not essential for mediating its anabolic effects on muscle.

 

[Michael Scally MD]

Gruntmanis U. The Role of 5?-Reductase Inhibition in Men Receiving Testosterone Replacement Therapy. JAMA: The Journal of the American Medical Association 2012;307(9):968-70. The Role of 5?-Reductase Inhibition in Men Receiving Testosterone Replacement Therapy, March 7, 2012, Gruntmanis 307 (9): 968 — JAMA

Testosterone has a variety of well-known effects including bone accrual, building and maintaining muscle mass, and promoting erectile function and libido. Of the 5 mg of testosterone manufactured daily by the testes, about 6% to 8% is metabolized by 5?-reductase to make 0.3 mg of dihydrotestosterone (DHT). Local conversion of testosterone to DHT by 5?-reductase in the skin and prostate can create locally high concentrations of the potent androgen DHT. Dihydrotestosterone stimulates prostate growth and may promote scalp hair loss. 5?-Reductase inhibition is the principal treatment for benign prostatic hypertrophy but the ramifications of treatment with drugs that inhibit this enzyme on the effects of androgen on the many tissues it influences is incompletely understood.

This uncertainty exists because research exploring the role of testosterone and DHT on different tissues has been confounded by complex hormonal interactions typical of replacement or inhibitor studies. When the 5?-reductase inhibitors finasteride or dutasteride are administered, levels of plasma DHT decrease whereas levels of testosterone and estradiol increase. When exogenous testosterone is administered, plasma levels of testosterone, DHT, and estradiol increase. If DHT is administered, plasma testosterone levels decrease. Changes in the various hormone levels resulting from physiological regulatory systems have made it difficult to isolate the role of testosterone or DHT alone on muscle, bone, prostate, and other androgen-dependent tissues in adult men.

The study by Bhasin et al reported in this issue of JAMA provides information to better understand the potential roles of testosterone and DHT. The investigators performed a meticulously designed and executed study to answer an almost 5-decades-old question: are testosterone, DHT, or both in physiological and supraphysiological levels important in the gain of lean body mass? The study was designed to minimize the effects of physiological responses to exogenous testosterone by first blocking endogenous testosterone production by pretreatment of eugonadal men with gonadotropin-releasing hormone agonists. This caused complete suppression of endogenous testosterone, making individual men in each testosterone replacement therapy dose group as comparable as possible in regard to their testosterone and DHT levels. To control for endogenous DHT production, a group of men were randomly selected to receive a large dose of the 5?-reductase inhibitor dutasteride.

The study by Bhasin et al selectively evaluating the effects of testosterone and DHT is important because of 3 common clinical scenarios. The first pertains to men with prostatic hyperplasia treated with 5?-reductase inhibitors. Prostatic hyperplasia is highly prevalent, affecting 40% to 50% of men aged 51 to 60 years and more than 80% of men older than 80 years.7 When these men are treated with finasteride or dutasteride, plasma DHT levels decline by 60% to 95% and testosterone levels increase by 15% to 22%. The intraprostatic concentrations of DHT and testosterone change by similar proportions. Reduced intraprostatic DHT likely causes shrinkage of hyperplastic prostate tissue.

However, bone does not seem to be affected significantly by 5?-reductase inhibitors. Markers of bone turnover and bone mineral density do not change with the use of these agents, and the use of finasteride is not associated with increased fracture risk, suggesting that DHT has little effect on bone. Body mass is slightly decreased by finasteride, particularly among men who have low testosterone levels before starting treatment. However, sexual dysfunction is slightly more common in men using 5?-reductase inhibitors, but disentangling the hormonal effect from aging alone has proven difficult.

A second common clinical scenario involving the relationship between testosterone and DHT relates to treatment of hypogonadal men. In the Massachusetts Male Aging Study, 20% of men were found to be biochemically hypogonadal by the age of 60 years. Hypogonadism has driven a marked increase in the use of testosterone replacement therapy with the number of prescriptions in the United States increasing from 692 000 in 2000 to 2.66 million in 2008. Despite this increase in use, the long-term risks and benefits of testosterone replacement therapy are unknown. Currently, testosterone replacement therapy can be recommended to symptomatic men (eg, those with sexual dysfunction, impotence, or decreased energy) who have low serum testosterone levels, have no contraindications to such therapy, and understand that the benefits and risks of testosterone therapy beyond 3 years have not been studied.

Short-term testosterone replacement therapy in men increases plasma testosterone and DHT levels resulting in increased bone mineral density, reduced fat-free mass, and improved sexual function. Because skin expresses high 5?-reductase activity, testosterone gel applied to the skin achieves much higher DHT levels than a comparable dose of testosterone enanthate. Levels of testosterone and DHT in prostate tissue do not change with testosterone replacement therapy, yet testosterone replacement therapy increases prostate volume in most studies of hypogonadal men. However, according to a meta-analysis, there were no significant changes in prostate-specific antigen levels or in the International Prostate Symptom Score for urinary obstruction among men receiving testosterone replacement therapy short term.

In contrast to testosterone replacement, DHT replacement in men increases plasma DHT levels but decreases testosterone levels; however, there is no change in levels of prostate tissue with use of these hormones, and prostate volume does not increase. Dihydrotestosterone replacement results in decreased fat mass and reduced spinal bone mineral density but does not change lean body mass.

A third common clinical scenario likely involves the relatively large group of men for whom a 5?-reductase inhibitor is prescribed together with testosterone replacement due to the coexistence of prostate hyperplasia and symptomatic hypogonadism. Short-term studies of these combinations have shown that bone mineral density, bone turnover markers, lean body mass, and fat mass did not differ between men receiving testosterone replacement therapy with or without finasteride use. However, patients receiving exogenous testosterone and finasteride had significantly lower increases in prostate volume than those who did not receive 5?-reductase inhibition. Yet, given the complex interactions between the various forms of androgens and its metabolites, none of the above observations can definitively show if both testosterone and DHT are obligatory, nonobligatory, or perhaps serve as amplifiers to each other in adults.

The main outcome of the study by Bhasin et al was that there was no statistically significant difference in fat-free mass between groups of men who did (n = 48) or did not (n = 54) receive a high dose of dutasteride (2.5 mg/d) regardless of dose of testosterone enanthate, administered for 20 weeks. Participants of the study received 50, 125, 300, or 600 mg of testosterone per week. The mean fat-free mass gained by the dutasteride groups was 0.6 kg (95% CI, ?0.1 to 1.2 kg) when receiving 50 mg/wk of testosterone enanthate, 2.6 kg (95% CI, 0.9 to 4.3 kg) for 125 mg/wk, 5.8 kg (95% CI, 4.8 to 6.9 kg) for 300 mg/wk, and 7.1 kg (95% CI, 6.0 to 8.2 kg) for 600 mg/wk. The mean fat-free mass gained by the placebo groups was 0.8 kg (95% CI, ?0.1 to 1.7 kg) when receiving 50 mg/wk of testosterone enanthate, 3.5 kg (95% CI, 2.1 to 4.8 kg) for 125 mg/wk, 5.7 kg (95% CI, 4.8 to 6.5 kg) for 300 mg/wk, and 8.1 kg (95% CI, 6.7 to 9.5 kg) for 600 mg/wk.

The main clinical message from the study by Bhasin et al is that for patients receiving exogenous testosterone, the gain in muscle mass was not affected by concurrent 5?-reductase inhibition. Because the study was not powered to detect differences in other clinically important outcomes, conclusions regarding changes in fat mass, muscle strength, hematocrit level, sebum production, or serum lipid levels resulting from these drugs cannot be definitively made. Future studies should address these important secondary outcomes, and by doing so, will provide clinicians with additional useful information to better understand the risks and benefits of 5?-reductase inhibition and testosterone replacement therapy.