Testosterone and estrogen exert independent effects in the pathogenesis of male hypogonadism

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1. In men, androgen deficiency was associated with decreases in lean body mass, muscle size, and strength while estrogen deficiency led to increases in body fat. Both appear to regulate sexual function in men. 

2. The level of testosterone required to maintain lean body mass, fat mass, strength, and sexual function varied widely in men. 

Evidence Rating Level: 1 (Excellent) 

Study Rundown: Male hypogonadonism is associated with decreases in levels of both testosterone and estrogen. While low levels of estrogen have been shown to contribute to decreases in bone density, its other function in the pathogenesis of hypogonadonism is not well understood. This study demonstrated that estrogen and testosterone exert specific effects in the maintenance of male physiology. Their findings suggest that therapies designed to increase levels of estradiol may be more suitable for certain patients. In addition, current testosterone therapies do not take into account differences in levels of testosterone required to maintain various male characteristics.  Better understanding of the effect of gonadal steroids at varying levels would allow clinicians to target treatment to meet the needs of individual patients.

The study was limited to 16 weeks and thus, may not account for long term changes in body composition. The study simulated gonadal steroid deprivation in an acute setting, which may produce different effects as those resulting from a slow decline in steroid production. Additional studies of longer duration are needed to further assess these changes.

Click to read the study published today in NEJM

Click to read the accompanying editorial in NEJM

Relevant Reading: Measures of bioavailable serum testosterone and estradiol and their relationships with muscle strength, bone density, and body composition in elderly men

In-Depth [randomized, controlled trial]: This study was a single-blinded randomized controlled trial of healthy males who were 20 to 50 years of age. All participants received goserelin acetate to suppress endogenous gonadal steroids and patients in a second cohort also received anastrozole to block the conversion of testosterone to estrogen. Participants in both cohorts were randomly assigned to receive placebo or 1.25 g, 2.5 g, 5 g, or 10 g of testosterone. In both cohorts, sexual desire decreased with declining testosterone doses. In the cohort receiving anastrozole, there was a significant decrease in total body lean mass, thigh-muscle area, and leg-press strength in participants receiving placebo as compared to those receiving testosterone, implying independent effects of testosterone. Comparisons of outcomes between the two cohorts found significant differences in body fat percentage (P=0.001), intraabdominal-fat area (P=0.021), subcutaneous-fat area (P = 0.029), sexual desire (P = 0.045), and erectile function (P = 0.032). These findings indicate the independent effect of estradiol on these variables.

By Xu Gao and Adrienne Cheung

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