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Sex steroid deprivation adversely affects body composition in healthy men
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Adverse changes in body composition in healthy men may be caused by short-term sex steroid withdrawal.
“This study demonstrates that significant body composition changes occur in healthy, eugonadal men after only 4 weeks of sex steroid deprivation,” the researchers wrote. “Significant changes in fat mass were observed and attribution to estrogen withdrawal.”
Stephanie T. Page, MD, PhD, of the division of metabolism, endocrinology and nutrition in the department of medicine at the University of Washington in Seattle, and colleagues evaluated 45 healthy men (median age, 36 years; median BMI, 25 kg/m2) to determine the effects of selective sex steroid withdrawal on insulin sensitivity.
Stephanie T. Page
Participants received acyline, a gonadotropin-releasing hormone and were randomly assigned to one of the following: placebo gel (n = 10), 1.25 g testosterone gel (AndroGel, AbbVie Inc.; n = 11; low testosterone group), 5 g testosterone gel (n = 11; normal testosterone group) or 5 g testosterone gel with letrozole (n = 13; normal testosterone plus letrozole group) for 4 weeks. Study visits were conducted at baseline and at 2, 4 and 10 weeks. The Matsuda index was used to quantify insulin sensitivity.
During the treatment period, there were no differences in insulin resistance (P = .16 in overall repeated measure analysis of variance [RM-ANOVA]), time-by-group interaction for insulin sensitivity (P = .14 in overall RM-ANOVA) or pancreatic beta-cell function (P = .66 in overall RM-ANOVA) between the treatment groups.
Over the treatment period, body weight remained stable for all treatment groups whereas significant differences were observered in the change in fat mass over time (P = .003 in overall RM-ANOVA). Between baseline and week 4, fat mass increased significantly in the placebo group (+1.1 kg; P = .004); there were smaller increases in the low testosterone (+0.7 kg) and the normal testosterone plus letrozole groups (+0.5 kg) and no change in the normal testosterone group.
Between baseline and week 4, significant differences in lean mass were observed across the groups (P = .03 in overall RM-ANOVA). Significant decreases in lean mass between baseline and week 4 were found in the placebo group (=1.2 kg; P = .003) and the low testosterone group (-1.4 kg; P = .01) whereas lean mass was unchanged in the other two groups.
Between baseline and week 4, changes in serum estradiol were a significant determinant of changes in fat mass (P = .016), and changes in serum testosterone levels were related to changes in lean mass (P = .003).
“Our findings indicate that even a very brief period of sex steroid deprivation causes metabolic perturbations characterized predominantly by increased adiposity without changes in body weight,” the researchers wrote. “Changes in body composition are apparent with partial as well as complete sex steroid withdrawal, and findings fail to demonstrate body composition-independent effects of sex steroid deprivation on insulin insensitivity.
Disclosure: Page reports receiving drug supplies for an investigator-initiated study from Besins Healthcare.
Perspective
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Sundeep Khosla
The traditional notion had been that estrogen was predominantly, perhaps exclusively, important in women whereas testosterone played the analogous role in men. This was first challenged by findings more than 15 years ago using sex steroid withdrawal and selective replacement with estrogen vs. testosterone that, in fact, estrogen was the dominant regulator of bone turnover in men (Falahati-Nini A, et al. J Clin Invest. 106:1553-1560). Using an analogous study design, a more recent study conclusively demonstrated that over 16 weeks, sex steroid deficiency in otherwise healthy men led to increases in body fat mass and decreases in lean mass (Finkelstein JS, et al. N Engl J Med. 363;1011-1022). Interestingly, the increases in fat mass were due to estrogen deficiency, whereas the decreases in lean mass were due to testosterone deficiency.
The current paper by Chao and colleagues extends these data and shows that the changes in body composition following sex steroid deficiency occur as early as 4 weeks and may not be fully reversible, at least over 6 weeks of follow up. Thus, the collective data now demonstrate that estrogen is a dominant regulator in men of bone turnover and fat mass, whereas testosterone regulates lean/muscle mass. In terms of the body composition changes, the clinical implications are that physicians should consider these changes for the long-term health of their patients undergoing androgen deprivation therapy, or otherwise hypogondal men who are incompletely replaced with testosterone (and via aromatization, estrogen).
Even though Chao and colleagues could not clearly demonstrate concomitant changes in insulin sensitivity, there are other data demonstrating increased insulin resistance with hypogonadism, so these body composition changes may well translate into metabolic dysfunction and increased diabetes risk. If sex steroid replacement is not an option (eg, for the treatment of prostate cancer), other lifestyle changes, such as diet and exercise, may attenuate the adverse effects of sex steroid deficiency on body composition. In the longer term, development of compounds (eg, new selective estrogen receptor modulators or selective androgen receptor modulators) that offset these body composition and perhaps metabolic and skeletal changes is clearly an important priority.
Disclosure: Khosla reports no relevant financial disclosures.
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