Short-Term Estrogen Withdrawal Increases Adiposity in Healthy Men

Context: T deprivation increases risk of insulin resistance in men, but whether this risk is independent of changes in body composition is unknown. Further, the metabolic roles of T and its metabolite estradiol have not been clearly defined in men. Objective: This study sought to establish the effects of selective sex steroid withdrawal on insulin sensitivity in healthy men. Design, Setting, and Participants: This was a double-blinded, placebo-controlled, randomized trial at an academic medical center of 56 healthy men, 19–55 years of age. Interventions: Subjects received the GnRH antagonist acyline plus one of the following: placebo gel (Castrate), 1.25 g testosterone gel (Low T/E), 5 g testosterone gel (Normal T/E), or 5 g testosterone gel with letrozole (Normal T/Low E) daily for 4 weeks. Body composition and glucose tolerance were assessed at baseline and end of treatment. Main Outcome Measure: Insulin sensitivity was quantified by the Matsuda index. Results: Predicted circulating sex steroid concentrations were achieved in all treatment groups. The time-by-group interaction for Matsuda index did not achieve significance in overall repeated measures ANOVA (baseline vs week 4; P = .16). A significant time-by-group interaction was observed for fat mass (P = .003), with changes in fat mass attributable predominantly to estrogen exposure in linear regression analysis (P = .016). A time-by-group interaction also was observed for lean mass (P = .03) and influenced by androgen exposure (P = .003). Conclusions: Short-term sex steroid withdrawal in healthy men causes adverse changes in body composition. These findings support the role of estradiol as a determinant of adiposity in men. Body composition and glucose tolerance were assessed in healthy men before and after short-term sex steroid withdrawal. Changes in body composition were due to both estrogen and androgen deprivation.