Effects of Testosterone and Estradiol Deficiency on Vasomotor Symptoms in Hypogonadal Men

Context: The hormonal basis of vasomotor symptoms (VMS) in hypogonadal men is incompletely understood. Objective: To determine the contributions of testosterone and estradiol deficiency to VMS in hypogonadal men. Design: Two randomized trials were conducted sequentially between September 2004 and April 2011. Controls were recruited separately. Setting: A single-site academic medical center. Participants: Healthy men ages 20-50, with normal serum testosterone levels. Intervention: Cohort 1 (n = 198, 81% completion) received goserelin acetate every 4 weeks to suppress gonadal steroids and were randomized to placebo or 1.25, 2.5, 5, or 10 g of testosterone gel daily for 16 weeks. Cohort 2 (n = 202, 78% completion) received the same regimen as cohort 1 plus anastrozole to block aromatization of testosterone. Controls (n = 37, 89% completion) received placebos for goserelin acetate and testosterone. Main Outcome Measures: Incidence of visits with VMS. This was a preplanned secondary analysis. Results: VMS were reported at 26% of visits in cohort 1, and 35% of visits in cohort 2 (P = .02), demonstrating an effect of estradiol deficiency. When adjacent estradiol level groups in cohort 1 were compared, the largest difference in VMS incidence was observed between the 5-9.9 and 10-14.9 pg/mL groups (38% vs 16%, P = .001). In cohort 2, the 10-g testosterone group differed significantly from placebo(16% vs 43%, P = .048) after adjustment for small differences in estradiol levels, indicating that high testosterone levels may suppress VMS. Conclusions: Estradiol deficiency is the key mediator of VMS in hypogonadal men. At high levels, testosterone may have a suppressive effect.