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

The hormonal basis of vasomotor symptoms (VMS) in hypogonadal men is incompletely understood.

To determine the contributions of testosterone and estradiol deficiency to VMS in hypogonadal men.

Two randomized trials were conducted sequentially between September 2004 and April 2011. Controls were recruited separately.

A single-site academic medical center.

Healthy men ages 20-50, with normal serum testosterone levels.

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.

Incidence of visits with VMS. This was a preplanned secondary analysis.

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.

Estradiol deficiency is the key mediator of VMS in hypogonadal men. At high levels, testosterone may have a suppressive effect.