Vasomotor symptoms in men with hypogonadism may be mediated be estradiol deficiency and high levels of testosterone may suppress the effects, according to study findings published in The Journal of Clinical Endocrinology & Metabolism.
Joel S. Finkelstein, MD
of the department of medicine at Massachusetts General Hospital in Boston, and colleagues conducted two randomized trials between September 2004 and April 2011 on men aged 20 to 50 years with normal testosterone levels to determine the contributions of testosterone and estradiol deficiency to vasomotor symptoms in men with hypogonadism. The primary outcome was incidence of visits with vasomotor symptoms. Participants were from a single-setting academic medical center.
In the first cohort, 198 men received Zoladex 3.6 mg subcutaneously (goserelin acetate, AstraZeneca) every 4 weeks to suppress gonadal steroids and were randomly assigned to placebo or 1.25 g, 2.5 g, 5 g or 10 g of AndroGel (1% topical testosterone gel, AbbVie) daily for 16 weeks. In the second cohort, 202 men received the same regimen as the first cohort plus Arimidex 1 mg daily (anastrozole, AstraZeneca) to block aromatization of testosterone. Thirty-seven controls received placebos for goserelin acetate and testosterone. All participants were seen every 4 weeks for 16 weeks.
In cohort 1, mean testosterone levels were 44 ng/dL in the group receiving goserelin and 0 g testosterone, 191 ng/dL in the group receiving 1.25 g testosterone, 337 ng/dL in the group receiving 2.5 g testosterone, 470 ng/dL in the group receiving 5 g testosterone and 788 ng/dL in the group receiving 10 g testosterone; mean estradiol levels were 3.6 pg/mL, 7.9 pg/mL, 11.9 pg/mL, 18.2 pg/mL and 33.3 pg/mL, respectively, from weeks 4 through 16.
In cohort 2, mean testosterone levels were 41 ng/dL in the group receiving 0 g testosterone, 231 ng/dL in the group receiving 1.25 g, 367 in the group receiving 2.5 g, 485 in the group receiving 5 g and 924 in the group receiving 10 g; mean estradiol levels were 1 pg/mL, 1.2 pg/mL, 2 pg/mL, 2.1 pg/mL and 2.8 pg/mL, respectively, from weeks 4 through 16. In controls, mean serum testosterone was 589 ng/dL and mean serum estradiol level was 28.8 pg/mL from weeks 0 through 16.
Twenty-six percent of visits in cohort 1 and 35% of visits in cohort 2 had vasomotor symptoms reported, demonstrating an effect of estradiol deficiency (P = .02); 4% of control visits had vasomotor symptoms reported.
The largest difference in vasomotor symptoms in cohort 1 was observed between the 5 pg/mL and 9.9 pg/mL estradiol levels and 10 pg/mL and 14.9 pg/mL estradiol levels when adjacent estradiol levels were compared (P < .001). After adjustment for small differences in estradiol levels, the 10-g testosterone group (16%) in cohort 2 differed significantly from placebo (43%; P = .048) suggesting that high testosterone levels may suppress vasomotor symptoms.
“We created a series of dose-response relationships to determine the relative roles of testosterone and estradiol in the pathogenesis of [vasomotor symptoms] in men,” the researchers wrote. “We found that estradiol is the primary hormonal regulator of male [vasomotor symptoms]. These data suggest that aromatizable androgens may have advantages over nonaromatizable androgens in the management of symptomatic male hypogonadism, and add to the growing body of evidence that estrogen deficiency should be considered as a discrete hormone deficiency syndrome in men.” – by Amber Cox
Disclosure: One of the researchers reports grant support from Merck and consulting for Merck, Mitsubishi Tanabe, NeRRe Therapeutics, Noven and SAGE Therapeutics.