Effect of postmenopausal estrogen replacement on circulating androgens

Objective: To determine the effect of estrogen replacement therapy (ERT) on serum androgen levels in postmenopausal women. Methods: We measured serum dehydroepiandrosterone (DHEA), DHEA-sulfate, testosterone, estradiol (E2), LH, FSH, and sex hormone binding globulin in 8:00 AM fasting serum samples from a previous randomized, blinded, placebo-controlled crossover study in which 28 postmenopausal women (27 naturally menopausal) were given 2 mg/day of oral micronized estradiol. The treatment arms were 12 weeks with a 6-week washout. Results: Estrogen replacement therapy raised mean (± standard error of the mean [SEM]) serum E2 from 8.7 ± 1.0 to 117 ± 18.7 pg/mL (P < .001 from baseline). Concurrently, mean (±SEM) DHEA-sulfate fell from 67.3 ± 9.6 to 52.1 ± 6.4 μg/dL (P < .001), and mean (±SEM) testosterone fell from 16.1 ± 2.4 to 9.4 ± 1.4 ng/dL (P = .006). Both FSH and LH declined significantly. Sex hormone binding globulin increased by 160% with ERT (P < .001). Conclusion: Menopausal ERT decreases serum androgen levels, decreasing DHEA-sulfate and testosterone by 23% and 42%, respectively. Whereas the decline in testosterone is likely due to decreased LH-driven ovarian stromal steroidogenesis, the declining levels of DHEA-sulfate also may imply a direct adrenal effect of estrogen. Bioavailable testosterone likely is reduced even more profoundly because sex hormone binding globulin is increased 160% by estrogen. Thus, menopausal ERT may induce relative ovarian and adrenal androgen deficiency, creating a rationale for concurrent physiologic androgen replacement.