Differential effects of estrogen-androgen and estrogen-only therapy on vasomotor symptoms, gonadotropin secretion, and endogenous androgen bioavailability in postmenopausal women.

OBJECTIVE: To investigate somatic symptom relief, gonadotropin secretion, and endogenous androgen bioavailability (protein-bound and free) during 3 months of estrogen-androgen therapy or matched estrogen-only replacement therapy. DESIGN: Ninety-three naturally menopausal outpatients with 6 or more months of amenorrhea, who were experiencing mild-to-moderate vasomotor symptoms, were randomized to receive one of five treatments: oral esterified estrogens (0.625 mg or 1.25 mg), oral esterified estrogens combined with methyltestosterone (0.625 mg combined with 1.25 mg methyltestosterone or esterified estrogens 1.25 mg combined with 2.5 mg methyltestosterone), or placebo for 12 weeks. All treatments were preceded by a 4-week placebo lead-in period. RESULTS: Patients receiving the lower dose of estrogen-androgen therapy had fewer somatic menopausal symptoms than patients receiving the lower dose estrogen (0.625 mg), and they experienced somatic symptom relief similar to those patients receiving the higher dose of estrogen (1.25 mg). Significantly greater luteinizing hormone suppression (p < or = 0.03) occurred in estrogen-androgen groups compared to estrogen groups, suggesting that added androgen might mediate a more pronounced negative feedback on the hypothalamic-pituitary axis. Sex hormone-binding globulin increased significantly in both estrogen-treated groups (p < or = 0.01), whereas decreases occurred in both estrogen-androgen groups (p < or = 0.006). The higher dose estrogen-only preparation significantly reduced androstenedione (p < or = 0.01) and dehydroepiandrosterone sulfate (p < or = 0.005). CONCLUSION: The extent of relief with lower dose estrogen-androgen therapy was similar to higher dose estrogen-only treatment. The greater efficacy of combination therapy on somatic symptoms could be mediated by the same mechanism responsible for the suppressive effects of estrogen-androgen therapy on luteinizing hormone secretion. The marked differences in circulating levels of sex hormone building globulin, which were increased by estrogen and decreased by estrogen-androgen, and the resulting impact on bioavailable androgens and estrogens could also explain the differential somatic relief with both treatments. Endogenous adrenal androgens were lower in women treated with esterified estrogens 1.25 mg/day, suggesting that estrogen therapy can produce a significant hypoandrogenic state by inhibiting production or accelerating clearance of adrenal androgens.