Interim Safety Analysis of a Two-Year Study Comparing Oral Estrogen-Androgen and Conjugated Estrogens in Surgically Menopausal Women

This article describes an interim safety analysis of an ongoing 2-year, double-blind study to compare two doses of estrogen-androgen therapy (0.625 or 1.25 mg esterified estrogens combined with 1.25 mg or 2.5 mg methyltestosterone, respectively) with two doses of conjugated estrogens (0.625 mg or 1.25 mg conjugated equine estrogens) in 291 surgically menopausal women. Except for an excess of nausea in the estrogen-only group, reported adverse events (headache, breast pain, weight increase, vaginitis, and hirsutism) did not differ significantly between groups. The majority of adverse events were manifest by 6 months and were not dose related. Only four estrogen-androgen and two conjugated estrogen participants reported hirsutism as an adverse event, but Ferriman-Gallwey evaluations at 12 months detected increased hair growth in 14%–22% of women in each treatment group, with a slight but nonsignificant increment in the higher dose estrogen-androgen group. No significant differences between groups for weight increase or blood pressure were observed at 6 or 12 months. At 6 and 12 months, decreases in triglycerides and HDL cholesterol were observed for both doses of estrogen-androgen, whereas increases were observed in women assigned to conjugated estrogen. Total cholesterol and LDL decreased in all treatment groups by 6 months. No adverse effects on serum creatinine or liver function tests were observed in any treatment group. These results demonstrate that estrogen therapy in combination with androgens is generally as well tolerated as estrogen therapy alone for at least 1 year of treatment. The clinical implications of the more frequent nausea and higher triglycerides with unopposed estrogen and of the lower HDL cholesterol levels with estrogen-androgen treatment are unknown.