Relative androgen excess during the menopausal transition predicts incident metabolic syndrome in midlife women

In Brief Objective: During the menopausal transition, total testosterone (T) remains unchanged, whereas estrogen decreases markedly, creating a state of relative androgen excess. We hypothesized that change in the T-to-estradiol (T/E2) ratio during the menopausal transition would be associated with incident metabolic syndrome. Methods: The association between incident metabolic syndrome and total E2, total T, sex hormone-binding globulin, the free androgen index, baseline total T/E2 ratio, and the change of this ratio over time was evaluated in a multiethnic cohort of 1,862 premenopausal and perimenopausal women without diabetes enrolled in the Study of Women's Health Across the Nation. Results: New cases (n = 257) of metabolic syndrome were identified in the cohort during 6,296 woman-years of follow-up. The age-adjusted total T/E2 ratio increased by 10.1% per year during the 5 years of follow-up. Neither baseline nor change in E2 was associated with incident metabolic syndrome. Low sex hormone-biding globulin, free androgen index, and high total T at baseline all increased the risk of metabolic syndrome, but their change over time did not. Both baseline total T/E2 ratio (1.41; 95% CI = 1.17-1.69; P < 0.001) and its rate of change (1.24; 95% CI = 1.01-1.52; P < 0.04) were associated with increased incident metabolic syndrome independent of ethnicity. Conclusions: The interaction between T and E2 during the menopausal transition, rather than the individual change of each over time, is a factor in the determination of risk of developing metabolic syndrome during the menopausal transition. This relationship was independent of ethnicity and other factors associated with prevalent metabolic syndrome before the onset of the menopausal transition. With the onset of menopause, ovarian estradiol production declines dramatically, but the concomitant drop in sex hormone binding globulin and more modest drop in androgen production leads to an increase in the ratio of bioavailable testosterone to estradiol. In the Study of Women's Health Across the Nation, the magnitude of this ratio-called Relative Androgen Excess-is shown to be associated with incident cases of metabolic syndrome.