High Level of Plasma Estradiol as a New Predictor of Ischemic Arterial Disease in Older Postmenopausal Women: The Three-City Cohort Study

BACKGROUND: Despite evidence that estrogens may be involved in atherothrombosis, the role of endogenous sex steroid hormones in ischemic arterial disease among postmenopausal women remains uncertain. METHODS AND RESULTS: In the Three-City prospective cohort study of subjects (n=9294) >65 years of age, we investigated the association of total 17β-estradiol, bioavailable 17β-estradiol, and total testosterone with the 4-year incidence of ischemic arterial disease among postmenopausal women who did not use any hormone therapy. We designed a case-cohort study including a random sample of 537 subjects and 106 incident cases of first cardiovascular events. Weighted Cox proportional-hazards models with age as the time scale were used to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for ischemic arterial disease by a 1-standard deviation increase in sex steroid hormones. In univariate analysis, HR of ischemic arterial disease was positively and significantly associated with both total and bioavailable estradiol levels. These associations remained significant after adjustment for traditional cardiovascular risk factors, including body mass index, diabetes, hypercholesterolemia, hypertension, and smoking status (HR: 1.42, 95% CI: 1.12-1.79, P<0.01; and HR: 1.42, 95% CI: 1.12-1.78, P<0.01, respectively). Separate analysis for coronary heart disease yielded similar results (adjusted HR: 1.49, 95% CI: 1.10-2.02, P=0.01; and adjusted HR: 1.50, 95% CI: 1.11-2.04, P