Plasma estrogen levels, estrogen receptor gene variation, and ischemic arterial disease in postmenopausal women: the three-city prospective cohort study.

BACKGROUND: In older postmenopausal women, high levels of endogenous estrogen have been related to adverse health outcomes including ischemic arterial disease (IAD). Whether estrogen receptor-α (ESR1) and -ß (ESR2) polymorphisms modulate the effects of estrogens on IAD has not been investigated. METHODS: In the Three-City prospective cohort study among subjects older than 65 years, we used a case-cohort design in which plasma levels of total and bioavailable 17ß-estradiol were measured. After exclusion of postmenopausal women using hormone therapy, a random subcohort of 533 women and 105 incident cases of first IAD events over 4 years of follow-up were analyzed. Five common polymorphisms of ESR1 and ESR2 were genotyped. Hazard ratios (HRs) of IAD for a 1-SD increase in hormones levels by the genotypes were estimated from Cox models after adjustment for cardiovascular risk factors and a correction for multiple testing. We also investigated the role of hemostasis and inflammation as potential mediators. RESULTS: Neither estrogens nor IAD risk was significantly associated with estrogen receptor polymorphisms. Overall, IAD risk increased with total estradiol [HR1.40, 95% confidence interval (CI) 1.11-1.77]. Stratified analysis by genotypes showed that total estradiol was positively related to IAD risk in women with ESR1 rs9340799-AA genotype but not in women with the AG/GG genotype (HR 1.62, 95% CI 1.22-2.17 and HR 1.03, 95% CI 0.81-1.30, respectively; P for interaction <.05). An additional adjustment for hemostatic variables reduced the HR by about one third in women carrying the rs9340799-AA genotype (HR 1.41, 95% CI 1.06-1.90). CONCLUSION: The ESR1 rs9340799 genotype may modify the IAD risk related to high endogenous estrogens levels in older postmenopausal women. Hypercoagulability may act as a mediator.

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 17ß-estradiol, bioavailable 17ß-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<0.01, respectively), and a borderline significant trend was observed for ischemic stroke (HR: 1.34, 95% CI: 0.95-1.89, P=0.08; and HR: 1.32, 95% CI: 0.94-1.84, P=0.11, respectively). By contrast, no significant association was found between total testosterone and ischemic arterial disease in both univariate and adjusted analyses. CONCLUSIONS: High plasma level of endogenous estradiol emerges as a new predictor of ischemic arterial disease in older postmenopausal women. (J Am Heart Assoc. 2012;1:e001388 doi: 10.1161/JAHA.112.001388.).