Low endogenous estradiol levels are associated with elevated risk of cardiovascular disease mortality in young and middle-aged men in the United States

Background and aims: Evidence for the association of total estradiol (E2) with cardiovascular disease (CVD) in young men is limited. We investigated the association of total E2 or free estradiol (FE2) and CVD mortality in a nationally representative multiracial sample of young and middle-aged men in the United States.Methods: Data were from 954 men without CVD, cancer, diabetes and not on androgen therapy or taking anabolic steroids, who participated in the National Health and Nutrition Examination Survey (1988-1991), for whom E2 was measured, and were followed for mortality through to 2015. Fasting serum levels of E2 were measured using competitive electrochemiluminescence immunoassays. Free estradiol was estimated from the levels of estradiol, sex hormone binding globulin, and albumin. International Classification of Diseases codes were used to define CVD mortality. Cox regression models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI).Results: The average age of participants at baseline was 35.7 +/- 11.6 years, with 11% and 6% reporting Black and Hispanic race and ethnicity, respectively. During a median follow-up of 25.2 years, 40 CVD deaths were recorded. Controlling for baseline demographic and CVD risk factors, and total testosterone levels, a 1 standard deviation decrement in log E2 (HR: 2.33, 95%CI: 1.11-5.00) or FE2 (HR: 1.89, 95%CI: 1.01-3.57) was associated with elevated risk of CVD mortality. This elevated risk was largely limited to non-Hispanic White men.Conclusions: In this study, low levels of E2 or FE2 were associated with elevated risk of CVD mortality.