Age Trends in Estradiol and Estrone Levels Measured Using Liquid Chromatography Tandem Mass Spectrometry in Community-Dwelling Men of the Framingham Heart Study

THE estrogens have been linked to the pathophysiology of gynecomastia, osteoporosis, inflammation, and cardiovascular disease (CVD), but the precise biologic role of the circulating estrone and estradiol in men remains poorly understood (1,2). The function of estrone, which is at least as abundant in the circulation as estradiol but is less potent than estradiol in some bioassays (3), has been even less well studied as compared with estradiol. In men, circulating estradiol is derived partly from direct testicular secretion and partly from peripheral aromatization of testosterone, whereas circulating estrone is derived predominantly from peripheral conversion of delta 4-androstenedione (3–10). A decline in testosterone and androstenedione levels with aging would, therefore, be expected to result in lower estradiol and estrone levels, respectively, in older men as compared with younger men. However, the data on age-related changes in estradiol levels are conflicting. Although some studies have reported lower estradiol levels in older men than in young men (11–15), others have noted stable (16,17) or even rising estradiol levels with age (18). Very few studies have investigated the age trends in estrone levels (14,15). Additionally, few studies have interpreted age trends in estrone and estradiol levels in the context of age-related changes in lifestyle and health-related factors. The estradiol levels were measured in most studies using direct immunoassays, whose accuracy in the low range prevalent in men has been questioned (19–21). Using cross-sectional data from the Framingham Heart Study (FHS), we examined the age distribution of estradiol and estrone concentrations and the relationship of these hormones to body mass index (BMI), total testosterone, sex hormone–binding globulin (SHBG), diabetes mellitus, C-reactive protein, and lifestyle factors such as smoking and alcohol consumption in a sample of community-dwelling men. We also determined how comorbid conditions, lifestyle factors, inflammation, testosterone, and SHBG levels influence the age trends in estrone and estradiol levels. We adjusted the analyses for SHBG, the major binding protein for circulating estradiol that has been associated with metabolic disorders, which may indirectly affect estrogen levels. We measured estrone and estradiol levels using liquid chromatography tandem mass spectrometry (LC-MS/MS), widely accepted as the method with the highest accuracy and sensitivity (19–21).