Background: Postmenopausal hormone therapy has been examined extensively in relation to cardiovascular disease. However, research relating serum levels of sex hormones to cardiovascular disease is sparse, and the results are inconclusive.

Methods: We measured sex hormones in longitudinally collected samples of 180 postmenopausal women, 91 randomized to 17beta-estradiol and 89 to placebo, in the Estrogen in the Prevention of Atherosclerosis Trial. Repeated measures of sex hormone levels were tested for an association with carotid artery intima-media thickness (CIMT), which was also assessed longitudinally over 2 yr.

Results: In all women, changes in serum estrone (P = 0.02), total estradiol (P = 0.01), free estradiol (P = 0.02), and SHBG (P = 0.005) were significantly inversely associated with CIMT progression, controlling for age and body mass index. All the estrogen compounds and SHBG were significantly inversely related with low-density lipoprotein cholesterol and positively associated with high-density lipoprotein cholesterol (all P < 0.0001), whereas free testosterone was positively related with low-density lipoprotein cholesterol and inversely associated with high-density lipoprotein cholesterol (P < 0.003). Despite an increase in serum-free estradiol with estradiol therapy, women with unchanged SHBG and free testosterone levels had an average (se) progression in CIMT of 8.53 (4.72) microm/yr, whereas women with increased free estradiol and SHBG and decreased free testosterone had the largest reduction in CIMT progression [-5.45 (2.77) microm/yr; trend P = 0.03].

Conclusion: Estrogen and SHBG are associated with reduced subclinical atherosclerosis progression in healthy postmenopausal women. These associations are partially mediated by their beneficial effects on lipids. Among women taking estradiol, the most beneficial hormone profile for CIMT progression was increased free estradiol and SHBG with concomitant decreased free testosterone.