Postmenopausal androgens, sex hormone binding globulin, and cardiovascular risk: a cohort study - PROJECT SUMMARY / ABSTRACT Among women, cardiovascular (CV) event risk increases dramatically following postmenopause. Although it has been proposed that peri- and postmenopausal changes in endogenous sex hormones are important in this increased risk, most research has focused on the role of estrogens. In contrast, there is an incomplete understanding of postmenopausal androgen levels and profiles over time, and how these may relate to changes in markers of CV risk and in the risk of CV outcomes. An improved understanding of postmenopausal androgen levels, changes, and profiles in relation to postmenopausal CV risk is critical to elucidating mechanisms and informing future genetic and therapeutic targets aimed at reducing CV risk among older women. We propose to characterize postmenopausal androgens and sex hormone binding globulin (SHBG), a sex steroid transporter, across 20 to 30 years and to evaluate the association of postmenopausal androgens and SHBG levels, rates of change, and profiles in relation to markers of CV risk and CV event risk. We hypothesize that postmenopausal androgen levels and profiles will be associated longitudinally with markers of CV risk and with CV event risk among older women. To address this, we propose an ancillary study to the Women’s Health Initiative (WHI) that leverages existing stored biospecimens and markers of CV risk previously measured across two to three timepoints and spanning 20 to 30 years. These stored biospecimens and existing markers of CV risk were collected among postmenopausal participants aged 50 to 79 years at baseline who were followed for up to 30 years for CV events. Events include atherosclerotic cardiovascular disease (coronary heart disease, coronary revascularization, stroke, peripheral artery disease, carotid artery disease, other CV death) and total CV disease (ASCVD, heart failure, venous thromboembolism). This new cohort study nested within the WHI will include ~752 participants who have existing measures of many markers of CV risk from two to three timepoints across 20 to 30 years of postmenopause (systolic blood pressure, C-reactive protein, creatinine, Homeostatic Model Assessment for Insulin Resistance [HOMA-IR], total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), cholesterol, and triglycerides) and hemostatic factors of interest (factor VII antigen, factor VII activity, fibrinogen) measured at WHI baseline. In these same participants, we will newly measure postmenopausal levels of androgens (total testosterone, dihydrotestosterone, dehydroepiandrosterone sulfate), SHBG, and estrogens (estrone, estradiol) in stored biospecimens collected at the same time points as existing CV risk markers. Latent class analysis will be used to characterize postmenopausal androgens across 20 to 30 years, and we will evaluate hormone levels, rates of change, and latent classes in relation to CV risk markers and CV events. This work will advance our understanding of mechanisms of CV risk in postmenopause and could provide novel therapeutic targets as well as improved prediction of CV events, all of which are needed to improve healthy aging among women.
