Menopause-related changes in vascular signaling by sex hormones

Cardiovascular disease (CVD), such as hypertension and coronary artery disease, involves pathological changes in vascular signaling, function, and structure. Vascular signaling is regulated by multiple intrinsic and extrinsic factors that influence endothelial cells, vascular smooth muscle, and extracellular matrix. Vascular function is also influenced by environmental factors including diet, exercise, and stress, as well as genetic background, sex differences, and age. CVD is more common in adult men and postmenopausal women than in premenopausal women. Specifically, women during menopausal transition, with declining ovarian function and production of estrogen (E2) and progesterone, show marked increase in the incidence of CVD and associated vascular dysfunction. Mechanistic research suggests that E2 and E2 receptor signaling have beneficial effects on vascular function including vasodilation, decreased blood pressure, and cardiovascular protection. Also, the tangible benefits of E2 supplementation in improving menopausal symptoms have prompted clinical trials of menopausal hormone therapy (MHT) in CVD, but the results have been inconsistent. The inadequate benefits of MHT in CVD could be attributed to the E2 type, dose, formulation, route, timing, and duration as well as menopausal changes in E2/E2 receptor vascular signaling. Other factors that could affect the responsiveness to MHT are the integrated hormonal milieu including gonadotropins, progesterone, and testosterone, vascular health status, preexisting cardiovascular conditions, and menopause-related dysfunction in the renal, gastrointestinal, endocrine, immune, and nervous systems. Further analysis of these factors should enhance our understanding of menopause-related changes in vascular signaling by sex hormones and provide better guidance for management of CVD in postmenopausal women. SIGNIFICANCE STATEMENT: Cardiovascular disease is more common in adult men and postmenopausal women than premenopausal women. Earlier observations of vascular benefits of menopausal hormone therapy did not materialize in randomized clinical trials. Further examination of the cardiovascular effects of sex hormones in different formulations and regimens, and the menopausal changes in vascular signaling would help to adjust the menopausal hormone therapy protocols in order to enhance their effectiveness in reducing the risk and the management of cardiovascular disease in postmenopausal women.