Vascular Effects of Estrogenic Menopausal Hormone Therapy

Abstract

Cardiovascular disease (CVD) is more common in men and postmenopausal women (Post-MW) than premenopausal women (Pre-MW). Despite recent advances in preventive measures, the incidence of CVD in women has shown a rise that matched the increase in the Post-MW population. The increased incidence of CVD in Post-MW has been related to the decline in estrogen levels, and hence suggested vascular benefits of endogenous estrogen. Experimental studies have identified estrogen receptor ERα, ERβ and a novel estrogen binding membrane protein GPR30 (GPER) in blood vessels of humans and experimental animals. The interaction of estrogen with vascular ERs mediates both genomic and non-genomic effects. Estrogen promotes endothelium-dependent relaxation by increasing nitric oxide, prostacyclin, and hyperpolarizing factor. Estrogen also inhibits the mechanisms of vascular smooth muscle (VSM) contraction including [Ca2+]i, protein kinase C and Rho-kinase. Additional effects of estrogen on the vascular cytoskeleton, extracellular matrix, lipid profile and the vascular inflammatory response have been reported. In addition to the experimental evidence in animal models and vascular cells, initial observational studies in women using menopausal hormonal therapy (MHT) have suggested that estrogen may protect against CVD. However, randomized clinical trials (RCTs) such as the Heart and Estrogen/progestin Replacement Study (HERS) and the Women’s Health Initiative (WHI), which examined the effects of conjugated equine estrogens (CEE) in older women with established CVD (HERS) or without overt CVD (WHI), failed to demonstrate protective vascular effects of estrogen treatment. Despite the initial set-back from the results of MHT RCTs, growing evidence now supports the ‘timing hypothesis’, which suggests that MHT could increase the risk of CVD if started late after menopause, but may produce beneficial cardiovascular effects in younger women during the perimenopausal period. The choice of an appropriate MHT dose, route of administration, and estrogen/progestin combination could maximize the vascular benefits of MHT and minimize other adverse effects, especially if given within a reasonably short time after menopause to women that seek MHT for the relief of menopausal symptoms.

Estrogen Receptor Subtypes Mediate Distinct Microvascular Dilation and Reduction in [Ca2+]i in Mesenteric Microvessels of Female Rat

“…Also, earlier clinical observations suggested that climacteric women receiving E2 containing menopausal hormone therapy (MHT) to reduce menopausal symptoms have lower rates of CVD, supporting the vascular benefits of E2 (Reslan and Khalil, 2012;Gurney et al, 2014). The beneficial vascular effects of E2 have been ascribed to modification of circulating lipoproteins, inhibition of the vascular accumulation of collagen, and vasodilator effects on the endothelium and vascular smooth muscle (VSM) (Mendelsohn, 2002;Khalil, 2013).…”

“…Despite evidence from earlier clinical observations and experimental studies, randomized clinical trials in postmenopausal women with or without CVD have shown no vascular benefits from MHT (Reslan and Khalil, 2012;Gurney et al, 2014). Several factors could have contributed to the lack of vascular benefits of MHT, including preexisting CVD, the subject's age, and age-related changes in estrogen receptor (ER) amount, distribution, integrity, and post-ER signaling mechanisms (Reslan and Khalil, 2012;Gurney et al, 2014).…”

“…Several factors could have contributed to the lack of vascular benefits of MHT, including preexisting CVD, the subject's age, and age-related changes in estrogen receptor (ER) amount, distribution, integrity, and post-ER signaling mechanisms (Reslan and Khalil, 2012;Gurney et al, 2014). These observations have made it imperative to thoroughly investigate the vascular ERs, their tissue distribution in the arterial tree, and their downstream post-ER signaling mechanisms.…”

Introductory Chapter: Recent Trends in Cardiovascular Risk Factors

“…Its incidence and mortality is very low in reproductive age women, but it increases with age [12]. Estradiol (E2) reduces the development of the early atherosclerotic lesions, in some measure, by its efects on the lipid metabolism, with a reduction of the lipid deposits from the intima [13].…”

Plasma Steroids and Cardiorespiratory Fitness Response to Regular Exercise

“…The CARDIA Male Hormone Study showed that there are associations of androgens with PA and fitness in young black and white men (Wolin et al 2007). Estrogens have vasculo-protective actions that are thought to prevent atherosclerosis (Reslan and Khalil 2012). Estrogens contribute to the regulation of the delicate balance between fighting infections and protecting arteries from damage, thus lowering the risk of cardiovascular disease (Meyer and Barton 2016).…”