Sex hormones, vascular function and the outcome of hormone replacement therapy in cardiovascular disease

Abstract

Cardiovascular disease is more common in men and post-menopausal women than premenopausal women, suggesting that female sex hormones have vascular benefits. Cytosolic/nuclear estrogen and progesterone receptors mediate genomic transcriptional effects that stimulate endothelial cell growth and inhibit smooth muscle proliferation. Sex hormone receptors on the plasma membrane trigger nongenomic stimulation of endothelium-dependent nitric oxide–cyclic (c)GMP, prostacyclin–cAMP and hyperpolarizing vascular relaxation pathways, as well as inhibition of [Ca2+]i, protein kinase C and Rho-kinase-dependent mechanisms of smooth muscle contraction. Despite the vasodilator effects of sex hormones, the Heart and Estrogen/progestin Replacement Study (HERS), HERS-II and Women’s Health Initiative clinical trials have shown minimal benefits of hormone replacement therapy (HRT) in post-menopausal cardiovascular disease. The prospect of HRT relies on further mechanistic analysis of the vascular effects of natural sex hormones and phytoestrogens, and the identification of specific estrogen receptor modulators. Androgens have vascular effects, and modulators of the estrogen/testosterone ratio could provide better HRT combinations. The timing/duration and the type, dose and route of administration of HRT should be customized according to the subject’s age and pre-existing cardiovascular condition, thereby enhancing the outcome of HRT in cardiovascular disease.