Hormone Replacement Therapy and Cardiovascular Disease

Abstract

Mendelsohn and Karas² recently reviewed the physiological effects of estrogen on the cardiovascular system. Briefly, cardiovascular cells, as well as reproductive tissues, bone, liver, and brain, express both of the known estrogen receptors, estrogen receptor-α (ER-α) and estrogen receptor-β (ER-β). These receptors are important targets for endogenous estrogen, ERT, and pharmacological estrogen agonists. Estrogen–estrogen receptor complexes serve as transcription factors that promote gene expression with a wide range of vascular effects, including regulation of vasomotor tone and response to injury, that may be protective against development of atherosclerosis and ischemic diseases. Estrogen receptors in other tissues, such as the liver, may mediate both beneficial effects (eg, changes in apoprotein gene expression that improve lipid profiles) and adverse effects (eg, increases in gene expression of coagulation proteins and/or decreases in fibrinolytic proteins). Two general estrogen-mediated vascular effects are recognized. Rapid, transient vasodilation occurs within a few minutes after estrogen exposure, independently of changes in gene expression.² This rapid vasodilation appears to be due to the novel ER-α–mediated activation of the endothelial nitric oxide synthase enzyme, but it is of unclear physiological significance. Longer-term effects of estrogen on the vasculature, such as those related to limiting the development of atherosclerotic lesions or vascular injury, occur over hours to days after estrogen treatment and have as their hallmark alterations in vascular gene expression. Progesterone and other hormonal receptors are also expressed in the vasculature, although their role in the development of CVD is poorly defined. At present, the sum clinical impact of the genomic and nongenomic effects of ERT/HRT is uncertain. As the molecular mechanisms responsible for the effects of estrogen are further elucidated, therapies may evolve that optimize the benefits of estrogen therapy while minimizing the risks.