Hormone Replacement Therapy and Cardiovascular Disease

or more than 50 million American women, and millions of women in other countries who are over the age of 50 years, the decision whether or not to use estrogen replacement therapy (ERT) for chronic disease prevention is often a difficult one. Established benefits of treatment for meno- pausal symptoms and prevention of osteoporosis must be weighed against documented risks of therapy, including venous thromboembolic events (VTE), gallbladder disease, and a possible increased risk of breast cancer. Unopposed ERT is also associated with an increased risk of endometrial cancer in women with a uterus. Therefore, it is typically combined with a progestin and is referred to as hormone replacement therapy (HRT). The impact of ERT/HRT on cardiovascular disease (CVD) is of great public health im- portance, because CVD is the leading cause of death and a major contributor to disability in women.1 The purpose of this advisory is to summarize the currently available data con- cerning potential CVD benefits and risks associated with ERT/HRT and to provide updated clinical recommendations regarding its use in the secondary and primary prevention of CVD. Biological Basis for a Role of ERT in CVD 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 recep- tors, estrogen receptor-a (ER-a) and estrogen receptor-b (ER-b). These receptors are important targets for endogenous estrogen, ERT, and pharmacological estrogen agonists. Es- trogen- 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 develop- ment 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 vascu- lar effects are recognized. Rapid, transient vasodilation oc- curs within a few minutes after estrogen exposure, indepen- dently of changes in gene expression.2 This rapid vasodilation appears to be due to the novel ER-a-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 vascu- lar 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 respon- sible for the effects of estrogen are further elucidated, therapies may evolve that optimize the benefits of estrogen therapy while minimizing the risks.