Hormone Replacement Therapy and Cardiovascular Disease

Abstract

In Canada, cardiovascular diseases (CVD) are the leading cause of mortality. In 1998, CVD were responsible for 39,447 deaths among Canadian women (almost 38% of all deaths in women), which is greater than the number of deaths for women due to all cancers combined. The proportion of deaths due to CVD in women increases significantly after menopause and continues to increase with advancing age. It remains unclear, however, whether this increase in incidence of CVD in middle-aged and elderly women is caused by lower estrogen levels or is an overall manifestation of advancing age. The use of hormone replacement therapy (HRT), especially estrogen, has been advocated as a means to reduce the risk of CVD. Menopause is associated with adverse effects on blood lipids including an increase in total cholesterol, LDL cholesterol, and triglycerides, and a decrease in HDL cholesterol. Reduced estrogen levels after menopause can also lead to adverse changes in blood pressure, obesity, body fat distribution, blood clotting factors, glucose metabolism and diabetes, all of which increase the risk of coronary heart disease. Laboratory studies have found evidence for both beneficial and adverse effects of estrogen. Oral estrogen has been shown to lower LDL cholesterol, lipoprotein (a), and increase HDL cholesterol. There is accumulating evidence that estrogen improves endothelial function, thus enhancing vasodilatation. In addition, estrogen replacement is associated with reduced blood levels of fibrinogen and plasminogen activator inhibitor-1, and may thus have anti-thrombotic and pro-fibrinolytic effects. However, other effects may be pro-inflammatory (increased C-reactive protein) and pro-coagulant and therefore detrimental to the overall cardiovascular risk profile. As estrogen is usually prescribed with progestin in those women with a uterus in order to protect against endometrial cancer, some of the beneficial cardiovascular effects may be attenuated by the addition of progestin (such as a lesser effect on HDL cholesterol). Other routes of administration of estrogen may have less favourable effects on plasma lipoproteins, but may be beneficial in other ways. Selective estrogen receptor modulators (SERMs) are also being studied because these may result in direct cardiovascular effects. The evidence for a protective effect of estrogen on coronary heart disease is based on over 30 observational epidemiologic studies conducted over the last two decades. These studies have shown a 40% reduction in the risk of coronary heart disease for current users of estrogen or estrogen and progestin compared to women who have never used these hormones. Recent updates have confirmed this conclusion, even with lower doses of estrogen, and have also found no effect of HRT on stroke. However, these types of studies are hampered by an inability to control completely for confounding factors, including the fact that women who are compliant with HRT