Postmenopausal Hormone Replacement Therapy— Where Are We Now?

More and more women are entering their postmenopausal years, requiring more training of women’s health care professionals and greater research efforts to further uncover the benefits and risks of hormone replacement therapy (HRT). In the Western world, menopause occurs at about 51.4 years, and currently close to 42 million women in the United States are older than 50 years [1]. With a life expectancy of almost 80 years [1], most women can expect to spend one third to one half of their lives as postmenopausal women. During the time from the reproductive years to and beyond the last menstrual period, ovarian function is progressively lost; this loss is accompanied by endocrine, somatic, and physiologic changes. The loss of estrogen that characterizes menopause is associated with vasomotor symptoms (hot flashes and night sweats), sleep disturbances, and urogenital problems [2]. In addition, the loss of estrogen has been associated with an increased risk of cardiovascular disease (CVD) and osteoporosis in postmenopausal women [2]. Currently, approximately 38% of American women between the ages of 50 and 74 years take HRT [3]. Established benefits of HRT include relief of vasomotor symptoms, prevention and treatment of vaginal dryness and urethritis, improvement in serum lipoprotein profiles, and prevention of osteoporosis [4–7]. In addition, it has been proposed that HRT reduces the risk of cognitive decline [8], depression [9], colorectal cancer [10], and Alzheimer’s disease [8,11]. These potential benefits are currently under investigation. Established risks of HRT use include an increased risk of venous thrombosis [12,13], increased levels of triglycerides [14], and an increased risk of developing gallbladder disease [15]. The big questions about HRT are not about short-term use for vasomotor symptoms and long-term use for prevention of osteoporosis, but about long-term systemic use of HRT and its possible adverse effects. Controversy still remains regarding the role of HRT in CVD and breast cancer [16]. Thus, the goal of this review is to provide the latest information from the literature, analyze the issues, offer guidelines for primary care physicians, and provide information about ongoing clinical trials that may clarify the role of HRT in CVD and breast cancer in postmenopausal women. HRT and Primary Prevention of CVD Since CVD is the single leading cause of death among postmenopausal women [17], understanding the potential cardioprotective effects of HRT is critically important. Although data from observational studies largely support the use of HRT in postmenopausal women for reducing the risk of CVD, recent randomized controlled clinical trials have raised more questions about the risks and benefits of HRT. For physicians, these new data make counseling postmenopausal women regarding HRT and CVD extremely complex and challenging. An impressive body of evidence has suggested that estrogen is cardioprotective. Studies indicate that the rate of coronary heart disease (CHD) is higher in men than in premenopausal women but that the risk for women substantially increases after menopause, a time characterized by low estrogen levels [18,19]. Studies also indicate that an increased risk of CHD is associated with bilateral oophorectomy and that this risk may be prevented by HRT [20]. Mendelsohn and Karas recently reviewed the physiologic effects of estrogen on the cardiovascular system [21]. Data presented in their review suggest that estrogen has both rapid and long-term direct effects on the blood vessel wall. The rapid effects of estrogen, such as vasodilatation, occur within few minutes after estrogen exposure and are not dependent on changes in gene expression. Long-term effects of estrogen, such as inhibition of response to vascular injury and prevention of atherosclerosis, occur over hours or days after estrogen exposure and are dependent on changes in gene expression. In addition, estrogen has been associated with favorable changes in several factors that are thought to be markers of CVD. Several studies indicate that high-density lipoprotein (HDL) and low-density lipoprotein (LDL) levels as well as plasma viscosity, fibrinogen levels, plasminogen activator inhibitor-1 levels [22], and