HRT for Management of Menopause

HRT gained wide acceptance over 30 years ago and gradually became a staple in the treatment of estrogen deficiency. Patients were pleased by the relief of menopausal symptoms offered by HRT, and physicians were generally eager to embrace this fairly convenient therapy that delayed or prevented the onset of osteoporosis through positive effects on bone turnover. In the decades since HRT was introduced, its efficacy in preventing or ameliorating vasomotor instability and genitourinary atrophy has been well established, and its efficacy in preventing osteoporosis has been confirmed by a sizable body of studies.

Early population-based retrospective analyses suggested that HRT reduced overall cardiovascular mortality through beneficial effects on the heart and vasculature. Initial enthusiasm for the use of HRT to address the increased risk of coronary heart disease (CHD) associated with estrogen deficiency was reflected in a position statement by the American Collegeof Physicians (Guidelines for counseling…, 1992) proposing that all postmenopausal women be offered HRT.

However, conflicting reports periodically emerged that raised doubts about the cardiovascular benefits of HRT and suggested that HRT might increase the risk of not only thromboembolism but also breast cancer. Over the past several years, a series of prospective trials designed to answer these questions has led to a paradigm shift in the management of estrogen deficiency and its sequelae.

Observational studies have differed in their assessments regarding the impact of HRT on CHD risk. For example, the Framingham Heart Study (Wilson et al., 1985) found no decrease in CHD risk in estrogen users, but the first part of the Nurse's Health Study (Stampfer et al., 1985) found a significant decrease in CHD events with estrogen use. In the Heart and Estrogen/Progestin Replacement Study (Hulley et al., 1998; Grady et al., 2002), a large randomized trial specifically designed to study the effect of HRT on secondary prevention of CHD, postmenopausal patients with established heart disease were followed for 6.8 years. HRT use was associated with an increased risk of CHD events in the first year and a decreased risk of CHD events during years 3-5, but the cumulative risk of CHD was no different from that of the placebo group.

Another large randomized trial, the landmark Women's Health Initiative (WHI) trial (Rossouw et al., 2002; Anderson et al., 2004), evaluated the use of HRT for primary prevention of CHD. The study was made up of two parallel trials that compared estrogen or estrogen plus progesterone with placebo in healthy postmenopausal women. In patients treated with estrogen plus progesterone, a significant increase of 29% was observed in CHD events, most of which were nonfatal myocardial infarctions; no significant difference was observed in CHD deaths or revascularization procedures. The estrogenonly arm showed a 9% decrease in CHD events, but this finding was not statistically significant.