Until recently, approximately 38 % of post-menopausal women received hormone replacement therapy in the USA. Particularly, the suspected benefit for the course of cardiovascular disease based on initial observational studies led to the wide spread use of hormone replacement therapy. Observational studies supported the hypothesis that hormone replacement therapy may provide cardiovascular protection via reduction of atherosclerosis. However, these early studies also reported an increased risk for the development of breast cancer and venous thromboembolism. Randomised placebo-controlled studies to investigate the role of hormone replacement therapy in the primary and secondary prevention of atherosclerotic disease were urgently needed. Results of most of these hormone replacement therapy trials are now published and allow for a new evaluation of the use of hormone replacement therapy, at least for the use of estrogens and gestagens.
The conclusion from the data now available from those randomised placebo-controlled trials is, that there is no net benefit for hormone replacement therapy regarding primary prevention (WHI, 1,2,3), secondary prevention (HERS, 4; HERS II, 5,6; ESPRIT, 7; WEST, 8) or angiographic endpoints (WAVE, 9; ERA, 10) of cardiovascular disease. This also accounts for women on higher risk due to risk factors, known atherosclerosis, previous myocardial infarction or stroke. Recommendations of the American Heart Association were published in 2001 (11).
Those almost consistently negative results were only slightly put into perspective by a recent meta-analysis of data from 30 randomised, placebo-controlled hormone replacement therapy trials between 1966 and September 2002 (12). Overall mortality associated with hormone replacement therapy remained unchanged, however, mortality in the age group under 60 years was significantly reduced. Thus, at best hormone replacement therapy can be recommended as early as possible following menopause. Also, hormone replacement therapy should only be temporarily used and terminated before the more critical higher age has been reached.
A potential alternative to estrogens and gestagens for hormone replacement therapy are the selective estrogen receptor modulators (SERMs), such as raloxifene. Placebo-controlled data are available for raloxifene in a larger cohort of patients from the MORE study (13). Primary endpoint of this study was the influence of raloxifene on osteoporosis. In a secondary analysis of women with multiple cardiovascular risk factors also coronary and cerebrovascular endpoints were investigated. No significant change of cardiovascular events was observed in the overall cohort, however, a significant reduction of events was found in women with increased cardiovascular risk. Moreover, a reduction of risk for breast cancer is expected in the currently conducted placebo-controlled RUTH trial with cardiovascular events as primary endpoints (14).
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