The role of randomized controlled trials in assessing the benefits and risks of long-term hormone replacement therapy: Example of the women's health initiative

Observational studies suggest that hormone replacement therapy among postmenopausal women may have important benefits, particularly in relation to heart disease and bone fractures, but may also convey important risks, most notably for breast cancer. The magnitude of these potential benefits and risks and the prevalence of use of hormone replacement therapy in the United States make the question of benefits versus risks a very pressing public health issue. This public health importance, along with the fact that reliable answers are likely to depend on accurate quantitative assessments of the impact of hormone replacement therapy on a range of clinical outcomes? implies a critical role for randomized controlled clinical trials of adequate size, duration, and quality in an overall replacement hormone research strategy. Some limitations of cohort and case-control studies of long-term hormone replacement therapy are briefly mentioned toward establishing the need for the type of logistically complicated clinical trial included in the Women's Health Initiative. This is followed by a description of the hormone replacement therapy component of the Women's Health Initiative Clinical Trial, along with some comments on the methods to be used for benefit-versus-risk monitoring and analysis of this trial. It is recommended that long-term hormone replacement therapy, in the form of estrogen alone for hysterectomized women or estrogen plus progestin for women with a uterus, should be prescribed conservatively until more reliable data on risks and benefits are available from randomized controlled trials or from other sources.