Perspectives on the Women's Health Initiative trial of hormone replacement therapy

The premature termination of one comparison in the Women's Health Initiative primary prevention trial due to stopping rules being reached necessitates a reconsideration of hormone replacement therapy (HRT). This part of the Women's Health Initiative trial, however, examined only one popular HRT regimen (conjugated equine estrogen [0.625 mg] and medroxyprogesterone acetate [2.5 mg] daily) in asymptomatic postmenopausal women. To help clinicians understand this large, complex trial, we describe several pervasive biases in earlier observational studies, review the principal findings of the trial, summarize recent systematic reviews, and offer clinical suggestions for HRT. Observational studies of HRT have found consistent, powerful protection against heart disease; this now appears due to consistent, powerful selection biases. These biases have the same net effect: Women using HRT in observational studies were healthier than those not using it. The Women's Health Initiative trial found that the overall risk-benefit ratio tipped against using HRT for prevention. Cardiovascular disease and breast cancer were increased among users, whereas colorectal cancer and osteoporotic fractures were reduced. Whether these findings relate to women with menopausal symptoms and to different HRT regimens is unknown. Hormone replacement therapy remains the best treatment for menopausal symptoms. Although estrogen has proven benefit for osteoporosis prevention, alternatives include raloxifene, alendronate, and risedronate. For women needing HRT, use of a low dose, with reassessments at least annually, appears prudent. Heart disease prevention strategies of proven value include exercise, weight control, blood pressure and lipid control, and avoidance of smoking. Hormone replacement therapy should not be used for this purpose.