The randomized world is not without its imperfections: reflections on the Women's Health Initiative Study

In May 2002, the Women's Heath Initiative (WHI) clinical trial, designed to clarify the risks and benefits of combination hormone replacement therapy, came to a premature halt. An interim safety review after an average follow-up of 5.2 years found that a combination of estrogen and progestin often prescribed to postmenopausal women increased the risk of invasive breast cancer, heart disease, stroke, and pulmonary embolism. The combination hormone therapy reduced bone fractures and colorectal cancer, but not enough to outweigh the other risks. The WHI trial presents a challenge for patients, physicians, and epidemiologists, since many observational studies have shown cardiovascular benefits of long-term hormone replacement therapy (HRT). At the same time, a companion paper in the same journal reported an epidemiologic study with a 13.4-year mean follow-up suggesting that estrogen replacement therapy, when used alone for 10 years or more, increases the risk of ovarian cancer. The medical community is still recovering from these twin shocks and trying to digest the results of both of these studies. The WHI study calls into question the long-term use of HRT in healthy women. The benefit of the temporary use of estrogen in controlling disruptive symptoms of the menopause is not being contested. Absent from many news releases are the hedging and equivocation typical of other reported clinical trials. There are still some "hanging chads" out there, and this commentary is designed to examine the uncertainties that remain after the WHI report. It is also intended to suggest development of alternative strategies to control symptoms of the menopausal transition that will reduce risks of HRT. The evidence from the WHI study will need to be incorporated into medical decision making, but clinical decisions, like most human decisions, are complex and in the final analysis must be based on information from many sources.