The Women's Health Initiative—A Victory for Women and Their Health

The history of medicine abounds with dogmas assumed and later overcome. Nowhere is that dynamic more evident than in women’s health. Several decades ago, menopausal hormone therapywaswidelyassumedtobebeneficial forwomen, not only to relieve vasomotor symptoms, but also to reduce a woman’s risk for chronicdiseasesof aging, includingheartdisease. Observational studies suggested a slight net benefit of hormonetherapy,andbythemid-1990s,at least40%ofwomen in the United States were prescribed hormone therapy.1 The Women’s Health Initiative (WHI), funded by the National Institutes of Heath (NIH) with taxpayer dollars, has now set the record straight. Evidence first from the original primary end point studies published in 20022 and2004,3 andnow fromthe 13-year follow-up study published byManson et al4 in this issue of JAMA clearly demonstrates that the hormone therapy story is farmore complicated than suggestedby the initial observational studies. In addition, there are many lessons to be learnedabout thevalueof publicly funded, objective, prevention-oriented clinical studies. TheWHI was launched in 1991 by then NIH Director Bernadine Healy, MD, in response to public outcry regarding the paucityofmedical research findings involvingwomenandminorities.Cardiovascular careguidelines, forexample,hadbeen basedonphase3clinical trials conducted predominantly in whitemenwithout attention to possible sex or ethnic differences in treatment outcomes. The NIH Revitalization Act of 1993establishedguidelines5 for the inclusionofwomenand minorities in clinical research. The guidelines ensure that all NIH-fundedclinical research isconducted inamanner thatelicits information about individuals of both sexes anddiverse racial andethnicgroupsand,particularly inphase3clinical trials, that examines differential effects on these groups. This is important because scientific evidence often leads to a change in health policy or standard of care. Nowhere is this more evident than in theWHI. TheWHI consists of a set of clinical trials and an observational study, which together were conducted with the consent of 161 808generally healthypostmenopausalwomenbetween the ages of 50 and 79 years. The clinical trials were designed to test the effects of postmenopausal hormone therapy,dietmodification, andcalciumandvitaminDsupplementationonheart disease, bone fractures, andbreast andcolorectal cancer. These clinical trials consisted of (1) hormone therapy trials, (2) a dietary modification trial, and (3) a calciumand vitaminD trial. The hormone therapy trial included a studyof theeffectsof estrogenplusprogestin inwomenwith auterus and a studyof the effects of estrogen alone inwomen without a uterus. (Womenwith a uteruswere givenprogestin incombinationwithestrogen,which isapracticeknowntoprevent endometrial cancer.) In both hormone therapy studies, womenwere randomly assigned to either thehormonemedication being studied or placebo; women were enrolled from 1993 to 1998. In 2002, the National Heart, Lung, and Blood Institute, which bears responsibility for funding and oversight of the WHI, announced that it had stopped the estrogen plus progestin trial when investigators found that the health risks of the combination hormone therapy outweighed the benefits after participants were followed up for an average of 5.6 years.2 The estrogen alone study was stopped in 2004 for safety concerns as well; risks of hormone therapy were greater than overall benefits in women followed up for an average of 7 years.3 The women in both of these hormone studies participated in a follow-up phase, which was completed in 2010, and these findings are reported in this issue of JAMA.4 The observational study enlisted 93 676 women whose health was tracked during an average of 8 years through the completion of periodic health forms and clinic visits. These women were not required to take any medication or change their health habits. What were the lessons from the primary end point studies, and what happens to the risks and benefits of hormone therapy following intervention and over time? Results reported in2002and2004demonstrated thatbothestrogenplus progestinandestrogenalone increased the riskof stroke,problems with memory and dementia, thrombosis in the legs or lungs, urinary incontinence, and gallbladder disease; however, both treatments reduced the risk of fractures andof diabetes. Estrogen plus progestin increased the risk of heart disease and breast cancer, whereas estrogen alone did not; however, both treatments had no effect on colorectal cancer. Subsequently, the trials studyingdietarymodificationandcalciumandvitaminD, respectively, found thatwomenwhoconsumed a low-fat diet had a tendency toward a reduced risk of breast cancer andminimal change in risk of heart disease and stroke,6,7 whereas calcium and vitamin D provided a modest benefit in preserving bone mass and preventing hip fractures, but increased the risk of kidney stones.8 The current 13-year follow-up study confirms the initial findings from the estrogen plus progestin and estrogen alone trials; postintervention, most risks and benefits were reduced but persisted in the estrogen plus progestin group, Related article page 1353 Opinion