The women's health initiative—curse or blessing?

Some 15 years ago, 3 weeks into her tenure as the first female director of the National Institutes of Health, Bernadine Healy, MD, announced to Congress plans for a new and ‘holistic’ study: the Women’s Health Initiative (WHI). Hopes were high for the ambitious project. The largest randomized controlled trial (RCT) in history, costing the government an estimated $700 million, was expected to provide definitive answers to three key questions in women’s health: (i) whether hormone replacement therapy (HRT) reduces the risk of heart disease, (ii) whether a high fat consumption increases the incidence of breast cancer, and (iii) whether calcium and vitamin D supplements prevent fractures. The main results for all three trial arms have now been released. 1–4 The outcome of the mega-trial including more than 50 000 postmenopausal women randomized to one, two, or three of the factorial trials has left consumers confused and timid and doctors puzzled. What, if anything, can we make of these data? When the first trial of the WHI was stopped short in June 2002, an unexpected 24% higher incidence of coronary heart disease (CHD) had been observed among women randomized to HRT including oestrogen plus progestin than among women randomized to placebo. At the time the trial was prematurely halted, participants randomized to oestrogen plus progestin were advised to discontinue their medication. This news awakened alarm among postmenopausal women around the globe, many of whom discontinued their HRT. Physicians found themselves in a difficult situation, unsure what to advise. A closer look at the WHI, however, may help to disentangle some of the mysteries. The WHI was building on the premise that oestrogen may aid the heart drawing largely on the results from observational studies. After the WHI news broke, observational studies were criticized as biased and unreliable. However, many important differences between the observational studies and the WHI may help explain the apparent discrepancy in findings: while observational studies follow women who choose together with their physician to take HRT and initiate it usually because they experience menopausal symptoms as they transition into menopause, WHI participants were randomized to start HRT, mostly for the first time, at ages 50–79 years when they entered the trial and they had no or only modest menopausal symptoms. 5 While the observational studies reflected clinical practice, the treatment regimen laid out in the WHI differed from clinical practice in randomizing women to first use of HRT years or decades into menopause. In fact, the observational studies and the WHI addressed different questions. The observational studies asked whether HRT use among women with menopausal symptoms initiated at the onset of menopause affected the risk of heart disease; the WHI explored whether HRT use among women largely free of menopausal symptoms and initiated at any time between the ages of 50 and 79 may have an effect on the incidence of CHD. Subsequent investigations into both types of studies have consistently revealed that the timing of HRT initiation may indeed be critical in its impact on the heart. 6,7 Time since the onset of menopause at initiation of HRT and severity of menopausal symptoms may be important modifiers of the effect of HRT on CHD. Women a decade or more into their menopause may be unlikely to derive cardiovascular benefit from HRT and may even have an increased risk of a thromboembolic event precipitated by treatment. In February 2006, the long-awaited results from the dietary component of the WHI were released. Unlike the HRT component of the trial, 1,2 the diet part was not prematurely terminated but ended after 8.1 years as initially planned. The intervention, aiming to reduce fat intake from ~38% of calories to ~20% of calories did not produce a significant change in the incidence of the primary endpoints, breast cancer and colorectal cancer, or in the secondary endpoint, cardiovascular disease (CVD). How should these results be interpreted? Or can they be interpreted at all? As we suggested when the WHI was in its planning stages, randomizing diet is a problematic endeavour since healthy individuals are unlikely to maintain a drastically altered dietary regimen over many years. 10,11 We were concerned that it would be impossible for individuals accustomed for many years to a diet with 38% of calories from fat to suddenly change to a diet with 20% of calories from fat—even if they agreed to do so at the time of randomization. Conversely, it seemed likely that women in the control group while not advised to change their diet would do so on their own merely by being part of the study and being fully informed of its interventions and goals. We expected that over time, no meaningful difference in fat consumption between intervention and control group would be maintained. Now the results of 1 Obstetrics and Gynecology Epidemiology Center, Department of Obstetrics, Gynecology and Reproductive Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA. 2 Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.