In 2002 the Women’s Health Initiative (WHI) which is the largest randomized controlled trial ever to look at hormone replacement therapy was halted early.
At the time the reason given for the early termination was increased risks of breast cancer and heart disease. This news had an immediate impact as millions of women stopped taking hormones abruptly and millions more never started. Now, 15 years later it continues to be the primary influence on both women and their health care providers on the decision whether or not to start hormone therapy.
In a review, published in March 2017 in Climacteric, Dr. Robert Langer, who was one of the principal investigators for the WHI states “the ‘facts’ that most women and clinicians consider in making the decision to use, or not use, HRT are frequently wrong or incorrectly applied.”
Dr. Langer says that in the 1980s and 90s numerous smaller observational studies showed a risk reduction in cardiovascular disease sometimes by as much as 50% for women taking estrogen alone. Cardiovascular disease is more common for women in their 60s: yet, all of the earlier studies were in younger women who were recently (within ten years) in menopause. The WHI was designed specifically to look at risk reduction in older women, women who were well beyond menopause but who were, based on their age, at higher risk for CV disease.
Did starting hormone therapy well after menopause lead to a reduction in CV disease? Was it cardio-protective to start closer to the age when cardiovascular disease is most common? The answer is now a well known, no. The data from the earlier trials that supported a benefit for younger women was entirely disregarded.
Dr. Langer states “The WHI HRT trial was well designed to assess the questions it set out to answer, i.e. the effects of regimens being used in 1993 on the incidence of major chronic diseases in older menopausal women. It was not designed to test the effects of HRT in recently menopausal women and did not have the statistical power to do that. A major failing of the study has been the generalization of the results in older menopausal women to younger menopausal women.”
He goes on to discuss the unusual way the results, which precipitated the early termination, were written and published.
“The investigators most capable of correcting the critical misinterpretations of the data were actively excluded from the writing and dissemination activities. The initial results paper was written by a small group from the coordinating center and program office and submitted to the journal without informing or consulting the clinical site principal investigators.” The investigators were not allowed to contribute, comment, or change any of the language in the paper as it had already been printed for publication.
So the single study that has informed millions of decisions about hormone therapy likely doesn’t apply to the women who would most likely benefit from hormone therapy, i.e., younger women within ten years of menopause. The reach of the WHI even extends to much younger, premenopausal women who are considering birth control pills and are concerned about the risk of breast cancer.
Long-term follow-up on the women in the WHI trial, who were taking just estrogen, was published in JAMA in April 2011. This study considered age-specific outcomes. In the women who were within ten years of menopause they found “12 fewer acute myocardial infarctions, 13 fewer deaths, and net 18 fewer adverse events in the global index, per 10, 000 women, compared to women receiving placebo.” In other words, younger menopausal women taking just estrogen did better overall than the women on placebo.
According to Philip M. Sarrel, the lead author on a paper published in September 2013 in the American Journal of Public Health in 2002 when the WHI results came out, “almost no one emphasized or even seemed to recognize the fact that the worst findings might not apply to hormones other than Prempro or might not apply to all age groups.” In fact, the authors estimate that as many as 91,610 women have died prematurely over a ten year period because they did not use estrogen.
After all these years the flawed and misrepresented results from the WHI are still impacting women. The WHI made clear that hormone therapy should not be used for disease prevention, but in younger women, with symptoms of menopause, hormone therapy can be safe and possibly even beneficial. Not all women want or need to take hormone therapy. It is a decision to consider carefully, but for those women whose quality of life is affected by menopausal symptoms, it is an option well worth considering.