Robert D. Langer
Robert D. Langer, MD, MPH, University of California, San Diego, USA
Prior to the unexpected early termination of the Women’s Health Initiative (WHI) trial of conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA), the prevailing view was that postmenopausal Hormone Replacement Therapy (HRT) was a low-risk intervention with immediate value for symptom relief in recently menopausal women, and that HRT could provide long-term protection against major chronic diseases that become increasingly important after menopause. Coronary heart disease (CHD) is the leading cause of death in women in developed countries, and a treatment that affects this risk has enormous implications for women’s health. On the basis of non-experimental studies, and a major trial of intermediate markers (the Postmenopausal Estrogen Progestins Interventions [PEPI] trial), HRT was believed to be cardioprotective in women.
The results of larger randomized controlled clinical trials, including the Heart and Estrogen Replacement Study (HERS) and the WHI, challenged that expectation. Critically, the HERS and WHI HRT trials were not designed to assess outcomes of typical use of HRT beginning near menopause. Instead, they were designed to test whether the associations seen in women who started near menopause would be replicated in women starting a decade or more afterwards. The prevailing view of the relative benefits and risks of HRT changed dramatically shortly after the initial publication from the WHI. Use plummeted, driven by the fear of breast cancer together with skepticism about cardiovascular benefits.
Stunningly, the contrasting findings of the WHI trial of CEE alone reported two years later – which suggested prevention of coronary heart disease in women who began treatment before the age of 60, and a reduction in breast cancer overall — were largely ignored. Those findings were lost in the cloud of negative press from the original report, and because the CEE alone trial was also ended prematurely for concern about stroke, again driven by the effects in women who were well past menopause at study baseline.
The WHI HRT trials have contributed significant knowledge, but not necessarily through the publications by the WHI group. The findings helped to generate the Timing Hypothesis that has largely been confirmed, indicating that starting HRT before age 60, or within 10 years of menopause is generally associated with benefit, while starting later is not. They contributed to the understanding of progestogen effects in the vasculature and the breast. They proved that HRT is effective primary prevention for fracture and provided further support for possible HRT protection against dementias in a manner similar to the cardiovascular timing effect.
Incorrect interpretation of the WHI results has led to misleading labeling on HRT products. And the misleading publicity suggesting that the HRT trial was stopped because of breast cancer, which was not a statistically significant finding, has caused millions of women to avoid HRT, with likely poorer health as a result. It is important to understand the WHI trial design and results from a scientific standpoint in order to interpret them correctly.
The demonizing of HRT largely due to the WHI may already have set in motion a downstream burden of chronic disease that could have been mitigated or delayed. There is urgent need to correct these wrong impressions and re-establish an appropriate context for current therapeutic options in HRT.