Despite almost two decades of research, it is not yet clear how hormone replacement therapy affects a woman’s risk of getting Alzheimer’s disease. The curators of the AlzRisk database, hosted by Alzforum, undertook a review of what the literature on this controversial topic amounts to. Released on 27 October 2011, their meta-analysis of seven observational studies reveals a modest protective effect from estrogen or estrogen plus progesterone therapy. Women who reported using any estrogen had about 20 percent less risk of developing AD than women who used none, curator Jennifer Weuve at Rush University, Chicago, Illinois, told ARF. However, the authors, who also include Deborah Blacker at Massachusetts General Hospital, Boston, and Jacqueline O’Brien at the Harvard School of Public Health, hasten to add significant caveats. No randomized controlled trials met AlzRisk’s inclusion criteria, because the trials considered only risk for total dementia and did not look specifically at AD risk. Randomized controlled trials have shown that estrogen therapy begun late in life increases the risk for dementia, breast cancer, stroke, and heart disease (see ARF related news story). The AlzRisk results, which are comprehensively discussed here, highlight the stark differences between positive epidemiologic and negative trial data, and the need for better answers.
A possible explanation for this difference, favored by many scientists, is that hormone replacement therapy must be initiated at menopause to be protective (see, e.g., ARF Live Discussion). Two large trials, the Kronos Early Estrogen Prevention Study (KEEPS) and the Early Versus Late Intervention Trial With Estradiol (ELITE), are currently testing this “critical window” hypothesis, with data expected to come out over the next two years.
Other factors may account for the divergent results obtained from randomized, placebo-controlled clinical trials and analysis of epidemiological data, Weuve told ARF. In the past, women who took hormone replacement therapy were more likely to be well educated and health conscious than those who did not. This “healthy user bias” might have led to better cognitive outcomes among the group using hormones. Moreover, there are many different hormone formulations and ways of taking them: estrogen alone, or estrogen plus progesterone, higher versus lower doses, continuous versus sequential dosing, oral versus transdermal administration. Many epidemiological studies do not include these data, or if others do, sample sizes are too small to get meaningful data from comparing subgroups, Weuve said. This lack of data makes it difficult to make specific public health recommendations.
Francine Grodstein at Brigham and Women’s Hospital, Boston, wrote to ARF: “The meta-analysis was conducted across studies of ‘any’ hormone use versus no use…. However, ‘any’ hormone use is a construct used in research studies, and has no clinical relevance. One cannot tell a woman to take hormone therapy ‘any’ time; she must know when to take it, what to take, and when to stop taking it. Since such information is largely lacking from the literature, we cannot make any meaningful conclusions regarding the relation of hormone therapy to AD risk” (see full comment below).
Answering these questions will require large studies with well-characterized populations, Weuve agreed. “Right now it’s pretty clear that a 65-year-old woman who has never used estrogen should not start it,” Weuve noted, but other issues remain murky. The North American Menopause Society currently recommends against hormone replacement therapy to prevent dementia, but allows that short-term hormone use may be appropriate to treat menopausal symptoms.
ARF invites the scientific community to comment on this latest addition to the AlzRisk database.—Madolyn Bowman Rogers.