The immediate future of hormone replacement therapy in the treatment or prevention of diseases does not look promising. A large-scale, prospective study of the most common formulation in the United States-estrogen with progestin-has been stopped early because of evidence that the hormone combination does more harm than good.

In the today’s issue of the Journal of the American Medical Association, the investigators of the Women's Health Initiative announce that they have halted the portion of the trial comparing estrogen plus progestin versus placebo in healthy postmenopausal women (n = 16,608). After approximately 5 years of follow-up (of a planned 8.5 years), the statistic for invasive breast cancer in the study group had exceeded the stopping boundary for this adverse effect. In addition, the global index that factors in both negative and positive effects of estrogen had tilted too far toward the negative. Small increases in the risk of breast cancer, coronary heart disease, stroke, and pulmonary embolism outweighed small decreases in the risk of hip fractures and colorectal cancer. The study found that for each 10,000 women in the estrogen/progestin group, there would be 8 more cases of invasive breast cancer a year than in the placebo group, 7 more heart attacks, 8 more strokes, and 8 more lung blood clots. On the other hand, there would be 5 fewer hip fractures and 6 fewer cases of colorectal cancer.

It is unclear what effect the findings will have on ongoing or planned trials of estrogen as a protective intervention for AD. The WHI authors stress that they could not distinguish the relative effects of estrogen versus progestin. They also note that they have not yet analyzed the data in this trial for endpoints such as gall bladder disease, diabetes, quality of life, or cognitive function. Such analyses might affect the equation both for individual women trying to decide whether to use hormone replacement therapy and for investigators conducting or planning hormone trials.—Hakon Heimer


  1. Does estrogen have a future in treating Alzheimer Disease?

    Comment by Mary Sano

    The Women’s Health Initiative (WHI) has provided startling and disappointing news about hormone replacement therapy (HRT). The authors have thoroughly addressed the issue of cardiovascular disease, osteoporosis and cancers while acknowledging the limitations of this study to answer other questions. For those of us studying Alzheimer’s disease and memory loss this report can help us further define the risks and benefits of a treatment with an unknown role in dementia.

    The (WHI) is a 15 -year study, which examines ways to prevent heart disease, breast and colorectal cancer, and osteoporosis. This study did not include dementia or memory loss as a primary outcome measures in its design. Results have recently been reported from over 16,000 women who were taking Prempro, a combination of estrogen and progestin. This large group of post-menopausal women, between the ages of 50 and 79 were followed for a mean of 5.2 years. Findings support an increased risk of breast cancer, stroke, coronary heart disease and thrombo-embolic disease and a decreased risk of colorectal cancer, hip fractures and total fractures. Overall the increased risk of negative outcomes attributed to this treatment was small, about 19 per 10,000 person years. There was no increased risk in mortality and no significant overall effect in these outcomes in the each of the 6 month data reviews until the eighth year of the study. It is important to note that the overall rate was very low, and in most cases, less than 2 % of the group reached these outcomes (1).

    But what of Alzheimer’s disease? Given these results is it reasonable to ask does HRT protect against AD or memory loss?. There is sufficient evidence to suggest that HRT does not have a role in treating those with AD (2). However there is significant epidemiological evidence that HRT use may prevent AD, and basic science data provides evidence for a role of estrogen in neural protection and in reduction of amyloid load. These results support potential efficacy, but how do we balance safety?

    Study designs to examine the prevention of AD typically select populations at high risk for disease such those over 75 where the incidence ranges from 2 to 5 % per year (3), or those who have a risk factor such as family history which predicts up to a three fold increase over age matched cohorts (4) or the presence of memory impairment which predicts incidence of up to 15% percent per year. Based on these numbers, in a typical cohort for an AD prevention trial the estimate of incident cases would range from 200 to 1500 cases in 10,000 person years (5). As little as a 10 % reduction in the rate of dementia (i.e. 20 cases) would balance the increased risk projected from the WHI to a typical clinical trial cohort. Certainly a 30% reduction in dementia projected from the several meta-analyses of observational epidemiological studies (6,7) would far outweigh the WHI finding. While such a benefit of HRT is only hypothesized, not demonstrated, it is this potential risk-benefit ratio that must be considered and weighed when deciding if a research question has public health value.

    There are no cures for Alzheimer’s disease, no treatments for cognitive loss and no known modifiable risk factors. AD is a progressive, degenerative disease that remains the major source of disability in people over 65 and the loss of quality of life is well documented and undeniable.

    It has taken many years to raise public awareness, to acknowledge that cognition is an important aspect of health. In an aging society, with the increasing risk of Alzheimer’s disease and memory loss, and in a world of growing technological complexity requiring intact cognition, it would be shortsighted to abandon studies of an agent that has the potential to prevent cognitive loss and AD. Thanks to the WHI we now know with confidence the small but apparent cardiovascular and breast cancer risks of HRT and we have a clearer view of the magnitude of benefit in AD prevention needed to outweigh these risks.

    View all comments by Mary Sano

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Primary Papers

  1. . Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA. 2002 Jul 17;288(3):321-33. PubMed.