. 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.

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  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.

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  1. Safety Concerns Derail Estrogen/Progestin Trial