EMBARGOED by Journal of the American Medical Association for 4 pm EDT May 27, 2002

Rates of Dementia Increase With Combination Hormone Therapy

Older women taking combination hormone therapy had twice the rate of dementia, including Alzheimer's disease (AD), compared with women who did not take the medication, according to new findings from a memory substudy of the Women's Health Initiative (WHI). The research, part of the Women's Health Initiative Memory Study (WHIMS) and reported in the May 28, 2003, Journal of the American Medical Association (JAMA), found the heightened risk of developing dementia in a study of women 65 and older taking PremproTM, a particular form of estrogen plus progestin hormone therapy.

The study also found that the combination therapy did not protect against the development of Mild Cognitive Impairment, or MCI, a form of cognitive decline less severe than dementia.

Leon Thal, M.D., chair of the UCSD Department of Neurosciences and director of the national Alzheimer's Disease Cooperative Study, was a co-author of the paper. He noted that "whether unopposed estrogens can reduce dementia remains to be seen."

The findings were reported from data collected at 39 sites, including UCSD, involved in the study. Funding for the WHIMS substudy was provided by Wyeth Pharmaceuticals, which manufactures PremproTM, and provided it for use in the WHI trials. The larger WHI trials are supported by the National Heart, Lung, and Blood Institute (NHLBI) of the NIH. The National Institute on Aging has been involved in reviewing the current findings as the NIH's lead institute on age-related memory change and dementia.

Importantly, the women in the combined estrogen plus progestin (E+P) arm of the WHI and substudies such as WHIMS are no longer taking the combination therapy as part of the research trials. In July 2002, all combination therapy components of the WHI were halted when it was found that increased risk of breast cancer, heart disease, stroke, and blood clots among participating women on combined estrogen plus progestin therapy outweighed benefits for hip fractures and colorectal cancer.

As they did in the July 2002 report on increased risk of breast cancer, heart disease, and stroke, researchers stress with today's announcement that the data should be viewed in perspective. While the increased risk of dementia is significant when calculated over a large population of women, the risk to any individual older woman is actually relatively small.

The current findings address combined estrogen plus progestin therapy, specifically PremproTM, among women 65 years of age and older. For younger women, the cognitive risks and benefits of this combination therapy are unknown. Short-term hormone therapy in younger women for some symptoms of menopause has been approved by the U.S. Food and Drug Administration and the new findings do not directly address decisions about such treatment. Researchers and officials at the NIH suggest that women of any age consult with a physician about their individual risks and benefits.

The memory study findings on women 65 and older showed that over a 5-year period:

About 4,500 women participated in the WHIMS substudy of women 65 and older. Once the women met the criteria for participation, including screening tests to make sure they did not have dementia at the study's start, they were randomly assigned to take estrogen plus progestin therapy (one pill per day of conjugated equine estrogen (CEE), 0.625 mg, plus medroxyprogesterone acetate (MPA), 2.5 mg brand name PremproTM or a look-alike placebo. Cognitive status was evaluated annually, and women who showed signs of decline were examined in greater depth to further characterize their cognitive status.

The researchers looked at several other factors that might influence cognitive status, including socioeconomic status, educational attainment, prior estrogen or progestin use history, and use of cholesterol lowering medications or aspirin or other non-steroidal anti-inflammatory drugs. These factors were not significantly different between the therapy group and the placebo group and did not account for the differences in rates of cognitive decline, the researchers said.

A second report in the same issue of JAMA showed general cognitive status to be adversely affected by the combination therapy in older women. WHIMS investigator Stephen Rapp, Ph.D., Wake Forest University School of Medicine, and colleagues at the other sites examined the participants' performance on an often-used test, the Modified Mini-Mental State Exam (3MS). All participants' average performance on the cognitive tests actually improved over time, which researchers suggest may be due to a "practice effect" as a result of taking the same tests every year. However, the rate of increase in the performance of women on the 3MS was somewhat lower for women in the combination therapy group when compared with women receiving the placebo.

About 3,000 women are continuing to participate in a second arm of the WHIMS research, a study of the effects on cognition of estrogen-only therapy in women who have had a hysterectomy. A Data Safety Monitoring Board will continue to monitor the risks and benefits for that part of the study.

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