Hutch News Stories

Combined hormone-replacement therapy: Risk of dementia adds to list of concerns

After linking estrogen plus progestin to increased risk of breast cancer, heart disease and stroke, Women's Health Initiative researchers discover cognitive connection
woman holding prescription drugs
Two Women's Health Initiative memory studies reveal that combined hormone-replacement therapy doubles the risk of dementia in women 65 and older and is also associated with an overall decline in cognitive ability. The results may aid women still undecided about use of the therapy. Photo by Jim Linna

Postmenopausal women who are undecided about whether to use hormone- replacement therapy now have another health risk to ponder. Research published last month by the Women's Health Initiative (WHI) memory study shows combined-hormone therapy can double the risk of dementia-including Alzheimer's disease-in women age 65 and older.

Researchers also reported that combination-hormone therapy (estrogen plus progestin) did not protect against the development of mild cognitive impairment, or MCI, a form of cognitive decline less severe than dementia. In an accompanying study, scientists found that hormone use was associated with an overall decline in general cognitive ability as measured by a commonly used test to evaluate mental status.

The conclusions are based on data collected from a large, randomized trial evaluating the health risks and benefits of estrogen plus progestin. The trial, supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health (NIH) ended abruptly last July when scientists found combination-hormone therapy was associated with increased incidence of breast cancer, heart disease and stroke.

Center connection

The results of the cognitive analyses, led by researchers at Wake Forest University Medical School, appear in two papers in the May 28 issue of the Journal of the American Medical Association. Dr. Deborah Bowen, an investigator in the Public Health Sciences Division is a co-author of one of the papers. Fred Hutchinson houses the clinical coordinating center for the WHI, a 15-year, nationwide randomized trial and observational study designed to find ways to prevent cardiovascular disease, osteoporosis and cancer.

Bowen said that the cognitive analyses were initiated to determine the validity of earlier reports that hormone therapy could reduce risk of dementia and memory loss.

"Both animal studies and human observational studies, as well as short-term, human randomized trials, suggested that hormone-replacement therapy protected against dementia," she said. "In fact, at least for combination therapy, the risk doubles."

Although the overall risk of dementia is low in the general population and remains so even for those taking hormones, Bowen said that the study findings are significant enough to impact the decisions of women who are still weighing the risks and benefits of the therapy.

Dr. Andrea LaCroix, co-principal investigator of the clinical coordinating center and a PHS investigator, agreed.

"Despite the known risks associated with its use, some women have been holding out hope that hormone replacement would be good for memory, but that clearly doesn't seem to be the case for estrogen-plus-progestin therapy," she said. "The results will ease the decision-making process for those women."

Dementia risk doubled

LaCroix said that the WHI study to assess the effects of estrogen-only therapy in women is continuing.

The memory studies were funded by Wyeth Pharmaceuticals, which manufactures Prempro, the combined-hormone medication provided for use in the WHI trials.

The new findings are based on an evaluation of combined estrogen-plus-progestin therapy among women 65 years of age and older. For younger women, the cognitive risks and benefits of this combination therapy are unknown.

In one of the two papers, researchers reported that the risk of dementia among women taking estrogen and progestin was about twice that of women taking placebo pills. Of the 61 cases of dementia diagnosed among the 4,500 women who participated in the study, 40 of those cases occurred among women on combination therapy while 21 occurred in women taking placebo.

Alzheimer's disease

Most of the dementia found among women participating in the study was classified as probable Alzheimer's disease, with vascular dementia ranking second. There were 20 cases of Alzheimer's disease among the 40 dementia cases in women in the combination therapy group (50 percent of the cases); in women on placebo, 12 of the 21 cases (57 percent) of dementia were deemed Alzheimer's disease.

There was no significant difference in the risk of being diagnosed with MCI alone when the placebo and combination-therapy groups were compared, meaning that hormone use did not protect against this condition.

The researchers looked at several other factors that might influence cognitive status, including socioeconomic status, educational attainment, history of prior estrogen or progestin use, and use of cholesterol-lowering medications or aspirin or other nonsteroidal anti-inflammatory drugs. These factors were not significantly different between the therapy and the placebo groups.

The second study showed general cognitive status to be adversely affected by the combination-therapy in older women. Researchers evaluated study participants' performance on the Modified Mini-Mental State (3MS) Exam. The exam measures more than 10 different aspects of thinking, including short- and long-term memory and the ability to orient three-dimensional figures in space.

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 memory 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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