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Stanford Report, May 28, 2003

Study links adverse memory, dementia effects to HRT Letters about the findings have been sent to study participants


By MITZI BAKER

The final nail may have been driven into the coffin for the most commonly prescribed combination hormone replacement therapy for women.

The largest study of HRT to date has found that a woman’s risk of developing dementia, including Alzheimer’s disease, doubles when taking estrogen plus progestin. HRT also failed to protect cognitive function.

The results of this analysis, one of three published from the same large study in the Journal of the American Medical Association today, were unexpected and in marked contrast to earlier research on the effects of hormone therapy on Alzheimer’s disease and dementia, which found half as many cases of Alzheimer’s among women taking estrogen.

The study investigated whether taking estrogen (for women with a hysterectomy) or estrogen plus progestin also known as combination therapy (for women with a uterus) prevents dementia or normal age-related memory decline. Progestin is added to estrogen to counteract the increased rates of uterine cancer seen in menopausal women on estrogen.

The findings are part of the analysis of data from the Women’s Health Initiative Memory Study, or WHIMS, a substudy of the federally funded Women’s Health Initiative.

Last July, the combination therapy component of the entire study was halted when it became clear that the increased risk of heart disease, breast cancer, blood clots and stroke among the women on combination therapy outweighed its potential benefits of fewer fractures and colorectal cancers.

"For women age 65 and over, the balance is now so far tipped in the direction of harm for going on estrogen plus progestin that it’s pretty difficult to justify starting any woman in her 60s on these hormones, no matter how much you worry about her bones," said Marcia Stefanick, PhD, associate professor of medicine at the Stanford Center for Research in Disease Prevention, and one of the researchers involved in the nationwide study.

The combination therapy arm of WHIMS, which was funded by Wyeth Pharmaceuticals, included 4,532 postmenopausal women age 65 and older who were followed for an average of 4.2 years at 39 clinical centers including Stanford. Almost half of the women received Prempro, the combination therapy drug produced by Wyeth, while the other women received a placebo.

In order to address the question of whether estrogen alone or combination therapy could lower rates of cognitive decline and/or prevent dementia, the researchers annually asked participants questions to test memory and other cognitive function, such as attention, abstract reasoning and ability to do calculations. Some women were further analyzed by a specialist in cognitive function.

These new findings about dementia add to the gloomy picture painted by the failure of previously suspected benefits of HRT to materialize.

Out of more than 4,500 women questioned, 61 developed dementia during the course of the study; 66 percent of those cases occurred among women on combination therapy while 34 percent occurred in women taking a placebo. This represents an increase per year from 22 women per 10,000 with dementia in the placebo group to 45 women per 10,000 in the combination therapy group.

The figures presented in the new analysis add to the concerns raised by study officials when they halted the combination therapy investigations last July.

Along with increased risks of heart disease, stroke and breast cancer in the range of 26 to 41 percent, they are also now seeing more than a 200 percent increase in dementia.

In addition to evaluating the effects of the combination hormone therapy on dementia and mild cognitive impairment, the study also looked at global cognitive function including concentration, language, memory and abstract reasoning.

In this area, women taking the combination therapy performed slightly worse than the placebo group.

The WHIMS investigators continue to monitor women in the combination hormone therapy study arm. The study of estrogen alone continues and will be analyzed when the trial concludes.

"Most people realize that it’s not very wise to start women on hormones at age 60-plus, but there is still a lot of debate about starting women on hormones at the time of menopause when the risks for breast cancer, heart attacks, strokes and dementia are relatively low," Stefanick said.

She added that at an early age, the benefits to bones are also low, so the only clear reason to use HRT would be to treat unusually severe menopausal symptoms.

Stefanick’s group at Stanford has prepared letters to the 700 local participants in the combination therapy and the estrogen arms of the study, explaining what these findings mean.

In addition to Stefanick, the Stanford team included Barbara Sommer, MD, director of geriatric psychiatry, John Barry, MD, assistant professor of psychiatry and behavioral sciences and Allison Akana, clinic coordinator.





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