The brain-volume findings, published in today's issue of Neurology, are the latest from the Women's Health Initiative, a landmark government study of postmenopausal women. Over the last six years, it has firmly established that, contrary to decades of conventional wisdom, the risks of hormone therapy outweigh the benefits.

Today's finding also came with a surprise. Researchers had theorized that supplemental estrogen, with or without the synthetic hormone progestin, caused memory and thinking problems by triggering tiny, symptomless strokes. But the new research, which involved magnetic resonance imaging (MRI) of the brains of 1,400 Women's Health Initiative participants, linked cognitive problems to brain shrinkage - not strokes.

"This was a surprise to many of us," said Susan Resnick, a National Institute on Aging neuropsychologist who conducted the new research.

Like many other scientists, Resnick conducted studies in the 1990s that suggested, based on indirect evidence, that hormone therapy could ward off dementia, even Alzheimer's disease.

The Women's Health Initiative was the first huge study to randomly assign to women to take hormones or a placebo, then follow them for years.

For the new analysis in Neurology, MRIs were conducted and read by University of Pennsylvania radiologists who had no idea which women had taken hormones and which had taken placebo.

The women, now ages 71 to 89, were at least 65 when they joined the Women's Health Initiative, and took hormone therapy or fake pills for four to six years.

The two groups had no differences in the amount of brain scarring, a sign of strokes. The hormone-takers, however, had significant changes in the frontal lobe and the hippocampus, two areas critical to thinking and memory. Compared with nonhormone-takers, these women had small but significant losses in volume in these two areas.

The hormone-takers' total brain volume was also smaller by 3.3 cubic centimeters, but this was not statistically significant. The average brain size of women in both groups was about 1,090 cubic centimeters, so such a tiny shrinkage could have been by chance.

Women who had scored poorly on mental-function tests when they enrolled in the Women's Health Initiative had the greatest shrinkage of their hippocampus. (All Women's Health Initiative participants were given baseline mental tests at enrollment.)

Resnick and her coauthors speculate that the women with the greatest loss were already suffering from a neurodegenerative disease process that hormone therapy worsened.

Exactly how remains unclear. Hormone-therapy formulas contain so many chemical components that pinpointing a potentially toxic one is difficult, Resnick said.

Wyeth Pharmaceuticals, based in Collegeville, donated the hormone therapy used in the Women's Health Initiative.

James H. Pickar, the company's assistant vice president for clinical research, pointed out that the latest research does not change the current advice for menopausal women: Take hormones only to relieve transitory menopausal symptoms, notably hot flashes. Use the lowest effective dose for the shortest possible time.

Nor can the brain-volume data be extrapolated to hormone users younger than 65. Indeed, Pickar said, in 2007, an analysis of Women's Health Initiative data found that participants who took hormone therapy before age 65 were 50 percent less likely to develop Alzheimer's or dementia than those who did not take therapy before 65.

Some evidence suggests that giving hormones to women only during the menopausal transition - around age 50 - is beneficial, especially for their hearts. Although the Women's Health Initiative showed that therapy increased the risks of heart attacks, strokes, breast cancer, and dangerous blood clots, most of the 27,500 participants were long past menopause.

To try to tease out the importance of the timing of therapy on cognitive function, Laura H. Coker of Wake Forest University, an author of today's research, is planning to give updated mental tests to women who were about 50 when they enrolled in the Women's Health Initiative. She also hopes to do MRIs of their brains.