Updated: December 04, 2018

Getty Images

 By Anne Harding

MONDAY, Jan. 12, 2008 ( — Not too long ago, millions of postmenopausal women were taking estrogen as part of hormone therapy to protect their hearts, prevent cancer, and keep their brains sharp.

But two new studies in the journal Neurology show that not only does hormone replacement therapy increase the risk of heart attack, stroke, blood clots, and breast cancer in women over the age of 65, but it also shrinks their brains.

“This is extra-double-triple reason not to go on estrogen after 65,” says Constantine Lyketsos, MD, of the Johns Hopkins Bayview Medical Center in East Baltimore, Md. Dr. Lyketsos, an expert on dementia treatment, was not involved in the research.

Experts say the findings should not be cause for alarm among younger women who are taking estrogen according to the current guidelines. The U.S. Food and Drug Administration recommends that women who take hormones to treat hot flashes and other menopausal symptoms start doing so as early as possible, at the lowest effective dose, for the shortest time possible. (Women who haven’t had a hysterectomy need to take a combination of estrogen and progestin, because estrogen alone increases the risk of cancer of the lining of the uterus; women who’ve had their uterus removed can take estrogen alone.)

There is good evidence that for younger women, estrogen can actually help defog the brain, improve mental function, and possibly even protect against Alzheimer’s disease decades later, says Pauline Maki, PhD, who runs a research program on steroid hormones’ effect on cognitive function at the University of Illinois at Chicago. She was not involved with the new studies.

One of the most plausible explanations for this paradox is the “healthy cell bias of estrogen.” In other words, estrogen is good for healthy cells, and bad for unhealthy cells, she explains. In her own research, Maki has shown that women who experience an unusually high number of hot flashes during menopause have worse verbal memory.

“What I think happens is that women’s brains during hot flashes, while they’re not sleeping as well, the brain material is still fine,” Maki says. “When you introduce estrogen to these women, you’re introducing it into a healthy cell, and the results cognitively are generally beneficial.”

Older women’s brain cells are likely to be in worse shape than younger women’s, especially if their mental faculties are already fading. “The scenario that seems to arise is one where [hormone therapy] at the dose of this trial is harmful to the frailest brains, but perhaps not to the strongest ones,” Giovanni Frisoni, of the National Center for Research and Care of Alzheimer’s Disease in Brescia, Italy, says. Dr. Frisoni has studied estrogen’s effects on brain volumes, but was not involved in the new research.

Next: The amount of atrophy is small, but real

The two news studies are offshoots of the Women’s Health Initiative Memory Study (WHIMS), which found an increased risk of dementia in women on hormone therapy. WHIMS is a parallel study to the Women’s Health Initiative, the landmark clinical trial, which in 2002 found that hormone therapy was hurting some women more than it helped them.

The WHIMS researchers had suspected that the women on hormone therapy would have blood vessel disease in the brain, which can destroy brain tissue by restricting blood flow to cells, leading to mental impairment and resulting in vascular dementia. To investigate, two WHIMS teams examined brain MRI scans from 1,403 women participating in the study.

“Much to our surprise,” something else was going on," says Susan M. Resnick, PhD, of the National Institute on Aging’s Intramural Research Program, who led one of the studies. Two memory-related brain regions, the frontal lobes and the hippocampus, were slightly but definitely smaller among women taking hormones. “These negative effects were really most evident in women who seemed to already be having some low cognitive function and possibly some memory problems,” Resnick says.

Among the women with the smallest amount of vascular damage in their brains, she adds, hormone therapy had no effect on the volume of these brain regions.

The degree of atrophy suggests a small but real increase in the dementia risk, according to Resnick. Starting hormone therapy likely accelerated the disease process in already-vulnerable women, she explains.

In the second study, Laura H. Coker, PhD, of Wake Forest University Health Sciences, in Winston-Salem, N.C., and colleagues, found that women taking estrogen and progestin had slightly larger areas of vascular damage in their brains than those on placebo, but the difference wasn’t significant, making it clear that vascular disease wasn’t behind the women’s increased dementia risk.

“When this type of hormone therapy is initiated, you get volume loss in these key brain areas, and where there’s loss of volume, there’s loss of function,” says Maki.

Investigators are looking into other formulations of estrogen and progestin, as well as very low doses of the hormones, to see if they might be safer than the formulation and relatively higher dose taken by participants in the Women's Health Study.

In the 1990s, more than half of menopausal women said they had taken hormones at some point, and one-third took them for at least five years. About 38% of women ages 50 to 70 were taking hormones, according to surveys at the time.

Prescriptions for the two most commonly prescribed hormone products, Premarin and Prempro, dropped from 61 million prescriptions in 2001 to 21 million in 2004, according to the National Cancer Institute.