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Online First: In the Clinic-Cognition: The Latest Study on Estrogen’s Effects on the Brain — It’s Complicated


The latest study on whether taking estrogen around the time of menopause is good or bad for the brain offers a few clues for researchers but falls short of settling the long-running debate.

The update comes from a follow-up study of women who had participated in a four-year randomized, controlled trial of estrogen replacement therapy, either receiving oral estrogen, transdermal estrogen, or placebo around menopause. Mayo Clinic researchers went back and evaluated 75 of the original 727 participants three years after the trial ended to see if there were any recent changes in cognitive status and brain structure.

Published in the March 21 online issue of Neurology, the follow-up found no differences in cognitive function between women who had received estrogen replacement around the time of menopause and those who had not.

Brain structure evaluations using magnetic resonance imaging (MRI) and in some cases positron emission tomography (PET) scans found varying results, but there was one difference in particular that the researchers reported as noteworthy: At the seven-year mark there was better preservation of dorsolateral prefrontal cortical volume in women who had used the estrogen patch compared to women on placebo, a finding that suggests that menopausal hormone replacement therapy (HRT) may have long-term effects in the brain.

The better volume in that region of the brain also correlated with less amyloid deposition throughout the entire brain, a possible hint that menopausal HRT might play a role in preventing Alzheimer's disease, said lead researcher Kejal Kantarci, MD, professor of radiology in the division of neuroradiology at Mayo Clinic in Rochester, MN.

Her group is now planning another follow-up study to reconnect with more of the original study cohort to see if any differences emerge now that the bulk of the women are into their mid-sixties. "It is possible that the effects of taking menopausal HRT become apparent only later in life," Dr. Kantarci told Neurology Today.


The new report is an outgrowth of the Kronos Early Estrogen Prevention Study (KEEPS), a randomized, controlled trial involving 727 participants who were in good cardiovascular health, ranged in age from 42 to 59, and were five to 36 months past their last menses. The women were randomly assigned to oral conjugated equine estrogen (Premarin, 0.45 mg per day), an estrogen patch (Climara 50µg a day), or a placebo pill or placebo patch. Cognitive testing and MRI exams were done at the start and at 18, 36, and 48 months.

For the follow-up study, MRI and cognitive testing were repeated three years after women stopped getting estrogen (or placebo), which amounted to seven years from the start. Of the 75 women in the follow-up, 68 also underwent a PET scan of the brain to check for amyloid deposition, a hallmark of Alzheimer's disease.

In addition to the finding of greater dorsolateral prefrontal cortical volume in women who had used the estrogen patch compared to placebo, the follow-up testing also found no significant differences on cognitive tests between the women on menopausal HRT and those on placebo.

While ventricular volumes had increased more in the oral estrogen group compared to placebo during the active phase of the study, there were no such differences observed three years after the therapy was halted.

There was increased volume of white matter hyperintensities in both the oral estrogen and estrogen patch groups compared to placebo, but the difference was only statistically significant in the oral therapy group.

What each of those findings means, or doesn't mean, is likely to be debated by researchers. For instance, the finding that there were no differences in cognition between the women who had taken HRT and those who did not could be seen as a good thing since fears that menopausal HRT could lead to negative cognitive consequences such as dementia did not pan out. But neither did taking HRT seem to provide any cognitive advantage over time.

The question of the increased white matter hyperintensities volume is another point of debate because it could suggest a continuing undesirable cardiovascular effect from menopausal HRT. Dr. Kantarci said the matter needs to be further explored using a larger cohort of KEEPS participants.

The researchers noted in their report in Neurology that while the density of estrogen receptors in the brain tend to decline with aging, HRT early in menopause may help delay the decline, thus allowing the receptor-mediated effects of estrogen on the brain, such as the ones observed in this study, to be maintained.

The study, funded by the National Institutes of Health and the Aurora Foundation, also had limitations, including the fact that the follow-up group was relatively small. The cohort —relatively young women with no cardiovascular risk matters — does not represent the overall universe of women.

Dr. Kantarci said she and a collaborator, Carey Gleason, PhD, a neuropsychologist from the University of Wisconsin, have received funding from the National Institute on Aging, to do another follow-up of the original KEEPS cohort. It will aim to re-evaluate close to 500 participants and will study multiple factors, including Alzheimer's disease pathology and cerebrovascular, cognitive, and mood health, Dr. Kantarci said.

"We will study the risks and benefits (of estrogen) on brain aging, cognitive health, and Alzheimer's disease pathology in the long-term," she said, information that may help women who are making decisions about whether they want to take estrogen to relieve immediate symptoms of menopause to have a longer view of the pros and cons.


Margaret McCarthy, PhD, professor and chair of the department of pharmacology at the University of Maryland School of Medicine, said the new report is unlikely to influence clinical decision-making around estrogen in the short term.

"We are not done understanding how post-menopausal hormone therapy can hurt and helps the aging brain," said Dr. McCarthy. She said the question is complicated for many reasons, including the fact that estrogen comes in varying formulations and is handled by the body differently depending on its form. Oral estrogen passes through the liver before entering the bloodstream, transdermal estrogen does not. The addition of progesterone to the estrogen regimen to protect against uterine cancer adds another possibly confounding factor in analyzing the pros and cons of estrogen, she said.

Dr. McCarthy said she personally feels that HRT has received a bad rap, in large part because of the results of the Women's Health Initiative Memory Study, which studied post-menopausal women older than 65 years old to see if estrogen could protect against dementia and mild cognitive impairment. The study caused alarm when it instead indicated that estrogen therapy can increase the risk of those conditions, at least in that study of older women, some long past menopause.

"I think a lot of people were scared off (of estrogen) inappropriately," Dr. McCarthy said.

She said gynecologists often report that their patients tell them that taking estrogen for menopause helps clear the fog in their brain and lifts their mood. She notes there are animal studies, and some observational studies, to suggest that taking estrogen around the time of menopause may provide some long-term benefits for the brain as well.

"The story hasn't been completely told yet," Dr. McCarthy said. "We need more information."

Victor W. Henderson, MD, FAAN, professor of health research & policy (epidemiology) and of neurology & neurological sciences at Stanford University, said the follow-up study from Mayo Clinic was very well done, but he said its findings don't lend themselves to sweeping pronouncements about estrogen.

"It tells us in part that the global cognitive effect of estrogen in healthy women isn't necessarily good or bad," Dr. Henderson said. He said the results of the follow-up MRI and PET scans — for instance, slightly less volume change in the dorsolateral prefrontal cortex in women on the estrogen patch and a correlation between that finding and less overall amyloid in the brain — will likely interest Alzheimer's researchers. But he cautioned that "biomarkers in and of themselves aren't important endpoints," unless they go hand-in-hand with clinical findings. "Ultimately the clinical finding is what is most important," said Dr. Henderson, who is director of the Stanford Alzheimer's Disease Research Center.

He said the study illustrates the complexity of studying hormonal effects on the brain. "Estrogen might have one effect on Alzheimer's disease — an effect on amyloid for example — and there might a different effect on cognitive aging," he said. "With respect to Alzheimer's disease risk in middle-age women, I don't think the estrogen question is fully settled."

Claudia Kawas, MD, professor of neurology and neurobiology & behavior at the University of California, Irvine, agreed that "the jury is still out" on the effects of HRT on the brain. She's been interested in the cognitive effects of estrogen for decades. She was a co-investigator for a clinical trial of estrogen that began in 1998 to assess whether it had a protective effect in women with a family history of Alzheimer's disease. But the trial was halted after the Women's Health Initiative Memory Study results came out in 2002, she said.

 Dr. Kawas said the negative cognitive findings, on top of findings that HRT can increase the risk of cardiovascular events, led to the belief among many health practitioners that "no one should go on it."

Dr. Kawas, who is also the Al and Trish Nichols Chair in Clinical Neuroscience, said studies such as the new one from Mayo Clinic, while of interest to researchers studying aging and Alzheimer's, can be frustrating in general because "people want an easy answer." She said that often clinical trial findings don't all go in the same direction, which doesn't necessarily mean that a therapy isn't beneficial.

Regardless of how HRT research continues to unfold, Dr. Kawas said women tend to have strong opinions about whether estrogen will help get them through menopause. "Women seem to either love it or not like it at all," she said.


Kantarci K, Tosakulwong N, Lesnick TG, et al. Brain structure and cognition 3 years after the end of an early menopausal hormone therapy trial​. Neurology 2018; Epub 2018 Mar 21.