COMMENTARY

Estrogen and Cognition: Another Piece in the Puzzle

JoAnn E. Manson, MD, DrPH

Disclosures

August 05, 2016

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Hello. This is Dr JoAnn Manson, professor of medicine at Harvard Medical School and Brigham and Women's Hospital. I would like to talk about two interesting studies on estrogen and cognition that were published in July, one from the ELITE trial published in the journal Neurology[1] and one from the KEEPS trial published in the Journal of Alzheimer's Disease.[2]

The research on hormone therapy and cognition has been somewhat inconsistent. Observational studies have suggested that women who start hormone therapy in early menopause may have a lower risk of developing Alzheimer's disease. Some small-scale randomized trials of women with early surgical menopause have suggested that there may be some cognitive benefits of estrogen therapy. But overall there is very little research on hormone therapy and cognition. The trials that have been done among women in early menopause have shown generally neutral results. For example, in the Women's Health Initiative, among women who were randomized within 5 years of the onset of menopause, cognitive testing done at the end of the trial suggested neutral results for the WHIMS-Y study,[3] in contrast with the increased risk for cognitive decline that was found in WHIMS[4] among women who were randomized at age 65 or older. And in the overall KEEPS trial, there were neutral effects on cognition with both the transdermal and the oral estrogen therapy.

In the ELITE trial, which tested the timing hypothesis comparing women who started hormone therapy within 6 years of the onset of menopause versus women starting at least a decade after menopause, the results for cognition were overall neutral. This was in contrast to the results for atherosclerosis progression[5] which showed that in the women who started earlier, there was slowing of progression by carotid intima media thickness (IMT) in women within 6 years of the onset of menopause compared with placebo, but not in the women who started more than a decade past menopause.

In the KEEPS trial,[2] which was a substudy at the Mayo Clinic site, there was a suggestion that the women who were randomized to transdermal estradiol (a 50-µg patch) had less amyloid beta deposition by PET scanning than the women who were randomized to placebo. The differences were not seen in the oral conjugated estrogen arm. The reduction in amyloid beta with transdermal estradiol was particularly pronounced among the women who had the APOE-Ɛ4 genotype, suggesting that women with higher genetic risk were more likely to have this effect. It will be particularly important to look at whether the overall KEEPS trial participants in a larger group—hopefully this will be done in the future in several hundred women as opposed to 68 women at the Mayo site—also show evidence for less amyloid beta deposition with transdermal estradiol.

It also will be particularly important to look at women who have moderate to severe hot flashes and night sweats and have clear indications for hormone therapy, and see whether estrogen has an effect on cognition in those women. At the present time, we do not recommend that hormone therapy be used expressly for the purpose of trying to prevent cognitive decline, but it remains appropriate for management of distressing, bothersome hot flashes, night sweats, and treatment of menopausal symptoms in appropriate candidates.

Thank you for your attention. This is JoAnn Manson.

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