Estrogen, Cognition, and Mood: Surprising Findings From the KEEPS Trial

JoAnn E. Manson, MD, DrPH


July 31, 2015

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This is Dr JoAnn Manson, professor of medicine at Brigham and Women's Hospital and Harvard Medical School. I would like to talk today about a recent report on estrogen, cognition, and mood from the KEEPS trial (Kronos Early Estrogen Prevention Study)[1] that was published in PLOS Medicine last month. I would like to acknowledge that I'm one of the coauthors of this report and also one of the investigators on the KEEPS trial.

The study included 693 women. The average age was 53 years and all women were within 3 years of the onset of menopause. The women were randomized to one of three treatment groups. One group received oral conjugated estrogen at a daily dose of 0.45 mg with cyclical oral micronized progesterone at a daily dose of 200 mg (taken the first 12 days of the month). The second group received a transdermal estradiol (50 µg patch) with cyclical micronized progesterone for 12 days a month, and the third group received placebo. Over 4 years the investigators conducted detailed, in-clinic assessments of cognition, including verbal learning and memory, executive function, visual attention, and other domains, as well as assessments of affect and mood. After 4 years of treatment and follow-up, the results for both the oral and the transdermal estrogen were neutral for cognition and favorable for adverse events, in contrast to the adverse effects seen for cognition in the Women's Health Initiative (WHI) among women aged 65 years and older.[2]

The findings for mood were surprising and intriguing. Oral conjugated estrogen had a favorable effect on anxiety and depressive symptoms, whereas the transdermal estradiol had neutral effects.

Overall, the literature has been mixed and somewhat inconsistent in terms of the effects of estrogen on cognition, but in general the results have been more favorable for younger, newly menopausal women than for older women. The results in younger women generally have been neutral, as in the KEEPS trial, or favorable for cognition. In older women, the findings have been adverse, as in the WHI among women aged 65 and older. We certainly need more information on the effect of formulation and regimen on mood and cognition outcomes, and it would be good to have replication of the findings from this study in relation to these intriguing effects on mood.

What can we make of these findings? Can we further personalize hormone therapy decision-making? The study might suggest that for women with vasomotor and mood symptoms, there could be some advantages to oral conjugated estrogen. However, there are also advantages to transdermal estradiol. For example, we know that transdermal estrogen is less likely to increase sex hormone binding globulin and lead to a reduction in free or bioavailable testosterone.[2] Also, for women who have cardiometabolic syndrome or traits, transdermal estradiol has some advantages compared with oral estrogen because of the lack of first-pass liver metabolism.[2] This increasing body of research really does help to personalize the decision-making process for hormone therapy and suggests that we can make use of this information for tailoring treatment to women based on their personal preferences, symptoms, and risk-factor status.


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