Hormones Soon After Menopause Do Not Affect Cognition

Menopausal hormone therapy (MHT) for up to 4 years after the last menstrual period did not improve cognition but did improve some mood symptoms, according to results of a study published online June 2 in PLOS Medicine.

Hormone therapy to suppress symptoms of menopause has been associated with increased risk for cognitive decline in women older than 65 years, but not much is known about its effects on recently postmenopausal women. The “critical window” hypothesis states that MHT begun near the start of menopause may reduce future risk of developing neurodegenerative disorders and/or improve cognition. However, the study design addressed changes in markers of cognition and mood, not dementia.

As part of the KEEPS-Cog (Cognitive and Affective Study of the Kronos Early Estrogen Prevention Study) trial of the National Institutes of Health’s National Institute on Aging, Carey Gleason, PhD, from the University of Wisconsin - Madison, and colleagues randomly assigned 693 recently postmenopausal women to take estrogen pills daily and progesterone pills for the first 12 days of each month (220 women), wear transdermal estradiol patches and take progesterone pills for the first 12 days of each month (211 women), or take placebo pills and patches (262 women).

The researchers followed the participants for up to 4 years and assessed effects on cognition (verbal learning/memory, auditory attention/working memory, visual attention/executive function, and speeded language/mental flexibility) and mood. The average age of study participants was 52.6 years, and the average time past the last menstrual period was 1.4 years.

Neither treatment regimen improved cognition, but women who took pills only improved in depression and anxiety symptoms (tension-anxiety and depression-dejection) compared with women receiving placebo. Mood did not improve for women wearing patches. The researchers had hypothesized improvement in cognition and mood among the women wearing the patches, but not among those taking pills, on the basis of differences in how the body processes drugs from different routes of administration.

The investigators also genotyped 568 women for the apolipoprotein E (APOE) ε4 gene variant associated with increased risk for Alzheimer disease, but found it was not overrepresented in any of the three study groups. Time since last menstrual period also did not influence mood or cognitive response to MHT.

The results are consistent with those of the Women’s Health Initiative Memory Study of Younger Women trial, that “MHT is neither deleterious nor beneficial for cognition in younger women,” the researchers write. They suggest that the findings be used in clinical decision-making, such as informing a patient that MHT may improve vasomotor symptoms but not menopause-related cognitive fuzziness, and that a few years on the therapy shortly after menopause is recognized does not appear to have negative cognitive effects, as seen in older women receiving MHT.

Limitations of the study include its covering only 4 years, the inability to truly blind the protocol because women could recognize abatement of menopause symptoms, and limited generalizability beyond the participants, most of whom were white, well-educated, and at low risk for cardiovascular disease. The results also do not apply to women who had had hysterectomies.

One coauthor receives funds from Nora Therapeutics and Ferring Pharmaceuticals. Another coauthor has stock options from Menogenix. Another coauthor consults for Bayer, AbbVie, Pfizer, and Therapeutics MD. The other authors have disclosed no relevant financial relationships.


PLoS Med. Published online June 2, 2015.

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