Estradiol Has No Effect On Memory, Cognition After Menopause Onset

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No effect seen at 6 or 10+ years after menopause onset.

Initiation of estradiol within 6 years or 10 or more years after menopause onset demonstrated no differences in verbal memory, global cognition, or executive function.

Typically, menopausal hormone therapy (MHT) is prescribed for the relief of vasomotor symptoms. However, there is inconsistent data on the impact of MHT on cognition and memory and if the timing of MHT initiation changes the outcome.

In order to assess the impact of MHT on cognition in early and late menopause, Victor Henderson, MD, MS, of Stanford University in Los Angeles, California, and colleagues conducted the randomized, double-blind, placebo-controlled Early vs Late Intervention Trial with Estradiol (ELITE). Participants included women within 6 years or more than 10 years after menopause onset who were randomized to receive either 1 mg daily of oral 17β-estradiol or progesterone vaginal gel (for those with a uterus) or placebo. Standard neuropsychological assessments for verbal episodic memory, executive function, and global cognition were conducted at 2.5 and 5 years.

Cognitive assessment at baseline and at 2.5 years was available for 567 participants, while 455 participants (71%) completed assessments at year 5. The mean treatment duration was 57 months. The investigators noted a high adherence rate to placebo or estradiol of more than 98% for both the early and late groups.

The researchers found no significant difference in mean composite scores for verbal memory between the treatment groups and placebo (-0.06, 95% CI: -0.22 to 0.09). Likewise, the differences were similar for both the early and late MHT treatment groups (2-tailed interaction P=.88).  Further, there were no significant differences for the interactions between menopause groups and treatment groups for global cognition (-0.025, 95% CI: -0.18 to 0.13) or executive function (-0.04, 95% CI: -0.21 to 0.14).

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“Results of this randomized, double-blind, placebo-controlled trial fail to confirm the timing hypothesis for cognitive outcomes in healthy postmenopausal women,” the researchers wrote.  Although the study was not powered to detect small differences, the authors noted that subgroup analysis did not detect differences in cognition outcomes for natural vs surgical menopause, those with or without vasomotor symptoms, past use of MHT, presence or absence of a uterus, and a history of the APOE ε4 allele.

“These results indicate that postmenopausal women near the time of menopause — in addition to women further from the time of menopause — should not expect MHT to enhance cognition,” the authors concluded.

The study was funded by a grant from the National Institutes of Health and study drugs were supplied by Teva Pharmaceuticals and Abbott Laboratories. Several authors reported research support from the NIH.


Henderson VW, St. John JA, McCleary CA, et al. Cognitive effects of estradiol after menopause: A randomized trial of the timing hypothesis. Neurology. 2016;87:1–10.