Long-term effects of conjugated equine estrogen therapies on domain-specific cognitive function: results from the Women's Health Initiative study of cognitive aging extension

Abstract

Objectives: To determine whether small decrements in global cognitive function that conjugated equine estrogen (CEE) therapies have been shown to produce in older women persist after cessation and extend to specific cognitive domains.

Design: Randomized controlled clinical trial.

Setting: Fourteen clinical centers of the Women's Health Initiative.

Participants: Two thousand three hundred four women aged 65 to 80 free of probable dementia at enrollment.

Intervention: CEE 0.625 mg/d with or without medroxyprogesterone acetate (MPA, 10 mg/d) and matching placebos.

Measurements: Annual administrations of a battery of cognitive tests during and after the trial.

Results: Assignment to CEE-based therapies was associated with small mean relative decrements in global cognitive function and several domain-specific cognitive functions during the trial, which largely persisted through up to 4 years after the trial. The strongest statistical evidence was for global cognitive function (0.07-standard deviation decrements during (P=.007) and after (P=.01) the trial. For domain-specific scores, the mean decrements were slightly smaller, were less significant, and tended to be larger for CEE-alone therapy.

Conclusion: CEE-based therapies, when initiated after the age of 65, produce a small broad-based decrement in cognitive function that persists after their use is stopped, but the differences in cognitive function are small and would not be detectable or have clinical significance for an individual woman. Differences in effects between cognitive domains suggest that more than one mechanism may be involved.

Figure 1

Follow-up during WHISCA and the WHISCA Extension

Figure 2a

Fitted mean (with 95% confidence intervals) standardized global cognition test scores over time from women grouped by WHI treatment assignment with adjustment for baseline 3MS score, trial (CEE+MPA vs CEE-Alone), age, education, race/ethnicity, smoking status, body mass index, hypertension, alcohol intake, prior cardiovascular disease, diabetes, prior use of hormone therapy, and prior use of oral contraceptives. The left-hand axis provides units in the original scale. The lower panel provides the number of women who contributed to each data point and the percentage of measurements that were collected during on-trial.

Figure 2b

Fitted mean (with 95% confidence intervals) standardized verbal fluency test scores from women grouped by WHI treatment assignment with adjustment for baseline 3MS score, trial (CEE+MPA vs CEE-Alone), age, education, race/ethnicity, smoking status, body mass index, hypertension, alcohol intake, prior cardiovascular disease, diabetes, prior use of hormone therapy, and prior use of oral contraceptives.