Long-term cognitive effects of menopausal hormone therapy: Findings from the KEEPS Continuation Study

Abstract

Background: Findings from Kronos Early Estrogen Prevention Study (KEEPS)-Cog trial suggested no cognitive benefit or harm after 48 months of menopausal hormone therapy (mHT) initiated within 3 years of final menstrual period. To clarify the long-term effects of mHT initiated in early postmenopause, the observational KEEPS Continuation Study reevaluated cognition, mood, and neuroimaging effects in participants enrolled in the KEEPS-Cog and its parent study the KEEPS approximately 10 years after trial completion. We hypothesized that women randomized to transdermal estradiol (tE2) during early postmenopause would show cognitive benefits, while oral conjugated equine estrogens (oCEE) would show no effect, compared to placebo over the 10 years following randomization in the KEEPS trial.

Methods and findings: The KEEPS-Cog (2005-2008) was an ancillary study to the KEEPS (NCT00154180), in which participants were randomized into 3 groups: oCEE (Premarin, 0.45 mg/d), tE2 (Climara, 50 μg/d) both with micronized progesterone (Prometrium, 200 mg/d for 12 d/mo) or placebo pills and patch for 48 months. KEEPS Continuation (2017-2022), an observational, longitudinal cohort study of KEEPS clinical trial, involved recontacting KEEPS participants approximately 10 years after the completion of the 4-year clinical trial to attend in-person research visits. Seven of the original 9 sites participated in the KEEPS Continuation, resulting in 622 women of original 727 being invited to return for a visit, with 299 enrolling across the 7 sites. KEEPS Continuation participants repeated the original KEEPS-Cog test battery which was analyzed using 4 cognitive factor scores and a global cognitive score. Cognitive data from both KEEPS and KEEPS Continuation were available for 275 participants. Latent growth models (LGMs) assessed whether baseline cognition and cognitive changes during KEEPS predicted cognitive performance at follow-up, and whether mHT randomization modified these relationships, adjusting for covariates. Similar health characteristics were observed at KEEPS randomization for KEEPS Continuation participants and nonparticipants (i.e., women not returning for the KEEPS Continuation). The LGM revealed significant associations between intercepts and slopes for cognitive performance across almost all domains, indicating that cognitive factor scores changed over time. Tests assessing the effects of mHT allocation on cognitive slopes during the KEEPS and across all years of follow-up including the KEEPS Continuation visit were all statistically nonsignificant. The KEEPS Continuation study found no long-term cognitive effects of mHT, with baseline cognition and changes during KEEPS being the strongest predictors of later performance. Cross-sectional comparisons confirmed that participants assigned to mHT in KEEPS (oCEE and tE2 groups) performed similarly on cognitive measures to those randomized to placebo, approximately 10 years after completion of the randomized treatments. These findings suggest that mHT poses no long-term cognitive harm; conversely, it provides no cognitive benefit or protective effects against cognitive decline.

Conclusions: In these KEEPS Continuation analyses, there were no long-term cognitive effects of short-term exposure to mHT started in early menopause versus placebo. These data provide reassurance about the long-term neurocognitive safety of mHT for symptom management in healthy, recently postmenopausal women, while also suggesting that mHT does not improve or preserve cognitive function in this population.

Fig 1. Timeline for KEEPS, KEEPS-Cog, and KEEPS Continuation studies.

The KEEPS initiated randomization in July of 2005. In some instances, ancillary studies were started later. The KEEPS-Cognitive and Affective study was started in August of 2005. KEEPS, Kronos Early Estrogen Prevention Study. Parent study examining cardiovascular effects of early postmenopausal hormone therapy in women at low risk for cardiovascular disease. KEEPS-Cog, KEEPS Cognitive and Affective study, an ancillary study to the KEEPS, enrolled most but not all women enrolled in the KEEPS and studied cognitive and mood effects. KEEPS Continuation, Re-enrolled women in KEEPS to study long-term effects of mHT administered in early postmenopause.

Fig 2. Study flowchart.

*COVID-19-related concerns, inconvenient to travel, scheduling conflicts, or moved. KEEPS, Kronos Early Estrogen Prevention Study; oCEE, oral conjugated equine estrogens; PI, principal investigator; tE2, transdermal 17β-estradiol.

Fig 3. Cross-sectional Cognitive results.

Distribution of cognitive factor scores and the modified mini-mental state examination (global cognition) by treatment group in the KEEPS Continuation study. oCEE, oral conjugated equine estrogens; tE2, transdermal estradiol. Total possible score was 100 points on the Modified Mini-Mental State Examination (3MS).