Long-term cognitive effects of menopausal hormone therapy: Findings from the KEEPS Continuation Study
Authors: Gleason Carey E. , Dowling N. Maritza , Kara Firat , James Taryn T. , Salazar Hector , Simo Carola Ferrer , Harman Sherman M. , Manson JoAnn E. , Hammers Dustin B. , Naftolin Frederick N. , Pal Lubna , Miller Virginia M. , Cedars Marcelle I. , Lobo Rogerio A. , Malek-Ahmadi Michael , Kantarci Kejal 
Published: July 2024

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 three years of menopause onset. Long-term effects of mHT exposure during early postmenopause remain understudied. 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 the participants randomized to one of two active estrogen formulations during early postmenopause would demonstrate differential longitudinal change in cognitive performance during the approximately ten years following randomization in the parent KEEPS trial when compared to women who received placebo. Specifically, transdermal estradiol (tE2) would demonstrate benefit over placebo, and oral conjugated equine estrogens (oCEE) demonstrate no effect compared to placebo.

Methods and Findings

The KEEPS-Cog was an ancillary study to the KEEPS, in which women were randomized to placebo or one of two forms of mHT, oCEE (Premarin, 0.45 mg/d) or tE2 (Climara, 50 µg/d) for 48 months. Micronized progesterone (Prometrium, 200 mg/d) was used by those in mHT arms. Approximately 10 years (M(SD)=9.57(1.08) years; range: 8-14 years) after randomization, women returned to repeat the original KEEPS-Cog test battery. Cognitive tests were analyzed as 4 factor scores and a global cognitive score. Because KEEPS-Continuation visits occurred 8-14 years post-randomization, linear latent growth models with distal outcomes tested whether cognitive performance at baseline in KEEPS and the change-in-cognition across KEEPS visits predicted “distal” KEEPS cognition, and whether mHT randomization of KEEPS modified this relationship. Covariates included education, age at continuation visit, andAPOEe4allele carrier status.

All 727 postmenopausal participants in the KEEPS interventions were eligible for the KEEPS-Continuation. Among those participants, 622 (86%) had valid contact information and were invited to the study. Of these, 194 did not respond, 10 were deceased, and 119 declined to participate, resulting in 299 participants enrolled in the KEEPS-Continuation at seven sites. Of the 299 KEEPS-Continuation participants, 275 had cognitive data to estimate cognitive factors scores both at KEEPS and KEEPS-Continuation. Similar health characteristics were observed at KEEPS randomization for KEEPS-Continuation participants and nonparticipants (i.e. women not returning for the KEEPS-Continuation).

Among the women enrolled in the KEEPS-Continuation, cognitive performance was not influenced by either mHT formulation employed in KEEPS. Models showed strong associations between baseline cognition and change-in-cognition during KEEPS and the same measures in KEEPS-Continuation, i.e., the strongest predictor of cognitive performance in KEEPS-Continuation was cognitive performance in KEEPS. KEEPS-Continuation 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 women completion of the randomized treatments.

Conclusions

In these KEEPS-Continuation analyses, there were no long-term cognitive effects of short-term exposure to mHT started in early menopause vs. placebo. These data offer reassurance regarding long term neurocognitive safety of mHT used by healthy recently postmenopausal women for symptom management.

Author summary

Why was this study done?

Little is known about the long-term cognitive effects of short-term use of menopausal hormone therapies (mHT) – i.e, the use of mHT during the menopausal transition or in early postmenopause for symptoms of menopause, leaving women and their providers with concerns about long-term consequences of short-term mHT use. We invited women who participated in a study examining the cognitive effects of short-term mHT to return for re-evaluation approximately a decade after they were randomized to 4 years of treatment with one of two forms of mHT or a placebo. Importantly, the original study only enrolled women who were recently postmenopausal and at low cardiovascular risk. The goals for the follow-up study were to examine the long-term cognitive effects of using mHT for a brief period shortly after menopause onset and to assess if these effects differed for the two forms of mHT.

What did the researchers do and find?

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The observational Kronos Early Estrogen Prevention Study (KEEPS)-Continuation explored cognitive effects of short-term (4 year) randomized assignment to mHT vs. placebo, initiated within 3 years of menopause onset, after an average of 10 years following randomization in the original KEEPS trial.

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We tested whether long term cognitive performance was influenced by prior exposure to HT formulation (e.g., transdermal 17β-estradiol or oral conjugated equine estrogens), controlling for covariates using linear latent growth models.

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Among the women enrolled in the KEEPS-Continuation, cognitive performance was not influenced by earlier exposure to either HT formulation.

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Linear growth models showed strong associations between baseline cognition (intercept) and its change (slope) during KEEPS and the same measures in the KEEPS-Continuation.

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KEEPS-Continuation cross-sectional comparisons confirmed that both oral and transdermal mHT groups performed similarly to placebo on cognitive measures approximately 10 years after they were randomized to either HT or placebo.

What do these findings mean?

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We detected no long-term cognitive benefit or harm of short-term mHT vs placebo.

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Our findings suggest that there are no long-term cognitive effects of exposure to short-term mHT vs placebo in recently postmenopausal women who have low cardiovascular risk.

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These data offer reassurance to recently postmenopausal women with good cardiovascular health who are considering mHT for the management of menopausal symptoms.