In Brief | Neurology | Women's Health

10 Years On: Menopausal Hormone Therapy Shows No Cognitive Harm  in Early Postmenopausal Women

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This article is a review of recent studies originally published in PLos Medicine, 21 November 2024 . It does not represent the original research, nor is it intended to replace the original research. Access the full Disclaimer Information.

 

An estimated 75% of women experience symptoms related to menopausal transition, with approximately 25% describing these symptoms as moderate to severe. 
 

Menopausal hormone therapy (mHT) is considered the most effective treatment for these symptoms. However, concerns regarding the safety of mHT persist, driven mainly by the findings from the Women's Health Initiative (WHI) and its ancillary study, the Women's Health Initiative Memory Study (WHIMS).
 

The WHI, a large-scale, randomized controlled trial, found that the combination of oral conjugated equine estrogens (oCEE) and medroxyprogesterone acetate (MPA) increased the risk of coronary heart disease, cerebrovascular events, and breast cancer in older women, particularly those more than 10 years post-menopause.²

WHIMS, which focused on the cognitive effects of mHT, showed that both oCEE with MPA and oCEE alone were associated with adverse effects on global cognitive function, as well as an increased risk of mild cognitive impairment and dementia, particularly in women aged 65 and older.³
 

These findings raised significant concerns about the safety of mHT in older women and led to questions about the timing of treatment initiation.

The concept of a "critical window" for mHT initiation emerged, suggesting that the benefits of mHT may be more pronounced when started around the onset of menopause rather than in older women, where risks appear more prominent. 

In contrast, the findings from the Kronos Early Estrogen Prevention Study (KEEPS)-Cog trial, which built on the earlier findings of its parent study KEEPS¹, suggested no cognitive benefit or harm after 48 months of menopausal hormone therapy (mHT). It found no evidence of harm to cognitive performance with short-term use of two forms of menopausal hormone therapy - oCEE and transdermal estradiol -when initiated within 3 years of a final menstrual period.

 

Study Purpose
 

This study aimed to clarify the long-term effects of mHT initiated in early post-menopause on cognition, mood, and neuroimaging effects of patients enrolled in KEEPs and KEEP-Cog trials approximately ten years after the trials concluded.

Specifically, the authors hypothesised that women randomised to transdermal estradiol (tE2) during early post-menopause would show cognitive benefits. In contrast, those randomised to oral conjugated equine estrogens (oCEE) would show no effect, compared to placebo over the 10 years following randomization in the Kronos Early Estrogen Prevention Study (KEEPS) trial.

 

Study Methodology
 

The KEEPS-Cog (2005–2008) was an ancillary study to the KEEPS trial.

Participants were randomly assigned to three treatment groups: oCEE (Premarin 0.45 mg/day), tE2 (Climara 50 μg/day), both with micronized progesterone (Prometrium 200 mg/day for 12 days/month), or placebo for 48 months.

This study, the KEEPS Continuation Study, was a longitudinal follow-up study conducted between 2017 and 2022, approximately ten years after the original KEEPS trial.

272 participants completed the original KEEPS-Cog test battery, which assessed cognitive function using four cognitive factor scores and a global cognitive score. 

Data from both KEEPS and the KEEPS Continuation Study were then analysed to assess baseline cognition, cognitive changes during the original KEEPS trial, and the influence of mHT randomization on cognitive performance at the ten-year follow-up, adjusting for relevant covariates.

 

Findings

The analysis of the five primary outcomes in the KEEPS study showed that randomisation to mHT, whether oCEE or tE2, did not significantly influence cognitive outcomes, either during the original trial or 10 years later.

Cognitive trajectories for women on either mHT treatment were similar to those on placebo across all cognitive measures, including global cognition (3MSE). 

The strongest predictor of cognitive performance at the KEEPS Continuation visit was baseline cognition and cognitive changes observed during the original KEEPS trial rather than the mHT treatment itself.

The comparison of cognitive performance at the KEEPS Continuation visit revealed no significant differences between the mHT and placebo groups across the four cognitive factors and global cognition. 

Additionally, a comparison of 257 participants who continued using systemic mHT after the KEEPS trial did not show statistical significance between the treatment groups (p = 0.097).

 

Discussion
 

There has been ongoing debate regarding the long-term effects of mHT. By conducting a longitudinal observational follow-up of a clinical cohort, the researchers found no long-term cognitive benefit or harm associated with short-term mHT when compared to a placebo. This is a novel finding, as it is based on an observational cohort that extends the results of a placebo-controlled randomized clinical trial.
 

 

Access the original study
 

Gleason, C. E., Dowling, N. M., Kara, F. et al. (2024). Long-term cognitive effects of menopausal hormone therapy: Findings from the KEEPS Continuation Study. PLoS medicine, 21(11), e1004435. https://doi.org/10.1371/journal.pmed.1004435


Additional References
 

1. Miller VM, Naftolin F, Asthana S, et al. The Kronos Early Estrogen Prevention Study (KEEPS): what have we learned? Menopause. 2019 Sep;26(9):1071-1084. doi: 10.1097/GME.0000000000001326. PMID: 31453973; PMCID: PMC6738629.

2. Manson JE, Chlebowski RT, Stefanick ML, et al.. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. JAMA. 2013 Oct 2;310(13):1353-68. doi: 10.1001/jama.2013.278040. PMID: 24084921; PMCID: PMC3963523.
 

3. Shumaker, S. A., Reboussin, B. A., Espeland, M. A., et al. (1998). The Women's Health Initiative Memory Study (WHIMS): a trial of the effect of estrogen therapy in preventing and slowing the progression of dementia. Controlled clinical trials, 19(6), 604–621. https://doi.org/10.1016/s0197-2456(98)00038-5


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