Hormone therapy in early menopause proves safe but lacks cognitive benefits

While early hormone therapy is safe for menopause symptom relief, it fails to preserve cognition—what does this mean for women seeking long-term brain health solutions?

In a recent study published in the journal PLOS Medicine, a team of researchers in the United States investigated the long-term cognitive effects of menopausal hormone therapy when initiated early after menopause.

The study followed up with women from the Kronos Early Estrogen Prevention Study (KEEPS) approximately a decade after the initial treatment to evaluate cognitive outcomes and assess whether different forms of menopausal hormone therapy impact memory and mental functions over time.

Menopausal hormone therapy

"Critical window" hypothesis challenged: Despite theories suggesting cognitive benefits if therapy starts early, the study showed no long-term advantages for transdermal estradiol or oral conjugated estrogens.

Many women experience cognitive challenges and mood disturbances during menopause, which is often treated with menopausal hormone therapy. While menopausal hormone therapy is effective for symptom relief, its long-term effects on cognition remain unclear, especially when initiated in the early post-menopausal period.

Previous studies, such as the Women’s Health Initiative Memory Study, have found that late-onset menopausal hormone therapy in older women was linked to increased risks of cognitive decline and dementia. These findings led to concerns about the safety of menopausal hormone therapy. However, later trials, including the Kronos Early Estrogen Prevention Study (KEEPS), suggested no short-term harm when therapy was initiated closer to menopause.

Moreover, findings from neuroimaging studies suggested that transdermal estradiol (tE2) might confer cognitive benefits, raising the hypothesis of a "critical window" for initiating therapy during early post-menopause. However, these theories had not been definitively tested over the long term.

The current study

The present study was a follow-up to the KEEPS initiative to clarify whether early menopausal hormone therapy initiation influenced cognitive aging or protected against age-related decline. The researchers aimed to gain insights into optimal timing and safety for menopausal hormone therapy while examining cognitive outcomes approximately a decade after initiating the treatment.

The participants included postmenopausal women at low cardiovascular risk enrolled in the original KEEPS trial. The original trial randomized the participants into three groups: oral conjugated equine estrogens (oCEE), transdermal estradiol (tE2), or placebo, with all groups receiving cyclic progesterone for 48 months.

This continuation study re-enrolled the participants across seven sites and focused on cognitive assessments using a standardized battery of tests. These tests measured four cognitive domains — verbal learning, working memory, executive function, and mental flexibility — along with global cognition using the modified Mini-Mental State Examination (modified MMSE). The data from the original KEEPS trial and the continuation were integrated to model the changes over time and assess the influence of initial menopausal hormone therapy exposure.

The researchers used statistical methods such as latent growth models to evaluate associations between baseline cognitive performance, changes during the trial, and cognition at follow-up. This analysis also incorporated variables like education, age, and genetic risk for Alzheimer’s disease (APOEε4 carrier status) to ensure robust findings. Furthermore, the study ensured that no medications or new interventions were administered during the follow-up to retain focus on the long-term impact of the original menopausal hormone therapy exposure.

Major findings

Short-term relief, long-term neutrality: While menopausal hormone therapy effectively manages menopausal symptoms like hot flashes and mood swings, it neither protects against nor worsens cognitive decline in the long term.

The results showed that menopausal hormone therapy initiated early after menopause had no long-term effects — beneficial or harmful — on cognitive performance. Women treated with oCEE, tE2, or placebo during the original trial showed similar cognitive outcomes approximately ten years later.

The strongest predictor of cognitive performance at follow-up was the participants’ baseline cognition and changes observed during the trial period. The linear growth models confirmed that there were no significant differences in cognitive trajectories across the treatment groups for the four cognitive domains examined through the modified MMSE or in global cognition. Additionally, the cross-sectional analyses at follow-up also showed no advantage or disadvantage for either menopausal hormone therapy group compared to the placebo group.

The findings also indicated that early menopausal hormone therapy does not protect against cognitive decline, contradicting a previous hypothesis that tE2 might confer long-term benefits. Moreover, no harmful effects associated with the treatments were observed, which also addressed the safety concerns raised by prior studies involving older populations.

Notably, while this study focused on a healthy population at low cardiovascular risk, it highlighted that findings might not generalize to populations with different health characteristics, such as higher cardiovascular risk or those starting therapy later in life.

Conclusions

Overall, the study provided reassuring evidence that menopausal hormone therapy, initiated early after menopause, does not harm or benefit long-term cognitive function in healthy women. However, while menopausal hormone therapy effectively manages menopausal symptoms, it also does not prevent cognitive decline.

These results offer valuable insights for women considering menopausal hormone therapy, emphasizing its safety for symptom relief while highlighting its limitations for cognitive preservation. The researchers also underscored the need for future studies to explore other potential long-term effects of menopausal hormone therapy, such as its impact on mood or biomarkers associated with Alzheimer’s disease.

Journal reference:

• Gleason, C. E., Maritza, D. N., Kara, F., James, T. T., Salazar, H., Carola, Harman, S. M., Manson, J. E., Hammers, D. B., Naftolin, F. N., Pal, L., Miller, V. M., Cedars, M. I., Lobo, R. A., MalekAhmadi, M., & Kantarci, K. (2024). Longterm cognitive effects of menopausal hormone therapy: Findings from the KEEPS Continuation Study. PLOS Medicine, 21(11), e1004435-. DOI: 10.1371/journal.pmed.1004435, https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004435