Hormone therapy during early menopause is proven safe but lacks cognitive benefits

Although early hormone therapy is safe for reducing menopausal symptoms, it cannot preserve cognitive function. What does this mean for women seeking long-term brain health solutions?

study: Long-term cognitive effects of menopausal hormone therapy: Results from the KEEPS continuation study. Image credit: Neirfy / Shutterstock

In a recent study published in the journal PLOS medicinea US research team investigated the long-term cognitive effects of menopausal hormone therapy when started early after menopause.

This study followed women in the Kronos Early Estrogen Prevention Study (KEEPS) approximately 10 years after initial treatment to assess cognitive outcomes and determine how different forms of menopausal hormone therapy affect memory and mental function over time. We evaluated whether to give

menopausal hormone therapy

Many women experience cognitive and mood disorders during menopause, which are often treated with menopausal hormone therapy. Although menopausal hormone therapy is effective in reducing symptoms, its long-term effects on cognition remain unclear, especially when initiated early after menopause.

Previous studies, such as the Women's Health Initiative Memory Study, have found that delayed menopausal hormone therapy in older women is associated with increased risk of cognitive decline and dementia. These findings have led to concerns about the safety of menopausal hormone therapy. However, subsequent trials, including the Kronos Early Estrogen Prevention Study (KEEPS), suggested that there were no short-term harms in starting treatment near menopause.

Additionally, results from neuroimaging studies suggested that transdermal estradiol (tE2) may confer cognitive benefits and raised the hypothesis of a “critical window” for starting treatment early after menopause. However, these theories have not been clearly tested over time.

current research

This study was a follow-up to the KEEPS initiative to determine whether early initiation of menopausal hormone therapy affects cognitive aging or prevents age-related decline. The researchers aimed to gain insight into the optimal timing and safety of menopausal hormone therapy, as well as to examine cognitive outcomes approximately 10 years after starting treatment.

Participants included postmenopausal women with low cardiovascular risk enrolled in the original KEEPS trial. The first trial randomly assigned participants to three groups: oral conjugated equine estrogen (oCEE), transdermal estradiol (tE2), or placebo, with all groups receiving cyclic progesterone for 48 months. .

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

The researchers used statistical methods such as latent growth models to assess the association between baseline cognitive ability, change during the test, and cognition at follow-up. This analysis also incorporated variables such as education, age, and genetic risk for Alzheimer's disease (APOEε4 carrier status) to provide robust results. Additionally, this study ensured that no medications or new interventions were administered during follow-up to maintain a focus on the long-term effects of initial menopausal hormone therapy exposure.

Main findings

The results showed that menopausal hormone therapy started early after menopause has no long-term effects, either beneficial or harmful, on cognitive performance. Women treated with oCEE, tE2, or a placebo during the initial trial had similar cognitive outcomes approximately 10 years later.

The strongest predictors of cognitive performance at follow-up were participants' baseline cognition and changes observed during the study period. Linear growth models confirmed no significant differences in cognitive trajectories between treatment groups for the four cognitive domains examined through modified MMSE or global cognition. Additionally, cross-sectional analyzes at follow-up showed no advantage or disadvantage for either menopausal hormone therapy group compared with the placebo group.

The findings also show that early menopausal hormone therapy is not effective in preventing cognitive decline, contradicting previous hypotheses that tE2 may have long-term effects. Additionally, no treatment-related adverse effects were observed, also addressing safety concerns raised in previous studies in older adults.

Of note, this study focused on a healthy population with low cardiovascular risk, but with different health characteristics, including those at higher cardiovascular risk and those who begin treatment later in life. It emphasizes that research results may not be generalizable to populations.

conclusion

Overall, this study provided encouraging evidence that menopausal hormone therapy initiated early after menopause neither harms nor benefits long-term cognitive function in healthy women. However, while menopausal hormone therapy effectively manages menopausal symptoms, it cannot prevent cognitive decline.

These results provide valuable insight for women considering menopausal hormone therapy and highlight its safety for symptom relief while highlighting its limitations for preserving cognitive function. The researchers also highlighted the need for future studies to investigate other potential long-term effects of menopausal hormone therapy, such as effects on mood and biomarkers associated with Alzheimer's disease.