Association between serum estradiol levels and cognitive function in older women

Summary

Estradiol is a sex steroid hormone, which has been implicated in the pathogenesis of Alzheimer’s disease (AD) and cognitive impairment. Bearing this in mind, Xu et al. [1] performed a cross-sectional study aimed at examining the relationship between serum estradiol levels and cognitive performance in older American women. Data were obtained from the National Health and Nutrition Examination Survey 2013-2014. A total of 731 women aged ≥ 60 years who met the inclusion criteria were included in this analysis. Serum estradiol levels were measured using isotope dilution liquid chromatography tandem mass spectrometry, a method developed by the Centers for Disease Control and Prevention for routine analysis. Measured serum levels were divided into three categories (tertiles): T1, <3.68 pg/mL; T2, 3.68-7.49 pg/mL; T3, >7.49 pg/mL. The cognitive abilities of participants were evaluated using the Vocabulary Learning Subtest (CERAD), Animal Fluency Test (AFS), and the digital symbol substitution test (DSST). Scores for each test were calculated as means, and the relationship between serum estradiol tertiles and cognitive scores were analyzed with multiple linear regression models, controlling for ethnicity, educational level, hypertension, diabetes, and insomnia. The authors found that mean age of the participants was 69.57 ± 6.68 years. A 78.95% of women were non-Hispanic white and 60.62% had completed at least some college-level education. Mean body mass index was 29.30 ± 6.79 k/m2, and 10.85% had a history of smoking. Further, 73.41% did not have a history of alcohol consumption, and 63.03% had hypertension (63.03%). An 81.81% and 88.3% did not have a history of diabetes mellitus and did not have sleep disorders, respectively. Mean serum estradiol level was 8.48 ± 0.77 pg/mL. Multivariate linear regression of the reference group consisting of participants in tertiles of serum estradiol levels revealed that one unit increase in serum estradiol levels increased DSST scores by 0.61 (0.87, 6.34) in the T3 group. However, no significant correlation was found in the CERAD and AFS tests. The researchers conclude that participants with higher estradiol levels had higher DSST scores and better processing speed, sustained attention, and working memory, suggesting that serum estradiol may serve as a biomarker for cognitive decline in older women.

Commentary

Sex steroids are able to modify several functions including behavior, cognition and memory, sleep, mood, pain and coordination, amongst others. They exert their function through receptors both in the nuclei and along the membranes at synapsis, spine and mitochondria. They have also been found in the glia providing regulation in myelin formation and a potential role in demyelinating diseases [1]. The method by which estrogen exerts its action on the brain includes neurotrophic and neuroprotective actions specifically enhancing synaptic plasticity, neurite growth and hippocampal neurogenesis and protecting against neural injury and apoptosis [2,3].

The role of estrogen has been assessed not only in the maintenance of cognitive function in non-demented women but also in the prevention and/or treatment of AD. The Kronos Early Estrogen Prevention Study (KEEPS) showed that transdermal 17-beta estradiol therapy was linked to a decrease in amyloid-beta deposition on neuroimaging studies, particularly in apolipoprotein E (APOE) E4 carriers [4]. AD is the most common neurodegenerative cause of dementia. In fact, female sex is a key risk factor for AD, particularly after menopause, with a precipitous decline with estrogen level decrease.

The use of estrogen in a large cohort of elderly women was associated with larger gray and white matter volumes, in brain regions relevant to cognitive function including frontal, temporal, and parietal lobes. Estrogen administered near the time when normal endogenous hormone function ceases was maximally useful for brain health. In contrast, if too much time has elapsed since endogenous estrogen production and exogenous administration, no beneficial effect of estrogen on the brain has been observed [5].

Despite the complexities, future work to better understand the effects of estrogen on the brain may offer new leads for healthy brain aging and AD prevention.

Take home key points

• Estrogen action on the brain includes neuroprotection, enhance synaptic plasticity, neurite growth and hippocampal neurogenesis and exerts protection against neural injury and apoptosis.
• Estrogens play a role not only in the maintenance of cognitive function in non-demented women but also in the prevention and/or treatment of AD.
• The administration of transdermal 17-beta estradiol therapy decreases amyloid-beta deposition.
• Estrogen administered near the time when normal endogenous hormone function ceases is maximally useful for brain health.

Sandra C. Demayo, MD
Academy Director of the Argentine Society of Gynecological and Reproductive Endocrinology (SAEGRE)
Past President of the Argentinian Society of Gynecological and Reproductive Endocrinology (SAEGRE)
Chair of the Gynecological Endocrinology Area, Argerich Hospital, Buenos Aires, Argentina
Fellow of the American College of Obstetricians and Gynecologists

Prof. Blanca Campostrini, MD, PhD
General Secretary of the Argentinian Society of Gynecological and Reproductive Endocrinology (SAEGRE)
Past-President of the Argentine Association for Climacteric Studies (AAPEC)
Fellow of the American College of Obstetricians and Gynecologists
Full Professor of the Chair of Gynecology “A”, La Plata National University, Buenos Aires. Argentina
Adjunct Professor of the Chair of the Compulsory Final Practice of the Faculty of Medical Sciences of the National University of La Plata

References

1. 1. 1. Xu Q, Ji M, Huang S, Guo W. Association between serum estradiol levels and cognitive function in older women: a cross-sectional analysis. Front Aging Neurosci. 2024;16:1356791.
         https://pubmed.ncbi.nlm.nih.gov/38450384/
      2. Gava G, Orsili I, Alvisi S, Mancini I, Seracchioli R, Meriggiola MC. Cognition, Mood and Sleep in Menopausal Transition: The Role of Menopause Hormone Therapy. Medicina (Kaunas). 2019; 55(10):668.
         https://pubmed.ncbi.nlm.nih.gov/31581598/
      3. Hogervorst E, Craig J, O’Donnell E. Cognition and mental health in menopause: A review. Best Pract Res Clin Obstet Gynaecol. 2022; 81:69-84.
         https://pubmed.ncbi.nlm.nih.gov/34969617/
      4. Kantarci K, Lowe VJ, Lesnick TG, et al. Early Postmenopausal Transdermal 17β-Estradiol Therapy and Amyloid-β Deposition. J Alzheimers Dis. 2016;53(2):547-556.
         https://pubmed.ncbi.nlm.nih.gov/27163830/
      5. Boyle CP, Raji CA, Erickson KI, et al. Estrogen, brain structure, and cognition in postmenopausal women. Hum Brain Mapp. 2021;42(1):24-35.
         https://pubmed.ncbi.nlm.nih.gov/32910516/

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