Analysis of over a thousand postmenopausal women suggests that women with longer reproductive spans, earlier first period (menarche), and later menopause experience slower brain aging [1].
Linking sex hormones to brain health
The female reproductive system fails to work properly much earlier than other systems in the human body. The aging of the reproductive system not only prevents females from bearing children relatively early in life, it also impacts the aging process of other organs. The brain is a prominent example, as the risk of developing dementia increases around menopause [2].
The aging of the reproductive system is tightly linked to the levels of female sex hormones, including estrogen. The most prevalent form of estrogen in the female body is estradiol.
Changes in estradiol levels are linked to milestones in a woman’s reproductive life. Estradiol levels start to increase before menarche and remain elevated until the first age-related missed period (perimenopause). At perimenopause, estradiol levels begin to decrease. This decrease in estradiol levels persists through menopause and postmenopause, resulting in low estradiol levels.
The researchers suggest that a decrease in estradiol might be an essential factor in developing dementia and other age-related neuropathologies in the female population.
Such a link is supported by animal studies that demonstrate estradiol’s role in brain health-promoting processes, including the promotion of synaptic plasticity, enhancement of neurogenesis, and protection against oxidative stress and neuroinflammation [3-5]. In human studies, although some research suggests that the timing of menarche and menopause is an essential risk factor for dementia, the link between brain health and estradiol is not as definitive.
The authors of this study aimed to better understand of the relationship between brain aging and the female reproductive span (the period between menarche and menopause), which is characterized by high levels of estradiol.
The age of the brain
To assess brain age, 1,006 postmenopausal women underwent structural magnetic resonance imaging (MRI) scans: one initial brain scan and one follow-up brain scan approximately 2 years later.
The researchers used these images to estimate each brain’s age and then calculate BrainAGE, the difference between this estimate and the participant’s chronological age. BrainAGE combines complex changes in different areas of brain structure into a single biomarker that can be used as a predictor of dementia and age-related cognitive decline. The difference in BrainAGE between the two time points was used in the longitudinal analysis.
Longer reproductive span, younger brain
The researchers conducted two types of analysis: a cross-sectional analysis that examined a specific section of the population at a particular time point and a longitudinal analysis that tracked changes over time.
They analyzed the relationship between reproductive span, age at menarche, age at menopause, and BrainAGE for the cross-sectional analysis or the change in BrainAGE for the longitudinal study.
Both types of analysis revealed similar results. First, the researchers reported a significant negative association between BrainAGE and change in BrainAGE (depending on the analysis) and reproductive span, indicating that females with longer reproductive spans had younger brains compared to those with shorter reproductive spans. However, the effects are relatively small in both types of analyses.
There was also a negative association between BrainAGE, the change in BrainAGE, and age at menopause: each year older at menopause corresponded to 0.1 years younger in brain age in the cross-sectional analysis and 0.06 years younger in the longitudinal study.
The researchers observed a significant positive association between BrainAGE, the change in BrainAGE, and age at menarche. Their estimation shows that each year younger at menarche corresponded to a brain that is 0.32 years younger in the cross-sectional analysis and 0.08 years younger in the longitudinal study.
Even when the researchers accounted for many variables, such as the number of live births, hormone replacement therapy, removal of uterus or ovaries, body mass index, blood pressure, diabetes, education, income, and a composite lifestyle factor, the results were similar and statistically significant except for age of menarche in the longitudinal analyses.
While both menarche and menopause appear to contribute to brain aging, the strength of the association and the rate of change with age vary. The researchers suggest that different underlying biological mechanisms can cause it.
They suggest that during menopause, there are more biological mechanisms at play than just a decrease in estradiol levels, such as increasing levels of follicle-stimulating hormones, which might lead to an increased deposition of amyloid-β and tau [6]. Apart from hormonal changes, menopause is also associated with inflammation, which can play a role in brain health [7].
They also suggest that older women are less likely to accurately remember age at menarche, making those estimations less reliable.
The window of opportunity
The researchers discuss how the results of their study align with previous findings, which all point towards the positive impact of estradiol on brain health and its neuroprotective properties.
“These findings support the idea that estradiol, the most potent and prevalent form of estrogen during a woman’s reproductive years, may help protect the brain as it ages,” said lead researcher Associate Professor Eileen Lueders from the University of Auckland’s School of Psychology.
The study’s authors also believe their findings align with the concept of a ‘window of opportunity’ (which we discussed before). This concept suggests that hormonal interventions such as hormone replacement therapy, to be effective against dementia, should be started around the menopausal transition.
“It’s encouraging to see research shedding light on how a woman’s reproductive years may shape brain health later in life,” says Alicja Nowacka, a Ph.D. student at the University of Auckland who was not involved in the study.
“As more women weigh the benefits of hormone therapy during menopause, findings like these spark important conversations and open the door to more inclusive, focused research in women’s brain health.”
Expanding the research
While the study’s results were interesting and contributed to a better understanding of women’s health, the authors call for future expansion of the study, as this analysis had several limitations. First, the study sample was relatively small and lacked diversity in ethnicity and socioeconomic status, which restricts the generalizability of the results.
Additionally, while menarche and menopause correlate with changes in female sex hormones, including estradiol, those were not directly measured. Future studies should address this, as the interplay between brain health and estradiol levels may be complex and sensitive to subtle changes in estradiol levels. There may also be other factors that can impact brain health, such as lifestyle choices and genetic makeup, which should be taken into consideration in the analysis.
Literature
[1] Luders, E., Poromaa, I. S., Barth, C., & Gaser, C. (2025). A Case for estradiol: younger brains in women with earlier menarche and later menopause. GigaScience, 14, giaf060.
[2] Mosconi, L., Rahman, A., Diaz, I., Wu, X., Scheyer, O., Hristov, H. W., Vallabhajosula, S., Isaacson, R. S., de Leon, M. J., & Brinton, R. D. (2018). Increased Alzheimer’s risk during the menopause transition: A 3-year longitudinal brain imaging study. PloS one, 13(12), e0207885.
[3] Vegeto, E., Benedusi, V., & Maggi, A. (2008). Estrogen anti-inflammatory activity in brain: a therapeutic opportunity for menopause and neurodegenerative diseases. Frontiers in neuroendocrinology, 29(4), 507–519.
[4] Behl, C., Widmann, M., Trapp, T., & Holsboer, F. (1995). 17-beta estradiol protects neurons from oxidative stress-induced cell death in vitro. Biochemical and biophysical research communications, 216(2), 473–482.
[5] Tanapat, P., Hastings, N. B., Reeves, A. J., & Gould, E. (1999). Estrogen stimulates a transient increase in the number of new neurons in the dentate gyrus of the adult female rat. The Journal of neuroscience : the official journal of the Society for Neuroscience, 19(14), 5792–5801.
[6] Xiong, J., Kang, S. S., Wang, Z., Liu, X., Kuo, T. C., Korkmaz, F., Padilla, A., Miyashita, S., Chan, P., Zhang, Z., Katsel, P., Burgess, J., Gumerova, A., Ievleva, K., Sant, D., Yu, S. P., Muradova, V., Frolinger, T., Lizneva, D., Iqbal, J., … Ye, K. (2022). FSH blockade improves cognition in mice with Alzheimer’s disease. Nature, 603(7901), 470–476.
[7] Mishra, A., & Brinton, R. D. (2018). Inflammation: Bridging Age, Menopause and APOEε4 Genotype to Alzheimer’s Disease. Frontiers in aging neuroscience, 10, 312.
