In Vivo Imaging Reveals Increased Estrogen Receptors in the Post-Menopausal Brain

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A new study by Weill Cornell Medicine scientists sheds light on the brain activity changes that occur during menopause. The research, published in Scientific Reports, used a pioneering brain imaging tool to track estrogenic activity in healthy women for the first time.  

Menopause is characterized by a decline in estrogen

Most women experience menopause at midlife, a transition marked by declining estrogen levels. This process is a natural part of aging, resulting in the end of menstruation.

The menopausal transition is associated with various symptoms, including hot flushes, irregular periods, anxiety, mood swings and weight change, and can last around seven years. During this time, women may experience symptoms of menopause even though their periods haven’t stopped entirely. Menopause is officially diagnosed only after a woman hasn’t had a menstrual cycle for 12 consecutive months.

Menopause is also associated with neuropsychiatric symptoms such as brain fog and depression. 17β-estradiol (E2) is the most biologically active form of estrogen and previous research has highlighted its role in various neurological and cognitive functions. During the menopausal transition, E2 levels drop considerably, suggesting a possible cause for these neurological symptoms.

ER density reflects menopausal stages

Positron emission tomography (PET) is the only technique available that allows for in vivo analysis of estrogen receptor (ER) expression. ERs are found in multiple areas of the brain. The receptors bind to E2, mediating it’s many neurological effects. Until now, ER-PET scans have only been conducted in breast cancer patients.

The researchers scanned the brains of 54 healthy women, aged 40–65 years old, using PET imaging with a specific ER-binding tracer called 18F–fluoroestradiol (FES) to record the density of ERs in various brain regions. The participants, 18 premenopausal, 18 perimenopausal and 18 post-menopausal women,  also completed a menopause health questionnaire and the Menopause Rating Scale to provide further information on symptoms and menopausal-related changes.

Post-menopausal women showed significantly higher ER density in the brain compared to pre-menopausal women. An increase in density in the hippocampus and frontal cortex was also associated with a decrease in scores on some cognitive tests including memory scores. High densities in the thalamus were linked to changes in mood such as depression.

The results suggest the increase in ER density may be a compensatory response to the decline in estrogen levels in the brain.

The researchers were able to predict pre-menopausal versus post-menopausal status, with 100% accuracy, using a measurement based on ER density in four key brain regions: the pituitary gland, caudate nucleus, posterior cingulate cortex and middle frontal cortex. The effects of increased ER density were independent of age and instead depended on the stage of menopause the participants were in.

“Using this method, we were able for the first time to measure ER activity in the brain, and to identify potential predictors of some of these common symptoms of menopause,” said Dr. Lisa Mosconi, lead author and associate professor of neuroscience in neurology and radiology, and Director of the Women’s Brain Initiative at Weill Cornell Medicine.

Applications of estrogen therapy

The study offers a proof-of-principle demonstration using a reliable, minimally invasive method, which allowed the researchers to investigate the molecular mechanisms underlying the neurological symptoms associated with menopause.

Mosconi and her team plan to further investigate the long-term consequences of estrogen level changes in the brain using ER-PET.

“We hope to learn, for example, whether ER density changes with estrogen therapy, and if that leads to fewer symptoms and better performance on cognitive tests,” said Mosconi.

The team observed that ERs remained abundant in the brain, even up to a decade, after menopause. Combined with the findings that ER density increased during perimenopause, the results suggest that the “window of opportunity” for estrogen therapy may be longer than originally believed, said Mosconi.

Reference: Mosconi L, Nerattini M, Matthews DC, et al. In vivo brain estrogen receptor density by neuroendocrine aging and relationships with cognition and symptomatology. Sci Rep. 2024;14(1):12680. doi: 10.1038/s41598-024-62820-7

This article is a rework of a press release issued by Weill Cornell Medicine. Material has been edited for length and content.