Your Brain Might Try to Stockpile Estrogen During Menopause—And It Could Explain Brain Fog

FG Trade / Getty Images Key Takeaways

A new study shows that the menopause transition is associated with an increase in estrogen receptors in the brain.

This increase in estrogen receptors is also linked to brain fog and mood changes.

More research is needed, but researchers theorize that the increase in estrogen receptors is the brain’s way of compensating for a decline in circulating estrogen.

The research is important because of how symptoms impact quality of life and are a risk factor for dementia.

Shifting hormone levels contribute to dozens of symptoms during the menopause transition.1 Common menopause symptoms include cognitive and mood changes, such as brain fog, depression, and anxiety.2 For the first time, researchers have preliminary evidence showing why.

A first-of-its-kind study suggests these changes are related to an increase in the number of estrogen receptors in the brain, despite estrogen levels decreasing throughout the body.

Researchers from Weill Cornell Medicine used positron emission tomography (PET) imaging to analyze estrogen activity in the brain. They found that over the menopause trajectory, estrogen receptors increase across various brain regions. This increase was associated with worse cognitive performance and an increase in mood symptoms.3

The study lays a foundation for further research on menopause treatments and symptom prevention, which may be important for dementia prevention.

“My interest in this topic stemmed from the observation that hormonal changes during menopause have profound effects on women’s brain structure and function,” Lisa Mosconi, PhD , director of the Women’s Brain Initiative and associate director of the Alzheimer’s Prevention Program at Weill Cornell Medicine, told Verywell. “Yet there’s limited understanding of how these changes occur at a molecular level.” What Happens in the Brain During the Menopause Transition?

A hallmark of the menopause transition is a reduction in estrogen. By the time people reach their final menstrual period, estrogen levels will have decreased by 50%.4 Most symptoms of menopause have links to estrogen decline. But now Mosconi and her colleagues have shown how an increase in the number of sites that estrogen binds to in the brain—called receptors—might be leading to cognitive and mood symptoms.3

Their small proof-of-concept study included 54 healthy women aged 40 to 65. The researchers evenly categorized the participants as premenopausal, perimenopausal, and postmenopausal. The researchers then used PET scans to study their brains, including a tracer that binds to estrogen receptors. The technique offered the opportunity for insights not possible with other imaging tools.3

“This method allowed us to see directly where and how estrogen receptors respond to estrogen changes over the menopausal transition,” Mosconi said.

The scans showed progressively higher estrogen receptor density in participants who were perimenopausal and postmenopausal when compared to the premenopausal control group. A measure of estrogen receptor density in four key brain regions predicted with 100% accuracy whether a participant was premenopausal or postmenopausal.3

The study does have some limitations, including that it is observational, does not prove cause and effect, and has a small sample size. “I wish there could have been a larger study group,” Sonia Durairaj, MD , an internal medicine physician at Harbor Health and a Menopause Practitioner certified by the North American Menopause Society, told Verywell. She was not involved with the research. “But the group of 54 women was an overall well-selected group, and different variables were taken into account.” If Estrogen Levels Drop During Menopause, Why Is the Brain Creating More Estrogen Receptors?

The researchers don’t yet know why estrogen receptor density increases over the course of the menopausal transition. But they have a theory that the brain may be trying to capture any available estrogen.

“For now, it seems plausible that the brain may compensate for lower circulating estrogen levels by increasing estrogen receptors to maintain sensitivity to the hormone’s effects and minimize the impact of menopause on cognitive health and overall brain function,” Mosconi said.

Further analysis showed that higher estrogen receptor concentrations in specific brain regions were also associated with the participants’ self-reports of menopausal cognitive and mood symptoms.

In postmenopausal participants, the higher receptor concentrations in cognitive regions of the brain, such as the hippocampus and frontal cortex, were associated with lower scores on some cognitive tests. In the same participants, higher estrogen receptor density in different brain regions, including the thalamus, was linked to mood changes, such as depression.3

Mosconi said the study is the first, to the best of their knowledge, to show three things. First, it visualizes estrogen activity in the living human brain. Second, it demonstrates an increase in estrogen receptor density in specific areas of the brain at the perimenopausal and postmenopausal stages. And finally, it shows that these effects are associated with brain symptoms of menopause, such as low mood and poorer memory function.3

“Far too long, women’s symptoms have been chopped up to a phase of life with little to no [information] on the science or physiology of why,” Jillian LoPiano, MD , chief health officer at Wisp, told Verywell. LoPiano was not involved with the research. “The more we know about these physiological processes, the better we can provide specific and innovative care for symptomatic peri- and postmenopausal women.”

Is ‘Menopause Brain’ Real? Improving Mood During Menopause Would Enhance Quality of Life

Menopause symptoms can greatly affect quality of life. In an older 2013 survey of more than 8,000 women ages 40 to 64, self-reported menopause symptoms were associated with lower quality-of-life scores, higher work impairment, and higher healthcare utilization than those without symptoms. Mood changes, such as depression and anxiety, had the highest associations.5

More than half of people undergoing the menopause transition experience mood changes.6 Up to 62% experience brain fog, an umbrella term used to describe cognitive issues like difficulty concentrating, communicating, and remembering things.78

“We know that brain fog, cognitive changes, and mood impact many women during the perimenopause and menopausal years and lead to negative impacts on quality of life,” Mindy Goldman, MD , chief clinical officer of Midi Health and a clinical professor emeritus of obstetrics at UC San Francisco, told Verywell. “We know that these symptoms impact both […]

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