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

Shifting hormone levels contribute to dozens of symptoms during the menopause transition. Common menopause symptoms include cognitive and mood changes, such as brain fog, depression, and anxiety. 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.

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%. 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.

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.

“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.

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.

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.

“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.”

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.

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

“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 personal and professional lives.”

Goldman, who was not involved in the study, also notes that cognitive changes in menopause may be a reason why some people choose not to seek career advancement.

More Research on Menopause and Cognition Could Even Reduce Alzheimer’s Risk

More effective menopause symptom management has the potential to not only improve quality of life, but also to improve cognitive outcomes for women as they age, said Mosconi, whose research largely focuses on the brain health of women and Alzheimer’s prevention.

“By understanding these mechanisms, we can better address these symptoms by testing and/or developing treatments that enhance the brain’s ability to adapt to estrogen changes,” she said.

Self-reported cognitive issues such as brain fog carry a two-fold increase in dementia risk even when a person scores well on cognition tests. By the time mild cognitive impairment shows on tests, the person has a nine-fold increase in dementia risk. Late menstruation, early menopause, and a shorter overall reproductive period are associated with a nearly 25% increase in dementia risk. Just being female is a dementia risk factor.

Additionally, estrogen depletion, which occurs in perimenopause, is linked to beta-amyloid plaque accumulation. Beta-amyloid plaques have been implicated in Alzheimer’s disease, the most common form of dementia.

Hormone replacement therapy (HRT), specifically replacing estrogen, progesterone, or both, is a gold standard in menopause therapy for symptoms like hot flashes. However, the North American Menopause Society does not recommend HRT specifically for cognitive symptoms at any time during the menopause transition. Mosconi’s research is a new step in helping to determine if HRT may be of benefit.

“Knowing that elevations in [estrogen receptor] density are present up to 15 years after menopause suggests that the ‘window of opportunity’ for therapeutical intervention may be wider than previously thought,” Mosconi said. “We aim to investigate therapeutic strategies, such as HRT, that could modulate estrogen receptor activity to mitigate the risk of cognitive decline and Alzheimer’s.”

Mosconi notes that the study is preliminary. Her team has plans to expand on the research and try to understand any potential connections between the increase in estrogen receptor density and the development of dementia.

“Several lines of evidence suggest a link between reduced estrogen and increased Alzheimer’s risk in women,” she said. “Our current study shows a significant association between estrogen receptor density in regions like the hippocampus—an early site of Alzheimer’s pathology—and reduced memory performance among midlife women. It’s important to examine whether this may reflect a red flag for future Alzheimer’s.”