According to a new brain imaging study conducted by researchers at Weill Cornell Medicine, the transition to menopause it is marked by a progressively higher density of estrogen receptors (ERs) on brain cells, a measure that remains elevated in women into their sixties. In addition to revealing new evidence of the brain’s response to this major life change, the study paves the way for the use of positron emission tomography (PET) as a tool to study estrogen activity in the brain, which until now has not it had been possible to monitor.
Estrogen activity in the brain in menopause
In the study, published on Scientific Reportsresearchers scanned the brains of 54 healthy women between the ages of 40 and 65 using PET with a tracer that binds to ERs.
These receptors are found in multiple areas of the brain, especially in women, and mediate the many cognitive and behavioral effects of the female sex hormone estradiol, the most potent form of estrogen. ER-PET scans have been used in previous studies of women with cancer, but never before in a study of the brains of healthy women.
Scans comparing women at different stages of menopause revealed progressively higher ER density in several estrogen-regulated brain networks in the postmenopausal and perimenopausal groups compared to premenopausal controls. Researchers interpret this as a compensatory response to declining levels of available estrogen: as estrogen levels decline during the transition to menopause, cells express additional receptors to absorb as much estrogen as possible.
The researchers’ analyzes found that high ER density in some of these regions was associated not only with menopausal status but also with patient reports of cognitive and mood symptoms related to it.
The findings suggest that the technique may be a valuable tool for studying the brain effects of menopause and estrogen therapy.
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“Using this method, we were able for the first time to measure ER activity in the brain and identify potential predictors of some of these common menopausal symptoms,” said the study’s lead author, Dr. Lisa Mosconi, associate professor of neuroscience in neurology. and radiology and director of the Women’s Brain Initiative at Weill Cornell Medicine.
A central feature of menopause is the decline in the body’s production of estrogen. This leads to various bodily changes including the cessation of menstruation, but also to neuropsychiatric effects such as “brain fog”, depression and anxiety.
To understand the detailed molecular mechanisms underlying these estrogen-related brain symptoms, researchers would need a reliable, minimally invasive method to measure estrogen activity in the brain.
The new study was a proof of principle that PET imaging with a specific ER-binding tracer, called 18F-fluoroestradiol (FES), could meet that need.
The researchers analyzed 18 premenopausal, 18 perimenopausal, and 18 postmenopausal women between the ages of 40 and 65 and recorded ER density in various brain regions known to be regulated by estrogen.
The results showed significantly higher ER density in the brains of postmenopausal women compared to premenopausal women, with intermediate levels in perimenopausal women. A measure based on ER density in four key brain regions, the pituitary gland, caudate nucleus, posterior cingulate cortex, and middle frontal cortex, predicted postmenopausal versus premenopausal status with 100% accuracy.
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In postmenopausal women, higher densities in cognitive regions such as the hippocampus and frontal cortex were associated with lower scores on some cognitive tests. In the same group, higher densities in a different set of brain regions, including the thalamus, were associated with mood symptoms such as depression.
The researchers plan to use ER-PET imaging to study the long-term consequences of changes in estrogen levels in the brain, including persistently low levels after menopause and increasing levels with estrogen therapy.
“We hope to find out, for example, whether ER density changes with estrogen therapy and whether this leads to fewer symptoms and better performance on cognitive tests,” said Dr. Mosconi, who is also director of the Estrogen Prevention Program. Alzheimer’s at Weill Cornell. Medicine and NewYork-Presbyterian.
The finding that ERs, rather than disappearing rapidly after menopause, remain abundant in the brain for up to a decade after menopause, together with the findings that high ER density was observed during perimenopause, also suggests that the “window of opportunity” for estrogen therapy may be greater than thought, he said.
Removal of the ovaries before menopause associated with reduction of white matter in the brain
Women who have their ovaries removed before menopause, particularly before age 40, have reduced white matter integrity in multiple brain regions later in life. White matter refers to the nerve fibers that connect neurons in different areas of the brain.
“We know that removing both ovaries before natural menopause causes abrupt endocrine dysfunction, which increases the risk of cognitive impairment and dementia,” said Michelle Mielke, Ph.D., professor and chair of epidemiology and prevention at the Wake Forest University School of Medicine. . “But few neuroimaging studies have been conducted to better understand the underlying mechanisms.”
For the study, the research team looked at data from the Mayo Clinic Study of Aging to identify women over age 50 with available diffusion tensor imaging, a magnetic resonance imaging (MRI) technique that measures matter white in the brain. The cohort consisted of:
•22 participants underwent bilateral premenopausal oophorectomy (PBO) before age 40
•43 participants who had PBO between the ages of 40 and 45 years
•39 participants who had PBO between the ages of 46 and 49 years
•907 participants who did not have PBO before age 50.
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“Women who underwent premenopausal bilateral oophorectomy before age 40 had significantly reduced white matter integrity in multiple brain regions,” said Mielke, the study’s corresponding author.
“There were also trends in some brain regions such that women who had PBO between the ages of 40-44 or 45-49 also had reduced white matter integrity, but many of these findings were not statistically significant.”
Mielke said 80% of participants who had their ovaries removed also had a history of estrogen replacement therapy. Therefore, the study was unable to determine whether the use of estrogen replacement therapy after PBO mitigated the effects of PBO on white matter integrity. You noted that the ovaries secrete hormones both before (mainly estrogen, progesterone, and testosterone) and after menopause (mainly testosterone and androstenedione).
“Removal of both ovaries results in a sharp decrease in both estrogen and testosterone in women,” Mielke said. “Therefore, one possible explanation for our findings is the loss of both estrogen and testosterone.”
Mielke said more research is needed to better understand how white matter changes are associated with cognitive impairment.
“While it is important for women to consider these findings before undergoing a premenopausal bilateral oophorectomy for non-cancerous conditions, we need a larger and more diverse cohort of women to validate these findings.”
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