Does Estrogen Protect Against the Risk of Brain Shrinkage?

MINNEAPOLIS – A new study found that people with higher cumulative estrogen exposure over their lifetime had greater brain volumes and fewer indicators of brain disease on their brain scans in midlife . The research is published in the November 3, 2021, online issue of Neurology^®, the medical journal of the American Academy of Neurology.

“We found that a number of ways a woman is exposed to estrogen—not having reached menopause, having more total reproductive years, having a higher number of children, using menopause hormone therapy or hormonal contraceptives—were associated with larger gray matter volumes in midlife,” said  author Lisa Mosconi, PhD, of Weill Cornell Medicine in New York, N.Y.

The study looked at 99 women between the ages of 40 and 65 who did not have dementia. They did have risk factors for late-onset Alzheimer’s, such as family history of the disease or the APOE gene that is linked to a greater risk. Researchers compared them to 29 men, matched for age, with similar risk factors.

Then researchers looked at the association of reproductive history with the volume of gray matter in the brain, which is an indicator of brain health, and scores on thinking and memory tests.

When looking at people’s brain scans, several events that indicate longer estrogen exposure, like more than 39 reproductive years, a higher number of children and pregnancies, and use of hormone replacement therapy and/or hormone contraceptives, were associated with greater gray matter volume. This appeared mainly in the temporal cortex, frontal cortex, and precuneus, areas of the brain in which Alzheimer’s biomarkers often show up first. The results were the same after adjusting for factors like high blood pressure and smoking.

For example, for every year longer that a woman was exposed to estrogen in her life, average gray matter volume in certain areas of the brain increased by an average of 1%. People with total reproductive years of 39 years or longer had gray matter volume an average of 5% larger than people with total reproductive years of less than 39 years. Total reproductive years is the difference between the age at menopause and the age when a woman’s period begins.

For each additional child a woman had, gray matter volume in certain areas of the brain increased by an average of 2%.

When researchers looked at people’s scores on tests of thinking and memory, they found no association with reproductive history indicators. However, people’s gray matter volume in the temporal regions of the brain was associated with better scores.

“Previous research has shown that the midlife decline in estrogen that comes with menopause is a driver of brain aging and Alzheimer’s risk in women,” Mosconi said. “Our results confirm that, but there’s also good news. Other factors related to women’s reproductive history, such as a longer reproductive span and use of hormonal therapy, appear to offset the effects of menopause. While the age at which menopause starts is determined partly by a person’s genetics, lifestyle and environmental factors like smoking, obesity and exercise also play a role, and may modify a woman’s risk of brain aging.”

The study does not prove that estrogen reduces dementia risk, it only shows an association between the two.

A limitation of the study is that brain scans showing gray matter volume may indicate other types of brain disease, not just the kind related to Alzheimer’s.

The study was supported by the National Institutes for Health, National Institute on Aging, the Cure Alzheimer’s Fund, Maria Shriver’s Women’s Alzheimer’s Movement, and Harold W. McGraw III and Nancy McGraw, and Carol and Michael Weisman.

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The American Academy of Neurology is the world’s largest association of neurologists and neuroscience professionals, with over 36,000 members. The AAN is dedicated to promoting the highest quality patient-centered neurologic care. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as Alzheimer’s disease, stroke, migraine, multiple sclerosis, concussion, Parkinson’s disease and epilepsy.

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