STUDY: In Menopause, Estrogen Drops — Here’s How the Brain Reacts

By | July 10th, 2024

Menopause brain, explained? Scientists may have finally found the reason behind postmenopausal cognitive decline and behavioral changes. It all has to do with a certain protein building up in the brain.

By a woman’s late 40s, there is a good chance she’ll have started to experience the early phases of menopause. Menopause isn’t just the point when monthly periods cease. It’s a transitional period during which levels of the sex hormone estrogen drops off. This hormonal change causes all kinds of side effects: hot flashes, bladder weakness, joint pain, and what’s come to be known as “menopause brain.” Menopause’s cognitive symptoms might include things like confusion, forgetfulness, and difficulty focusing. 

Speaking of menopause and the brain, scientists are working to understand the complex relationship between Alzheimer’s and menopause. This connection could one day shed light on why women are more than twice as likely to develop Alzheimer’s than men. 

But, to date, the way all these menopausal estrogen changes actually affect brain health and brain chemistry has been a mystery. A study published in Scientific Reports might hold the key to solving it: Researchers discovered that as as estrogen levels drop, the quantity of a certain type of estrogen-responsive proteins — estrogen receptors — in the brain increases — and that could be the reason women are more likely to experience post-menopausal cognitive and behavioral changes.

“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,” Lisa Mosconi, director of the Weill Cornell Women’s Brain Initiative and Alzheimer’s Prevention Program, told Being Patient. “While this may reflect a red flag for future Alzheimer’s, the relationship is likely complex and involving multiple factors and pathways.”

Brain scans show how menopause changes the brain

The study used PET scans to measure the levels of estrogen receptors in the brains of 54 older women aged 40 to 65, divided evenly across premenopause, perimenopause, and postmenopause. 

Women who were perimenopausal or postmenopausal had a higher density of estrogen receptors in the brain. By looking at estrogen receptor density in four brain regions — the pituitary, caudate nucleus, posterior cingulate cortex, and middle frontal cortex — researchers could tell whether or not a participant was pre or postmenopause.

Less estradiol, more receptor proteins working in the brain

During menopause, the type of estrogen your body makes, changes. During a person’s reproductive years, the primary form of estrogen the body is producing is called estradiol. During pregnancy, that primary form is estriol. And as of menopause, the balance shifts to a type of estrogen called estrone. The receptors the researchers spotted respond specifically to estradiol.

So, the findings seem like a bit of a paradox: Despite declining estradiol levels during menopause, the brain starts producing more proteins that respond to it. The researchers think that this is the brain’s way of compensating. Since there’s less estradiol going around, this increase in receptor proteins is the body’s attempt to ensure that the brain can use what it has most efficiently. 

“Estradiol is often referred to as the ‘master regulator’ of the female brain because it helps regulate a variety of brain functions, including neurotransmitter synthesis, growth and survival of neurons, neuroprotection, energy metabolism, immunity, and much more,” said Mosconi.

A higher density of these receptors, irrespective of menopause stage, in these brain regions was associated with lower scores on various memory tests:

  • Hippocampus. The hippocampus is important for memory and learning and is one of the first affected by Alzheimer’s disease.
  • Amygdala. The amygdala is important for emotional responses and plays an important role in memory.
  • Posterior cingulate cortex. This part of the brain is important for attention and focus.
  • Frontal cortex. The frontal cortex is responsible for higher-level cognitive functions, impulse control, and problem-solving, and it also plays a role in memory.

In postmenopausal women, the higher estrogen receptor density in the amygdala, frontal cortex, post-cingulate cortex, and thalamus — the brain’s information relay station — was also linked to mood swings and memory problems.

Two experts who weren’t involved in the study told Being Patient that the findings were interesting but more more research is needed to confirm them and understand their significance.

Susan Davis, a professor at Monash University who researchers menopause found it “weird” that the researchers saw no association between estrogen receptor density and “cardinal symptoms”  like hot flushes and night sweats during menopause or postmenopause. She said that the researchers didn’t see a link might be that the participants in the study didn’t have a lot of menopause symptoms to start.

Liisa Galea, a senior scientist at the Center for Addiction and Mental Health who wasn’t involved in the study, said that the reason for this might be a technical one: PET scans might not be able to zero in on the right region closely enough to see the correlation.

She added that historically and still today, brain health research specifically in women is limited.

“Unfortunately, research on women, and related questions on women’s brain health, are not well studied in the medical literature, with only three percent of studies in neuroscience focusing on females and women,” Galea said. 

What’s next for the research?

Are these findings the explanation behind menopause brain fog? Mosconi says more research is needed — but it’s a possibility.

“We do not yet know if increases in estrogen receptor density during menopause are the cause of the cognitive and mood symptoms or a contributing factor,” said Mosconi. “It is plausible that these effects contribute to the symptoms, while being part of a complex interplay involving hormonal, genetic, and environmental factors.”

A growing body of research has shown that hormone replacement therapy (HRT) for estrogen can relieve the cognitive symptoms of menopause — and in women who are carriers of the Alzheimer’s risk gene APOE4, it may protect the brain against future cognitive decline. 

This research can be leveraged in the future to see whether estrogen therapy, which can treat some symptoms of menopause, also leads to changes in the levels of estrogen receptors in the brain.

In addition, Mosconi and her colleagues are investigating how the levels of these receptors influence the brain’s vulnerability to Alzheimer’s.


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