Menopause: More estrogen receptors in the brain

PET scans

The PET scans show the density of estrogen receptors in a woman’s brain before (left) and after menopause. Lighter colors indicate higher receptor density. © Mosconi Lab

In women going through menopause, the level of the hormone estrogen decreases. In addition to physical symptoms, many women during this phase also experience psychological and cognitive problems such as mood swings, memory problems and difficulty concentrating. A study has now shown how menopause changes the brain. Brain scans show that the number of estrogen receptors increases in numerous brain regions and remains high even after menopause. A high density of receptors is associated with typical menopausal symptoms. This finding could help to better understand the causes of the problems and treat them more specifically.

Hormones from the class of estrogens fulfill numerous functions in the body: Firstly, they control the female menstrual cycle and are therefore crucial for reproduction. Secondly, they also have an effect on metabolic processes independent of reproduction. The most biologically active form in particular, estradiol, can also influence our mood and cognitive performance via receptors in the brain. When estrogen levels drop during menopause, many women experience not only physical but also psychological and cognitive symptoms. However, it has been difficult to track exactly what happens in the brain during this process.

Less estrogen – more receptors

A team led by Lisa Mosconi from Weill Cornell Medicine in New York has now developed a technique that can be used to examine estrogen receptors in the brain. In a proof-of-concept study, the researchers scanned the brains of 18 healthy women before, during and after menopause using positron emission tomography (PET). To make the estrogen receptors in the brain visible, the team injected the test subjects with a tracer that binds to the receptors and lights up in the brain scan. The test subjects also completed cognitive tests and filled out questionnaires about possible menopausal symptoms.

“With this method, we were able to measure the activity of estrogen receptors in the brain for the first time and identify potential predictors for some common symptoms of menopause,” says Mosconi. The researchers found that the density of estrogen receptors increases as menopause progresses and is still high a decade after the end of menopause. “This is probably a compensatory mechanism triggered by the falling estrogen levels,” explains the team. The additional receptors are therefore formed in order to make the best possible use of the remaining estradiol.

Association with cognitive symptoms

The difference in receptor numbers between pre- and post-menopausal women was so significant that just looking at estrogen receptors in four key regions of the brain – the pituitary gland, caudate nucleus, posterior cingulate cortex and medial frontal cortex – it was possible to predict with 100 percent accuracy whether the corresponding brain scan came from a pre- or post-menopausal woman. “The effects were independent of age, blood plasma estradiol levels or sex hormone transport protein,” the team reports. In menopausal women, receptor density was at an intermediate level, which increased with increasing duration of menopause.

Comparing the brain scans with the results of the cognitive tests and the self-reported symptoms revealed clear associations: “Higher estrogen receptor density in the target regions was associated with poorer memory performance in women during and after menopause and predicted the presence of self-reported mood swings and cognitive symptoms after menopause,” the researchers report. The receptor density was particularly significant in cognitive brain regions such as the hippocampus and frontal cortex, as well as in regions such as the thalamus, which are associated with mood.

New research approaches

From the researchers’ point of view, the imaging technology they use can help to better understand the neurophysiological causes of mood swings, concentration problems, etc. Brain scans could also provide new insights into so-called hormone replacement therapies, which can help alleviate menopausal symptoms. “We hope, for example, to find out whether the density of estrogen receptors changes under estrogen therapy and whether this leads to fewer symptoms and better performance in cognitive tests,” explains Mosconi. The finding that the high number of receptors can still be observed long after the end of menopause also suggests, according to the researchers, that hormone replacement therapies could still be useful in old age.

Source: Lisa Mosconi (Weill Cornell Medicine, New York) et al., Scientific Reports, doi: 10.1038/s41598-024-62820-7

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