Higher levels of estrogen associated with greater gray matter volume in mid-life women

Premenopausal status, longer reproductive times, higher numbers of children, and the use of hormone therapy (HT) and hormonal contraceptives (HC) are associated with greater gray matter volume (GMV) in women, according to study results published in Neurology connected to the middle of life.

Previous research suggests that specific indicators of reproductive history are linked to the prevalence of Alzheimer’s disease (AD) in women. Researchers note that AD pathology begins in the presymptomatic phase of 10-20 years, which correlates with the transition to mid-life menopause in women. However, the effects of estrogen on the risk of developing AD are mixed. The aim of the current study was to assess the associations between reproductive history indicators and brain magnetic resonance imaging (MRI) biomarkers for AD in mid-life women at risk of AD and to compare them with age-controlled men.

The observational cohort study examined the relationship between reproductive history indicators and MRI-based GMV, a biomarker for neuronal aging and AD-associated neurodegeneration, in women with risk factors for late-onset AD such as family history and / or apolipoprotein E epsilon 4 (APOE4) genotype and compared with men. The participants were cognitively normal and between 40 and 65 years old.

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A total of 99 women (mean [SD] Age, 52 [6] Years; 80% white) and 29 men (average age 52.) [7] Years; 76% white) were included.

The researchers found negative associations between menopausal status and GMV in the inferior temporal gyrus (P = .049) and borderline negative associations in the inferior frontal gyrus (P = .059) in the right hemisphere. Post hoc analyzes showed that the perimenopausal and postmenopausal groups in these regions had a lower GMV than premenopausal women (P ≤.033).

The postmenopausal and perimenopausal groups had a lower GMV in the medial temporal lobe (MTL), in the fusiform gyrus and in the basal ganglia compared to men (P <.05) as well as in the precuneus, frontal and temporal regions (P <.05).

No significant associations between hysterectomy status and GMV, age at menarche and GMV, or age at menopause and GMV were observed in any region.

Positive associations were found between the reproductive margin and GMV in a cluster of the upper parietal lobe and the precuneus of the left hemisphere (corrected P = 0.025). The number of children in women was positively associated with GMV in the inferior and medium frontal gyri and inferior temporal gyri (p <0.021).

Positive associations between the use of HT and GMV were found bilaterally in the superior frontal and supramarginal gyrus; in the middle temporal gyrus and frontal pole of the right hemisphere; and in the inferior temporal, fusiform and frontal gyrus of the left hemisphere (P <0.015). Positive associations between the intake of HC and GMV were also observed in the precuneus, fusiform gyrus, superior parietal lobule, angular and inferior frontal gyrus of the left hemisphere, and in the fusiform gyrus of the right hemisphere (P <0.005).

The volume-of-interest approach showed that MTL GMV was negative with menopausal status (P ≤ .041) and positive with HC consumption (P = .017) and the number of children (P = .026) Was associated with women.

The researchers found that their results are based on healthy, well-educated, and predominantly white participants, and that they were unable to generalize to gender-specific patient populations and those receiving gender-affirming HT.

“Some reproductive history indicators that signal prolonged exposure to estrogen have been linked to greater MRI-derived GMV in areas of the brain prone to cognitive aging and AD,” the researchers explained. “These indicators included premenopausal status, longer reproductive times, higher numbers of children and pregnancies, and the use of HT and HC. The results were independent of age, APOE-4 status, health indicators in mid-life and exposure-specific confounding factors. “


Schelbaum E., Loughlin L., Jett S. et al. Association of reproductive history with brain MRI biomarkers of dementia risk in mid-life. Neurology. Published online November 3, 2021. doi: 10.1212 / WNL.0000000000012941

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