Higher Estrogen Exposure Tied to Larger Gray Matter Volume in Midlife Women

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Researchers sought to examine associations between women’s reproductive history indicators, including estrogen exposure, and brain MRI biomarkers of Alzheimer disease in midlife.

Premenopausal status, longer reproductive span, higher number of children, and use of hormonal therapy (HT) and hormonal contraceptives (HC) are associated with larger gray matter volume (GMV) in midlife women, according to study results published in Neurology.

Previous research suggests specific reproductive history indicators may be tied to the prevalence of Alzheimer disease (AD) in women. Researchers note AD pathology starts in the 10-20 year presymptomatic phase, which correlates with midlife menopause transition in women. Yet, the effects of estrogen on the risk of developing AD are mixed. The objective of the current study was to evaluate the associations between reproductive history indicators and brain magnetic resonance imaging (MRI) biomarkers of AD in midlife women at risk for AD and compare them to age-controlled men.

The observational cohort study assessed the association between reproductive history indicators and MRI-based GMV, a biomarker of neuronal aging and AD-related neurodegeneration, among women with risk factors for late-onset AD such as a family history and/or apolipoprotein E epsilon 4 (APOE4) genotype and compared with men. Participants were cognitively normal and aged 40 to 65 years.

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

The researchers found negative associations between menopause 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 analysis showed that the perimenopausal and postmenopausal groups had smaller GMV in these regions vs premenopausal women (P ≤.033).

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

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

Positive associations were found between reproductive span and GMV in a cluster of the superior parietal lobule and precuneus of the left hemisphere (corrected P =.025). The number of children among women was positively associated with GMV in the inferior and middle frontal gyri and middle and inferior temporal gyri (P <.021).

Positive associations between HT use and GMV were found bilaterally in the superior frontal gyrus and supramarginal gyrus; in the middle temporal gyrus and frontal pole of the right hemisphere; and in the inferior temporal gyrus, fusiform gyrus, and medial frontal gyrus of the left hemisphere (P <.015). Positive associations were also observed between HC use and GMV in the precuneus, fusiform gyrus, superior parietal lobule, angular gyrus, and inferior frontal gyrus of the left hemisphere and in the fusiform gyrus of the right hemisphere (P <.005).

The volumes-of-interest approach showed that MTL GMV was negatively associated with menopause status (P ≤.041) and was positively associated with HC use (P =.017) and number of children (P =.026) among women.

The researchers noted that their results are based on healthy, well-educated, and mostly White participants, and they were unable to generalize to sex-diverse patient populations and those receiving sex-affirming HT.

“Some reproductive history indicators signaling longer estrogen exposure were associated with larger MRI-derived GMV in brain regions vulnerable to cognitive aging and AD,” the researchers stated. “These indicators included pre-menopausal status, a longer reproductive span, higher number of children and pregnancies, and use of HT and HC. Results were independent of age, APOE-4 status, midlife health indicators, and exposure-specific confounders.”


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