Lifespan exposure to hormone therapies and structural brain morphometry in older women

BACKGROUND: Although many studies support a neuroprotective role for estrogens and other ovarian hormones in women, findings across imaging studies remain mixed. Few studies have explored both early- and midlife- hormone exposures simultaneously or incorporated whole-brain, voxel-wise approaches. This study examined the effects of early- and midlife exposure to ovarian hormones- via hormonal birth control (BC), menopausal hormone therapy (MHT)- and their timing on brain health in older women. We also studied the relationship of age of menopause (i.e., greater endogenous exposure to ovarian hormones) to brain health in older adulthood. METHODS: We analyzed baseline data from 459 women (ages 65-80) in the multi-site IGNITE study, a 12-month randomized aerobic exercise study. We examined retrospective self-report of BC and MHT use in relation to structural MRI metrics using voxel-based morphometry (VBM) for gray matter volume and surface-based morphometry (SBM) for cortical thickness. FINDINGS: BC use compared to no BC use was associated with greater gray matter volume in temporal, occipital, and frontal regions in older adulthood. Longer BC duration was linked to larger fusiform gyrus volume. Combined BC and MHT use compared to no use was associated with greater volume in parietal and temporal areas and thicker cortex in the posterior cingulate and temporal gyri. Later menopause onset correlated with greater posterior cortical thickness. No associations were found for MHT timing or BC start age. INTERPRETATIONS: Both endogenous and exogenous lifetime exposure to ovarian hormones were associated with structural brain measures generally consistent with preserved brain aging. These findings highlight the importance of exposure timing in women's brain health and AD risk prevention.