Longitudinal Impacts of Sex-Steroid Hormones on Cerebellar Structure in Adulthood are Sex Differentiated

Sex-steroid hormones influence brain structure across aging, but their relationship to the cerebellum, a region implicated in cognition and vulnerable to age-related decline, remains poorly characterized, particularly longitudinally and across both sexes. We examined whether 17{beta}-estradiol, progesterone, and testosterone relate to cerebellar volume across two timepoints, and whether these relationships differ by sex. In a mixed-sex sample of aging adults (Baseline N = 137; Year 1 N = 93), free salivary hormones and cerebellar lobular volumes were quantified. Linear regression tested cross-sectional, predictive, and change-score hormone-volume associations, and formal hormone-by-sex interactions, in a priori primary and secondary cerebellar lobules of interest. Hormone-cerebellum relationships were consistently sex-differentiated. Estradiol change related to Crus I volume change in opposite directions in males and females, a dissociation extending across bilateral Crus I and Lobule VI, and Right Crus II. In females, greater increases in testosterone were associated with greater decline in Left Crus I and Right Lobule V volumes. In males, testosterone showed no significant associations in primary analyses, however, increases in estradiol were associated with larger volumes. Progesterone showed a male-specific cross-sectional association with Crus II. Several relationships ran opposite to the direction predicted by estradiols established neurotrophic role. Sex-steroid influences on the aging cerebellum are sex-differentiated, regionally specific, and may not be predicted exclusively by cortical or female-focused models. These findings establish the cerebellum as a potential site of sex-specific hormonal influence on brain aging and also further highlight the complexity of the impact of sex-steroid hormones on the aging brain.