Relating sex differences in cortical and hippocampal microstructure to sex hormones

Abstract

Sex hormone receptors are expressed widely in both neurons and glial cells, which allows them to interact with the brain’s major cell groups via several molecular mechanisms. These mechanisms lead to sex differences in brain structure as well as hormone-induced plasticity in the female brain across the menstrual cycle. Adding to the literature on volumetric changes in cortical structure, here we set out to investigate sex differences in the microstructure of the human cortex in relation to sex hormones. We assessed regional variation in cortical microstructure as a function of sex, hormonal status and sex hormone receptor gene expression distribution based on quantitative intracortical profilingin vivousing the magnetic resonance imaging based T1w/T2w ratio in 992 healthy females and males of the Human Connectome Project young adult sample. We demonstrate that microstructure in isocortex and hippocampus differs regionally between males and females, that this effect varies with hormone levels of females and that implicated brain regions overlap with estrogen receptor and sex steroid synthesis gene expression. Lastly, we show that sex and sex hormone related brain structure variations are most pronounced in areas of low laminar cortical complexity (agranular cortex), which are also predicted to be most plastic based on their cytoarchitectural properties. Together, our data thus are suggestive of sex differences in cortical and hippocampal microstructure, as well as the modulatory function of sex hormones on these measures. Albeit correlative, this study underscores the importance of incorporating sex hormone variables into the investigation of brain structure and plasticity.

Microstructural asymmetry in the human cortex

“…Looking ahead, the implementation of a normative model could elucidate the developmental trajectory of microstructural asymmetry across the lifespan, facilitating the identification of individual trajectories (Bethlehem et al, 2022). Previous work has also reported marked sex-differences in various indices of cortical structure (DeCasien et al, 2022; Küchenhoff et al, 2023; Liu et al, 2020; Serio et al, 2023), possibly related to differential sex hormonal expression and physiological markers (Wisniewski, 1998). Indeed, in the current work we observed an overall stronger asymmetry in males relative to females.…”

“…Indeed, in the current work we observed an overall stronger asymmetry in males relative to females. In related work, reported overall decreases in mean microstructure and increases in skewness were observed in women relative to men, and varied as a function of (self-reported) hormonal status (Küchenhoff et al, 2023). However, in the current work we could only touch upon these neuroendocrine, physiology, and age-related factors shaping microstructural brain asymmetry.…”