Relating sex differences in cortical and hippocampal microstructure to sex hormones

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 profiling in vivo using 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.