Sex hormones partially explain the sex-dependent effect of lifetime alcohol use on adolescent white matter microstructure

Previous studies demonstrate profound sex-specific patterns of white matter microstructural neurodevelopment (i.e. fractional anisotropy; FA, and mean diffusivity; MD) during adolescence. While alcohol use has been associated with alterations in FA and MD, no studies have addressed the potential for sex-specific, alcohol-dose dependent effects, during development. This prospective longitudinal study (2-4 visits, 310 total scans) used voxel-wise multilevel modeling, in 132 (68 female) adolescents (ages 12-21), to assess the sex-specific effects of lifetime alcohol use on FA and MD, during development. Follow-up analyses tested the role of sex hormones, testosterone and estradiol, in explaining the effects of alcohol use on FA and MD. In the splenium of the corpus callosum and posterior thalamic radiation, male adolescents demonstrated lower FA and greater MD as a function of more lifetime alcohol use, while female adolescents demonstrated the opposite. Further, significant associations between sex hormones and FA/MD partially explained the effect of alcohol use on FA and MD in male adolescents. These results provide evidence for sex-specific and dose-related effects of alcohol use on white matter microstructure, which are partially explained by sex hormones, and highlight the importance of studying sex and hormones when investigating the effects of alcohol use on the adolescent brain.