Abstract
Diffusion-weighted imaging (DWI) is used to measure gray matter tissue density and white matter fiber organization/directionality. Recent studies show that DWI also allows for assessing neuroplastic adaptations in the human hypothalamus. To this end, we investigated a potential influence of testosterone replacement therapy on hypothalamic microstructure in female-to-male (FtM) transgender individuals. 25 FtMs were measured at baseline, 4 weeks, and 4 months past treatment start and compared to 25 female and male controls. Our results show androgenization-related reductions in mean diffusivity in the lateral hypothalamus. Significant reductions were observed unilaterally after 1 month and bilaterally after 4 months of testosterone treatment. Moreover, treatment induced increases in free androgen index and bioavailable testosterone were significantly associated with the magnitude of reductions in mean diffusivity. These findings imply microstructural plasticity and potentially related changes in neural activity by testosterone in the adult human hypothalamus and suggest that testosterone replacement therapy in FtMs changes hypothalamic microstructure towards male proportions.
Highlights
As control center of the neuroendocrine system, the hypothalamus is the main locus of action of sex hormones in triggering sexual motivation, cognition, and behavior
Our results show that female-to-male transgender individuals (FtMs) had female mean diffusivity (MD) values at baseline, which decreased towards male levels after testosterone treatment
Regression analysis further indicates that increases in free androgen index and in bioavailable testosterone plasma levels are associated with the observed MD reduction in the hypothalamus
Summary
As control center of the neuroendocrine system, the hypothalamus is the main locus of action of sex hormones in triggering sexual motivation, cognition, and behavior. There is growing appreciation that sex hormones shape hypothalamic and other subcortical brain structures in adolescence (McCarthy et al 2009; Campbell and Herbison 2014; Ahmed et al 2008). In adulthood, these ‘‘organizational’’ effects are replaced by ‘‘activational’’, plastic and reversible actions of sex hormones. These ‘‘organizational’’ effects are replaced by ‘‘activational’’, plastic and reversible actions of sex hormones These include feedback actions on gonadotropin releasing hormone (GnRH) neuron firing and GnRH release (Mizuno and Terasawa 2005; Kenealy et al 2013), and influence ventromedial nucleus neuron firing involved in the control of glucose and lipid metabolism (Xu et al 2011), as well as preoptic neuron firing involved in the regulation of body temperature (Silva and Boulant 1986). Structural neuroimaging in humans further indicates state-dependent changes in hypothalamus volume across the menstrual cycle (Tu et al 2013)
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