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Context Hormonal interventions in adolescents with gender dysphoria may have adverse effects such as reduced bone mineral accrual. Objective To describe bone mass development in adolescents with gender dysphoria treated with gonadotropin-releasing hormone analogues (GnRHa), subsequently combined with gender affirming hormones. Design Observational prospective study.. Subjects 51 transgirls and 70 transboys receiving GnRHa and 36 transgirls and 42 transboys receiving GnRHa and gender affirming hormones, subdivided in early and late pubertal groups. Main outcome measures bone mineral apparent density (BMAD), age and sex specific BMAD Z-scores, and serum bone markers. Results At start of GnRHa treatment, mean areal bone mineral density (aBMD) and BMAD values were within the normal range in all groups. In transgirls the mean Z-scores were well below the population mean. During two years of GnRHa treatment BMAD stabilized or showed a small decrease, whereas Z-scores decreased in all groups. During three years of combined administration of GnRHa and gender affirming hormones, a significant increase of BMAD was found. Z-scores normalised in transboys but remained below zero in transgirls. In transgirls and early pubertal transboys all bone markers decreased during GnRHa treatment. Conclusions BMAD Z-scores decreased during GnRHa treatment and increased during gender affirming hormone treatment. Transboys had normal Z-scores at baseline and at the end of the study. However, transgirls had relatively low Z-scores, both at baseline and after three years of estrogen treatment. If this results in adverse outcomes such as increased fracture risk in transgirls as they grow older is currently unclear.

The sexual differentiation of the brain is primarily driven by gonadal hormones during fetal development. Leading theories on the etiology of gender dysphoria (GD) involve deviations herein. To examine whether there are signs of a sex-atypical brain development in GD, we quantified regional neural gray matter (GM) volumes in 55 female-to-male and 38 male-to-female adolescents, 44 boys and 52 girls without GD and applied both univariate and multivariate analyses. In girls, more GM volume was observed in the left superior medial frontal cortex, while boys had more volume in the bilateral superior posterior hemispheres of the cerebellum and the hypothalamus. Regarding the GD groups, at whole-brain level they differed only from individuals sharing their gender identity but not from their natal sex. Accordingly, using multivariate pattern recognition analyses, the GD groups could more accurately be automatically discriminated from individuals sharing their gender identity than those sharing their natal sex based on spatially distributed GM patterns. However, region of interest analyses indicated less GM volume in the right cerebellum and more volume in the medial frontal cortex in female-to-males in comparison to girls without GD, while male-to-females had less volume in * Corresponding author. the bilateral cerebellum and hypothalamus than natal boys. Deviations from the natal sex within sexually dimorphic structures were also observed in the untreated subsamples. Our findings thus indicate that GM distribution and regional volumes in GD adolescents are largely in accordance with their respective natal sex. However, there are subtle deviations from the natal sex in sexually dimorphic structures, which can represent signs of a partial sex-atypical differentiation of the brain.