Mapping hypothalamic development in transgender and cisgender youth

The neurodevelopmental basis of gender incongruence is poorly understood. Histological studies have suggested sex-atypical hypothalamic structures in transgender individuals, forming the basis for the brain sexual differentiation hypothesis. However, existing neuroimaging studies have typically involved small, mostly adult samples, have assessed only the whole hypothalamic structure, and lacked a developmental perspective. Utilizing an advanced manual delineation technique of the hypothalamus and four sub-structures in a unique sample of 401 magnetic resonance images acquired in 306 trans- and cisgender participants (7 – 23 years old), we charted the effects of gender identity, birth-assigned sex, age, puberty (suppression) and gender-affirming hormone treatment on volumetric differences and changes across adolescence. We found reduced hypothalamic volumes, of both the total as well as of certain sub-structures, in transgender compared to cisgender youth, including pre-pubertal and treatment-naïve children. Our results suggest early differences in neurodevelopment in relation to gender incongruence. These differences became more pronounced with age, during puberty, and when trans adolescents received puberty suppression and gender-affirming hormone treatment, suggesting that both endogenous puberty and exogenous hormones play an important role in hypothalamic volume changes during adolescence. This study provides valuable new knowledge on the neurodevelopmental basis of gender incongruence.