Changes to hypothalamic volume and associated subfields during gender-affirming hormone treatment in gender dysphoria

1. Sex steroid hormones influence hypothalamic micro- and macrostructure in humans and animal models. Neuroimaging studies have suggested that estrogen and anti-androgen treatment decreases volumes of multiple cortical and subcortical brain areas in transgender individuals, including total hypothalamus volume. Here, we aim to further explore potential effects of gender-affirming hormone treatment (GHT) in transgender individuals on hypothalamic volume by providing additional information on hypothalamic subfields. 38 transgender men (TM) and 15 transgender women (TW), with gender dysphoria (DSM-5), as well as 32 cisgender women (CW) and 21 cisgender men (CM) underwent two magnetic resonance imaging (MRI) measurements with an interval of at least four months (median interval TM= 134.5 days (interquartile range (IQR): 126-152.25); TW= 149 days (IQR: 126-178.5); CW= 147 days (IQR: 139.75-170.5); CM= 146 days (IQR: 132-247)) between both sessions. In transgender individuals GHT, consisting of estrogen and anti-androgen treatment in TW and testosterone treatment in TM, was initiated directly after the first measurement. To assess how GHT interacts with hypothalamic structures, the hypothalamus and its subunits were segmented using FreeSurfer. Subject group x time interaction effects were evaluated using repeated measures ANCOVA models. The Bonferroni method was used to correct for multiple comparisons. Significant decreases of total hypothalamic volume and associated subunits were detected in TW after estrogen and anti-androgen treatment compared to cisgender groups. Effects were found in the total hypothalamus volume (p corr = 0.001), the left and right hypothalamus (p corr = 0.002), the inferior tubular subunit bilaterally (right: p corr = 0.001; left: p corr = 0.001), the left superior tubular subunit (p corr = 0.003) the right anterior inferior subunit (p corr = 0.002), as well as the right anterior superior subunit (p corr = 0.0002) of the hypothalamus. Here, we observed significant volumetric effects on the adult human hypothalamus after an interval of at least four months of estrogen and anti-androgen treatment in TW and added knowledge on associated subfields. Further studies investigating influences of sex steroid hormones on brain structure and functional connections are still needed.