The influence of sex steroid treatment on insular connectivity in gender dysphoria

The influence of sex hormones on brain function has been investigated in multiple neuroimaging studies. Sexually dimorphic characteristics were found for the insular cortex, though little is known about hormonal effects on sex-specific functional connectivity patterns and insular functions ranging from emotion regulation to interoception and higher-level cognition. Thus, better understanding of direct sex steroid effects on insular connectivity remains essential. Thereby, gender-dysphoric individuals receiving gender-affirming hormone therapy represent an interesting cohort to address this gap in available knowledge. To analyze the potential effect of sex steroids on insular connectivity at rest, 14 transgender women, 19 transgender men, 24 cisgender women, and 15 cisgender men were recruited. All participants underwent two magnetic resonance imaging sessions involving resting-state acquisitions separated by a median time period of 4.5 months. Between scans, transgender subjects received gender-affirming hormone therapy. A seed based functional connectivity analysis revealed a significant 2-way interaction effect of group-by-time between right insula, cingulum, left middle frontal gyrus and left angular gyrus. Post-hoc tests revealed an increase in connectivity for transgender women when compared to cisgender men. Furthermore, spectral dynamic causal modelling showed reduced effective connectivity from the posterior cingulum and left angular gyrus to the left middle frontal gyrus as well as from the right insula to the left middle frontal gyrus. These findings suggest a considerable influence of long-term estrogen administration and androgen suppression on brain networks implicated in interoception, own-body perception and higher-level cognition. Nevertheless, further studies are needed to shed light on the underlying mechanisms.