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

Background: Sex-specific differences in brain connectivity were found in various neuroimaging studies, though little is known about sex steroid effects on insular functioning. Based on well-characterized sex differences in emotion regulation, interoception and higher-level cognition, gender-dysphoric individuals receiving gender-affirming hormone therapy represent an interesting cohort to investigate how sex hormones might influence insular connectivity and related brain functions. Methods: To analyze the potential effect of sex steroids on insular connectivity at rest, 11 transgender women, 14 transgender men, 20 cisgender women, and 11 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 and also completed the Bermond-Vorst alexithymia questionnaire at the initial and final examination. Between scans, transgender subjects received gender-affirming hormone therapy. Results: 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 demonstrated 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. Alexithymia changes were found after gender-affirming hormone therapy for transgender women in both fantasizing and identifying. Conclusion: These findings suggest a considerable influence of estrogen administration and androgen suppression on brain networks implicated in interoception, own-body perception and higher-level cognition.