Abstract
An extreme incongruence between sex and gender identity leads individuals with gender dysphoria (GD) to seek cross-sex hormone therapy (CSHT), and gender-affirming surgery (GAS). Although few studies have investigated the effects of CSHT on the brain prior to GAS, no studies in the extant literature have evaluated its impact during hypogonadism in post-GAS individuals. Here, we aimed to evaluate the effects of estradiol on resting-state functional connectivity (rs-FC) of the sensorimotor cortex (SMC) and basal ganglia following surgical hypogonadism. Eighteen post-GAS (male-to-female) participants underwent functional magnetic resonance imaging (fMRI) and neuropsychiatric and hormonal assessment at two time points (t1, hormonal washout; t2, CSHT reintroduction). Based on the literature, the thalamus was selected as a seed, while the SMC and the dorsolateral striatum were targets for seed-based functional connectivity (sbFC). A second sbFC investigation consisted of a whole-brain voxel exploratory analysis again using the thalamus as a seed. A final complementary data-driven approach using multivoxel pattern analysis (MVPA) was conducted to identify a potential seed for further sbFC analyses. An increase in the rs-FC between the left thalamus and the left SCM/putamen followed CSHT. MVPA identified a cluster within the subcallosal cortex (SubCalC) representing the highest variation in peak activation between time points. Setting the SubCalC as a seed, whole-brain analysis showed a decoupling between the SubCalC and the medial frontal cortex during CSHT. These results indicate that CSHT with estradiol post-GAS, modulates rs-FC in regions engaged in cognitive, emotional, and sensorimotor processes.
Highlights
Gender dysphoria (GD) is characterized by incongruence between the sex assigned at birth and the gender identity
Cross-sex hormone therapy prescribed to transgender women was associated with an increase in the Resting-state functional connectivity (rs-FC) between the left thalamus and the left SMC /left putamen after GASrelated gonadectomy
This finding was confirmed by a wholebrain analysis demonstrating an increase in the rs-FC between the left thalamus and a cluster comprising contiguous voxels from the sensory and motor cortices
Summary
Gender dysphoria (GD) is characterized by incongruence between the sex assigned at birth and the gender identity. People who experience profound gender incongruence are referred for cross-sex hormone therapy (CSHT) and genderaffirming surgery (GAS) (Hembree et al, 2017). Apart from their effects on the body, sex hormones are known to be neuroactive (Zheng, 2009), and several studies have demonstrated the impact of CSHT on brain structure and functional connectivity (Rametti et al, 2012; Mueller et al, 2016, 2017). Considering these numbers, it is a matter of public health concern to better investigate the impact of CSHT on a transgender person’s brain after completion of gonadectomy
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