Neuroendocrine implications for brain activity: a burden or a blessing: Studies in transgender individuals and women with PCOS

Summary Chapter two examined the development of sex differences and the impact of suppressed endogenous hormones during adolescence. A verbal fluency task, typically favouring females, was used to investigate neural correlates of gender dysphoria. Participants included cisgender boys, cisgender girls, trans boys, and trans girls (mean age 14.5 years). Transgender participants were studied before initiation of puberty suppression with GnRH agonists. No significant performance differences emerged between cis boys and girls, yet cis boys showed greater activation in the right Rolandic operculum. Trans girls produced more words than trans boys, but neural activation did not differ between the transgender groups. A trend toward a linear increase in Rolandic operculum activation was observed across groups (cis girls → trans men → trans women → cis boys), suggesting adolescent brain activity patterns already reflect sex-related differences, with transgender youth showing intermediate activation. This represents the first demonstration of such effects in adolescents. Chapter three explored the organizing effects of sex steroids on emotion processing. We investigated whether gonadal suppression in individuals assigned female at birth, resulting in reduced estradiol, altered neural activity. Trans men receiving GnRH analogues were compared to cis women. Both groups activated the right superior temporal lobe in response to positive affective images, though trans men showed reduced activation, independent of hormonal levels. As this region modulates limbic structures, reduced activation may indicate altered cortical control of emotional stimuli. This aligns with prior models positing estrogen-enhanced cortical regulation of the amygdala. Chapter four assessed the effects of hyperandrogenism on working memory in women with polycystic ovary syndrome (PCOS). Using an N-back task, untreated PCOS participants exhibited greater activation in parietal and superior temporal regions than controls, despite comparable performance. Group differences in activation were not directly linked to androgen levels. Following anti-androgen treatment, activation patterns between groups converged, while PCOS participants made fewer errors than controls. These findings suggest that androgen exposure may affect neural processing efficiency, and that functional alterations in PCOS may persist independently of current hormone concentrations. Increased baseline activation in PCOS women could reflect compensatory mechanisms sustaining task performance. Chapter five investigated the activating effects of sex steroids on visuospatial processing. We hypothesized that gonadal suppression in transgender individuals would reduce sex differences, while subsequent gender-affirming hormone treatment would shift activation patterns toward those of the affirmed gender. Participants completed a mental rotation task before and after 16 weeks of hormone treatment; cisgender men and women were tested at matched intervals without intervention. Contrary to prior literature, no significant performance or activation differences were found between cis men and cis women. Similarly, transgender groups showed no significant changes in task performance. However, after testosterone administration, trans men demonstrated increased activation in the anterior cingulate cortex, bilateral putamen, left supramarginal gyrus, and bilateral premotor cortex, suggesting testosterone modulates visuospatial processing at the neural level, though mechanisms remain unclear due to absent direct correlations with hormone levels. Conclusion Across studies, sex steroids demonstrated organizing and activating effects on brain activity during adolescence and adulthood. Findings highlight that: (1) sex-related neural differences emerge early in adolescence, with transgender youth showing intermediate patterns; (2) suppression of endogenous gonadotrophins modulates emotion processing independent of estradiol levels; (3) hyperandrogenism in PCOS alters neural recruitment during working memory, potentially reflecting compensatory mechanisms; and (4) testosterone administration in trans men modifies visuospatial brain activation without affecting task performance. Together, these studies contribute novel evidence on the interplay between sex steroids, gender identity, and brain function, underscoring the complexity of hormonal and neural mechanisms underlying cognitive and affective processes.