The effects of gender-affirming sex steroids on brain development in adolescents

Transgender and gender-nonbinary (TNB) adolescents may receive gender-affirming hormone therapy (GAHT) with estradiol or testosterone to induce desired secondary sex characteristics, relieve gender dysphoria, and improve mental health. Because GAHT is given during a crucial phase of brain development, many parents

and caregivers raise concerns about the potential effects of GAHT on brain development. Currently, the field lacks empirical data on the effects of GAHT on brain structure and function in TNB adolescents. To address this gap, we will conduct an observational, longitudinal study that will enroll 80 TNB adolescents (40

transfeminine and 40 transmasculine) who are starting GAHT as a part of their clinical care, and we will study participants before and after 12 months of GAHT using state-of-the-art neuroimaging techniques. We will specifically evaluate the structure and functional connectivity of the dorsolateral prefrontal cortex (DLPFC)

region of the brain, which is involved in regulating core executive functions, which are key determinants of goal-directed behaviors, academic success, and personal autonomy. To account for normal age-related changes in these neuroimaging outcomes, we will compare changes in our cohort to developmental changes

seen in cisgender adolescents from the general population using data from the Adolescent Brain and Cognitive Development (ABCD) study, a prospective investigation of 11,878 children recruited nationwide that has made data freely available to researchers. We will also investigate the association of neuroimaging changes in our

cohort with changes in the three core executive functions: response inhibition, cognitive flexibility, and working memory. In addition, we will explore the correlations between changes in neuroimaging findings and changes in symptoms of anxiety and depression. To account for changes in these neurocognitive and psychological

outcomes that occur normally with age, we have carefully selected measures that give scores that are standardized for age. Our study will a) evaluate the effects of GAHT (estradiol and testosterone) on DLPFC structure and function, and b) characterize the associations of GAHT-related changes with executive function

tasks and with symptoms of anxiety and depression. Our investigation will provide pragmatic data about the effects of GAHT on brain changes in TNB adolescents and its relation to executive function to enable clinicians to counsel patients and families about these effects and to eventually develop approaches to optimize

cognitive and educational outcomes.