PROJECT SUMMARY/ABSTRACT Transgender children and adolescents are a poorly understood and a distinctly understudied population in the United States. The limited available data suggest that youth with gender dysphoria are at increased risk for negative mental and medical health outcomes including anxiety, depression, HIV acquisition, suicide, and substance use compared to their peers. Therefore, medical intervention is aimed at alleviating gender dysphoria and ameliorating potential negative outcomes. In 2011, the Institute of Medicine called for research to understand and improve the lives of gender minority populations. In 2015, Children’s Hospital Los Angeles/USC, Boston Children’s Hospital/Harvard Medical School, Benioff Children’s Hospitals/UCSF and Lurie Children’s Hospital of Chicago/Northwestern University were awarded NIH grant R01HD082554 to develop and implement a multidisciplinary, prospective, observational study: The Impact of Early Medical Treatment in Transgender Youth (TYC). The original aims were to examine physiological and psychosocial effects of medical intervention for transgender and gender diverse (TGD) youth with gender dysphoria observed for 24-months. To date, TYC has successfully recruited beyond its targeted baseline sample in two cohorts: (i) 95 youth initiating pubertal suppression with gonadotropin releasing hormone analogs (GnRHa) along with one parent/guardian (n=95), as well as (ii) 316 youth initiating gender-affirming hormone (GAH) therapy (testosterone or estrogen). Early results have demonstrated a positive trend regarding mental health response to gender affirming interventions. The primary objective of this observational, longitudinal, multicenter renewal study is to evaluate the longer-term physiological and psychological impact of existing medical treatment protocols initiated in adolescence on youth with gender dysphoria for up to an additional 4 years. A second objective is to enhance the diversity and size of existing cohorts by enrolling additional youth of color (YOC) into both cohorts (n=89) and enroll additional assigned males at birth specifically into the GAH cohort (n=110). The final objective is to add measurements of psychosocial variables required to answer new questions posed in this renewal application. A key feature of the renewal period is that most individuals in the original GnRHa cohort will be starting GAH treatment. By examining outcomes of TGD youth who initiated GAH treatment with and without histories of puberty suppression, TYC will be well positioned to examine key questions about the sequencing of puberty suppression and GAH treatment on health outcomes. Continuing our current research is imperative to expand the scant evidence-base currently guiding the clinical care of TGD youth and thus, is of considerable public health significance. Results from this study have the potential to significantly impact services provided to TGD youth in the U.S. by making available rigorous scie...