Transgender individuals increasingly present themselves at gender services during childhood. The long-term impact of gender-affirming therapy started in early puberty on metabolic tissues including the liver is unknown. Based on our preliminary data, we hypothesize that early puberty suppression causes hepatic cell dysfunction, which may not be fully restored by subsequent gender-affirming hormone administration. As a consequence, the liver may be primed to react more profoundly upon future (metabolic) insults, resulting in severe functional impairment during adult life. We will address these questions using mouse models that mimic the clinical strategy applied in transgender youth, thereby providing important and novel insights in the underlying mechanisms, which may ultimately be leveraged for optimizing medical care for young-adolescent transgender individuals.