Abstract Efforts to alleviate the psychological distress of gender dysphoria have included the use of exogenous estrogen (often with anti-androgens) to alter secondary sex characteristics of natal males. In response to the rapid increase in presenting cases among young people, extensive scrutiny has now been brought to bear on these medical interventions for minors, with ESCAP reporting “an urgent need for safeguarding clinical, scientific, and ethical standards.” However, due to the lack of systematic outcome data, the associated risk–benefit profile is unknown. Several recent systematic reviews have found the evidence of benefit to be of low or very low certainty,...