Safeguarding Gaps in the PATHWAYS Trial: Insights from GnRH Analogue Use in Gynecology

The PATHWAYS trial offers an important opportunity to evaluate the benefits and harms of gonadotropin-releasing hormone analogue (GnRHa) treatment in adolescents with gender incongruence. Drawing on evidence from GnRHa use for gynecological indications, this commentary argues that the trial omits evidence-based risk-mitigation practices relevant to late pubertal female participants, who represent a substantial proportion of those prescribed GnRHas for gender incongruence in the United Kingdom and other countries. This omission exposes participants to foreseeable and preventable harm. Additionally, the use of a waitlist control may amplify expectancy and nocebo effects among adolescents who begin GnRHa therapy in late puberty when commonly proposed mechanisms of psychological benefit, such as preventing distress from developing secondary sex characteristics, are less biologically plausible. Closer alignment of the PATHWAYS protocol with established risk-mitigation practices would enhance its scientific credibility and help ensure participants are adequately safeguarded.