111 Trajectories of adolescents treated with gonadotropin‑releasing hormone analogues for gender dysphoria 6 INTRODUCTION Increasing numbers of minors diagnosed with gender dysphoria are seen by paediatric endocrinologists. Gender dysphoria is the persistent feeling of incongruence between gender identity (sense of being a man, woman, or other) and the sex assigned at birth. The diagnosis gender dysphoria can be made if the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria are met (American Psychiatric Association, 2013). The prevalence of gender dysphoria among Dutch adolescents aged 12-18 years was recently estimated to be one in 6300 based on numbers of adolescents seeking medical treatment, with a ratio of transboys (assigned female at birth) to transgirls (assigned male at birth) of 1.9:1 (Wiepjes et al., 2018). Genetic, hormonal, psychological, and social factors may play a role, but the exact aetiology of gender dysphoria remains unknown (de Vries & Cohen-Kettenis, 2012; Hembree et al., 2017; Martinerie et al., 2018). Gender dysphoria in prepubertal children can be expressed by dislike of their physical sex characteristics and gender incongruent behaviour. In many children, gender dysphoria will not persist, but if the gender dysphoric feelings intensify during puberty, they are thought to be unlikely to subside (de Vries & Cohen-Kettenis, 2012; Hembree et al., 2017; Zucker et al., 2011). When puberty starts (Tanner genital/breast stage 2) and gender dysphoria persists, adolescents are eligible to start with puberty suppression (PS) using gonadotropin-releasing hormone analogues (GnRHa) (Coleman et al., 2012; Hembree et al., 2017). Treatment with GnRHa aims to give the adolescent the opportunity to explore their gender identity and time to consider if they wish to pursue gender-affirming medical treatment (GAMT) while development of unwanted secondary sex characteristics is suppressed in order to reduce distress (Hembree et al., 2017; Zucker et al., 2011). Effects of GnRHa on pubertal development are reversible. This is in contrast to gender-affirming hormones (GAH) which have largely irreversible effects on secondary sex characteristics and may compromise fertility after prolonged use (de Roo, Tilleman, T’Sjoen, & de Sutter, 2016; Hembree et al., 2017). Short-term adverse effects of GnRHa are hot flushes at the start of the treatment and sometimes mood alterations and fatigue (Delemarre-van de Waal & Cohen-Kettenis, 2006; Hembree et al., 2017; Schagen, Cohen-Kettenis, Delemarre-van de Waal, & Hannema, 2016). Few data are available on long-term adverse effects. Bone mineral density may be affected (Klink et al., 2015; Vlot et al., 2017), and since puberty is an important period for brain development (Sisk & Zehr, 2005), PS with GnRHa might also influence brain development. There is a lack of studies investigating effects of GnRHa on the brain. One study examined executive function and concluded that treatment with GnRHa had no detrimental effects on performance (Staphorsius et al., 2015). However, a longitudinal study among 25 adopted girls treated with GnRHa for early puberty reported a decrease in IQ from
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