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Background: In the Netherlands, treatment with puberty suppression is available to transgender adolescents younger than age 18 years. When gender dysphoria persists testosterone or oestradiol can be added as gender-affirming hormones in young people who go on to transition. We investigated the proportion of people who continued gender-affirming hormone treatment at follow-up after having started puberty suppression and gender-affirming hormone treatment in adolescence. Methods: In this cohort study, we used data from the Amsterdam Cohort of Gender dysphoria (ACOG), which included people who visited the gender identity clinic of the Amsterdam UMC, location Vrije Universiteit Medisch Centrum, Netherlands, for gender dysphoria. People with disorders of sex development were not included in the ACOG. We included people who started medical treatment in adolescence with a gonadotropin-releasing hormone agonist (GnRHa) to suppress puberty before the age of 18 years and used GnRHa for a minimum duration of 3 months before addition of gender-affirming hormones. We linked this data to a nationwide prescription registry supplied by Statistics Netherlands (Centraal Bureau voor de Statistiek) to check for a prescription for gender-affirming hormones at follow-up. The main outcome of this study was a prescription for gender-affirming hormones at the end of data collection (Dec 31, 2018). Data were analysed using Cox regression to identify possible determinants associated with a higher risk of stopping gender-affirming hormone treatment. Findings: 720 people were included, of whom 220 (31%) were assigned male at birth and 500 (69%) were assigned female at birth. At the start of GnRHa treatment, the median age was 14·1 (IQR 13·0–16·3) years for people assigned male at birth and 16·0 (14·1–16·9) years for people assigned female at birth. Median age at end of data collection was 20·2 (17·9–24·8) years for people assigned male at birth and 19·2 (17·8–22·0) years for those assigned female at birth. 704 (98%) people who had started gender-affirming medical treatment in adolescence continued to use gender-affirming hormones at follow-up. Age at first visit, year of first visit, age and puberty stage at start of GnRHa treatment, age at start of gender-affirming hormone treatment, year of start of gender-affirming hormone treatment, and gonadectomy were not associated with discontinuing gender-affirming hormones. Interpretation: Most participants who started gender-affirming hormones in adolescence continued this treatment into adulthood. The continuation of treatment is reassuring considering the worries that people who started treatment in adolescence might discontinue gender-affirming treatment. Funding: None.

BackgroundTwenty years ago, the Dutch Protocol—consisting of a gonadotropin-releasing hormone agonist (GnRHa) to halt puberty and subsequent gender-affirming hormones (GAHs)—was implemented to treat adolescents with gender dysphoria.AimTo study trends in trajectories in children and adolescents who were referred for evaluation of gender dysphoria and/or treated following the Dutch Protocol.MethodsThe current study is based on a retrospective cohort of 1766 children and adolescents in the Amsterdam Cohort of Gender Dysphoria.OutcomesOutcomes included trends in number of intakes, ratio of assigned sex at birth, age at intake, age at start of GnRHa and GAH, puberty stage at start of GnRHa, proportions of adolescents starting and stopping GnRHa, reasons for refraining from GnRHa, and proportions of people undergoing gender-affirming surgery.ResultsA steep increase in referrals was observed over the years. A change in the AMAB:AFAB ratio (assigned male at birth to assigned female at birth) was seen over time, tipping the balance toward AFAB. Age at intake and at start of GnRHa has increased over time. Of possibly eligible adolescents who had their first visit before age 10 years, nearly half started GnRHa vs around two-thirds who had their first visit at or after age 10 years. The proportion starting GnRHa rose only for those first visiting before age 10. Puberty stage at start of GnRHa fluctuated over time. Absence of gender dysphoria diagnosis was the main reason for not starting GnRHa. Very few stopped GnRHa (1.4%), mostly because of remission of gender dysphoria. Age at start of GAH has increased mainly in the most recent years. When a change in law was made in July 2014 no longer requiring gonadectomy to change legal sex, percentages of people undergoing gonadectomy decreased in AMAB and AFAB.Clinical ImplicationsA substantial number of adolescents did not start medical treatment. In the ones who did, risk for retransitioning was very low, providing ongoing support for medical interventions in comprehensively assessed gender diverse adolescents.Strengths and LimitationsImportant topics on transgender health care for children and adolescents were studied in a large cohort over an unprecedented time span, limited by the retrospective design.ConclusionTrajectories in diagnostic evaluation and medical treatment in children and adolescents referred for gender dysphoria are diverse. Initiating medical treatment and need for surgical procedures depends on not only personal characteristics but societal and legal factors as well.

Background/Aims: Length and weight of all children in Flanders are monitored every three years at school from the age of 3 years. The current criteria used for referral to specialized care are: height SDS < -2.5, height SDS between -2 and -2.5 SDS with a height SDS adjusted for parental height < -1.64, or a decrease in height SDS of more than 1 SDS in the past 3 years. The aim of this study is to investigate the sensitivity of the Flemish referral criteria to detect idiopathic/congenital growth hormone deficiency (GHD) and Turner syndrome (TS). Methods: A cross-sectional analysis of data from children with idiopathic/congenital GHD and girls with TS included in the BELGROW register – a national register of all GH treated children – from January 2018 through December 2020. Height at the start of GH treatment and 2-3 years before GH treatment and parental heights (reported or measured) were retrieved from the database. Height SDS adjusted for parental height was calculated according to Hermanussen & Cole. The referral analysis only included prepubertal children below 10 years of age. Results: In the 112 children with GHD (78 male), GH treatment was started at a median age of 8.86 years (P10, P90: 2.86, 13.11) and a median height SDS of -2.99 (-4, -1.77). In the 43 girls with Turner syndrome this was 9.63 years (5.42, 14.44) and a height SDS of -2.79 (-3.77, -1.83). In the 97 children younger than 10 years of age, a height SDS < -2.5 was reported in 56 (76 %) out of 74 children with GHD and in 14 (61 %) out of 23 girls with TS. The SDS adjusted for parental height was < -1.64 in 60 (81 %) and 18 (78 %) respectively. In children older than 3 years with data on pre-treatment height, 5 (10 %) out of 49 with GHD and 1 (6 %) out of 17 with TS had a height decrease > 1 SDS before the start of GH treatment. Conclusion: In Belgium, GH treatment is started relatively late in children with congenital/idiopathic growth hormone deficiency and Turner syndrome, despite systematic growth monitoring at school. Height SDS adjusted for parental height was the most sensitive criterium for auxological detection of growth hormone deficiency and Turner syndrome, stressing the need of collection of parental height in school health surveys

RFC10.2Background/Aim: Over the past 6 years, the IGF1/ IGFBP3generation test (IGFGT) has been used in Belgium in a standardized form to identify children with severe primary IGF1 deficiency(SPIGFD). In this study, the discordance of the IGF1 and IGFBP3responses during an IGFGT and the prevalence of SPIGFD wereanalyzed in a cohort of children with short stature (height SDS 7 µg/L).Methods: In total, 56 (35 male) children aged between 1.3 and14.8 years (median 7.5) underwent an IGFGT. Only 34 IGFGT were analyzed, because of non-persisting low serum IGF1 valuesand/or an underlying chronic disease in 22 children. Morningserum IGF1 and IGFBP3 concentrations were measured by theIDS-iSYS assay before and after 7 daily injections of GH (0.05 mg/kg bodyweight somatotropin) in the evening. An abnormal IGF1/IGFBP3 response was defined by a stimulated value remainingbelow gender and age specific basal reference limits. SPIGFD wasdefined by a low basal IGF1 together with a IGF1 response < 15µg/L and a IGFBP3 response < 400 µg/L during the IGFGT.Results: In 16/34 (47%) children, a normal basal serum IGF1by the IDS-iSYS assay was measured and paralleled with a normalserum IGFBP3 in 13 cases. Twelve (67 %) of the 18 children witha confirmed low basal IGF1 had a low serum IGFBP3, 6 (33 %) hadan abnormal IGF1 response and the same 6 cases had an abnormalIGFBP3 response, whereas 6 had a IGF1 response < 15 µg/L, 5 hada IGFBP3 response < 400 µg/L and 4 had both responses below thedefined limits. Genetic studies in 3 of these 4 cases confirmed apathogenic heterogenous GHR gene mutation (c.899 dup p. andc.876G>T) in 2 cases and a pathogenic PTPN11 mutation inanother case.Conclusion: In short children with persistent low IGF1 valuesand a normal stimulated GH peak, a low IGF1 status could be confirmed in only half of the cases using the IDS-iSYS assay. In thosechildren, a 100 % concordance between low stimulated IGF1 andlow stimulated IGFBP3 levels was observed during a standardized(high dose and prolonged up to 7 days) IGF1/ IGFBP3 generationtest, permitting finally the biochemical diagnosis of a severe primary IGF1 deficiency in 12 %.

Gender affirming treatment for transgender people requires a multidisciplinary approach in which endocrinologists play a crucial role. The aim of this paper is to review recent data on hormonal treatment of this population and its effect on physical, psychological and mental health. The Endocrine Society guidelines for transgender women include estrogens in combination with androgen lowering medications. Feminizing treatment with estrogens and anti-androgens has desired physical changes, such as enhanced breast growth, reduction of facial and body hair growth and fat redistribution in a female pattern. Possible side effects should be discussed with patients, particularly those at risk of venous thromboembolism. The Endocrine Society guidelines for transgender men include testosterone therapy for virilization with deepening of the voice, cessation of menses plus increase of muscle mass, facial and body hair. Due to the lack of evidence, treatment for gender non-binary people should be individualized. Young people may receive pubertal suspension, consisting of gonadotrophin-releasing hormone analogs, later followed by sex steroids. Options for fertility preservation should be discussed before any hormonal intervention. Morbidity and cardiovascular risk with cross-sex hormones is unchanged among transgender men and unclear among transgender women. Sex steroid-related malignancies can occur, but are rare. Mental health problems such as depression and anxiety have been found to reduce considerably following hormonal treatment. Future studies should aim to explore the long-term outcome of hormonal treatment in transgender people and provide evidence as to effect of gender affirming treatment in the non-binary population.