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Objective: Bone mineral density (BMD) Z-scores decrease during puberty suppression in transgender youth. Assessment of treatment impact has been based on the assumption that without intervention, BMD Z-scores remain stable. However, the natural course of BMD in this population is unknown., Design: Retrospective cross-sectional study., Methods: Dual-energy X-ray absorptiometry scans prior to medical intervention were included from 333 individuals assigned male at birth (AMAB) and 556 individuals assigned female at birth (AFAB) aged 12-25 years. The relationship between age and BMD Z-scores of sex assigned at birth was analysed for the lumbar spine (LS), total hip (TH), femoral neck (FN), and total-body-less-head (TBLH), adjusted for height SDS, height-adjusted lean mass Z-score, and whole body percentage fat Z-score., Results: In individuals AMAB, the BMD Z-score was negatively associated with age between 12 and 22 years: LS -0.13/year (95% confidence interval, CI -0.17; -0.10); TH -0.05/year (95% CI -0.08; -0.02); FN -0.06/year (95% CI -0.10; -0.03); and TBLH -0.12/year (95% CI -0.15; -0.09). Adjusting for height-adjusted lean mass Z-score attenuated the association at the LS and TBLH and eliminated the association at the TH and FN. BMD Z-scores and age were not associated between 22 and 25 years. In individuals AFAB, BMD Z-scores were only associated with age at the TBLH (-0.08/year, 95% CI -0.12; -0.04) between age 12 and 20 years., Conclusion: In individuals AMAB aged 12-22 years prior to any treatment, BMD Z-scores were inversely correlated with age. This could imply that BMD increases less in individuals AMAB than in the general population, and that changes in Z-score during puberty suppression and subsequent hormone supplementation are not necessarily due to treatment, but possibly related to lifestyle factors., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology.)

Importance: Bone mineral density (BMD) z scores in transgender adolescents decrease during puberty suppression with a gonadotropin-releasing hormone (GnRH) agonist. Previous research found that after short-term use of gender-affirming hormones (GAH), pretreatment z scores were not restored. Long-term follow-up studies are lacking., Objective: To assess BMD after long-term GAH treatment in transgender adults who used puberty suppression in adolescence., Design, Setting, and Participants: This single-center cohort study with follow-up duration of 15 years selected participants from a database containing all people visiting a gender identity clinic at an academic hospital in the Netherlands between 1972 and December 31, 2018. Recruitment occurred from March 1, 2020, to August 31, 2021. A total of 75 participants diagnosed with gender dysphoria who had used puberty suppression before age 18 years prior to receiving at least 9 years of long-term GAH were included., Exposures: Puberty suppression with a GnRH agonist followed by GAH treatment., Main Outcomes and Measures: Lumbar spine, total hip, and femoral neck BMD and z scores before the start of puberty suppression, at start of GAH, and at short- and long-term follow-up., Results: Among 75 participants, 25 were assigned male at birth, and 50 were assigned female at birth. At long-term follow-up, the median (IQR) age was 28.2 (27.0-30.8) years in participants assigned male at birth and 28.2 (26.6-30.6) years in participants assigned female at birth. The median (IQR) duration of GAH treatment was 11.6 (10.1-14.7) years among those assigned male at birth and 11.9 (10.2-13.8) years among those assigned female at birth. The z scores decreased during puberty suppression. In individuals assigned male at birth, the mean (SD) z score after long-term GAH use was -1.34 (1.16; change from start of GnRH agonist: -0.87; 95% CI, -1.15 to -0.59) at the lumbar spine, -0.66 (0.75; change from start of GnRH agonist: -0.12; 95% CI, -0.31 to 0.07) at the total hip, and -0.54 (0.84; change from start of GnRH agonist: 0.01; 95% CI, -0.20 to 0.22) at the femoral neck. In individuals assigned female at birth, after long-term GAH use, the mean (SD) z score was 0.20 (1.05; change from start of GnRH agonist: 0.09; 95% CI, -0.09 to 0.27) at the lumbar spine, 0.07 (0.91; change from start of GnRH agonist: 0.10; 95% CI, -0.06 to 0.26) at the total hip, and -0.19 (0.94; change from start of GnRH agonist: -0.20; 95% CI, -0.26 to 0.06) at the femoral neck., Conclusions and Relevance: In this cohort study, after long-term use of GAH, z scores in individuals treated with puberty suppression caught up with pretreatment levels, except for the lumbar spine in participants assigned male at birth, which might have been due to low estradiol concentrations. These findings suggest that treatment with GnRH agonists followed by long-term GAH is safe with regard to bone health in transgender persons receiving testosterone, but bone health in transgender persons receiving estrogen requires extra attention and further study. Estrogen treatment should be optimized and lifestyle counseling provided to maximize bone development in individuals assigned male at birth.

Objective: Treatment in transgender girls can consist of puberty suppression (PS) with a gonadotropin-releasing hormone agonist (GnRHa) followed by gender-affirming hormonal treatment (GAHT) with estrogen. Bone mineral density (BMD) Z-scores decrease during PS and remain relatively low during GAHT, possibly due to insufficient estradiol dosage. Some adolescents receive high-dose estradiol or ethinyl estradiol (EE) to limit growth allowing comparison of BMD outcomes with different dosages., Design: Retrospective study., Methods: Adolescents treated with GnRHa for ≥1 year prior to GAHT followed by treatment with a regular estradiol dose (gradually increased to 2 mg), 6 mg estradiol or 100-200 µg EE were included to evaluate height-adjusted BMD Z-scores (HAZ scores) on DXA., Results: Eighty-seven adolescents were included. During 2.3 ± 0.7 years PS, lumbar spine HAZ scores decreased by 0.69 [95% confidence interval (CI) -0.82 to -0.56)]. During 2 years HT, lumbar spine HAZ scores hardly increased in the regular group (0.14, 95% CI -0.01 to 0.28, n = 59) vs 0.42 (95% CI 0.13 to 0.72) in the 6 mg group (n = 13), and 0.68 (95% CI 0.20 to 1.15) in the EE group (n = 15). Compared with the regular group, the increase with EE treatment was higher (0.54, 95% CI 0.05 to 1.04). After 2 years HT, HAZ scores approached baseline levels at start of PS in individuals treated with 6 mg or EE (difference in 6 mg group -0.20, 95% CI -0.50 to 0.09; in EE 0.17, 95% CI -0.16 to 0.50) but not in the regular group (-0.64, 95% CI -0.79 to -0.49)., Conclusion: Higher estrogen dosage is associated with a greater increase in lumbar spine BMD Z-scores. Increasing dosage up to 2 mg estradiol is insufficient to optimize BMD and approximately 4 mg may be required for adequate serum concentrations., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology.)

Background: Twenty 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., Aim: To study trends in trajectories in children and adolescents who were referred for evaluation of gender dysphoria and/or treated following the Dutch Protocol., Methods: The current study is based on a retrospective cohort of 1766 children and adolescents in the Amsterdam Cohort of Gender Dysphoria., Outcomes: Outcomes 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., Results: A 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 Implications: A 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 Limitations: Important 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., Conclusion: Trajectories 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., (© The Author(s) 2023. Published by Oxford University Press on behalf of The International Society of Sexual Medicine.)

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., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background and Objectives: The effects of endocrinological treatment on cardiovascular risk profile in transgender adolescents are unknown. In this retrospective cohort study, we aim to investigate these effects and assess obesity and dyslipidemia prevalence in transgender adolescents at 22 years compared with peers., Methods: Changes in BMI, systolic blood pressure (SBP), diastolic blood pressure (DBP), glucose, homeostatic model assessment for insulin resistance (HOMA-IR), and lipid values during treatment, along with the prevalence of obesity and dyslipidemia at 22 years, were recorded in 71 transwomen and 121 transmen who started gonadotropin-releasing hormone agonists in their adolescence (15 years), with a subsequent addition of sex hormones (17 years)., Results: In transwomen, changes in BMI (+3.0; 95% confidence interval [CI] 1.6 to 4.4), SBP (-2 mm Hg; 95% CI -7 to 3), DBP (+10 mm Hg; 95% CI 7 to 14), glucose (0.0 mmol/L; 95% CI -0.2 to 0.2), HOMA-IR (+0.6; 95% CI -0.6 to 1.9), and lipid values were similar or more favorable compared with peers. The same was true for transmen regarding changes in BMI (+2.3; 95% CI 1.7 to 2.9), SBP (+7 mm Hg; 95% CI 3 to 10), DBP (+7 mm Hg; 95% CI 5 to 10), glucose (+0.1 mmol/L; 95% CI -0.1 to 0.3), HOMA-IR (-0.2; 95% CI -0.8 to 0.3), and lipid values. At age 22, obesity prevalence was 9.9% in transwomen, 6.6% in transmen, 2.2% in ciswomen, and 3.0% in cismen., Conclusions: Generally, endocrinological treatment in transgender adolescents is safe regarding cardiovascular risk. Because obesity is more prevalent in transgender adolescents compared with peers, body weight management should be important during the medical trajectory., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)