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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.)

Background: Knowledge regarding the effects and side effects of gender-affirming hormone therapy (GAHT) in adults is rapidly growing, partly through international research networks such as the European Network for the Investigation of Gender Incongruence (ENIGI). However, data on the effects of puberty suppression (PS) and GAHT in transgender and gender diverse (TGD) youth are limited, although these data are of crucial importance, given the controversies surrounding this treatment., Aim: We sought to present a detailed overview of the design of the ENIGI Adolescents study protocol, including the first baseline data., Methods: The ENIGI Adolescents study is an ongoing multicenter prospective cohort study. This study protocol was developed by 3 European centers that provide endocrine care for TGD adolescents and were already part of the ENIGI collaboration: Amsterdam, Ghent, and Florence., Outcomes: Study outcomes include physical effects and side effects, laboratory parameters, bone mineral density, anthropometric characteristics, attitudes toward fertility and fertility preservation, and psychological well-being, which are measured in the study participants during PS and GAHT, up to 3 years after the start of GAHT., Results: Between November 2021 and May 2023, 172 TGD adolescents were included in the ENIGI Adolescents protocol, of whom 51 were assigned male at birth (AMAB) and 121 were assigned female at birth (AFAB); 3 AFAB participants reported a nonbinary gender identification. A total of 76 participants were included at the start of PS, at a median (IQR) age of 13.7 (12.9-16.5) years in AMAB and 13.5 (12.4-16.1) years in AFAB individuals. The remaining 96 participants were included at start of GAHT, at a median (IQR) age of 15.9 (15.1-17.4) years in AFAB and 16.0 (15.1-16.8) years in AMAB individuals. At the time of this report the study was open for inclusion and follow-up measurements were ongoing., Clinical Implications: In response to the rising demand for gender-affirming treatment among TGD youth, this ongoing study is fulfilling the need for prospective data on the effects and safety of PS and GAHT, thus providing a foundation for evidence-based healthcare decisions., Strengths and Limitations: This study has a strong multicenter, prospective design that allows for systematic data collection. The use of clinical and self-reported data offers a broad range of outcomes to evaluate. Nevertheless, the burden of additional measurements and questionnaires may lead to withdrawal or lower response rates. Few participants with a non-binary gender identity have been included., Conclusion: With the ENIGI Adolescents study we aim to create a comprehensive dataset that we can use for a wide range of studies to address current controversies and uncertainties and to improve healthcare for TGD adolescents., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society of Sexual Medicine.)

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.

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.)

Context: Growth is an important topic for many transgender boys. However, few studies have investigated the impact of puberty suppression (PS) and gender-affirming hormone treatment (GAHT) on growth and adult height., Objective: To evaluate the effect of PS and GAHT on growth and adult height., Design: Retrospective cohort study., Setting: Specialized gender identity clinic., Participants: A total of 146 transgender boys treated with GnRH analogues and testosterone who reached adult height., Main Outcome Measures: Growth, bone age (BA), adult height, and difference between adult height and predicted adult height (PAH) and midparental height., Results: In those with BA ≤14 years at start (n = 61), a decrease in growth velocity and bone maturation during PS was followed by an increase during GAHT. Adult height was 172.0 ± 6.9 cm; height SD score was similar to baseline (0.1; 95% CI, -0.2 to 0.4). Adult height was 3.9 ± 6.0 cm above midparental height and 3.0 ± 3.6 cm above PAH at start of PS. A younger BA at start PS was associated with an adult height significantly further above PAH., Conclusion: During PS, growth decelerated followed by an acceleration during GAHT. Although adult height SD score was similar to baseline, adult height was taller than predicted based on BA at baseline, especially in those who started treatment at a younger BA. It is reassuring that PS and GAHT do not have a negative impact on adult height in transgender boys and might even lead to a slightly taller adult height, especially in those who start at a younger age., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

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: Transgender healthcare is a rapidly evolving interdisciplinary field. In the last decade, there has been an unprecedented increase in the number and visibility of transgender and gender diverse (TGD) people seeking support and gender-affirming medical treatment in parallel with a significant rise in the scientific literature in this area. The World Professional Association for Transgender Health (WPATH) is an international, multidisciplinary, professional association whose mission is to promote evidence-based care, education, research, public policy, and respect in transgender health. One of the main functions of WPATH is to promote the highest standards of health care for TGD people through the Standards of Care (SOC). The SOC was initially developed in 1979 and the last version (SOC-7) was published in 2012. In view of the increasing scientific evidence, WPATH commissioned a new version of the Standards of Care, the SOC-8. Aim: The overall goal of SOC-8 is to provide health care professionals (HCPs) with clinical guidance to assist TGD people in accessing safe and effective pathways to achieving lasting personal comfort with their gendered selves with the aim of optimizing their overall physical health, psychological well-being, and self-fulfillment. Methods: The SOC-8 is based on the best available science and expert professional consensus in transgender health. International professionals and stakeholders were selected to serve on the SOC-8 committee. Recommendation statements were developed based on data derived from independent systematic literature reviews, where available, background reviews and expert opinions. Grading of recommendations was based on the available evidence supporting interventions, a discussion of risks and harms, as well as the feasibility and acceptability within different contexts and country settings. Results: A total of 18 chapters were developed as part of the SOC-8. They contain recommendations for health care professionals who provide care and treatment for TGD people. Each of the recommendations is followed by explanatory text with relevant references. General areas related to transgender health are covered in the chapters Terminology, Global Applicability, Population Estimates, and Education. The chapters developed for the diverse population of TGD people include Assessment of Adults, Adolescents, Children, Nonbinary, Eunuchs, and Intersex Individuals, and people living in Institutional Environments. Finally, the chapters related to gender-affirming treatment are Hormone Therapy, Surgery and Postoperative Care, Voice and Communication, Primary Care, Reproductive Health, Sexual Health, and Mental Health. Conclusions: The SOC-8 guidelines are intended to be flexible to meet the diverse health care needs of TGD people globally. While adaptable, they offer standards for promoting optimal health care and guidance for the treatment of people experiencing gender incongruence. As in all previous versions of the SOC, the criteria set forth in this document for gender-affirming medical interventions are clinical guidelines; individual health care professionals and programs may modify these in consultation with the TGD person., Competing Interests: Conflict of interests were reviewed as part of the selection process for committee members and at the end of the process before publication. No conflicts of interest were deemed significant or consequential., (© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Bone geometry can be described in terms of periosteal and endocortical growth and is partly determined by sex steroids. Periosteal and endocortical apposition are thought to be regulated by testosterone and estrogen, respectively. Gender-affirming hormone (GAH) treatment with sex steroids in transgender people might affect bone geometry. However, in adult transgender people, no change in bone geometry during GAH was observed. In this study, we investigated changes in bone geometry among transgender adolescents using a gonadotropin-releasing hormone agonist (GnRHa) and GAH before achieving peak bone mass. Transgender adolescents treated with GnRHa and subsequent GAH before the age of 18 years were eligible for inclusion. Participants were grouped based on their Tanner stage at the start of GnRHa treatment and divided into early, mid, and late puberty groups. Hip structure analysis software calculating subperiosteal width (SPW) and endocortical diameter (ED) was applied to dual-energy X-ray absorptiometry scans performed at the start of GnRHa and GAH treatments, and after ≥2 years of GAH treatment. Mixed-model analyses were performed to study differences over time. Data were visually compared with reference values of the general population. A total of 322 participants were included, of whom 106 were trans women and 216 trans men. In both trans women and trans men, participants resembled the reference curve for SPW and ED of the experienced gender but only when GnRHa was started during early puberty. Those who started during mid and late puberty remained within the reference curve of the gender assigned at birth. A possible explanation might be sought in the phenomenon of programming, which conceptualizes that stimuli during critical windows of development can have major consequences throughout one's life span. Therefore, this study adds insights into sex-specific bone geometry development during puberty of transgender adolescents treated with GnRHa, as well as the general population. © 2021 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research., (© 2021 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.)

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.)

Click-evoked otoacoustic emissions (CEOAEs) are echo-like sounds, generated by the inner ear in response to click-stimuli. A sex difference in emission strength is observed in neonates and adults, with weaker CEOAE amplitudes in males. These differences are assumed to originate from testosterone influences during prenatal male sexual differentiation and to remain stable throughout life. However, recent studies suggested activational, postnatal effects of sex hormones on CEOAEs. Adolescents diagnosed with gender dysphoria (GD) may receive gonadotropin-releasing hormone analogs (GnRHa) in order to suppress endogenous sex hormones and, therefore, pubertal maturation, followed by cross-sex hormone (CSH) treatment. Using a cross-sectional design, we examined whether hormonal interventions in adolescents diagnosed with GD (62 trans boys, assigned female at birth, self-identifying as male; 43 trans girls, assigned male at birth, self-identifying as female), affected their CEOAEs compared to age- and sex-matched controls (44 boys, 37 girls). Sex-typical differences in CEOAE amplitude were observed among cisgender controls and treatment-naïve trans boys but not in other groups with GD. Treatment-naïve trans girls tended to have more female-typical CEOAEs, suggesting hypomasculinized early sexual differentiation, in support of a prominent hypothesis on the etiology of GD. In line with the predicted suppressive effects of androgens, trans boys receiving CSH treatment, i.e., testosterone plus GnRHa, showed significantly weaker right-ear CEOAEs compared with control girls. A similar trend was seen in trans boys treated with GnRHa only. Unexpectedly, trans girls showed CEOAE masculinization with addition of estradiol. Our findings show that CEOAEs may not be used as an unequivocal measure of prenatal androgen exposure as they can be modulated postnatally by sex hormones, in the form of hormonal treatment.

Gender-affirming treatment of 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 antiandrogens 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 for venous thromboembolism. The Endocrine Society guidelines for transgender men include testosterone therapy for virilization with deepening of the voice, cessation of menses, and increases of muscle mass and facial and body hair. Owing to the lack of evidence, treatment of gender nonbinary people should be individualized. Young people may receive pubertal suspension, consisting of GnRH 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 the effect of gender-affirming treatment in the nonbinary population.

Background: Transgender adolescents aspiring to have the body characteristics of the affirmed sex can receive hormonal treatment. However, it is unknown how body shape and composition develop during treatment and whether transgender persons obtain the desired body phenotype., Aim: To examine the change in body shape and composition from the start of treatment with gonadotropin-releasing hormone agonists (GnRHa) until 22 years of age and to compare these measurements at 22 years with those of age-matched peers., Methods: 71 transwomen (birth-assigned boys) and 121 transmen (birth-assigned girls) who started treatment from 1998 through 2014 were included in this retrospective study. GnRHa treatment was started and cross-sex hormonal treatment was added at 16 years of age. Anthropometric and whole-body dual-energy x-ray absorptiometry data were retrieved from medical records. Linear mixed model regression was performed to examine changes over time. SD scores (SDS) were calculated to compare body shape and composition with those of age-matched peers., Outcomes: Change in waist-hip ratio (WHR), total body fat (TBF), and total lean body mass (LBM) during hormonal treatment. SDS of measures of body shape and composition compared with age-matched peers at 22 years of age., Results: In transwomen, TBF increased (+10%, 95% CI = 7-11) while total LBM (-10%, 95% CI = -11 to -7) and WHR (-0.04, 95% CI = -0.05 to -0.02) decreased. Compared with ciswomen, SDS at 22 years of age were +0.3 (95% CI = 0.0-0.5) for WHR, and 0.0 (95% CI = -0.2 to 0.3) for TBF. Compared with cismen, SDS were -1.0 (95% CI = -1.3 to -0.7) for WHR, and +2.2 (95% CI = 2.2-2.4) for TBF. In transmen, TBF decreased (-3%, 95% CI = -4 to -1), while LBM (+3%, 95% CI = 1-4) and WHR (+0.03, 95% CI = 0.01-0.04) increased. Compared with ciswomen, SDS at 22 years of age were +0.6 (95% CI = 0.4-0.8) for WHR, and -1.1 (95% CI = -1.4 to -0.9) for TBF. Compared with cismen, SDS were -0.5 (95% CI = -0.8 to -0.3) for WHR, and +1.8 (95% CI = 1.6-1.9) for TBF., Clinical Implications: Knowing body shape and composition outcomes at 22 years of age will help care providers in counseling transgender youth on expectations of attaining the desired body phenotype., Strengths and Limitations: This study presents the largest group of transgender adults to date who started treatment in their teens. Despite missing data, selection bias was not found., Conclusions: During treatment, WHR and body composition changed toward the affirmed sex. At 22 years of age, transwomen compared better to age-matched ciswomen than to cismen, whereas transmen were between reference values for ciswomen and cismen. Klaver M, de Mutsert R, Wiepjes CM, et al. Early Hormonal Treatment Affects Body Composition and Body Shape in Young Transgender Adolescents. J Sex Med 2018;15:251-260., (Copyright © 2017 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Counseling and treatment of transgender youth can be challenging for mental health practitioners, as increased availability of gender-affirming treatments in recent years raises ethical and clinical questions. Is a gender identity diagnosis helpful? What is the right time to treat, and should the adolescent's age matter in decision making? In this article, we discuss these questions in light of a case in which an adolescent wishes to pursue hormone therapy. Our analysis focuses on the importance of balanced decision making when counseling and treating adolescents with nonconforming gender identities. We argue that clinicians' communicating appropriate expectations about the effectiveness and limitations of hormone therapy and the risks of psychological and physical iatrogenic effects is critical., (© 2017 American Medical Association. All Rights Reserved.)

Puberty is highly important for the accumulation of bone mass. Bone turnover and bone mineral density (BMD) can be affected in transgender adolescents when puberty is suppressed by gonadotropin-releasing hormone analogues (GnRHa), followed by treatment with cross-sex hormone therapy (CSHT). We aimed to investigate the effect of GnRHa and CSHT on bone turnover markers (BTMs) and bone mineral apparent density (BMAD) in transgender adolescents. Gender dysphoria was diagnosed based on diagnostic criteria according to the DSM-IV (TR). Thirty four female-to-male persons (transmen) and 22 male-to-female persons (transwomen)were included. Patients were allocated to a young (bone age of <15years in transwomen or <14 in transmen) or old group (bone age of ≥15years in transwomen or ≥14years in transmen). All were treated with GnRHa triptorelin and CSHT was added in incremental doses from the age of 16years. Transmen received testosterone esters (Sustanon, MSD) and transwomen received 17-β estradiol. P1NP, osteocalcin, ICTP and BMD of lumbar spine (LS) and femoral neck (FN) were measured at three time points. In addition, BMAD and Z-scores were calculated. We found a decrease of P1NP and 1CTP during GnRHa treatment, indicating decreased bone turnover (young transmen 95% CI -74 to -50%, p=0.02, young transwomen 95% CI -73 to -43, p=0.008). The decrease in bone turnover upon GnRHa treatment was accompanied by an unchanged BMAD of FN and LS, whereas BMAD Z-scores of predominantly the LS decreased especially in the young transwomen. Twenty-four months after CSHT the BTMs P1NP and ICTP were even more decreased in all groups except for the old transmen. During CSHT BMAD increased and Z-scores returned towards normal, especially of the LS (young transwomen CI 95% 0.1 to 0.6, p=0.01, old transwomen 95% CI 0.3 to 0.8, p=0.04). To conclude, suppressing puberty by GnRHa leads to a decrease of BTMs in both transwomen and transmen transgender adolescents. The increase of BMAD and BMAD Z-scores predominantly in the LS as a result of treatment with CSHT is accompanied by decreasing BTM concentrations after 24months of CSHT. Therefore, the added value of evaluating BTMs seems to be limited and DXA-scans remain important in follow-up of bone health of transgender adolescents., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Sex differences in performance and regional brain activity during mental rotation have been reported repeatedly and reflect organizational and activational effects of sex hormones. We investigated whether adolescent girls with gender dysphoria (GD), before and after 10 months of testosterone treatment, showed male-typical brain activity during a mental rotation task (MRT)., Methods: Girls with GD underwent fMRI while performing the MRT twice: when receiving medication to suppress their endogenous sex hormones before onset of testosterone treatment, and 10 months later during testosterone treatment. Two age-matched control groups participated twice as well., Results: We included 21 girls with GD, 20 male controls and 21 female controls in our study. In the absence of any group differences in performance, control girls showed significantly increased activation in frontal brain areas compared with control boys ( p FWE = 0.012). Girls with GD before testosterone treatment differed significantly in frontal brain activation from the control girls ( p FWE = 0.034), suggesting a masculinization of brain structures associated with visuospatial cognitive functions. After 10 months of testosterone treatment, girls with GD, similar to the control boys, showed increases in brain activation in areas implicated in mental rotation., Limitations: Since all girls with GD identified as gynephilic, their resemblance in spatial cognition with the control boys, who were also gynephilic, may have been related to their shared sexual orientation rather than their shared gender identity. We did not account for menstrual cycle phase or contraceptive use in our analyses., Conclusion: Our findings suggest atypical sexual differentiation of the brain in natal girls with GD and provide new evidence for organizational and activational effects of testosterone on visuospatial cognitive functioning.

Click-evoked otoacoustic emissions (CEOAEs) are echo-like sounds that are produced by the inner ear in response to click-stimuli. CEOAEs generally have a higher amplitude in women compared to men and neonates already show a similar sex difference in CEOAEs. Weaker responses in males are proposed to originate from elevated levels of testosterone during perinatal sexual differentiation. Therefore, CEOAEs may be used as a retrospective indicator of someone's perinatal androgen environment. Individuals diagnosed with Gender Identity Disorder (GID), according to DSM-IV-TR, are characterized by a strong identification with the other gender and discomfort about their natal sex. Although the etiology of GID is far from established, it is hypothesized that atypical levels of sex steroids during a critical period of sexual differentiation of the brain might play a role. In the present study, we compared CEOAEs in treatment-naïve children and adolescents with early-onset GID (24 natal boys, 23 natal girls) and control subjects (65 boys, 62 girls). We replicated the sex difference in CEOAE response amplitude in the control group. This sex difference, however, was not present in the GID groups. Boys with GID showed stronger, more female-typical CEOAEs whereas girls with GID did not differ in emission strength compared to control girls. Based on the assumption that CEOAE amplitude can be seen as an index of relative androgen exposure, our results provide some evidence for the idea that boys with GID may have been exposed to lower amounts of androgen during early development in comparison to control boys.

The odorous steroid androstadienone, a putative male chemo-signal, was previously reported to evoke sex differences in hypothalamic activation in adult heterosexual men and women. In order to investigate whether puberty modulated this sex difference in response to androstadienone, we measured the hypothalamic responsiveness to this chemo-signal in 39 pre-pubertal and 41 adolescent boys and girls by means of functional magnetic resonance imaging. We then investigated whether 36 pre-pubertal children and 38 adolescents diagnosed with gender dysphoria (GD; DSM-5) exhibited sex-atypical (in accordance with their experienced gender), rather than sex-typical (in accordance with their natal sex) hypothalamic activations during olfactory stimulation with androstadienone. We found that the sex difference in responsiveness to androstadienone was already present in pre-pubertal control children and thus likely developed during early perinatal development instead of during sexual maturation. Adolescent girls and boys with GD both responded remarkably like their experienced gender, thus sex-atypical. In contrast, pre-pubertal girls with GD showed neither a typically male nor female hypothalamic activation pattern and pre-pubertal boys with GD had hypothalamic activations in response to androstadienone that were similar to control boys, thus sex-typical. We present here a unique data set of boys and girls diagnosed with GD at two different developmental stages, showing that these children possess certain sex-atypical functional brain characteristics and may have undergone atypical sexual differentiation of the brain.

Introduction: In our hospital, female-to-male (FtM) transgender adolescents from the age of 16 are treated with two- or four-weekly intra-muscular injections of testosterone-esters. Some patients treated with four-weekly injections have complaints of fatigue and experience mood swings towards the end of the inter-injection period, which calls for an evaluation of the time-course of testosterone levels between injections. Evaluation of salivary testosterone is a practical approach for sequential measurements. Since only ∼2% of total serum testosterone is present in saliva, a sensitive assay is necessary. The objective was to develop an isotope dilution-liquid chromatography-tandem mass spectrometry method (ID-LC-MS/MS) for salivary testosterone measurements and to evaluate the testosterone profiles after testosterone-ester mixture injections in FtM-adolescents., Experimental: FtM treated with 125 mg/2 weeks or with 250 mg/4 weeks depots of testosterone-ester mixture collected saliva at different time intervals. Salivary testosterone was measured by a thoroughly validated ID-LC-MS/MS assay., Results: An ID-LC-MS/MS method for measuring salivary testosterone was developed with adequate accuracy and specificity. The reference range was established at 135-400 pmol/L. Testosterone levels peaked supra-physiologically immediately post-injection, and decreased to levels within the male reference range after nine days in all patients. 250 mg/4 weeks depots resulted in values below the reference range at the end of the 4 weeks., Discussion: The development of an adequate ID-LC-MS/MS method for measuring salivary testosterone allowed us to investigate the testosterone profile in FtM-adolescents after testosterone-esters mixture injections. These injections lead to extreme concentrations which may affect the wellbeing of the patients., (Copyright © 2012 Elsevier Inc. All rights reserved.)

We describe the effect on the neonate of administration of rituximab to a woman with idiopathic thrombocytopenic purpura (ITP). Rituximab, an anti-CD20 antibody, was given weekly for 4 weeks to a woman with ITP in her third trimester of pregnancy. One month after the last rituximab administration a healthy girl was born. She had normal growth and development during the first six months. At birth, B-lymphocytes were not detectable. Rituximab levels in mother and neonate were 24000 and 6700 ng/mL, respectively. Only 7 cases of rituximab administration during pregnancy were described. No adverse events are described for fetus and neonate. We demonstrate that rituximab passes the placenta and inhibits neonatal B-lymphocyte development. However, after 6 months B-lymphocyte levels normalized and vaccination titres after 10 months were adequate. No infection-related complications occurred. Rituximab administration during pregnancy appears to be safe for the child but further studies are warranted.

Cystic fibrosis is a disease for which a number of Phase I clinical trials of gene therapy have been initiated. Several factors account for the high level of interest in a gene therapy approach to this disease. CF is the most common lethal inherited disease in Caucasian populations. The lung, the organ that is predominantly responsible for the morbidity and mortality in CF patients, is accessible by a non-invasive method, the inhalation of aerosols. The vectors employed in the Phase I trials have included recombinant adenoviruses, adeno-associated viruses and cationic lipids. While there have been some positive results, the success of the vectors until now has been limited by either immunogenicity or low efficiency. A more fundamental obstacle has been the absence of appropriate receptors on the apical surface of airway epithelial cells. Molecular conjugates with carbohydrate substitution to provide targeting offer several potential advantages. Lactosylated polylysine in which 40% of the lysines have been substituted with lactose has been shown to provide a high efficiency of transfection in primary cultures of CF airway epithelial cells. Other important features include a relatively low immunogenicity and cytotoxicity. Most importantly, the lactosylated polylysine was demonstrated to give nuclear localization in CF airway epithelial cells. Until now, most non-viral vectors did not have the capability to provide nuclear localization. These unique qualities provided by the lactosylation of non-viral vectors, such as polylysine may help to advance the development of molecular conjugates sufficiently to warrant their use in future clinical trials for the gene therapy of inherited diseases of the lung.

Poly-l-lysine, with 40% of its amino groups substituted with lactose, is an effective vector to transfer the CFTR gene into CF airway epithelial cells and correct the chloride channel dysfunction. The intracellular fate of the lactosylated poly-l-lysine/cDNA complex was studied using confocal microscopy. In the presence of chloroquine the complex remained intact during internalization, intracellular transport, and, most importantly, transport into the nucleus. When cells were transfected in the presence of agents that enhance transfection efficiency such as E5CA peptide, a fusogenic peptide, or glycerol a similar fate of the lactosylated poly-l-lysine/cDNA complex was seen. However, when these agents were omitted from the transfection medium, the complex remained in the perinuclear region. Uncomplexed lactosylated poly-l-lysine reached the nucleus efficiently. In contrast mannosylated poly-l-lysine or unsubstituted poly-l-lysine complexed to plasmid did not. Therefore the nuclear accumulation of the complex may be attributed to the substitution of poly-l-lysine with lactose. It is hypothesized that the lactose residues provide for nuclear localization by means of targeting a potential lectin-like protein with galactose/lactose specificity. This mechanism may be responsible for the nuclear internalization of the complex.