Challenges in developing a quantitative method of measuring breast development using 3D imaging: An example of a novel method for use in induced breast development with exogenous oestrogen.

OBJECTIVE: Optimal breast development is an essential part of exogenous oestrogen treatment in females undergoing pubertal induction. We set out to develop a novel technique using three-dimensional (3D) imaging to determine change in breast volume that is applicable when no pre-existing breast contours are present. DESIGN: A prospective observational study. PATIENTS: The imaging methodology was developed using a single male subject to assess reproducibility and validity. The technique was then applied to 29 participants undergoing pubertal induction with exogenous oestradiol who were recruited from Paediatric Gynaecology and Reproductive Endocrinology clinics at University College London Hospital. MEASUREMENTS: Breast images were taken using a 3D photographic system. Two images, taken at different times, were manually superimposed to produce a differential breast volume. The initial step of method development set out to show that volume change was not secondary to positioning artefact or image manipulation. This was established by using images of a male participant taken on different occasions. The technique was then used to assess reproducibility in participants undergoing pubertal induction treatment. RESULTS: Good intraobserver reproducibility (intraclass correlation (ICC) 0.77) was demonstrated with static image manipulation. Validity of the imaging technique was established as there was no significant difference between the known reference volume produced by computer generated warping and that calculated by manual image manipulation. There was excellent intraobserver reproducibility for breast volume calculation in participants undergoing induced breast development (ICC 0.99). CONCLUSIONS: 3D imaging is a promising novel tool to provide quantitative breast volume assessment in individuals undergoing breast induction with exogenous oestradiol treatment.

Growth pattern evaluation of the Edinburgh and Gothenburg cohorts by QEPS height model.

BACKGROUND: The QEPS-growth-model, developed and validated in GrowUp-Gothenburg cohorts, used for developing growth references and investigating healthy/pathological growth, lacks external validation from other longitudinal cohorts of healthy individuals. AIM: To investigate if the QEPS-model can fit the longitudinal Edinburgh growth study of another design than GrowUp-Gothenburg cohorts, and to compare growth patterns in the individuals born in mid-1970s in North-Western Europe. METHODS: Longitudinal growth data were obtained from the Edinburgh and the GrowUp1974Gothenburg cohorts. The QEPS-model was used to describe length/height from birth to adult height with confidence interval, and the multivariable regression model for estimating the contribution of the different QEPS-functions to adult height. RESULTS: The QEPS-model fitted the Edinburgh cohort well, with high accuracy, and low confidence intervals indicating high precision. Despite 3 cm shorter stature (less QE-function growth) in Scottish children, the growth patterns of the cohorts were similar, especially for specific pubertal growth. The contribution to adult height from different QEPS functions was similar. CONCLUSION: The QEPS-model is validated for the first time in a longitudinal study of healthy individuals of another design and found to fit with high accuracy and precision. The Scottish and Western-Swedish cohorts born in mid-1970s showed similar growth patterns for both sexes, especially pubertal growth. IMPACT: For the first time, the QEPS height model was used and found to fit another longitudinal cohort of healthy individuals other than the Swedish longitudinal cohorts. With large numbers of individual measurements in each growth phase, the QEPS model calculates growth estimates with narrow confidence intervals (high precision) and high accuracy. The two different cohorts born in the mid-1970s from Scotland and Western Sweden have similar growth patterns, despite a 3 cm difference in adult height.

Incidence of gynaecomastia in Klinefelter syndrome adolescents and outcome of testosterone treatment.

The aim was to define the true incidence of gynaecomastia in adolescent boys with Klinefelter syndrome (KS) and to observe testosterone treatment effects on its duration by examination of the prospectively collected data from a specialist referral clinic for boys with KS, with comparison being made with KS boys identified by a historical newborn chromosome screening programme, together with chromosomally normal controls. Fifty-nine boys over age 13 years were referred to a specialist KS clinic; 21 developed gynaecomastia. The comparator was 14 KS boys identified at birth and 94 chromosomally normal control boys. Testosterone was routinely started at the onset of puberty if gynaecomastia, a manifestation of clinical hypogonadism, was present. Oral or transdermal testosterone was administered in the morning, in a reverse physiological rhythm, and doses were increased according to standard pubertal regimens. The incidence of gynaecomastia was not increased in both the KS cohorts compared with controls. The incidence and age of onset of gynaecomastia was 35.6%, at 12.3 (1.8) years in the KS clinic group; 36.0%, at 13.7 (0.6) years in the newborn survey group; and 34.0%, at 13.6 (0.8) years in the controls. Full resolution of the gynaecomastia occurred in the 12/14 KS clinic boys on testosterone treatment who had completed puberty and as long as adherence was maintained.Conclusion: The incidence of gynaecomastia in KS boys (overall 35.6%) is not increased over typically developing boys. Commencing testosterone when gynaecomastia develops with physiological dose escalation and full adherence can result in the resolution of the gynaecomastia. What is Known: • Gynaecomastia is a common feature in Klinefelter syndrome men. • Hypogonadism occurs from mid-puberty onwards with the absence of the usual rise in testosterone levels. What is New: • The incidence of pubertal gynaecomastia in Klinefelter syndrome is not different from typically developing boys. • Early and prompt starting of testosterone gel treatment and increasing the dose physiologically may help to resolve the gynaecomastia without the need for surgery.

Delayed puberty.

The onset of puberty may be late - in the latter part of the predicted normal range or truly delayed - beyond this range. The latest age to start is usually regarded as 13 years in girls and 14 years in boys. There may also be a delayed completion of puberty, 16 years in girls and 17 years in boys. The initial approach requires a detailed history and clinical examination to exclude other medical or psychological problems. The presence or absence or pubertal signs should be documented. Investigations should be targeted at ruling out any medical causes and determining whether the delay is due to central gonadotropin deficiency (hypogonadotropic hypogonadism) or a gonadal disorder (hypergonadotropic hypogonadism). Physiological or constitutional delay of growth and puberty (CDGP) is more common in boys but is a diagnosis of exclusion. Current research suggests that CDGP and congenital hypogonadotropic hypogonadism have distinct genetic profiles which may aid in the differential diagnosis. Treatment may be given using low doses of sex steroids, testosterone or estradiol initially in a short course of 3-6 months but continuing in escalating doses mimicking the normal course of puberty, watching regularly for the spontaneous resumption of progress and gonadotropin secretion. In gonadotropin deficiency, sex hormone treatment needs to be continued until completion of pubertal development and growth. Counselling, reassurance and support are key elements in the management of adolescents with delayed puberty.

Growth hormone treatment and health-related quality of life in children and adolescents: A national, prospective, one-year controlled study.

BACKGROUND: Health-related quality of life (HRQOL) may improve as an additional benefit of the growth hormone treatment (GHT) in children with short stature, but this effect has not been conclusively proven. OBJECTIVES: To explore the direct effect of GHT on HRQOL in children starting GHT due to isolated or multiple GH deficiency (IGHD), acquired GH deficiency (AGHD) and Turner syndrome (TS), in comparison with untreated short stature controls in 18 UK centres. METHODS: We used recognized measures of HRQOL, the PedsQL, the Strengths and Difficulties Questionnaire and Youth Life Optimism Test scales to investigate the effect of GHT at 0, 6 and 12 months in children and adolescents 6-16 years with IGHD (n = 73) and AGHD (n = 45), and 22 girls with TS. 49 children with non-GHD short stature served as the controls. RESULTS: Children rated their HRQOL better than their parents. Those with IGHD and TS rated their overall HRQOL lower than the controls at baseline, psychosocial scores significantly lower in IGHD. After 12 months, the control and TS groups scored higher than UK norms. Those with AGHD had lowest HRQOL scores at all time points, due to poorer physical functioning. The controls showed the greatest improvement in the strength and difficulties scale. All measures evaluated, whether from child, parent or teacher showed an equal improvement over the year of GHT with no discernible direct treatment effect, despite reduced numbers in some patient groups. CONCLUSIONS: Children with short stature resulting from GHD have lower functioning than controls but HRQOL appears to improve with GHT, most likely on account of greater attention and as a result of the retest phenomenon. We were not able to demonstrate an absolute and independent effect of GHT in itself. HRQOL should not be used as a primary measure, as in adults, to determine whether children should receive GHT.

Developing guidelines for disclosure or non-disclosure of bad news around life-limiting illness and death to people with intellectual disabilities.

BACKGROUND: There is insufficient evidence to guide decisions around (non-)disclosure of bad news of life-limiting illness and death to people with intellectual disabilities. AIM: The aim of this study was to develop guidelines for decisions about (non-)disclosure of bad news around life-limiting illness and death to people with intellectual disabilities, by examining stakeholders' preferences (and reasons) around disclosure and non-disclosure. MATERIALS AND METHODS: Focus groups and interviews were held with 109 participants: people with intellectual disabilities, family carers, intellectual disabilities professionals and medical healthcare professionals. RESULTS: People with intellectual disabilities had wide-ranging views about disclosure. Reasons for non-disclosure included: preventing distress; too difficult for the bearer of bad news; the bearer of bad news lacks knowledge; inability to understand; no sense of time; conflicting views among stakeholders. Reasons for disclosure included: a right to know; knowledge helps the person cope; need for involvement. CONCLUSION: Disclosure of bad news could cause harm in some situations, but this needs careful assessment. The authors present guidelines for disclosure that now need to be tested in practice.

Klinefelter syndrome: going beyond the diagnosis.

Although Klinefelter syndrome (KS) is common, it is rarely recognised in childhood, sometimes being identified with speech or developmental delay or incidental antenatal diagnosis. The only regular feature is testicular dysfunction. Postnatal gonadotropin surge (mini-puberty) may be lower, but treatment with testosterone needs prospective studies. The onset of puberty is at the normal age and biochemical hypogonadism does not typically occur until late puberty. Testosterone supplementation can be considered then or earlier for clinical hypogonadism. The size at birth is normal, but growth acceleration is more rapid in early and mid-childhood, with adult height greater than mid-parental height. Extreme tall stature is unusual. The incidence of adolescent gynaecomastia (35.6%) is not increased compared with typically developing boys and can be reduced or resolved by testosterone supplementation, potentially preventing the need for surgery. Around two-thirds require speech and language therapy or developmental support and early institution of therapy is important. Provision of psychological support may be helpful in ameliorating these experiences and provide opportunities to develop strategies to recognise, process and express feelings and thoughts. Boys with KS are at increased risk of impairment in social cognition and less accurate perceptions of social emotional cues. The concept of likely fertility problems needs introduction alongside regular reviews of puberty and sexual function in adolescents. Although there is now greater success in harvesting sperm through techniques such as testicular sperm extraction, it is more successful in later than in early adolescence. In vitro maturation of germ cells is still experimental.

Impact of Hormone Treatment on Psychosocial Functioning in Gender-Diverse Young People.

Purpose: Few studies have assessed the effects of hormonal treatments such as gonadotropin-releasing hormone agonists (GnRHa) and gender-affirming hormones (GAH) on mental health outcomes in clinically referred gender-diverse young people from a younger age. Where this research has been conducted, findings have been mixed. This study investigated a cohort of young people before treatment, 1 year into GnRHa, and 1 year into GAH treatment to understand psychological and behavioral impacts over time. Methods: Thirty-eight young people (28 assigned female and 10 assigned male) referred to endocrinology, younger than 15 years at/beyond Tanner stage two, who received GnRHa followed by GAH treatment, were assessed in a retrospective analysis study. Young people completed the Youth Self Report (YSR), the Body Image Scale, and the Utrecht Gender Dysphoria Scale, while caregivers completed the Child Behavior Checklist (CBCL) and the Social Responsiveness Scale-2 at all time points. Results: Dissatisfaction with primary sexual characteristics (p = 0.02), gender dysphoria (p = 0.01), and social motivation (p = 0.04) improved significantly over time. Self-harm and suicidality also showed a general decrease. Caregivers reported a significant reduction in internalizing (p = 0.03) behaviors on the CBCL after GnRHa. Other subcategories of the YSR and CBCL were within normal ranges with no significant difference (p > 0.05). Conclusion: These findings demonstrate some improvements in psychological and behavioral outcomes in young people concurrently receiving psychosocial support and hormone treatment. Future research with larger and more diverse samples is warranted to further understand generalizability.

Urological and Gynaecological Considerations for the Use of Gonadotropin-releasing Hormone Analogues in Transgender and Nonbinary Adolescents: A Narrative Review.

CONTEXT: Gonadotropin-releasing hormone analogues (GnRHAs) delay the progression of puberty in transgender and nonbinary (TGNB) adolescents and reduce the impact of dysphoria due to ongoing physical development. The intervention remains contentious despite growing evidence to support this practice. OBJECTIVE: To stimulate discussion on this topical issue in the urological and gynaecological community given potential ramifications for future fertility, physical development, and options for gender affirmation surgery (GAS). EVIDENCE ACQUISITION: We conducted searches of the MEDLINE (from 1946) and Embase (from 1974) databases for the benefits and potential challenges of hormone blockade in TGNB adolescents on February 1, 2022. Evidence with a primary focus on clinical issues of interest to urologists and gynaecologists was objectively synthesised and reported. EVIDENCE SYNTHESIS: The onset of puberty represents a period of distress for TGNB adolescents as secondary sexual characteristics develop. GnRHAs are prescribed to inhibit sex hormone production, but the decision to treat should be balanced against the known (and unknown) adverse effects. Fertility preservation is more likely to be successful if GnRHA treatment is delayed for as long as possible. Some adolescents may decide to stop GnRHA use to harvest spermatozoa or oocytes before starting gender-affirming hormone treatment. Transfeminine individuals should consider that options for genital GAS may become more limited, as vaginoplasty with penile skin inversion requires an adequate stretched penile length. Transmasculine individuals may no longer require chest reconstruction for breast development. CONCLUSIONS: Offers of GnRHA treatment to TGNB adolescents should be balanced by careful preparation and counselling. Urologists and gynaecologists can complement the expertise of specialist psychosocial and adolescent endocrinology teams, and should be involved early in and throughout the treatment pathway to maximise future functional and surgical outcomes. PATIENT SUMMARY: Puberty blockers for transgender and nonbinary adolescents have benefits, but timing is important to preserve fertility and surgical options.

Impact of puberty, sex determinants and chronic inflammation on cardiovascular risk in young people.

Worrying trends of increased cardiovascular disease (CVD) risk in children, adolescents and young people in the Modern Era have channelled research and public health strategies to tackle this growing epidemic. However, there are still controversies related to the dynamic of the impact of sex, age and puberty on this risk and on cardiovascular health outcomes later in life. In this comprehensive review of current literature, we examine the relationship between puberty, sex determinants and various traditional CVD-risk factors, as well as subclinical atherosclerosis in young people in general population. In addition, we evaluate the role of chronic inflammation, sex hormone therapy and health-risk behaviours on augmenting traditional CVD-risk factors and health outcomes, ultimately aiming to determine whether tailored management strategies for this age group are justified.

Key features of puberty onset and progression can help distinguish self-limited delayed puberty from congenital hypogonadotrophic hypogonadism.

Introduction: Delayed puberty (DP) is a frequent concern for adolescents. The most common underlying aetiology is self-limited DP (SLDP). However, this can be difficult to differentiate from the more severe condition congenital hypogonadotrophic hypogonadism (HH), especially on first presentation of an adolescent patient with DP. This study sought to elucidate phenotypic differences between the two diagnoses, in order to optimise patient management and pubertal development. Methods: This was a study of a UK DP cohort managed 2015-2023, identified through the NIHR clinical research network. Patients were followed longitudinally until adulthood, with a definite diagnosis made: SLDP if they had spontaneously completed puberty by age 18 years; HH if they had not commenced (complete, cHH), or had commenced but not completed puberty (partial, pHH), by this stage. Phenotypic data pertaining to auxology, Tanner staging, biochemistry, bone age and hormonal treatment at presentation and during puberty were retrospectively analysed. Results: 78 patients were included. 52 (66.7%) patients had SLDP and 26 (33.3%) patients had HH, comprising 17 (65.4%) pHH and 9 (34.6%) cHH patients. Probands were predominantly male (90.4%). Male SLDP patients presented with significantly lower height and weight standard deviation scores than HH patients (height p=0.004, weight p=0.021). 15.4% of SLDP compared to 38.5% of HH patients had classical associated features of HH (micropenis, cryptorchidism, anosmia, etc. p=0.023). 73.1% of patients with SLDP and 43.3% with HH had a family history of DP (p=0.007). Mean first recorded luteinizing hormone (LH) and inhibin B were lower in male patients with HH, particularly in cHH patients, but not discriminatory. There were no significant differences identified in blood concentrations of FSH, testosterone or AMH at presentation, or in bone age delay. Discussion: Key clinical markers of auxology, associated signs including micropenis, and serum inhibin B may help distinguish between SLDP and HH in patients presenting with pubertal delay, and can be incorporated into clinical assessment to improve diagnostic accuracy for adolescents. However, the distinction between HH, particularly partial HH, and SLDP remains problematic. Further research into an integrated framework or scoring system would be useful in aiding clinician decision-making and optimization of treatment. .

Trajectories of transgender adolescents referred for endocrine intervention in England.

OBJECTIVES: Some gender-diverse young people (YP) who experience clinically significant gender-related distress choose to pursue endocrine treatment alongside psychotherapeutic support to suppress pubertal development using gonadotropin-releasing hormone analogues (GnRHa), and then to acquire the secondary sex characteristics of their identified gender using gender affirming hormones (GAH). However, little is known about the demographics of transgender adolescents accessing paediatric endocrinology services while under the specialist Gender Identity Development Service (GIDS) in England. DESIGN: Demographics of referrals from the GIDS to affiliated endocrinology clinics to start GnRHa or GAH between 2017 and 2019 (cohort 1), with further analysis of a subgroup of this cohort referred in 2017-2018 (cohort 2) were assessed. RESULTS: 668 adolescents (227 assigned male at birth (AMAB) and 441 assigned female at birth (AFAB)) were referred to endocrinology from 2017 to 2019. The mean age of first GIDS appointment for cohort 1 was 14.2 (±2.1) years and mean age of referral to endocrinology postassessment was 15.4 (±1.6) years. Further detailed analysis of the trajectories was conducted in 439 YP in cohort 2 (154 AMAB; 285 AFAB). The most common pathway included a referral to access GnRHa (98.1%), followed by GAH when eligible (42%), and onward referral to adult services when appropriate (64%). The majority (54%) of all adolescents in cohort 2 had a pending or completed referral to adult services. CONCLUSIONS: This study highlights the trajectories adolescents may take when seeking endocrine treatments in child and adolescent clinical services and may be useful for guiding decisions for gender-diverse YP and planning service provision.

Gender-Diverse Inclusion in Immunological Research: Benefits to Science and Health.

The differences between male and female immune systems are an under-researched field, ripe for discovery. This is evidenced by the stark sex biases seen in autoimmunity and infectious disease. Both the sex hormones (oestrogen and testosterone), as well as the sex chromosomes have been demonstrated to impact immune responses, in multiple ways. Historical shortcomings in reporting basic and clinical scientific findings in a sex-disaggregated manner have led not only to limited discovery of disease aetiology, but to potential inaccuracies in the estimation of the effects of diseases or interventions on females and gender-diverse groups. Here we propose not only that research subjects should include both cis-gender men and cis-gender women, but also transgender and gender-diverse people alongside them. The known interaction between the hormonal milieu and the sex chromosomes is inseparable in cis-gender human research, without the confounders of puberty and age. By inclusion of those pursuing hormonal affirmation of their gender identity- the individual and interactive investigation of hormones and chromosomes is permitted. Not only does this allow for a fine-tuned dissection of these individual effects, but it allows for discovery that is both pertinent and relevant to a far wider portion of the population. There is an unmet need for detailed treatment follow-up of the transgender community- little is known of the potential benefits and risks of hormonal supplementation on the immune system, nor indeed on many other health and disease outcomes. Our research team has pioneered the inclusion of gender-diverse persons in our basic research in adolescent autoimmune rheumatic diseases. We review here the many avenues that remain unexplored, and suggest ways in which other groups and teams can broaden their horizons and invest in a future for medicine that is both fruitful and inclusive.

Investigating sex differences in T regulatory cells from cisgender and transgender healthy individuals and patients with autoimmune inflammatory disease: a cross-sectional study.

Background: Sexual dimorphisms, which vary depending on age group and pubertal status, have been described across both the innate and adaptive immune system. We explored the influence of sex hormones on immune phenotype in the context of adolescent health and autoimmunity. Methods: In this cross-sectional study, healthy, post-pubertal cisgender individuals (aged 16-25 years); healthy, pre-pubertal cisgender individuals (aged 6-11 years); transgender individuals (aged 18-19 years) undergoing gender-affirming treatment (testosterone in individuals assigned female sex at birth and oestradiol in individuals assigned male sex at birth); and post-pubertal cisgender individuals (aged 14-25 years) with juvenile-onset systemic lupus erythematosus (SLE) age-matched to cisgender individuals without juvenile-onset SLE were eligible for inclusion. Frequencies of 28 immune-cell subsets (including different T cell, B cell, and monocyte subsets) from each participant were measured in peripheral blood mononuclear cells by flow cytometry and analysed by balanced random forest machine learning. RNA-sequencing was used to compare sex and gender differences in regulatory T (Treg) cell phenotype between participants with juvenile-onset SLE, age-matched cis-gender participants without the disease, and age matched transgender individuals on gender-affirming sex hormone treatment. Differentially expressed genes were analysed by cluster and pathway analysis. Suppression assays assessed the anti-inflammatory function of Treg cells in vitro. Findings: Between Sept 5, 2012, and Nov 6, 2019, peripheral blood was collected from 39 individuals in the post-pubertal group (17 [44%] cisgender men, mean age 18·76 years [SD 2·66]; 22 [56%] cisgender women, mean age 18·59 years [2·81]), 14 children in the cisgender pre-pubertal group (seven [50%] cisgender boys, mean age 8·90 [1·66]; seven [50%] cisgender girls, mean age 8·40 [1·58]), ten people in the transgender group (five [50%] transgender men, mean age 18·20 years [0·47]; five [50%] transgender women, mean age 18·70 years [0·55]), and 35 people in the juvenile-onset SLE group (12 [34%] cisgender men, mean age 18·58 years [2·35]; 23 [66%] cisgender women, mean age 19·48 [3·08]). Statistically significantly elevated frequencies of Treg cells were one of the top immune-cell features differentiating young post-pubertal cisgender men from similarly aged cisgender women (p=0·0097). Treg cells from young cisgender men had a statistically significantly increased suppressive capacity in vitro compared with those from cisgender women and a distinct transcriptomic signature significantly enriched for genes in the PI3K-AKT signalling pathway. Gender-affirming sex hormones in transgender men and transgender women induced multiple statistically significant changes in the Treg-cell transcriptome, many of which enriched functional pathways that overlapped with those altered between cisgender men and cisgender women, highlighting a hormonal influence on Treg-cell function by gender. Finally, sex differences in Treg-cell frequency were absent and suppressive capacity was reversed in patients with juvenile-onset SLE, but sex differences in Treg-cell transcriptional signatures were significantly more pronounced in patients with juvenile-onset SLE compared with individuals without juvenile-onset SLE, suggesting that sex hormone signalling could be dysregulated in autoimmunity. Interpretation: Sex-chromosomes and hormones might drive changes in Treg-cell frequency and function. Young post-pubertal men have a more anti-inflammatory Treg-cell profile, which could explain inflammatory disease susceptibilities, and inform sex-tailored therapeutic strategies. Funding: Versus Arthritis, UK National Institute for Health Research University College London Hospital Biomedical Research Centre, Lupus UK, and The Rosetrees Trust.

Discharge outcome analysis of 1089 transgender young people referred to paediatric endocrine clinics in England 2008-2021.

INTRODUCTION: The destination of transgender and gender variant young people referred by the National Health Service (NHS) Gender Identity Development Service (GIDS) to, and discharged from the two English paediatric endocrine liaison clinics is not known. METHODS: 1151 young people referred after full assessment by the GIDS; 827 to University College London Hospital since 2008; 324 to Leeds Children's Hospital since 2013. Discharge categorisation was by agreed criteria. Eleven emigrated and 51 self-discharged. 1089 had known outcomes. RESULTS: 999/1089 (91.7%) continued identifying as gender variant. 867/999 (86.8%) were discharged to adult gender identity clinics (GICs). 166/867 (19.1%) of these were <16 years and 701/867 (80.9%) ≥16 years at initial endocrine referral. No sex differences were seen. 38/999 (3.8%) opted for non-NHS services.90/1089 ceased identifying as gender variant. In 32/1089 (2.9%), this was subsequent to their first clinic appointment.58/1089 (5.3%) stopped treatment either with the gonadotropin releasing hormone analogue (GnRHa) or gender-affirming hormones (GAH) and reverted to their birth gender: <16 years (20/217; 9.2%); ≥16 years (38/872; 4.4%).Subdividing further, 16/217 (7.4%) <16 years ceased GnRHa and 4/217 (1.8%) after GAH. Of those ≥16 years, 33/872 (3.8%) ceased GnRHa and 5/872 (0.6%) GAH. CONCLUSIONS: At discharge, 91.7% continued as transgender or gender variant, 86.8% sought ongoing care through NHS GICs. 2.9% ceased identifying as transgender after an initial consultation prior to any endocrine intervention and 5.3% stopped treatment either with GnRHa or GAH, a higher proportion in the <16 year compared with the ≥16 year groups.

Sex hormones drive changes in lipoprotein metabolism.

Women have a reduced cardiovascular disease (CVD) risk compared with men, which could be partially driven by sex hormones influencing lipid levels post puberty. The interrelationship between sex hormones and lipids was explored in pre-pubertal children, young post-pubertal cis-men/women, and transgender individuals on cross-sex-hormone treatment (trans-men/women) using serum metabolomics assessing 149 lipids. High-density lipoproteins (HDL, typically atheroprotective) were significantly increased and very-low- and low-density lipoproteins (typically atherogenic) were significantly decreased in post-pubertal cis-women compared with cis-men. These differences were not observed pre-puberty and were induced appropriately by cross-sex-hormone treatment in transgender individuals, supporting that sex hormones regulate lipid metabolism in vivo. Only atheroprotective apolipoprotein (Apo)A1 expressing lipoproteins (HDL) were differentially expressed between all hormonally unique comparisons. Thus, estradiol drives a typically atheroprotective lipid profile through upregulation of HDL/ApoA1, which could contribute to the sexual dimorphism observed in CVD risk post puberty. Together, this could inform sex-specific therapeutic strategies for CVD management.

Prediction of Adult Height by Machine Learning Technique.

CONTEXT: Prediction of AH is frequently undertaken in the clinical setting. The commonly used methods are based on the assessment of skeletal maturation. Predictive algorithms generated by machine learning, which can already automatically drive cars and recognize spoken language, are the keys to unlocking data that can precisely inform the pediatrician for real-time decision making. OBJECTIVE: To use machine learning (ML) to predict adult height (AH) based on growth measurements until age 6 years. METHODS: Growth data from 1596 subjects (798 boys) aged 0-20 years from the longitudinal GrowUp 1974 Gothenburg cohort were utilized to train multiple ML regressors. Of these, 100 were used for model comparison, the rest was used for 5-fold cross-validation. The winning model, random forest (RF), was first validated on 684 additional subjects from the 1974 cohort. It was additionally validated using 1890 subjects from the GrowUp 1990 Gothenburg cohort and 145 subjects from the Edinburgh Longitudinal Growth Study cohort. RESULTS: RF with 51 regression trees produced the most accurate predictions. The best predicting features were sex and height at age 3.4-6.0 years. Observed and predicted AHs were 173.9 ±â€…8.9 cm and 173.9 ±â€…7.7 cm, respectively, with prediction average error of -0.4 ±â€…4.0 cm. Validation of prediction for 684 GrowUp 1974 children showed prediction accuracy r = 0.87 between predicted and observed AH (R2 = 0.75). When validated on the 1990 Gothenburg and Edinburgh cohorts (completely unseen by the learned RF model), the prediction accuracy was r = 0.88 in both cases (R2 = 0.77). AH in short children was overpredicted and AH in tall children was underpredicted. Prediction absolute error correlated negatively with AH (P < .0001). CONCLUSION: We show successful, validated ML of AH using growth measurements before age 6 years. The most important features for prediction were sex, and height at age 3.4-6.0. Prediction errors result in over- or underestimates of AH for short and tall subjects, respectively. Prediction by ML can be generalized to other cohorts.

Longitudinal Outcomes of Gender Identity in Children (LOGIC): protocol for a prospective longitudinal cohort study of children referred to the UK gender identity development service.

INTRODUCTION: Gender identity development services (GIDS) worldwide have seen a significant increase in referrals in recent years. Many of these referrals consist of children and young people (CYP) who experience gender-related distress. This study aims to improve understanding of outcomes of CYP referred to the UK GIDS, specifically regarding gender identity, mental health, physical health and quality of life. The impact of factors such as co-occurring autism and early social transition on outcomes over time will be explored. METHODS AND ANALYSIS: This is a prospective cohort study of CYP aged 3-14 years when referred to the UK GIDS. Eligible participants will be ≤14 years at the time their referral was accepted and will be on the waitlist for the service when baseline measures are completed. Children aged under 12 years will complete the measures in an interview format with a researcher, while young people aged 12 years and over and their parents/caregivers will complete online or paper-based questionnaires. Participants will complete follow-up measures 12 months and 24 months later. The final sample size is expected to be approximately 500. Logistic regression models will be used to explore associations between prespecified explanatory variables and gender dysphoria. Appropriate regression models will also be used to investigate explanatory variables for other outcomes. Subgroup analyses based on birth-assigned gender, age at referral and co-occurring autistic traits will be explored. ETHICS AND DISSEMINATION: The study has been approved by the Health Research Authority and London - Hampstead Research Ethics Committee (reference: 19/LO/0857). The study findings will be published in peer-reviewed journals and presented at both conferences and stakeholder events. Findings will be used to inform clinical practice.