Gary Butler

Introduction: In healthy adolescents, there is significant interindividual variation in the dynamics of pubertal growth and in the timing and progression of physical changes of puberty. Our aim was to explore the relationship between pubertal growth and pubertal maturation through an analysis of data from a longitudinal growth study. Methods: The Edinburgh growth study included healthy children born between 1972 and 1976 with a birth weight of >2.5 kg. Anthropometric measurements and Tanner staging were undertaken twice a year. Total pubertal growth (TPG) was quantified using the QEPS growth model, which generates an individual growth curve from birth length to adult height (AH). Results: A total of 157 adolescents were included in analysis (89 boys, 68 girls). In girls, later age at reaching all the stages of breast maturation (B2–B5) was correlated with smaller TPG. Correlation coefficient between B3 and TPG was −0.64, p < 0.01. However, there was no correlation with AH (coefficient 0.15, p = 0.24). In boys, later age at reaching the later stages of external genitalia maturation (G4–G5) was correlated with smaller TPG. G4 was negatively correlated with TPG (−0.24, p < 0.04) but not with AH (0.02, p = 0.86). Conclusion: We found that the magnitude of the pubertal growth spurt was linked with the age at reaching Tanner landmarks of puberty in girls and boys; however, there was no association between the timing of these landmarks and AH. This new knowledge can provide reassurance for healthy children that the normal variation of pubertal timing does not have a significant influence on expected AH.

Background: It is not known whether the extent of pubertal development influences the treatment effects in very young transgender people undergoing puberty suppression (PS) and gender-affirming hormone therapy (GAHT). This study aimed to investigate how anthropometric parameters and body composition change according to birth-assigned sex and affirmed gender during PS and GAHT. Methods: This retrospective study included data from 201 adolescents starting PS under 15yr at a national gender service (139 trans boys and 62 trans girls). Data from 127 of them who subsequently received GAHT were available. Height, weight, BMI, total lean, fat and muscle mass (LM, FM and MM) were collected using Tanita body composition analyzer. Results: ‘In puberty’ trans boys (Tanner stage 2-3), total FM increased on PS (2.49 kg, 95% CI 1.66;3.33) similarly to LM (2.41 kg, 95% CI 1.85;2.97), while in ‘completing puberty’ trans boys (Tanner stage 4-5) the increase of total FM (1.80 kg, 95% CI 1.21;2.39) was higher than total LM (0.97 kg, 95% CI 0.63;1.30). ‘In puberty’ trans boys showed increasing mean FM z-scores from baseline after 3 years of PS (from 0.70 to 1.2). Mean LM z-scores decreased in both ‘in puberty’ (from 0.98 to 0.5) and ‘completing puberty’ (from 1.16 to 0.80) trans boys. During GAHT, ‘in puberty’ trans boys showed a greater increase of total LM and MM (respectively 6.28 kg, 95% CI 3.54;9.02 and 6.08 kg, 95% CI 3.64;8.51). Both groups ‘in puberty’ and ‘completing puberty’ trans boys did not show a further increase in total FM. In contrast, ‘completing puberty’ trans girls showed the greatest increase of total FM during PS (4.27 kg, 95% CI 1.50;7.03). MM and LM % decreased throughout PS in all trans girls, whereas body composition only changed slightly during GAHT. Conclusions: The effect of PS on body composition is more pronounced in ‘in puberty’ trans adolescents, and ‘in puberty’ trans boys are more responsive to GAHT, showing greater increases in MM and LM. In trans girls, the most significant increase in FM, along with reduction in LM and MM, occurs during PS, whereas no substantial changes were observed during subsequent GAHT. This suggests that any effect on physical performance may depend on pubertal development at the start of intervention.

Sex differences in immunity are well-documented, though mechanisms underpinning these differences remain ill-defined. Here, in a human-only ex vivo study, we demonstrate that postpubertal cisgender females have higher levels of CD19+CD27+IgD− class-switched memory B cells compared with age-matched cisgender males. This increase is only observed after puberty and before menopause, suggesting a strong influence for sex hormones. Accordingly, B cells express high levels of estrogen receptor 2 (ESR2), and class-switch–regulating genes are enriched for ESR2-binding sites. In a gender-diverse cohort, blockade of natal estrogen in transgender males (XX karyotype) reduced class-switched memory B cell frequency, while gender-affirming estradiol treatment in transgender females (XY karyotype) did not increase these levels. In postmenopausal cis-females, class-switched memory B cells were increased in those taking hormone replacement therapy (HRT) compared with those who were not. These data demonstrate that sex hormones and chromosomes work in tandem to impact immune responses, with estrogen only influencing the frequency of class-switched memory B cells in individuals with an XX chromosomal background.

Purpose: Growth hormone deficiency (GHD) causes decreased growth rate in children, resulting in short stature in childhood and adulthood. Daily subcutaneous injections with growth hormone (GH) have been standard treatment. Newer weekly GH formulations now exist. This study estimates utilities associated with GHD treatment for both people with the disease and caregivers by employing time trade-off (TTO) methodology. Methods: Three online surveys were conducted amongst the general population in the UK and Canada. Based on a pilot, data collection was conducted in two surveys only (Survey A and Survey B). In Survey A, adults aged ≥ 18 years evaluated health states as if they were receiving injections themselves. In Survey B, adults with a child < 15 years evaluated health states as if they were administering injections to a child. The surveys assessed device complexity, injection frequency, injection pain, needle visibility and storage possibilities. Results: 2026 and 2028 respondents completed Survey A and Survey B, respectively. Of these, 1782 respondents and 1678 respondents were valid for inclusion. Avoiding weekly injection pain was associated with a significant utility gain of 0.030 (95% CI 0.026– 0.035, p< 0.001) in Survey A and 0.044 (95% CI 0.038– 0.051, p< 0.001) in Survey B. Additionally, less complex injection devices and lower injection frequencies had a significant impact in both Survey A (0.020, 95% CI 0.016– 0.025, p< 0.001; 0.009, 95% CI 0.005– 0.014, p< 0.001) and Survey B (0.008, 95% CI 0.002– 0.014, p=0.006; 0.009, 95% CI 0.003– 0.014, p=0.003). Conclusion: Several aspects are associated with a significant impact on utilities for people with GHD and potential caregivers. Treatment options without injection pain, a time-consuming and complex injection process and daily injections are expected to result in higher health-related quality of life. These results may inform future economic evaluations and treatment choices.

Increasing numbers of transgender and gender diverse adolescents seek endocrine treatment to align their body to their gender identity. In this relatively young field of medicine, there is a limited body of evidence, and the available evidence generally is of low quality. However, in the absence of randomised trials, much can be learned from prospective observational studies. While evidence on somatic and psychosocial outcomes has increased in recent years, areas with little or no research rely on expert opinion. In order to reduce practice variation in paediatric endocrine care for transgender adolescents, we describe endocrine care for transgender and gender diverse adolescents in Europe in this statement, based on the available evidence as well as the experience of experts from the ESPE Working Group on Gender Incongruence and from the European Reference Network Endo-ERN, main thematic group 'Sexual Development and Maturation'. This document aims to provide practical information and tools for clinical care, with sections on the multidisciplinary team, counseling, fertility, hormone suppression, gender affirming hormone treatment, support for non-binary adolescents, long-term follow up and transition of care, altered treatment wishes, lifestyle and sexual health, and in addition includes a paragraph on ethical considerations regarding this care.

Sex differences in humoral immunity are well-documented, though the mechanisms underpinning these differences remain ill-defined. Here, we demonstrate that post-pubertal cisgender females have higher levels of class-switched B cells compared to age-matched cisgender males. However, whilst sex chromosome-encoded genes characterise most of the differences in total B cell transcriptomes between cisgender-females and -males, sex differences in class-switched B cells are only observed post-pubertally. Accordingly, B cells express high levels of oestrogen receptor 2 (ESR2) and genes known to regulate B cell class-switching are enriched for ESR2- binding sites. Using a gender-diverse cohort of young people, we show that in transgender males (XX chromosomal background), blockade of natal oestrogen reduced the frequency of class-switched B cells, whilst gender-affirming oestradiol treatment in transgender females (XY chromosomal background), did not increase the frequency of class-switched B cells. These data demonstrate that sex hormones and chromosomes work in tandem to impact immune responses, with oestrogen only supporting B cell class-switching on an XX chromosomal background. eTOC summary: Sex hormones and chromosomes work in tandem to impact immune responses, with oestrogen influencing B cell class-switching exclusively on an XX chromosomal background.

Preface: In the past 12 months, the search for “Differences of Sexual Development” or “disorders of sex development“ or “ambiguous genitalia” or “gonadal development” or “DSD” in PubMed yielded 625 publications. A similar search for gender incongruence revealed > 325 papers on a search between “transgender and hormones”. Among those, 16 are summarized in this chapter. The selection process has been very challenging given the space available but we prioritized the key publications chosen on the quality of methodology, the significance of the outcome, and particularly the impact on clinical practice. We have endeavored to balance basic research and clinical articles. We hope these selected publications will help with understanding and improve both knowledge and the clinical care of patients.

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.

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.

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 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.