In adolescents with severe and persistent gender dysphoria (GD), gonadotropin releasing hormone analogues (GnRHa) are used from early/middle puberty with the aim of delaying irreversible and unwanted ...pubertal body changes. Evidence of outcomes of pubertal suppression in GD is limited.
We undertook an uncontrolled prospective observational study of GnRHa as monotherapy in 44 12-15 year olds with persistent and severe GD. Prespecified analyses were limited to key outcomes: bone mineral content (BMC) and bone mineral density (BMD); Child Behaviour CheckList (CBCL) total t-score; Youth Self-Report (YSR) total t-score; CBCL and YSR self-harm indices; at 12, 24 and 36 months. Semistructured interviews were conducted on GnRHa.
44 patients had data at 12 months follow-up, 24 at 24 months and 14 at 36 months. All had normal karyotype and endocrinology consistent with birth-registered sex. All achieved suppression of gonadotropins by 6 months. At the end of the study one ceased GnRHa and 43 (98%) elected to start cross-sex hormones. There was no change from baseline in spine BMD at 12 months nor in hip BMD at 24 and 36 months, but at 24 months lumbar spine BMC and BMD were higher than at baseline (BMC +6.0 (95% CI: 4.0, 7.9); BMD +0.05 (0.03, 0.07)). There were no changes from baseline to 12 or 24 months in CBCL or YSR total t-scores or for CBCL or YSR self-harm indices, nor for CBCL total t-score or self-harm index at 36 months. Most participants reported positive or a mixture of positive and negative life changes on GnRHa. Anticipated adverse events were common.
Overall patient experience of changes on GnRHa treatment was positive. We identified no changes in psychological function. Changes in BMD were consistent with suppression of growth. Larger and longer-term prospective studies using a range of designs are needed to more fully quantify the benefits and harms of pubertal suppression in GD.
Type 1 interferons (IFN) are an antiviral cytokine family, important in juvenile onset systemic lupus erythematosus (jSLE) which is more common in females, around puberty. We report that plasmacytoid ...dendritic cells (pDC) from healthy females produced more type 1 IFN after toll like receptor (TLR) 7 signaling than males, even before puberty, but that puberty itself associated with increased production of type 1 IFN. A unique human model allows us to show that this was related to X chromosome number, and serum testosterone concentration, in a manner which differed depending on the number of X chromosomes present. In addition, we have showed that pDC were more activated in females overall, and immune cell
gene expression was higher in females after puberty. Therefore, sex hormones and X chromosome number were associated individually and interactively with the type 1 IFN response, which contributes to our understanding of why females are more likely to develop an IFN mediated disease like jSLE after puberty.
Abstract
Context:
Growth hormone (GH) is prescribed for an increasing range of indications, but there has been concern that it might raise cancer risk. Published data are limited.
Objective:
To ...examine cancer risks in relation to GH treatment.
Design:
Cohort study.
Setting:
Population-based.
Patients:
Cohort of 23,984 patients treated with recombinant human GH (r-hGH) in eight European countries since this treatment was first used in 1984. Cancer expectations from country-specific national population statistics.
Main Outcome Measures:
Cancer incidence and cancer mortality.
Results:
Incidence and mortality risks in the cohort were raised for several cancer sites, largely consequent on second primary malignancies in patients given r-hGH after cancer treatment. There was no clear raised risk in patients with growth failure without other major disease. Only for bone and bladder cancers was incidence significantly raised in GH-treated patients without previous cancer. Cancer risk was unrelated to duration or cumulative dose of r-hGH treatment, but for patients treated after previous cancer, cancer mortality risk increased significantly with increasing daily r-hGH dose (P trend < 0.001). Hodgkin lymphoma (HL) incidence increased significantly with longer follow-up (P trend = 0.001 for patients overall and 0.002 for patients without previous cancer).
Conclusions:
Our results do not generally support a carcinogenic effect of r-hGH, but the unexplained trend in cancer mortality risk in relation to GH dose in patients with previous cancer, and the indication of possible effects on bone cancer, bladder cancer, and HL risks, need further investigation.
A total of 23,984 patients treated with recombinant growth hormone in eight countries since 1984 were followed. Cancer incidence overall did not relate to growth hormone, but certain cancers showed raised risks.
Vitamin D and calcium deficiencies are common worldwide, causing nutritional rickets and osteomalacia, which have a major impact on health, growth, and development of infants, children, and ...adolescents; the consequences can be lethal or can last into adulthood. The goals of this evidence-based consensus document are to provide health care professionals with guidance for prevention, diagnosis, and management of nutritional rickets and to provide policy makers with a framework to work toward its eradication.
A systematic literature search examining the definition, diagnosis, treatment, and prevention of nutritional rickets in children was conducted. Evidence-based recommendations were developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system that describes the strength of the recommendation and the quality of supporting evidence.
Thirty-three nominated experts in pediatric endocrinology, pediatrics, nutrition, epidemiology, public health, and health economics evaluated the evidence on specific questions within five working groups. The consensus group, representing 11 international scientific organizations, participated in a multiday conference in May 2014 to reach a global evidence-based consensus.
This consensus document defines nutritional rickets and its diagnostic criteria and describes the clinical management of rickets and osteomalacia. Risk factors, particularly in mothers and infants, are ranked, and specific prevention recommendations including food fortification and supplementation are offered for both the clinical and public health contexts.
Rickets, osteomalacia, and vitamin D and calcium deficiencies are preventable global public health problems in infants, children, and adolescents. Implementation of international rickets prevention programs, including supplementation and food fortification, is urgently required.
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.
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
-gender men and
-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
-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.
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.
Display omitted
•Estradiol increases typically atheroprotective HDL/ApoA1 in cis- and trans-women•Differences in HDL/ApoA1 are induced in a dose-dependent manner by estradiol•Sex differences are not identified pre-puberty and are disrupted in autoimmunity•Serum lipid metabolites could inform sex-tailored strategies for CVD risk management
Biological sciences; Biochemistry; Metabolomics
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.
IntroductionGender 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 analysisThis 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 disseminationThe 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.
IntroductionSpecialist gender services for children and young people (CYP) worldwide have experienced a significant increase in referrals in recent years. As rates of referrals increase, it is ...important to understand the characteristics and profile of CYP attending these services in order to inform treatment pathways and to ensure optimal outcomes.Methods and analysisA retrospective observational study of clinical health records from specialist gender services for CYP in the UK and the Netherlands. The retrospective analysis will examine routinely collected clinical and outcome measures data including demographic, clinical, gender identity-related and healthcare resource use information. Data will be reported for each service and also compared between services. This study forms part of a wider programme of research investigating outcomes of gender identity in children (the Longitudinal Outcomes of Gender Identity in Children study).Ethics and disseminationThe proposed study has been approved by the Health Research Authority and London—Hampstead Research Ethics Committee as application 19/LO/0181. The study findings will be published in peer-reviewed journals and presented at both conferences and stakeholder events.
PDF
