A comparison of gender diversity in transgender young people with and without autistic traits from the Trans 20 cohort study.

Background: There is an elevated co-occurrence of autism in trans individuals, with recent meta-analyses suggesting that 11% of trans individuals are autistic. The presence of autism in trans young people can create clinical challenges by adding complexity to the presentation, assessment and management of those presenting to gender clinics. Although many trans young people display traits of autism, how these traits relate to the nature of their gender diversity is unclear. Methods: This study compared gender identity, gender expression and gender dysphoria (GD) in trans young people with and without autistic traits. Baseline data from a cohort study of trans children and adolescents who first attended the Royal Children's Hospital Gender Service (Victoria, Australia) between February 2017 and January 2020 were analysed cross-sectionally. Autistic traits were assessed via the Social Responsiveness Scale-2. Gender was assessed using tools that measure gender identity, social transition, GD, body dissatisfaction, voice dysphoria, and chest dysphoria. Findings: 522 participants were included, of whom 239 (45.8%) exhibited autistic traits (SRS total T-score ≥60). Those with and without autistic traits were similar in their age (mean (SD) age 14.0 (2.9) and 13.1 (3.6) years respectively) and gender identity: the majority (73.7% (n = 174) and 70.5% (n = 198) respectively) identified in a binary way. Higher rates of social transition (specifically, changing pronouns) were noted in those with autistic traits (Difference in proportion 11.7, 95% confidence interval [CI] 2.4-21.1, p = 0.014). GD was high in both groups with ∼95% displaying clinically relevant levels of GD. Chest dysphoria was similar between groups, while voice dysphoria was higher in those with autistic traits (standardised mean difference [SMD] = 0.3, 95% confidence interval [CI]: 0.1-0.5 p = 0.00087). Dissatisfaction with secondary gendered characteristics (SMD = 0.3, CI: 0.1-0.5 p = 0.0011) and hormonally unresponsive body characteristics (SMD = 0.2, CI: 0.1-0.4 p = 0.016) was higher in trans young people with autistic traits. Interpretation: The similarly high severity of GD in those with and without autistic traits reinforces the importance of trans young people with and without autistic traits being availed the same opportunities to access gender-affirming care. Subtle differences identified between the groups in other areas of gender diversity suggest trans young people with autistic traits may have distinct needs and that gender-affirming care may need to be tailored accordingly. Funding: The Royal Children's Hospital Foundation, Hugh D.T. Williamson Foundation; Australian National Health and Medical Research Council-Clinical Trials and Cohort Studies scheme (GNT 2006529).

Impact of Distinct Anti-Androgen Exposures on the Plasma Metabolome in Feminizing Gender-Affirming Hormone Therapy.

CONTEXT: The plasma metabolome is a functional readout of metabolic activity and is associated with phenotypes exhibiting sexual dimorphism, such as cardiovascular disease. Sex hormones are thought to play a key role in driving sexual dimorphism. OBJECTIVE: Gender-affirming hormone therapy (GAHT) is a cornerstone of transgender care, but longitudinal changes in the plasma metabolome with feminizing GAHT have not been described. METHODS: Blood samples were collected at baseline and after three and six months of GAHT from transgender women (n = 53). Participants were randomized to different anti-androgens, cyproterone acetate or spironolactone. NMR-based metabolomics was used to measure 249 metabolic biomarkers in plasma. Additionally, we used metabolic biomarker data from an unrelated cohort of children and their parents (n = 3,748) to identify sex- and age-related metabolite patterns. RESULTS: We identified 43 metabolic biomarkers altered after six months in both anti-androgen groups, most belonging to the very low- or low-density lipoprotein subclasses, with all but one showing a decrease. We observed a cyproterone acetate-specific decrease in glutamine, glycine, and alanine levels. Notably, of the metabolic biomarkers exhibiting the most abundant 'sex- and age-related' pattern (higher in assigned female children and lower in assigned female adults, relative to assigned males), 80% were significantly lowered after GAHT, reflecting a shift toward the adult female profile. CONCLUSION: Our results suggest an anti-atherogenic signature in the plasma metabolome after the first six months of feminizing GAHT, with cyproterone acetate also reducing specific plasma amino acids. This study provides novel insight into the metabolic changes occurring across feminizing GAHT.

Pelvic pain in transmasculine adolescents receiving testosterone therapy.

Background: Pelvic pain is a common complaint among individuals assigned female at birth. However, few studies have explored pelvic pain among transmasculine patients on gender-affirming testosterone treatment, and most of these were performed in adult populations. Aims: The aim of our study was to investigate the prevalence, risk factors, nature and treatment of pelvic pain among trans adolescents on testosterone. Methods: A retrospective cohort study was performed on all trans adolescents started on gender-affirming testosterone treatment at our institution between 2007 and 2020. Results: Among 158 trans adolescents who were started on testosterone therapy and followed-up for at least six months, 37 (23.4%) reported pelvic pain, with a median interval between testosterone initiation and reported onset of pain of 1.6 months (range 0.3-6.4). The prevalence of pelvic pain was higher in patients who were receiving menstrual suppression (n = 36, 26.3%) compared to those who were not (n = 1, 4.8%), giving a risk difference of 21.5% (95% CI 9.8% to 33.2%, p = 0.028). The most common descriptive terms were "cramps" (n = 17, 45.9%) and "similar to previous period pain" (n = 8, 21.6%). A range of different pharmacological strategies were employed, including paracetamol, NSAIDs, danazol, norethisterone, medroxyprogesterone, etonogestrel implant, intra-uterine device, goserelin and pelvic floor physiotherapy, with variable outcomes. Conclusion: In conclusion, we report here - in what is to our knowledge the first time - the prevalence rate of pelvic pain in trans adolescents on gender-affirming testosterone treatment, and observe that a quarter of them described pelvic pain. Limitations of our study include its retrospective nature, which is likely to be associated with under-reporting of pelvic pain, and the limited documentation of the nature and likely causes of this pain within the medical records. Prospective longitudinal studies to better understand the nature, etiology and optimal management of testosterone-associated pelvic pain are therefore warranted.

Evaluation of a codesigned group cognitive-behavioural therapy intervention for trans young people (TAG TEAM): protocol for a feasibility trial and a subsequent pilot RCT.

INTRODUCTION: Trans young people are at a higher risk of mental health difficulties such as depression, anxiety and suicidality than their cisgender peers, due in part to their experiences of minority stress. This protocol describes a feasibility trial and subsequent pilot randomised controlled trial (RCT) of a codesigned group cognitive-behavioural therapy intervention for trans young people, named Trans Adolescent Group ThErapy for Alleviating Minority stress (TAG TEAM). METHODS AND ANALYSIS: To evaluate TAG TEAM, we will conduct a feasibility trial followed by a pilot RCT with trans young people aged 14-16 years who have been referred to the Royal Children's Hospital Gender Service in Melbourne, Australia. In the feasibility trial, we aim to enrol 32 participants who will be randomised at a 1:1 ratio to either in-person or online intervention arms. Participants will be assessed at baseline and post-treatment, with a nested qualitative evaluation post-treatment. Primary outcomes are the feasibility and acceptability of the intervention and the study design and associated procedures, including comparison of the in-person and online delivery modes. In the subsequent pilot RCT, we aim to enrol 64 participants who will be randomised at a 1:1 ratio to an intervention or waitlist control arm, with delivery mode determined by the feasibility trial. Participants will complete assessments at baseline, post-treatment and 3-month follow-up. Primary outcomes are the feasibility and acceptability of the RCT study design. In both the feasibility trial and pilot RCT, participants will complete assessments related to mood, anxiety, suicidality, quality of life, minority stress, family support and social transition. Quantitative data will be analysed using descriptive statistics. Qualitative data will be analysed using thematic and interpretive analysis. ETHICS AND DISSEMINATION: The Royal Children's Hospital Human Research Ethics Committee has approved this study (#91162). Informed consent will be obtained in writing from all participants and a legal guardian. Findings will inform the development of a full-scale RCT to evaluate the efficacy of TAG TEAM and will be disseminated through conferences and peer-reviewed journals. TRIAL REGISTRATION NUMBER: ACTRN12623000302651, ACTRN12623000318684.

Prevalence of Eating Disorder Symptoms in Transgender and Gender Diverse Adolescents Presenting for Gender-Affirming Care.

PURPOSE: To describe the prevalence of eating disorder symptoms among adolescents seeking gender-affirming care. METHODS: Cross-sectional study of 660 gender-diverse adolescents who completed the Branched Eating Disorder Test to measure anorexia and bulimia symptoms. RESULTS: 23.9% (95% CI 20.7-27.4) reported both anorexia symptoms, namely overvaluation of weight and fear of (or recurrent interference with) weight gain. 0.9% (95% CI 0.3-2.0) reported all bulimia symptoms, namely overvaluation of weight, recurrent binge eating, and recurrent compensatory behaviors (e.g., weekly purging). For all symptoms, prevalence was higher among i) adolescents assigned female at birth compared to those assigned male at birth, and ii) adolescents who felt unsure about their gender identity compared to those who identified as trans or nonbinary. DISCUSSION: Clinicians should monitor eating disorder symptoms among adolescents presenting for gender-affirming care, especially among those assigned female at birth or who are unsure about their gender identity.

Characteristics of Menstrual Suppression and Its Association With Mental Health in Transgender Adolescents.

OBJECTIVE: To investigate the prevalence, nature, and effectiveness of menstrual suppression in transgender and gender-diverse (TGD) adolescents, and to explore whether there is an association between menstrual suppression and mental health in this population. METHODS: A cross-sectional study was performed of TGD adolescents assigned female at birth attending their first appointment at a specialist pediatric gender service between February 2017 and December 2021. Demographic and mental health data were collected using a questionnaire at the time of first visit, and information regarding menstrual suppression at this time was retrieved from the medical record. RESULTS: A total of 530 TGD individuals were included; 131 (24.7%) were on menstrual suppression at their initial visit, mainly to help alleviate gender dysphoria. Combined oral contraceptive pills were the most common agent used (n=61, 46.6%), followed by norethindrone (n=39, 29.8%) and intramuscular medroxyprogesterone (n=19, 14.5%). Rates of effectiveness (in stopping menstruation) and patient satisfaction were high. Among the 399 individuals not on menstrual suppression, there was strong interest in starting this treatment. No differences in the risk of gender dysphoria, depression, or anxiety were observed between those who were receiving menstrual suppression and those who were not. CONCLUSION: Effectiveness of and satisfaction with menstrual suppression were high in TGD adolescents receiving this treatment. These findings support the routine exploration and management of menstrual health in TGD adolescents. However, menstrual suppression was not associated with any difference in gender dysphoria, depression, or anxiety symptoms in this cross-sectional study, and longitudinal studies are required to better investigate this.

Assessment of Quality of Life of Transgender and Gender-Diverse Children and Adolescents in Melbourne, Australia, 2017-2020.

Importance: Transgender and gender-diverse (TGD) children and adolescents may experience not only gender dysphoria but also depression and anxiety, all of which are likely to be associated with reduced quality of life (QOL). Despite this, little is known about QOL in this population. Objectives: To identify demographic, social, and clinical characteristics associated with reduced QOL in TGD children and adolescents; compare their QOL with age-matched population-based norms and that of young people with common mental health problems; and evaluate the association between gender dysphoria and QOL. Design, Setting, and Participants: In this cohort study, baseline data were derived from questionnaires completed in a prospective cohort study (Trans20) of TGD children aged 6 to 12 years and adolescents aged 13 to 17 years first seen at the Royal Children's Hospital Gender Service (Melbourne, Australia) between February 2017 and February 2020. Main Outcomes and Measures: The main outcome was QOL, measured using the Child Health Utility 9D instrument (CHU-9D). Data collection included demographic information, social factors (eg, bullying, lack of support, and social transition), and clinical characteristics (eg, gender identity, gender dysphoria, and mental health difficulties). Population norms and CHU-9D data for Australian youths with mental health diagnoses were derived from published literature. Results: The TGD cohort comprised 525 children and adolescents aged 6 to 17 years (median age, 14 years [IQR, 12-16 years]; 364 [69.33%] presumed female at birth). The mean (SD) CHU-9D score was 0.46 (0.26). Compared with population norms, TGD children (0.58 [0.27] vs 0.81 [0.16]; P < .001) and adolescents (0.41 [0.25] vs 0.80 [0.14]; P < .001) had significantly lower scores. Within the TGD cohort, mean (SD) scores were significantly lower in adolescents (0.41 [0.24] vs 0.62 [0.25]; P < .001), those assigned female at birth (0.43 [0.26] vs 0.55 [0.25]; P < .001), those reporting mental health problems (0.37 [0.23] vs 0.57 [0.25]; P < .001) and physical health problems (0.41 [0.26] vs 0.48 [0.26]; P = .04), and those who were bullied (0.38 [0.24] vs 0.52 [0.25]; P < .001). Gender dysphoria alone was associated with a lower mean (SD) CHU-9D score (0.51 [0.23]) than that in control adolescents with serious mental health conditions such as depression (0.64 [0.26]) and anxiety (0.70 [0.24]) and was an independent factor associated with QOL. Conclusions and Relevance: In this cohort study of TGD children and adolescents in Australia, QOL was worse in this population than in age-matched, population-based peers. Quality of life associated with gender dysphoria was substantially worse than that seen in young people with common mental health conditions. These findings emphasize the risk of poor QOL among TGD young people and the need to better support them.

Successful restoration of spermatogenesis following gender-affirming hormone therapy in transgender women.

Increasing numbers of transgender individuals are presenting for gender-affirming medical care. For trans women, gender-affirming hormone therapy (GAHT) promotes feminization but also inhibits spermatogenesis. There is a common untested assumption that this inhibition is permanent, resulting in infertility. In this longitudinal study, we report the recovery of viable spermatozoa in nine trans women who stopped GAHT for reproductive purposes. Our preliminary findings suggest that the negative impact of GAHT on spermatogenesis can be reversed, casting doubt on previous claims that GAHT in trans women inevitably leads to permanent infertility. Larger studies are needed to confirm our findings, which have implications not only for fertility counseling and the reproductive options of transgender individuals but also efforts to restrict access to GAHT based on fertility grounds.

The clinical profile of patients attending a large, Australian pediatric gender service: A 10-year review.

Objectives: To better understand the clinical profile of patients attending a large Australian pediatric gender service. Retrospective clinical audit of patients seen at the Royal Children's Hospital Gender Service (RCHGS) over 10 years (2007-16). Setting: The RCHGS: Australia's largest pediatric gender service. Participants: Patients were eligible for inclusion if they had an appointment with the RCHGS between January 2007 - December 2016, and had either a self-reported gender which differed from what was presumed for them at birth or sought guidance regarding gender identity/expression. Main outcome measures: Demographic/developmental history, clinical presentation including information about gender identity/dysphoria, comorbidities, self-harm, suicidal ideation, gender-affirming treatment, psychosocial functioning. Results: 359 patients were first seen during the study period. Assigned females (54%) slightly outnumbered assigned males (46%), and presented at an older age (14.8 vs 12.4 years. Patients predominantly identified as transgender (87.2%) or non-binary (7.2%). Across the cohort, gender diversity was evident from a young age (median age 3), and symptoms of gender dysphoria were noted earlier in assigned males (median age 4) than assigned females (median age 11). Although 81% of patients met eligibility for GD, rates of hormonal treatment were much lower, with 29% of young people ≥10 years of age receiving puberty blocking treatment and 38% of adolescents ≥ 16 years of age receiving gender-affirming hormones (i.e. testosterone or estrogen). Many patients had mental health difficulties and/or neurodevelopment disorders, including major depressive disorder/low mood (51%), self-harm (25%), suicidal ideation (30%) and autism spectrum disorder (16%). Conclusion: This audit illustrates the complex profile and needs of transgender and gender diverse children and adolescents presenting to specialist gender services. Supplemental data for this article is available online at https://doi.org/10.1080/26895269.2021.1939221 .

Gender-affirming hormone therapy induces specific DNA methylation changes in blood.

BACKGROUND: DNA methylation is an epigenetic mark that is influenced by underlying genetic profile, environment, and ageing. In addition to X-linked DNA methylation, sex-specific methylation patterns are widespread across autosomal chromosomes and can be present from birth or arise over time. In individuals where gender identity and sex assigned at birth are markedly incongruent, as in the case of transgender people, feminization or masculinization may be sought through gender-affirming hormone therapy (GAHT). GAHT is a cornerstone of transgender care, yet no studies to date have investigated its effect on genome-wide methylation. We profiled genome-wide DNA methylation in blood of transgender women (n = 13) and transgender men (n = 13) before and during GAHT (6 months and 12 months into feminizing or masculinizing hormone therapy). RESULTS: We identified several thousand differentially methylated CpG sites (DMPs) (Δß ≥ 0.02, unadjusted p value < 0.05) and several differentially methylated regions (DMRs) in both people undergoing feminizing and masculinizing GAHT, the vast majority of which were progressive changes over time. X chromosome and sex-specific autosomal DNA methylation patterns established in early development are largely refractory to change in association with GAHT, with only 3% affected (Δß ≥ 0.02, unadjusted p value < 0.05). The small number of sex-specific DMPs that were affected by GAHT were those that become sex-specific during the lifetime, known as sex-and-age DMPs, including DMRs in PRR4 and VMP1 genes. The GAHT-induced changes at these sex-associated probes consistently demonstrated a shift towards the methylation signature of the GAHT-naïve opposite sex, and we observed enrichment of previously reported adolescence-associated methylation changes. CONCLUSION: We provide evidence for GAHT inducing a unique blood methylation signature in transgender people. This study advances our understanding of the complex interplay between sex hormones, sex chromosomes, and DNA methylation in the context of immunity. We highlight the need to broaden the field of 'sex-specific' immunity beyond cisgender males and cisgender females, as transgender people on GAHT exhibit a unique molecular profile.

Approach to the Patient: Pharmacological Management of Trans and Gender-Diverse Adolescents.

Internationally, increasing numbers of children and adolescents with gender dysphoria are presenting for care. In response, gender-affirming therapeutic interventions that seek to align bodily characteristics with an individual's gender identity are more commonly being used. Depending on a young person's circumstances and goals, hormonal interventions may aim to achieve full pubertal suppression, modulation of endogenous pubertal sex hormone effects, and/or development of secondary sex characteristics congruent with their affirmed gender. This is a relatively novel therapeutic area and, although short-term outcomes are encouraging, longer term data from prospective longitudinal adolescent cohorts are still lacking, which may create clinical and ethical decision-making challenges. Here, we review current treatment options, reported outcomes, and clinical challenges in the pharmacological management of trans and gender-diverse adolescents.

Small Extracellular Vesicle Enrichment of a Retrotransposon-Derived Double-Stranded RNA: A Means to Avoid Autoinflammation?

Small extracellular vesicles (SEVs) such as exosomes are released by multiple cell types. Originally believed to be a mechanism for selectively removing unwanted cellular components, SEVs have received increased attention in recent years for their ability to mediate intercellular communication. Apart from proteins and lipids, SEVs contain RNAs, but how RNAs are selectively loaded into SEVs remains poorly understood. To address this question, we profiled SEV RNAs from mouse dendritic cells using RNA-Seq and identified a long noncoding RNA of retroviral origin, VL30, which is highly enriched (>200-fold) in SEVs compared to parental cells. Bioinformatic analysis revealed that exosome-enriched isoforms of VL30 RNA contain a repetitive 26-nucleotide motif. This repeated motif is itself efficiently incorporated into SEVs, suggesting the likelihood that it directly promotes SEV loading. RNA folding analyses indicate that the motif is likely to form a long double-stranded RNA hairpin and, consistent with this, its overexpression was associated with induction of a potent type I interferon response. Taken together, we propose that preferential loading into SEVs of the VL30 RNA containing this immunostimulatory motif enables cells to remove a potentially toxic RNA and avoid autoinflammation. In this way, the original notion of SEVs as a cellular garbage bin should not be entirely discounted.

Predicting successful sperm retrieval in transfeminine adolescents after testicular biopsy.

PURPOSE: Increasing numbers of transgender adolescents are receiving gender-affirming treatments (GAT). Given GAT can impair reproductive function, clinical guidelines advise prior counselling regarding fertility preservation (FP). For transgender adults assigned male at birth, FP is usually achieved via a masturbatory sample and sperm cryopreservation. This is less straightforward in transgender adolescents, since they may not be developmentally ready to masturbate and/or masturbation may cause unacceptable gender dysphoria. Testicular biopsy represents an alternative method for sperm retrieval in these adolescents, but for those in early/mid puberty, it is difficult to predict whether sperm will be found. The purpose of this study was therefore to identify factors that predict successful sperm retrieval for cryopreservation via testicular biopsy. METHODS: A retrospective cohort study was undertaken at a tertiary-referral pediatric gender service. Subjects were included if they'd received a testicular biopsy in association with the commencement of GAT between 2010 and 2019. The primary outcome measure was successful sperm retrieval, and potential predictors included age, testicular volume and serum testosterone, LH and FSH levels. RESULTS: Of 25 subjects who received a biopsy prior to starting any GAT, 17 had successful sperm retrieval. While age, testosterone, LH and FSH levels showed minimal differences, testicular volume was significantly higher in those with successful sperm retrieval, and a threshold of ≥ 10 mL showed 92% sensitivity and 71% specificity in predicting successful retrieval. An additional 6 patients received a biopsy after starting puberty suppression and before commencement of oestrogen, and one of these individuals had sperm successfully retrieved despite > 2 years of regular puberty suppression. CONCLUSION: These findings suggest that testicular volume is most useful in predicting successful sperm retrieval following testicular biopsy in transgender adolescents and are likely to be of relevance to other young people undertaking FP, including those with cancer.