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.

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.

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.

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.

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.

Should clinicians make chest surgery available to transgender male adolescents?

Bioethicists are increasingly engaged in considering the ethical issues associated with the care of transgender people. One such issue facing paediatric clinicians is requests for chest surgery from transgender male adolescents. For transgender young people who identify as male but have already progressed through the mid to late stages of puberty, hormone treatment will not reverse breast development. Some of these young people are distressed by their chest, and request surgery to remove this tissue. Demand for this surgery during adolescence is increasing. However, few paediatric hospitals make this intervention available to adolescents. This paper focuses on the following ethical question: Should clinicians make chest surgery available to transgender male adolescents? We argue that making chest surgery available to transgender male adolescents under some circumstances is ethically justifiable for three reasons, based on the concepts of beneficence, privacy, and non-discrimination. Firstly, the limited evidence to date suggests that chest surgery is beneficial to transgender male adolescents who seek this intervention. Secondly, chest surgery protects transgender adolescents' privacy by enabling them to better control disclosure of their transgender identity. Thirdly, chest surgery is already performed on other adolescent males for psychosocial reasons, such as in the case of gynaecomastia; non-discrimination thus provides a further reason for making chest surgery available to transgender male adolescents whose male gender identity is consistent. We suggest that the ethical justifiability of chest surgery in any specific transgender adolescent's case will depend on the individual patient's circumstances.

A Waitlist Intervention for Transgender Young People and Psychosocial Outcomes.

BACKGROUND: Recent referrals of transgender young people to specialist gender services worldwide have risen exponentially, resulting in wait times of 1-2 years. To manage this demand, we introduced an innovative First Assessment Single-Session Triage (FASST) clinic that provides information and support to young people and their families and triages them onto a secondary waitlist for subsequent multidisciplinary care. Although FASST has been shown to substantially reduce initial wait times, its clinical impact is unknown. METHODS: FASST was evaluated by analysis of clinical surveys and qualitative interviews. A total of 142 patients were surveyed before and after FASST, and comparison was made to a historical control group of 120 patients who did not receive FASST. In-depth interviews were also held with FASST attendees (n = 14) to explore experiences of FASST, and inductive content analysis was performed. RESULTS: After FASST, there were improvements in depression (standardized mean difference [SMD] = -0.24; 95% confidence interval [CI]: -0.36 to -0.11; P < .001), anxiety (SMD = -0.14; 95% CI: -0.26 to -0.02; P = .025) and quality of life (SMD = .39; 95% CI: 0.23 to 0.56; P < .001). Compared with historical controls, those attending FASST showed reduced depression (SMD = -0.24; 95% CI: -0.50 to 0.01; P = .065) and anxiety (SMD = -0.31; 95% CI: -0.57 to -0.05; P = .021). FASST attendees qualitatively described an increased sense of agency, which was related to improved outlook, validation, sense of self, and confidence. CONCLUSIONS: Given burgeoning waitlists of pediatric gender services worldwide, this study suggests FASST may prove a useful model of care elsewhere.

Selective Estrogen Receptor Modulators: A Potential Option For Non-Binary Gender-Affirming Hormonal Care?

Gender dysphoria describes the distress associated with having a gender identity that differs from one's birth-assigned sex. To relieve this distress, transgender, and gender diverse (henceforth, trans) individuals commonly undergo medical transition involving hormonal treatments. Current hormonal treatment guidelines cater almost exclusively for those who wish to transition from male to female or vice versa. In contrast, there is a dearth of hormonal options for those trans individuals who identify as non-binary and seek an androgynous appearance that is neither overtly male nor female. Though prolonged puberty suppression with gonadotrophin releasing hormone agonists (GnRHa) could in theory be gender-affirming by preventing the development of unwanted secondary sex characteristics, this treatment option would be limited to pre- or peri-pubertal adolescents and likely have harmful effects. Here, we discuss the theoretical use of Selective Estrogen Receptor Modulators (SERMs) for non-binary people assigned male at birth (AMAB) who are seeking an androgynous appearance through partial feminization without breast growth. Given their unique range of pharmacodynamic effects, SERMs may represent a potential gender-affirming treatment for this population, but there is a lack of knowledge regarding their use and potentially adverse effects in this context.

Extracellular Vesicles in Synovial Fluid from Rheumatoid Arthritis Patients Contain miRNAs with Capacity to Modulate Inflammation.

In rheumatoid arthritis (RA), extracellular vesicles (EVs) are associated with both the propagation and attenuation of joint inflammation and destruction. However, the specific EV content responsible for these processes is largely unknown. Investigations into identifying EV content are confounded by the challenges in obtaining high-quality EV preparations from synovial fluid. Implementing a size exclusion chromatography-based method of EV isolation, coupled with small RNA sequencing, we accurately characterised EV miRNAs in synovial fluid obtained from RA patients and investigated the differences between joints with high- and low-grade inflammation. Synovial fluid was obtained from the joints of 12 RA patients and, based on leukocyte counts, classified as either high (n = 7)- or low (n = 5)-grade inflammation. Using size exclusion chromatography, EVs were purified and small RNA was extracted and sequenced on a NextSeq 500. Sequencing reads were aligned to miRBase v21, and differences in miRNA profiles between RA patients with high- and low-grade joint inflammation were analysed. In total, 1972 distinct miRNAs were identified from RA synovial fluid EVs. miRNAs with less than five reads in fewer than five patients were filtered out, leaving 318 miRNAs for analysis. Analysis of the most abundant miRNAs suggested that they negatively regulate multiple genes relevant to inflammation, including signal transducer and activator of transcription 3 (STAT3), which lies downstream of IL-6 and has a pro-inflammatory role in RA. Synovial fluid from joints with high-grade inflammation contained 3.5-fold more EV miRNA per mL of synovial fluid (p = 0.0017). Seventy-eight EV miRNAs were differentially expressed between RA joints with high- and low-grade inflammation, and pathway analysis revealed that their target genes were commonly involved a variety of processes, including cellular apoptosis, proliferation and migration. Of the 49 miRNAs that were elevated in joints with high-grade inflammation, pathway analysis revealed that genes involved in cytokine-mediated signalling pathways were significantly enriched targets. In contrast, genes associated with reactive oxygen species signalling were significantly enriched as targets of the 29 miRNAs elevated in joints with low-grade inflammation. Our study identified an abundance of EV miRNAs from the synovial fluid of RA patients with the potential to modulate inflammation. In doing so, we defined potential mechanisms by which synovial fluid EVs may contribute to RA pathophysiology.