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.

Does insulin pump therapy offer benefits for behaviour, mood, cognition and HbA1c in children and adolescents with type 1 diabetes? A randomised controlled trial with observational follow-up.

AIMS: Improved behaviour, mood, cognition and HbA1c have been reported with short-term use of continuous subcutaneous insulin infusion (CSII) in youth with type 1 diabetes (T1D). We sought to re-examine these findings in a randomised controlled trial (RCT), with longitudinal follow-up. METHODS: RCT of youth aged 7-15 years with T1D, at two tertiary paediatric centres. Participants were randomised to commence CSII or continue multiple daily injections (MDI). Behaviour, mood, cognition and HbA1c were assessed. Primary outcome was difference in parent-reported behaviour (BASC-2) at 4 months. After the 4-month RCT, MDI participants commenced CSII; outcomes were reassessed at +2 years. RESULTS: Participating youth (n=101) were randomised to CSII (n=56) or MDI (n=45). Significant differences favouring CSII were found at 4 months in parent-reported behaviour problems (Cohen's d 0.41 (95% CI 0.004 to 0.795); p=0.048) and HbA1c (mean (95% CI) difference: 7 (2.3 to 11.7) mmol/mol (0.6% (0.2 to 1.0%); p=0.001)). Improvements from baseline were documented in mood and cognitive outcomes in both study groups over the 4-month RCT; however, no between-group differences were evident at 4 months. Sixteen of 76 (21%) participants completing assessments at +2 years had discontinued CSII. In n=60 still using CSII, measurements of behaviour, mood and HbA1c were comparable to baseline. CONCLUSIONS: Parent-reported behaviour problems and HbA1c, but not mood or neurocognitive outcomes, were clinically significantly lower with CSII, relative to MDI, after 4 months. Observational follow-up indicated no impact of treatment modality at +2 years, relative to baseline levels. Taken together, these data indicate that use of CSII alone does not comprehensively benefit neuropsychological outcomes in childhood T1D.

Best Practice for Identification of Classical 21-Hydroxylase Deficiency Should Include 21 Deoxycortisol Analysis with Appropriate Isomeric Steroid Separation.

There are mixed reports on the inclusion and use of 21 deoxycortisol (21DF) as the primary decision marker for classical 21-hydroxylase deficiency. We hypothesize that this may be due to insufficient recognition of the presence and chromatographic separation of isomeric steroids. The aim of this study was to determine the comparative utility of 21DF for screening and diagnosis of CAH due to classical 21-hydroxylase deficiency using a second-tier LC-MS/MS method that included the separation of isomeric steroids to 17OHP and 21DF. For each baby sample, one 3.2 mm dried blood spot was eluted in a methanolic solution containing isotopically matched internal standards. Data were interrogated by univariate and receiver operator characteristic analysis. Steroid profile results were generated for 924 non-CAH baby samples (median gestational age 37 weeks, range 22 to 43 weeks) and 17 babies with 21-hydroxylase deficiency. The ROC curves demonstrated 21DF to have the best sensitivity and specificity for the diagnosis of classical 21-hydroxylase deficiency with an AUC = 1.0. The heatmap showed the very strong correlation (r = 0.83) between 17OHP and 21DF. Our data support 21DF as a robust marker for CAH due to 21-hydroxylase deficiency. We recommend that 21DF be incorporated into routine newborn screening panels as part of the second-tier LC-MS/MS method, follow-up plasma steroid panels, and external quality assurance material.

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.

Genetic Variants in SRD5A2 in a Spectrum of DSD Patients from Australian Clinics Highlight Importance of Genetic Testing alongside Typical First-Line Investigations.

INTRODUCTION: Steroid 5-alpha reductase deficiency (5α-R2D) is a rare condition caused by genetic variants that reduce the activity of the enzyme that converts testosterone into dihydrotestosterone. The clinical spectrum of 5α-R2D is known to overlap with other 46,XY differences of sex development (DSD) such as androgen insensitivity or gonadal dysgenesis. However, the clinical trajectories of the aetiologies can differ, with 5α-R2D presenting its own challenges. METHODS: In this study, we have collated clinical information for five individuals with variants in SRD5A2 identified using research genetic testing in an Australian paediatric setting. RESULTS: We describe how a genetic finding resolved or confirmed a diagnosis for these individuals and how it guided clinical management and family counselling. CONCLUSION: This work highlights the importance of early genetic testing in children born with 46,XY DSD where it complements traditional first-line testing.

Establishing a Molecular Genetic Diagnosis in Children with Differences of Sex Development: A Clinical Approach.

BACKGROUND: Despite distinct underlying aetiologies, the clinical phenotypes and hormonal profiles of children with various differences of sex development (DSD) are often similar, which presents challenges to ascertaining an accurate diagnosis on clinical grounds alone. Associated features and important clinical outcomes can, however, vary significantly in different DSD, thus establishing an accurate molecular diagnosis may have important implications for decision-making and management planning in a given individual. SUMMARY: The wider availability of next-generation sequencing techniques in recent years has led to recommendations for earlier integration of genetic testing in the diagnostic pathway of children with DSD. This review provides a practical overview of the clinical applications, advantages, and limitations of the more commonly available diagnostic genetic tests and outlines a suggested approach to testing. The potential clinical implications of a confirmed genetic diagnosis, subsequent management pathways for individuals with DSD, and challenges that remain to be addressed are also outlined. KEY MESSAGES: Despite significant improvements in our understanding of the complex genetic pathways that underlie DSD, an accurate diagnosis still eludes many affected individuals. Establishing a molecular diagnosis provides aetiological certainty, enabling improved information for families and individualized clinical management, including monitoring or prophylactic intervention where additional health risks exist. A stepwise approach to genomic testing is recommended to afford highest diagnostic yield from available resources. Looking forward, collaborative multicentre prospective studies will be required to assess the true impact of a genetic diagnosis on improving clinical care pathways and health, well-being and patient-reported outcomes for individuals with DSD.

Identifying the Resource Needs of Young People with Differences of Sex Development.

Adolescents with differences of sex development (DSD) often have complex medical, surgical, and psychological care needs and require age-appropriate resources. This cross-sectional study describes the past and current experiences of adolescents and young adults with DSD and their need for information and support. Participants aged 14−30 years with DSD diagnoses were identified, either from departmental records at the Royal Children's Hospital (RCH), Melbourne, Australia, or from the private practice of a gynecologist linked to RCH. Anonymized data were collected from a specifically designed online survey. Of the 314 successfully traced patients, 91 (28.9%) completed the survey. Amongst respondents, older age was strongly correlated with higher levels of distress at the time of disclosure (b = 0.67, p < 0.001). People who reported greater understanding of their condition (b = −0.45, p = 0.010) and higher levels of support (b = −0.40, p = 0.003) identified lower levels of current distress. Respondents preferred to receive information from a specialist doctor, GP, or websites and reported information needs being highest during adolescence. Only one in four respondents recalled ever being offered psychological support. A number of perceived barriers to accessing support were identified. Our findings indicate that young people's information and support needs may be best met by improving online resources, as well as increasing introductions to knowledgeable and appropriate primary care physicians, psychological services, and peer support groups. Further work to promote and increase engagement with psychological and peer support for those with DSD will be important.

Caries experience and gingival health in children and adolescents with type 1 diabetes mellitus-A cross-sectional study.

AIM: To investigate the oral health of children and adolescents with type 1 diabetes (T1D) and its associations with diabetes-related and lifestyle factors. DESIGN: Cross-sectional study at a large tertiary hospital pediatric diabetes clinic. Oral examination determined dental caries experience and gingival health. Secondary outcome measures included salivary characteristics, oral hygiene and dietary practices, and diabetes-related factors. RESULTS: Eighty children and adolescents with T1D participated; mean (SD) age and HbA1c were 13.4(2.6) years and 7.7(0.9)%, respectively. Forty-seven (59%) participants had one or more decayed, missing or filled teeth; 75 (94%) participants had gingivitis. Half (50%) reported ≥3 hypoglycemic episodes necessitating rapid-acting carbohydrate in the previous week. Sixty-two participants (78%) had normal saliva flow, however, 42 (52%) had reduced salivary buffering capacity. Glycemic control (HbA1c ) was not associated with caries experience, gingival health or salivary characteristics. Increased frequency of tooth brushing (OR, 0.11; 95%CI 0.01-0.97, p = 0.05) and interdental flossing (OR, 0.31; 95%CI 0.12-0.81, p = 0.02) were associated with lower caries experience. Interdental flossing (OR, 0.31; 95% CI 0.12-0.80, p = 0.02) and good oral hygiene (OR, 0.06; 95% CI 0.01-0.22, p < 0.001) were associated with less gingivitis. CONCLUSION: Poor oral health is common in children with T1D, regardless of HbA1c. Given potential implications for short- and long-term systemic health, this study demonstrates the need for targeted strategies to improve oral health in children with T1D.

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.

Is there an optimal approach to elective stabilisation of glycaemic control in children and adolescents with type 1 diabetes mellitus?

AIM: To investigate the effectiveness of inpatient and outpatient interventions in attaining improved glycaemic control in children/adolescents with type 1 diabetes mellitus and persistently high/deteriorating HbA1c. METHODS: A retrospective study at a tertiary paediatric centre. Admitted individuals who had prior attempts at ambulatory stabilisation were matched with intervention naïve controls who underwent outpatient intervention. The mean age was 14.6 years in the admitted group and 14.7 years in the ambulatory group. Mean duration of diabetes was 6.1 years in the admitted group and 7.3 years in the ambulatory group. Change in HbA1c from baseline was assessed to 12 months. RESULTS: Mean baseline HbA1c was 11.3% (100 mmol/mol), with 11.4% in the admitted group and 11.2% in the ambulatory group. Sustained reduction in HbA1c at 12 months was seen in both groups (n = 35 in each): mean (standard deviation) 10.1% (1.5) in admitted (mean reduction in HbA1c 1.4%) and 9.7% (1.4) in ambulatory (mean reduction in HbA1c 1.5%). Proportions achieving delta HbA1c ≥2% (22 mmol/mol) at 12 months were 25 and 31% in admitted and ambulatory groups, respectively. A sustained reduction in HbA1c of ≥2% (22 mmol/mol) after 12 months was more likely in those who attained this reduction by 6 months (17/24 who achieved this at 6 months vs. 3/41 who had not). CONCLUSIONS: Both inpatient and outpatient stabilisation strategies achieved sustained improvements in HbA1c. We recommend an individualised approach to stabilisation, with review of the intervention's success at 6 months with further intensification as needed.

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.

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.

Role of cross-campus multidisciplinary team meetings in decision-making for children and adolescents with differences of sex development/intersex.

AIM: Management of children with differences/disorders of sex development (DSD) is complex with limited evidence to guide clinical decisions. Regular multidisciplinary team meetings were set up in Sydney and Melbourne paediatric hospitals to enable systematic peer review of complex decision-making. We aim to describe the workload and role of these meetings. METHODS: The multidisciplinary team forum includes invited representatives from endocrinology, urology, gynaecology, genetics, psychology, social work, clinical ethics, laboratory and hospital executive and meetings occur 1-3 times monthly. Descriptive data were collected from de-identified meeting referrals and minutes between August 2012 to August 2018 (Sydney) and January 2014 to August 2018 (Melbourne). RESULTS: A total of 192 referrals (142 new and 50 follow-ups) aged 1 week to 17 years were discussed across the two sites. 46, XY DSD (n = 81) was the most common sub-classification. Consideration of surgical options and optimal management of gonads with malignant potential were amongst the common reasons for referral to the multidisciplinary team meetings. Surgical interventions were considered but not recommended after review for 38 of 154 (24.7%) procedures. Gonad retention to allow potential functional benefit was recommended in 15/46 (32.6%) referrals. Evidence of premalignant or malignant changes was found in 20/57 (35%) gonads removed, with dysgenetic features and atrophy/streak features in 6 (10.5%) and 27 (47.4%) gonads respectively. CONCLUSION: Formal DSD multidisciplinary team meetings provide a framework and opportunity for multi and interdisciplinary discussions amongst representatives from several specialities to help make complex decision-making.

A point-of-care test increases same-day referral and reduces DKA in children with new-onset type 1 diabetes.

BACKGROUND AND OBJECTIVES: Same-day referral for tertiary management of suspected childhood type 1 diabetes (T1D) is recommended as best practice. The aim of this study was to review recent primary care practice in managing suspected paediatric T1D and its impact on clinical outcomes. METHOD: This was a retrospective cross-sectional study of referral patterns and clinical outcomes of youth aged <18 years with new-onset T1D at two tertiary metropolitan paediatric diabetes centres. RESULTS: Almost half (73 out of 155) of children and adolescents later diagnosed with T1D had delayed referral; 56% (41 out of 73) had additional pre-referral investigations. Point-of-care (POC) blood/urine glucose testing was associated with increased same-day referral (odds ratio [OR] 14.6; 95% confidence interval [CI]: 5.9, 36.3, P <0.001), reduced pre-referral investigations (OR 0.4; 95% CI: 0.2, 0.9, P = 0.02) and reduced diabetic ketoacidosis (DKA) rates (60.3%, compared with 27.8%, P <0.001). DISCUSSION: POC testing facilitated early tertiary referral and reduced DKA rates and unnecessary investigations in children and adolescents with new presentation of T1D.

Has subsidized continuous glucose monitoring improved outcomes in pediatric diabetes?

INTRODUCTION: In 2017, the Australian Federal Government fully subsidized continuous glucose monitoring (CGM) devices for patients under 21 years of age with T1D with the aim of reducing rates of severe hypoglycaemia (SH) and improving metabolic control. The aim of this study was to reports on metabolic outcomes in youth from a single tertiary centre. METHODS: The study design was observational. Data were obtained on youth who commenced CGM between May 2017 and December 2019. RESULTS: Three hundred and forty one youth who commenced CGM and had clinical outcome data for a minimum of 4 months. 301, 261, 216, 172, and 125 had outcome data out to 8, 12, 16, 20, and 24 months, respectively. Cessation occurred between 27.9% and 32.8% of patients 12 to 24 months after CGM commencement. HbA1c did not change in patients who continued to use CGM. In the 12 months prior to starting CGM the rate of severe hypoglycaemia events were 5.0 per 100 patient years. The rates of severe hypoglycaemia in those continuing to use CGM at 4, 8, 12, 16, 20, and 24 months, were 5.2, 5.1, 1.6, 6.1, 2.4, and 0 per 100 patient years, respectively. DISCUSSION: Our experience of patients either ceasing or underusing CGM is less than reported in other cohorts but is nonetheless still high. There may have been a reduction in rates of severe hypoglycaemia over the 24 months follow up period; however, the absolute numbers of events were so low as to preclude meaningful statistical analysis.