Sex-specific adipose tissue imprinting of regulatory T cells.

Adipose tissue is an energy store and a dynamic endocrine organ1,2. In particular, visceral adipose tissue (VAT) is critical for the regulation of systemic metabolism3,4. Impaired VAT function-for example, in obesity-is associated with insulin resistance and type 2 diabetes5,6. Regulatory T (Treg) cells that express the transcription factor FOXP3 are critical for limiting immune responses and suppressing tissue inflammation, including in the VAT7-9. Here we uncover pronounced sexual dimorphism in Treg cells in the VAT. Male VAT was enriched for Treg cells compared with female VAT, and Treg cells from male VAT were markedly different from their female counterparts in phenotype, transcriptional landscape and chromatin accessibility. Heightened inflammation in the male VAT facilitated the recruitment of Treg cells via the CCL2-CCR2 axis. Androgen regulated the differentiation of a unique IL-33-producing stromal cell population specific to the male VAT, which paralleled the local expansion of Treg cells. Sex hormones also regulated VAT inflammation, which shaped the transcriptional landscape of VAT-resident Treg cells in a BLIMP1 transcription factor-dependent manner. Overall, we find that sex-specific differences in Treg cells from VAT are determined by the tissue niche in a sex-hormone-dependent manner to limit adipose tissue inflammation.

Paracrine signalling by cardiac calcitonin controls atrial fibrogenesis and arrhythmia.

Atrial fibrillation, the most common cardiac arrhythmia, is an important contributor to mortality and morbidity, and particularly to the risk of stroke in humans1. Atrial-tissue fibrosis is a central pathophysiological feature of atrial fibrillation that also hampers its treatment; the underlying molecular mechanisms are poorly understood and warrant investigation given the inadequacy of present therapies2. Here we show that calcitonin, a hormone product of the thyroid gland involved in bone metabolism3, is also produced by atrial cardiomyocytes in substantial quantities and acts as a paracrine signal that affects neighbouring collagen-producing fibroblasts to control their proliferation and secretion of extracellular matrix proteins. Global disruption of calcitonin receptor signalling in mice causes atrial fibrosis and increases susceptibility to atrial fibrillation. In mice in which liver kinase B1 is knocked down specifically in the atria, atrial-specific knockdown of calcitonin promotes atrial fibrosis and increases and prolongs spontaneous episodes of atrial fibrillation, whereas atrial-specific overexpression of calcitonin prevents both atrial fibrosis and fibrillation. Human patients with persistent atrial fibrillation show sixfold lower levels of myocardial calcitonin compared to control individuals with normal heart rhythm, with loss of calcitonin receptors in the fibroblast membrane. Although transcriptome analysis of human atrial fibroblasts reveals little change after exposure to calcitonin, proteomic analysis shows extensive alterations in extracellular matrix proteins and pathways related to fibrogenesis, infection and immune responses, and transcriptional regulation. Strategies to restore disrupted myocardial calcitonin signalling thus may offer therapeutic avenues for patients with atrial fibrillation.

A20 controls RANK-dependent osteoclast formation and bone physiology.

The anti-inflammatory protein A20 serves as a critical brake on NF-κB signaling and NF-κB-dependent inflammation. In humans, polymorphisms in or near the TNFAIP3/A20 gene have been associated with several inflammatory disorders, including rheumatoid arthritis (RA), and experimental studies in mice have demonstrated that myeloid-specific A20 deficiency causes the development of a severe polyarthritis resembling human RA. Myeloid A20 deficiency also promotes osteoclastogenesis in mice, suggesting a role for A20 in the regulation of osteoclast differentiation and bone formation. We show here that osteoclast-specific A20 knockout mice develop severe osteoporosis, but not inflammatory arthritis. In vitro, osteoclast precursor cells from A20 deficient mice are hyper-responsive to RANKL-induced osteoclastogenesis. Mechanistically, we show that A20 is recruited to the RANK receptor complex within minutes of ligand binding, where it restrains NF-κB activation independently of its deubiquitinating activity but through its zinc finger (ZnF) 4 and 7 ubiquitin-binding functions. Together, these data demonstrate that A20 acts as a regulator of RANK-induced NF-κB signaling to control osteoclast differentiation, assuring proper bone development and turnover.

Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum.

Loss- and gain-of-function mutations in the broadly expressed gene Lrp5 affect bone formation, causing osteoporosis and high bone mass, respectively. Although Lrp5 is viewed as a Wnt coreceptor, osteoblast-specific disruption of beta-Catenin does not affect bone formation. Instead, we show here that Lrp5 inhibits expression of Tph1, the rate-limiting biosynthetic enzyme for serotonin in enterochromaffin cells of the duodenum. Accordingly, decreasing serotonin blood levels normalizes bone formation and bone mass in Lrp5-deficient mice, and gut- but not osteoblast-specific Lrp5 inactivation decreases bone formation in a beta-Catenin-independent manner. Moreover, gut-specific activation of Lrp5, or inactivation of Tph1, increases bone mass and prevents ovariectomy-induced bone loss. Serotonin acts on osteoblasts through the Htr1b receptor and CREB to inhibit their proliferation. By identifying duodenum-derived serotonin as a hormone inhibiting bone formation in an Lrp5-dependent manner, this study broadens our understanding of bone remodeling and suggests potential therapies to increase bone mass.

The Utility of Preclinical Models in Understanding the Bone Health of Transgender Individuals Undergoing Gender-Affirming Hormone Therapy.

PURPOSE OF REVIEW: To summarise the evidence regarding the effects of gender-affirming hormone therapy (GAHT) on bone health in transgender people, to identify key knowledge gaps and how these gaps can be addressed using preclinical rodent models. RECENT FINDINGS: Sex hormones play a critical role in bone physiology, yet there is a paucity of research regarding the effects of GAHT on bone microstructure and fracture risk in transgender individuals. The controlled clinical studies required to yield fracture data are unethical to conduct making clinically translatable preclinical research of the utmost importance. Novel genetic and surgical preclinical models have yielded significant mechanistic insight into the roles of sex steroids on skeletal integrity. Preclinical models of GAHT have the potential inform clinical approaches to preserve skeletal integrity and prevent fractures in transgender people undergoing GAHT. This review highlights the key considerations required to ensure the information gained from preclinical models of GAHT are informative.

Effect of gender-affirming hormone therapy on hair growth: a systematic review of the literature.

Gender-affirming hormone therapy (GAHT) leads to changes in body composition, secondary sex characteristics and in the distribution and pattern of hair growth. Transgender individuals undergoing GAHT may experience altered hair growth patterns that may be affirming and desirable, or undesirable with a subsequent impact on their quality of life. Given increasing numbers of transgender individuals commencing GAHT worldwide and the clinical relevance of the impact of GAHT on hair growth, we systematically reviewed the existing literature on the impact of GAHT on hair changes and androgenic alopecia (AGA). The majority of studies used grading schemes or subjective measures of hair changes based on patient or investigator's examination. Very few studies used objective quantitative measures of hair parameters but demonstrated statistically significant changes in hair growth length, diameter and density. Feminizing GAHT with estradiol and/or antiandrogens in transgender women may reduce facial and body hair growth and also can improve AGA. Masculinizing GAHT with testosterone in transgender men may increase facial and body hair growth as well as induce or accelerate AGA. The impact of GAHT on hair growth may not align with a transgender person's hair growth goals and specific treatment for AGA and/or hirsutism may be sought. Further research on how GAHT affects hair growth is required.

Improved metabolic parameters of people with diabetes attending an Aboriginal health service in regional Victoria.

BACKGROUND: Aboriginal and Torres Strait Islander people have higher rates of diabetes and its complications than non-Aboriginal people. Rumbalara Aboriginal Co-operative is the major primary healthcare provider for Aboriginal people in the Greater Shepparton region. AIMS: To evaluate the baseline metabolic parameters and presence of diabetes complications in people with type 2 diabetes attending Rumbalara Aboriginal Co-operative in 2017 and compare it with other Aboriginal and Torres Strait Islander studies and Australian specialist diabetes services. METHODS: Clinical and biochemical characteristics, including diabetes type, age, weight, body mass index (BMI), blood pressure, micro- and macrovascular complications, glycosylated haemoglobin (HbA1c), haemoglobin, renal function, lipid profile, urine albumin:creatinine ratio, diabetes medications, renin angiotensin system inhibition therapies, HMG-CoA reductase inhibitors and antiplatelet agents, were determined. RESULTS: One hundred and twenty-six individuals had diabetes, 121 had type 2 diabetes. One hundred and thirteen identified as Aboriginal and/or Torres Strait Islander. Median age was 57.5 (48-68) years, median HbA1c was 7.8% (6.8-9.6) and median BMI was 33.4 kg/m2 (29-42.3). Compared with other Australian Aboriginal and Torres Strait Islander populations, this population was older and had more obesity, but with better glycaemia management. Compared with specialist diabetes services, this population was of similar age, with greater BMI but comparable HbA1c. CONCLUSIONS: Aboriginal people living with type 2 diabetes attending this regional Aboriginal health service have comparable glycaemic management to specialist diabetes services in Australia, managed largely by primary care physicians with limited access to specialist care for the past 5 years.

Effect of estradiol on cognition in men undergoing androgen deprivation therapy: A randomized placebo-controlled trial.

OBJECTIVE: Roles for estradiol in modulating cognition in men remain uncertain. We assessed the isolated effects of estradiol on cognition in men in the absence of testosterone. DESIGN: Randomized trial of transdermal estradiol 0.9 mg daily, or matched placebo, for 6 months, hypothesizing that estradiol would improve verbal learning, verbal memory, and spatial problem solving over time. PATIENTS: Men receiving androgen deprivation therapy (ADT) for prostate cancer. MEASUREMENTS: Cognition was assessed by a tablet-based cognitive battery (Cogstate) at baseline, Month 1, Month 3, and Month 6. Anxiety and depression symptoms were assessed using the Hospital Anxiety and Depression Scale. RESULTS: Seventy-eight participants were randomized. Baseline mean scores were 21.0 (standard deviation [SD] 4.1) for the International Shopping List test (ISL), assessing verbal learning and memory (higher scores better), and 60.4 (SD 19.5) for the Groton Maze Learning test (GML), assessing spatial problem solving (lower scores better). There was no significant difference in performance over time for the estradiol group versus the placebo group for the ISL, mean adjusted difference (MAD) 0.7 (95% confidence interval [CI] -1.2 to 2.5), p = .36, or the GML, MAD -3.2 (95% CI -12.0 to 5.6), p = 0.53. There was no significant difference between groups over time in performance in any other cognitive domain, or on depression or anxiety scores. CONCLUSIONS: We found no major effects of estradiol on cognition in men with castrate testosterone concentrations. Although the cognitive effects of ADT are debated, this study suggests that any such effects are unlikely to be prevented by the administration of estradiol.

Prescription Patterns and Testosterone Concentrations Achieved With AndroForte 5% Testosterone Cream in Transgender and Gender Diverse Individuals.

BACKGROUND: Masculinizing hormone therapy with testosterone is used to align an individual's physical characteristics with their gender identity in trans and gender diverse individuals. Standard testosterone doses and formulations recommended for hypogonadal cisgender men are typically administered. 100 mg AndroForte 5% testosterone cream is the recommended starting dose in hypogonadal cisgender men but there are no data evaluating the use of AndroForte 5% testosterone cream in gender-affirming hormone therapy regimens. AIM: To assess the prescription patterns and serum total testosterone concentrations achieved with AndroForte 5% testosterone cream in trans and gender diverse individuals. METHODS: A retrospective analysis was undertaken of trans and gender diverse individuals at a primary and secondary care clinic in Melbourne, Australia. Seventy-two individuals treated with AndroForte 5% testosterone cream to the torso were included. OUTCOMES: Testosterone dose and serum total testosterone concentration. RESULTS: Median age was 26 years (IQR 22-30) and median duration of testosterone therapy was 14 months (7-24). Fifty (69%) individuals had a non-binary gender identity. Initial median testosterone dose was 50 mg (50-100) daily. Thirty-eight (53%) commenced doses <100 mg daily, the recommended starting dose for hypogonadal cisgender men. Median total testosterone concentration achieved from 186 individual laboratory results was 11.9 nmol/L (8.1-16.4). Polycythemia was documented in 5 (7%) individuals. CLINICAL IMPLICATIONS: AndroForte 5% testosterone cream can be used in individuals with a binary and/or non-binary gender identity seeking masculinization. It can be commenced at a lower dose than that administered to hypogonadal cisgender men for individuals seeking slow masculinization goals. STRENGTHS & LIMITATIONS: Limitations include the retrospective study design, lack of clinical end points and lack of standardization of timing of laboratory tests in relation to the last dose. This is the first study to evaluate AndroForte 5% testosterone cream in trans and gender diverse individuals and provides insights into prescription patterns in individuals with a non-binary gender identity. CONCLUSION: AndroForte 5% testosterone cream represents an alternative formulation of testosterone administration for trans and gender diverse individuals seeking masculinization. Nolan BJ, Zwickl S, Locke P, et al. Prescription Patterns and Testosterone Concentrations Achieved With AndroForte 5% Testosterone Cream in Transgender and Gender Diverse Individuals. J Sex Med 2022;19:1049-1054.

A systematic review of antiandrogens and feminization in transgender women.

Antiandrogens are frequently used with estradiol in transgender women seeking feminization. Antiandrogens act by various mechanisms to decrease the production or effects of testosterone, but it is unclear which antiandrogen is most effective at feminization. A systematic review was performed using PRISMA guidelines. We searched online databases (Medline, Embase and PsycINFO) and references of relevant articles for studies of antiandrogens in transgender women aged 16+ years to achieve feminization (namely changes in breast size, body composition, facial or body hair) or changes in serum total testosterone concentration when compared to placebo, estradiol alone or an alternative antiandrogen. Four studies fulfilled eligibility criteria and were included in a narrative review. The addition of cyproterone acetate, leuprolide and medroxyprogesterone acetate may be more effective than spironolactone or estradiol alone at suppressing the serum total testosterone concentration. Body composition changes appear similar in transgender women treated with estradiol and additional cyproterone acetate or leuprolide. No eligible studies adequately evaluated the effects of antiandrogens on breast development or facial and body hair reduction. It remains unclear which antiandrogen is most effective at achieving feminization. Cyproterone acetate, medroxyprogesterone acetate and leuprolide may be more effective than spironolactone at suppressing the serum total testosterone concentration. However, due to spironolactone's antagonism of the androgen receptor, it is unclear whether this results in clinically meaningful differences in feminization. Further research with clinically meaningful endpoints is needed to optimize the use of antiandrogens in transgender women.

The Informed Consent Model of Care for Accessing Gender-Affirming Hormone Therapy Is Associated With High Patient Satisfaction.

BACKGROUND: There are 2 common approaches to assess an individual before commencing of gender-affirming hormone therapy (GAHT); a mental health practitioner assessment and approval or an informed consent model undertaken with a primary care general practitioner (GP). AIM: In a primary care clinic practising an Informed Consent Model of care to initiate GAHT, we aimed to firstly describe the proportion and characteristics of patients referred for secondary consultation to a mental health practitioner (MH referred) and secondly, we aimed to measure patient satisfaction. METHODS: A retrospective audit of all new patients with a transgender or gender diverse identity presenting to a primary care clinic in Melbourne, Australia was performed between March 2017 and March 2019. In those newly seeking GAHT, de-identified data were obtained including presence of secondary mental health practitioner referral, time to GAHT commencement and co-occurring mental health conditions. A separate survey assessed patient satisfaction. OUTCOMES: Mental health conditions and overall patient satisfaction in those referred for secondary mental health consultation (MH referred) were compared with those who were not (GP assessed). RESULTS: Of 590 new consultations, 309 were newly seeking GAHT. Referrals for secondary mental health assessment before GAHT occurred in 8%. The GP-assessed group commenced GAHT at median 0.9 months (0.5-1.8) after initial consultation compared with 3.1 months (1.3-4.0), P < .001 in the MH-referred group. The MH-referred group was more likely to have post-traumatic stress disorder (adjusted P = .036) and schizophrenia (adjusted P = .011). Of 43 respondents to the survey, a higher proportion in the GP-assessed group was extremely satisfied with their overall care compared with the MH-referred group (P < .01). Notably, 80% in the GP-assessed group chose to seek mental health professional support. CLINICAL IMPLICATIONS: Initiation of GAHT can be performed in primary care by GPs using an informed consent model and is associated with high patient satisfaction. Mental health professionals remain a key source of support. STRENGTHS & LIMITATIONS: This retrospective audit did not randomize patients to pathways to initiate GAHT. Follow-up duration was short. Responder bias to survey with low response rates may overestimate patient satisfaction. This is one of the first studies to evaluate an informed consent model of care. CONCLUSION: More widespread uptake of an informed consent model of care to initiate GAHT by primary care physicians has the potential for high patient satisfaction and may be a practical solution to reduce waiting lists in gender clinics. Spanos C, Grace JA, Leemaqz SY, et al. The Informed Consent Model of Care for Accessing Gender-Affirming Hormone Therapy Is Associated With High Patient Satisfaction. J Sex Med 2021;18:201-208.

Factors associated with suicide attempts among Australian transgender adults.

BACKGROUND: Transgender, including gender diverse and non-binary people, henceforth referred to collectively as trans people, are a highly marginalised population with alarming rates of suicidal ideation, attempted suicide and self-harm. We aimed to understand the risk and protective factors of a lifetime history of attempted suicide in a community sample of Australian trans adults to guide better mental health support and suicide prevention strategies. METHODS: Using a non-probability snowball sampling approach, a total of 928 trans adults completed a cross-sectional online survey between September 2017 and January 2018. The survey assessed demographic data, mental health morbidity, a lifetime history of intentional self-harm and attempted suicide, experiences of discrimination, experiences of assault, access to gender affirming healthcare and access to trans peer support groups. Logistic regression was used to examine the risk or protective effect of participant characteristics on the odds of suicide. RESULTS: Of 928 participants, 85% self-reported a lifetime diagnosis of depression, 63% reported previous self-harm, and 43% had attempted suicide. Higher odds of reporting a lifetime history of suicide attempts were found in people who were; unemployed (adjusted odds ratio (aOR) 1.55 (1.05, 2.29), p = 0.03), had a diagnosis of depression (aOR 3.70 (2.51, 5.45), p < 0.001), desired gender affirming surgery in the future (aOR 1.73 (1.14, 2.61), p = 0.01), had experienced physical assault (aOR 2.01 (1.37, 2.95), p < 0.001) or experienced institutional discrimination related to their trans status (aOR 1.59 (1.14, 2.23), p = 0.007). CONCLUSION: Suicidality is associated with barriers to gender affirming care, gender based victimisation and institutionalised cissexism. Interventions to increase social inclusion, reduce transphobia and enable timely access to gender affirming care, particularly surgical interventions, are potential areas of intervention.

Prevalence of polycythaemia with different formulations of testosterone therapy in transmasculine individuals.

BACKGROUND: Masculinising hormone therapy with testosterone is used to align an individual's physical characteristics with his or her gender identity. Testosterone therapy is typically administered via intramuscular or transdermal routes, and polycythaemia is the most common adverse event. AIMS: To compare the risk of polycythaemia with different formulations of testosterone therapy in transmasculine individuals. METHODS: A retrospective cross-sectional analysis was undertaken of transmasculine individuals at a primary and secondary care clinic in Melbourne, Australia. A total of 180 individuals who were on testosterone therapy for >6 months was included. Groups included those receiving: (i) intramuscular testosterone undecanoate (n = 125); (ii) intramuscular testosterone enantate (n = 31); or (iii) transdermal testosterone (n = 24). Outcome was prevalence of polycythaemia (defined as haematocrit > 0.5). RESULTS: Mean age was 28.4 (8.8) years, with a median duration of testosterone therapy of 37.7 (24.2) months; 27% were smokers. There was no difference between groups in serum total testosterone concentration measured. While there was no difference between groups in haematocrit, there was a higher proportion of patients with polycythaemia in those who were on intramuscular testosterone enantate (23.3%) than on transdermal testosterone (0%), P = 0.040. There was no statistically significant difference in polycythaemia between intramuscular testosterone undecanoate (15%) and transdermal testosterone, P = 0.066 nor between intramuscular testosterone enantate and undecanoate, P = 0.275. CONCLUSIONS: One in four individuals treated with intramuscular testosterone enantate and one in six treated with testosterone undecanoate had polycythaemia. No individual treated with transdermal testosterone had polycythaemia. This highlights the importance of regular monitoring of haematocrit in transmasculine individuals treated with testosterone, and findings may inform treatment choices.

Predicting all-cause unplanned readmission within 30 days of discharge using electronic medical record data: A multi-centre study.

OBJECTIVE: To develop a predictive model for identifying patients at high risk of all-cause unplanned readmission within 30 days after discharge, using administrative data available before discharge. MATERIALS AND METHODS: Hospital administrative data of all adult admissions in three tertiary metropolitan hospitals in Australia between July 01, 2015, and July 31, 2016, were extracted. Predictive performance of four mixed-effect multivariable logistic regression models was compared and validated using a split-sample design. Diagnostic details (Charlson Comorbidity Index CCI, components of CCI, and primary diagnosis categorised into International Classification of Diseases chapters) were added gradually in the clinically simplified model with socio-demographic, index admission, and prior hospital utilisation variables. RESULTS: Of the total 99 470 patients admitted, 5796 (5.8%) were re-admitted through the emergency department of three hospitals within 30 days after discharge. The clinically simplified model was as discriminative (C-statistic 0.694, 95% CI [0.681-0.706]) as other models and showed excellent calibration. Models with diagnostic details did not exhibit any substantial improvement in predicting 30-days unplanned readmission. CONCLUSION: We propose a 10-item predictive model to flag high-risk patients in a diverse population before discharge using readily available hospital administrative data which can easily be integrated into the hospital information system.

Australian endocrinologists need more training in transgender health: A national survey.

OBJECTIVE: An increasing number of trans and gender diverse (TGD) individuals are seeking gender-affirming hormone therapy for gender transition. Little is known about the levels of training, experience and confidence of endocrinologists in providing care and lack of training and experience is a potential barrier to individuals seeking appropriate and timely health care. We aimed to assess the level of training and confidence of Australian endocrinologists and trainees in the endocrine management of trans and gender diverse individuals in a representative sample. DESIGN: Endocrinologist and trainee members of the Endocrine Society of Australia were invited to participate in an anonymous 14-item survey. Of the 545 members, 147 clinicians (95 adult endocrinologists, 2 paediatric endocrinologists and 50 endocrinology trainees) responded. RESULTS: When presented with a scenario regarding commencement of gender-affirming hormone therapy, only 19% felt confident providing clinical care to TGD individuals. Compared to other areas of endocrinology, 75% felt less or not at all confident in commencing hormone therapy in a TGD patient. No training in transgender medicine during medical school or during their endocrinology training was reported by 96% and 60%, respectively. There were significantly higher levels of confidence in all aspects including performing a consultation in those who had previously seen a TGD patient. The desire for more training was high (91%). CONCLUSIONS: These results highlight the shortfall in training in TGD health care amongst endocrinologists and show that prior clinical experience is associated with higher levels of confidence. Medical schools and endocrinology fellowship training programmes will need to adapt to meet the increasing demand for quality TGD health services.

Androgens stimulate erythropoiesis through the DNA-binding activity of the androgen receptor in non-hematopoietic cells.

BACKGROUND: Androgens function through DNA and non-DNA binding-dependent signalling of the androgen receptor (AR). How androgens promote erythropoiesis is not fully understood. DESIGN AND METHODS: To identify the androgen signalling pathway, we treated male mice lacking the second zinc finger of the DNA-binding domain of the AR (ARΔZF2 ) with non-aromatizable 5α-dihydrotestosterone (5α-DHT) or aromatizable testosterone. To distinguish direct hematopoietic and non-hematopoietic mechanisms, we performed bone marrow reconstitution experiments. RESULTS: In wild-type mice, 5α-DHT had greater erythroid activity than testosterone, which can be aromatized to estradiol. The erythroid response in wild-type mice following 5α-DHT treatment was associated with increased serum erythropoietin (EPO) and its downstream target erythroferrone, and hepcidin suppression. 5α-DHT had no erythroid activity in ARΔZF2 mice, proving the importance of DNA binding by the AR. Paradoxically, testosterone, but not 5α-DHT, suppressed EPO levels in ARΔZF2 mice, suggesting testosterone following aromatization may oppose the erythroid-stimulating effects of androgens. Female wild-type mice reconstituted with ARΔZF2 bone marrow cells remained responsive to 5α-DHT. In contrast, ARΔZF2 mice reconstituted with female wild-type bone marrow cells showed no response to 5α-DHT. CONCLUSION: Erythroid promoting effects of androgens are mediated through DNA binding-dependent actions of the AR in non-hematopoietic cells, including stimulating EPO expression.

Non-Binary and Binary Gender Identity in Australian Trans and Gender Diverse Individuals.

Many trans and gender diverse (TGD) people have gender identities that are not exclusively male or female but instead fall in-between or outside of the gender binary (non-binary). It remains unclear if and how those with non-binary gender identity differ from TGD individuals with binary identities. We aimed to understand the sociodemographic and mental health characteristics of people with non-binary identities compared with binary TGD identities. We performed a retrospective audit of new consultations for gender dysphoria between 2011 and 2016 in three clinical settings in Melbourne, Australia; (1) Equinox Clinic, an adult primary care clinic, (2) an adult endocrine specialist clinic, and (3) the Royal Children's Hospital, a child and adolescent specialist referral clinic. Age (grouped by decade), gender identity, sociodemographic, and mental health conditions were recorded. Of 895 TGD individuals, 128 (14.3%) had a non-binary gender. Proportions differed by clinical setting; 30.4% of people attending the adult primary care clinic, 7.4% attending the adult endocrine specialist clinic, and 8.0% attending the pediatric clinic identified as non-binary. A total of 29% of people in the 21-30-year-old age-group had a non-binary gender identity, higher than all other age-groups. Compared to TGD people with a binary gender identity, non-binary people had lower rates of gender-affirming interventions, and a higher prevalence of depression, anxiety, and illicit drug use. Tailoring clinical services to be inclusive of non-binary people and strategies to support mental health are required. Further research to better understand health needs and guide evidence-based gender-affirming interventions for non-binary people are needed.