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.

Bone Microarchitecture in Transgender Adults: A Cross-Sectional Study.

Gender-affirming hormone therapy aligns physical characteristics with an individual's gender identity, but sex hormones regulate bone remodeling and influence bone morphology. We hypothesized that trans men receiving testosterone have compromised bone morphology because of suppression of ovarian estradiol production, whereas trans women receiving estradiol, with or without anti-androgen therapy, have preserved bone microarchitecture. We compared distal radial and tibial microarchitecture using high-resolution peripheral quantitative computed tomography images in a cross-sectional study of 41 trans men with 71 cis female controls, and 40 trans women with 51 cis male controls. Between-group differences were expressed as standardized deviations (SD) from the mean in age-matched cisgender controls with 98% confidence intervals adjusted for cross-sectional area (CSA) and multiple comparisons. Relative to cis women, trans men had 0.63 SD higher total volumetric bone mineral density (vBMD; both p = 0.01). Cortical vBMD and cortical porosity did not differ, but cortices were 1.11 SD thicker (p < 0.01). Trabeculae were 0.38 SD thicker (p = 0.05) but otherwise no different. Compared with cis men, trans women had 0.68 SD lower total vBMD (p = 0.01). Cortical vBMD was 0.70 SD lower (p < 0.01), cortical thickness was 0.51 SD lower (p = 0.04), and cortical porosity was 0.70 SD higher (p < 0.01). Trabecular bone volume (BV/TV) was 0.77 SD lower (p < 0.01), with 0.57 SD fewer (p < 0.01) and 0.30 SD thicker trabeculae (p = 0.02). There was 0.56 SD greater trabecular separation (p = 0.01). Findings at the distal radius were similar. Contrary to each hypothesis, bone microarchitecture was not compromised in trans men, perhaps because aromatization of administered testosterone prevented bone loss. Trans women had deteriorated bone microarchitecture either because of deficits in microstructure before treatment or because the estradiol dosage was insufficient to offset reduced aromatizable testosterone. Prospective studies are needed to confirm these findings. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Short-Term Effects of Gender-Affirming Hormone Therapy on Dysphoria and Quality of Life in Transgender Individuals: A Prospective Controlled Study.

Background: Gender affirming hormone therapy (GAHT), whilst considered the standard of care in clinical guidelines for the treatment of many transgender (trans) people is supported by low quality evidence. In this prospective longitudinal controlled study, we aimed to examine the effect of newly commencing GAHT on gender dysphoria and quality of life (QoL) over a 6 month period. Methods: Adult trans (including those with binary and/or non-binary identities) people newly commencing standard full-doses of masculinising (n = 42; 35 = trans masculine, 7 = non-binary) or feminising (n = 35; 33 = trans feminine, 2 = non-binary) GAHT and cisgender participants (n=53 male, n=50 female) were recruited to participate in this longitudinal prospective study. This analysis of gender dysphoria measured by the Gender Preoccupation and Stability Questionnaire and QoL measured by the RAND Short-Form 36 Health survey at baseline, 3 and 6 months after commencement of GAHT was a prespecified secondary outcome. Dysphoria and QoL over time in those starting GAHT compared to cisgender comparison group matched for their presumed sex at birth is reported as the mean difference (95% confidence interval) adjusted for age. Results: In trans people initiating masculinising GAHT, there was a decrease in gender dysphoria with adjusted mean difference -6.80 (-8.68, -4.91), p < 0.001, and a clinically significant improvement in emotional well-being [adjusted mean difference 7.48 (1.32, 13.64), p = 0.018] and social functioning [adjusted mean difference 12.50 (2.84, 22.15), p = 0.011] aspects of QoL over the first 6 months of treatment relative to the cisgender female comparison group. No significant differences were observed in other QoL domains. In trans people initiating feminising GAHT, there was a decrease in gender dysphoria [adjusted mean difference -4.22 (-6.21, -2.24), p < 0.001] but no differences in any aspects of QoL were observed. Conclusions: In the short-term, our findings support the benefit of initiating masculinising or feminising GAHT for gender dysphoria. Masculinising GAHT improves emotional well-being and social functioning within 6 months of treatment. Multidisciplinary input with speech pathology and surgery to support trans people seeking feminisation is likely needed. Further longitudinal studies controlled for other confounders (such as the presence of social supports) contributing to QoL are needed.

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.

Insulin resistance in transgender individuals correlates with android fat mass.

BACKGROUND: Transgender individuals receiving gender-affirming hormone therapy (GAHT) are at increased risk of adverse cardiovascular outcomes. This may be related to effects on body composition and insulin resistance. AIMS: To examine relationships between body fat distribution and insulin resistance in transgender individuals on established GAHT. METHODS: Comparisons of body composition (dual energy X-ray absorptiometry) and insulin resistance [Homeostasis Model of Insulin Resistance (HOMA2-IR)] were made between transgender individuals (43 trans men and 41 trans women) on established GAHT (>12 months) and age-matched cisgender controls (30 males and 48 females). Multiple linear regressions were used to examine the relationship between HOMA2-IR and fat mass with gender, adjusting for age and total duration of GAHT and Pearson correlation coefficients are reported. RESULTS: Compared with control cisgender women, trans men had mean difference of +7.8 kg (4.0, 11.5), p < 0.001 in lean mass and higher android:gynoid fat ratio [0.2 (0.1, 0.3), p < 0.001], but no difference in overall fat mass or insulin resistance. Compared with control cisgender men, trans women had median difference in lean mass of -6.9 kg (-10.6, -3.1), p < 0.001, fat mass of +9.8 kg (3.9, 14.5), p = 0.001, lower android:gynoid fat ratio -0.1 (-0.2,-0.0), p < 0.05), and higher insulin resistance 1.6 (1.3-1.9), p < 0.001). Higher HOMA2-IR correlated with higher android (r 2 = 0.712, p < 0.001) and gynoid (r 2 = 0.572, p < 0.001) fat mass in both trans men and trans women. CONCLUSION: Android fat more strongly correlates with insulin resistance than gynoid fat in transgender individuals. Higher fat mass and insulin resistance in trans women may predispose to increased cardiovascular risk. Despite adverse fat distribution, insulin resistance was not higher in trans men.

The Health and Well-Being of Transgender Australians: A National Community Survey.

Purpose: Transgender, including gender diverse and nonbinary (trans), people experience significant health disparities. We aimed to better understand the health status and needs of Australian trans people to guide resources and health and well-being programs. Methods: This anonymous, cross-sectional online survey utilized nonprobability snowball sampling of Australian adults (18 years and over) who self-identified as trans between September 2017 and January 2018. This descriptive study assessed demographic data, community views on access to health care, health burden, access to health resources, and priorities for government funding in transgender health. Results: Of 928 participants, 37% reported female, 36% reported male, and 27% reported nonbinary gender identities. Despite 47% having tertiary qualifications, the unemployment rate was 19%, with 33% reporting discrimination in employment due to being trans. Discrimination in accessing health care was reported by 26% and verbal abuse and physical assault were reported by 63% and 22%, respectively. Lifetime diagnosis of depression was reported by 73% and anxiety by 67%. Sixty-three percent reported previous self-harm and 43% had attempted suicide. Autism spectrum disorder and attention-deficit/hyperactivity disorder were reported by 15% and 11%, respectively. The most preferred method of receiving health information was through online resources, with the most popular source being Reddit, an online peer discussion board. Better training for doctors in trans health issues was the top priority for government funding. Conclusions: Barriers, including widespread discrimination and unemployment, contribute to health inequity and prevalent mental health conditions. Better training for health professionals in the provision of safe, gender-affirming and general health care for trans people is urgently required.

Relationships between body mass index with oral estradiol dose and serum estradiol concentration in transgender adults undergoing feminising hormone therapy.

AIM: Feminising hormone therapy with estradiol is used to align an individual's physical characteristics with their gender identity. Given considerable variations in doses of estradiol therapy administered as gender-affirming hormone therapy (GAHT), we aimed to assess if body mass index (BMI) correlated with estradiol dose/concentration and assess the correlation between estradiol dose and estradiol concentrations. METHODS: In a retrospective cross-sectional study, we analysed transgender individuals attending a primary or secondary care clinic in Melbourne, Australia who were prescribed oral estradiol valerate for at least 6 months and had estradiol dose and concentration available. Estradiol concentration was measured by immunoassay. Outcomes were the correlation between estradiol dose and BMI, and estradiol dose and estradiol concentration. RESULTS: Data were available for 259 individuals {median age 25.8 [interquartile range (IQR) 21.9, 33.5] years}. Median duration of estradiol therapy was 24 (15, 33) months. Median estradiol concentration was 328 (238, 434) pmol/l [89 (65, 118) pg/ml] on 6 (4, 8) mg estradiol valerate. Median BMI was 24.7 (21.8, 28.6) kg/m2. There was a weak positive correlation between estradiol dose and estradiol concentration (r = 0.156, p = 0.012). There was no correlation between BMI and estradiol concentration achieved (r = -0.063, p = 0.413) or BMI and estradiol dose (r = 0.048, p = 0.536). Estradiol concentrations were within the target range recommended in consensus guidelines in 172 (66%) individuals. CONCLUSION: Estradiol dose was only weakly correlated with estradiol concentration, suggesting significant interindividual variability. Prescription of estradiol dose should not be based upon an individual's BMI, which did not correlate with estradiol concentration achieved. In all, 66% of individuals achieved estradiol concentrations recommended in Australian consensus guidelines with a relatively high oral estradiol dose.

Effects of gender-affirming hormone therapy on insulin resistance and body composition in transgender individuals: A systematic review.

BACKGROUND: Transgender individuals receiving masculinising or feminising gender-affirming hormone therapy with testosterone or estradiol respectively, are at increased risk of adverse cardiovascular outcomes, including myocardial infarction and stroke. This may be related to the effects of testosterone or estradiol therapy on body composition, fat distribution, and insulin resistance but the effect of gender-affirming hormone therapy on these cardiovascular risk factors has not been extensively examined. AIM: To evaluate the impact of gender-affirming hormone therapy on body composition and insulin resistance in transgender individuals, to guide clinicians in minimising cardiovascular risk. METHODS: We performed a review of the literature based on PRISMA guidelines. MEDLINE, Embase and PsycINFO databases were searched for studies examining body composition, insulin resistance or body fat distribution in transgender individuals aged over 18 years on established gender-affirming hormone therapy. Studies were selected for full-text analysis if they investigated transgender individuals on any type of gender-affirming hormone therapy and reported effects on lean mass, fat mass or insulin resistance. RESULTS: The search strategy identified 221 studies. After exclusion of studies that did not meet inclusion criteria, 26 were included (2 cross-sectional, 21 prospective-uncontrolled and 3 prospective-controlled). Evidence in transgender men suggests that testosterone therapy increases lean mass, decreases fat mass and has no impact on insulin resistance. Evidence in transgender women suggests that feminising hormone therapy (estradiol, with or without anti-androgen agents) decreases lean mass, increases fat mass, and may worsen insulin resistance. Changes to body composition were consistent across almost all studies: Transgender men on testosterone gained lean mass and lost fat mass, and transgender women on oestrogen experienced the reverse. No study directly contradicted these trends, though several small studies of short duration reported no changes. Results for insulin resistance are less consistent and uncertain. There is a paucity of prospective controlled research, and existing prospective evidence is limited by small sample sizes, short follow up periods, and young cohorts of participants. CONCLUSION: Further research is required to further characterise the impact of gender-affirming hormone therapy on body composition and insulin resistance in the medium-long term. Until further evidence is available, clinicians should aim to minimise risk by monitoring cardiovascular risk markers regularly in their patients and encouraging healthy lifestyle modifications.

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.

Prevalence of Autism Spectrum Disorder and Attention-Deficit Hyperactivity Disorder Amongst Individuals with Gender Dysphoria: A Systematic Review.

Autism spectrum disorders (ASD) and attention-deficit hyperactivity disorder (ADHD) can compromise health and may be more prevalent amongst individuals with gender dysphoria (GD). Symptoms such as attention or social difficulties can impact assessment of GD, understanding of health information, and engagement in clinical care. To ensure neurodevelopmental conditions are adequately considered in gender health services, we aimed to systematically review the literature examining the prevalence of ASD and ADHD amongst individuals with GD. In this systematic review based on the PRISMA guidelines. MEDLINE and PsycINFO databases were searched for studies examining the prevalence of ASD and/or ADHD in individuals with GD or investigated the rate of GD in cohorts with ASD or ADHD. All English peer-reviewed publications were included. The search strategy identified 179 studies. After applying exclusion criteria, a total of 30 studies were identified, 22 studies which examined the prevalence of ASD or ADHD in people with GD. A further 8 studies examined the reverse; prevalence of GD in people with ASD. The few studies employing diagnostic criteria for ASD suggest a prevalence of 6-26% in transgender populations, higher than the general population, but no different from individuals attending psychiatry clinics. Few studies examine prevalence of ADHD. Low-level evidence exists to suggest a link between ASD and GD. Further population-based and controlled studies using diagnostic criteria for ASD and ADHD are required.

Health Needs of Trans and Gender Diverse Adults in Australia: A Qualitative Analysis of a National Community Survey.

There is an increasing demand for trans and gender diverse (TGD) health services worldwide. Given the unique and diverse healthcare needs of the TGD community, best practice TGD health services should be community-led. We aimed to understand the healthcare needs of a broad group of TGD Australians, how health professionals could better support TGD people, and gain an understanding of TGD-related research priorities. An anonymous online survey received 928 eligible responses from TGD Australian adults. This paper focuses on three questions out of that survey that allowed for free-text responses. The data were qualitatively coded, and overarching themes were identified for each question. Better training for healthcare professionals and more accessible transgender healthcare were the most commonly reported healthcare needs of participants. Findings highlight a pressing need for better training for healthcare professionals in transgender healthcare. In order to meet the demand for TGD health services, more gender services are needed, and in time, mainstreaming health services in primary care will likely improve accessibility. Evaluation of training strategies and further research into optimal models of TGD care are needed; however, until further data is available, views of the TGD community should guide research priorities and the TGD health service delivery.

Cross-sex hormone therapy in Australia: the prescription patterns of clinicians experienced in adult transgender healthcare.

BACKGROUND: Despite increasing demand for transgender healthcare, guidelines for cross-sex hormone therapy are based on low-level evidence only. As most data are based on international expert opinions, interpretations and practices vary significantly. AIMS: To aid the development of Australian clinical guidelines, we aimed to identify cross-sex hormone therapy prescribing patterns among medical practitioners experienced in adult transgender healthcare. METHODS: We conducted an anonymous online survey of experienced hormone prescribers who were members of the Australian and New Zealand Professional Association for Transgender Health (ANZPATH). RESULTS: We received 35 responses from 43 individuals listed with ANZPATH. Mental health assessments prior to commencement of hormonal therapy were recommended by 80% of prescribers. The preferred first-line masculinising hormone therapy was intramuscular testosterone undecanoate (46% of respondents). The most commonly prescribed feminising agents were oral estradiol valerate (first line in 71.4%), with either spironolactone or cyproterone acetate. Most respondents (>90%) targeted sex steroid reference ranges of the affirmed gender, and 71.4% reviewed individuals every 2-3 months in the first year. Better training for doctors was seen as the most pressing priority for government funding, and 79.3% supported the development of local Australian-based guidelines. CONCLUSIONS: Experienced hormone prescribers in Australia largely use medication regimens and monitor sex steroid levels and potential adverse effects of sex hormone therapy in accordance with broad, subjective recommendations listed in international guidelines. Additional practitioner training is necessary, and local Australian-based guidelines would offer specific, relevant guidance to clinicians in the initiation and monitoring of cross-sex hormone therapy for adult transgender individuals.

Sociodemographic and Clinical Characteristics of Transgender Adults in Australia.

Background: Over the last 10 years, increases in demand for transgender health care has occurred worldwide. There are few data on clinical characteristics of Australian adult transgender individuals. Understanding gender identity patterns, sociodemographic characteristics, gender-affirming treatments, as well as medical and psychiatric morbidities, including neurobehavioral conditions affecting transgender and gender-diverse adults will help to inform optimal health service provision. Purpose: In an Australian adult transgender cohort, we aimed to first, assess referral numbers and describe the sociodemographic and clinical characteristics, and second, to specifically assess the prevalence of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). Methods: We performed a retrospective audit of deidentified electronic medical records in a primary care and a secondary care gender clinic in Melbourne, Australia. Annual referral rates, sociodemographic data, and prevalence of medical and psychiatric conditions were obtained. Results: Data for 540 transgender individuals were available. Rapid rises were observed in referrals for transgender health services, more than 10 times the number in 2016 compared with 2011. Median age at initial presentation was 27 years (interquartile range (22, 36), range 16-74). Around 21.3% were unemployed and 23.8% had experienced homelessness despite high levels of education. Around 44.1% identified as trans male, 36.3% as trans female, and 18.3% as gender nonbinary. Medical morbidities were rare but mental illness was very common. The prevalence of depression was 55.7%, anxiety in 40.4%, ADHD in 4.3%, and ASD in 4.8%, all higher than reported age-matched general Australian population prevalence. Conclusions: Rising demand for transgender care, socioeconomic disadvantage, and high burden of mental health conditions warrants a comprehensive multidisciplinary approach to provide optimal care for transgender individuals. Given that ASD and ADHD are prevalent, in addition to gender-affirming treatments, psychosocial interventions may assist individuals in navigating health care needs and to support social aspects of gender transition. Further studies are required to understand links between ASD, ADHD, and gender identity and to evaluate optimal models of health service provision for transgender individuals.

An Endocrine Cause of Acute Post-partum Hypertension.

This is a case of acute peri-partum hypertension secondary to Conn's syndrome. The timing of presentation offers a rare insight into the hormonal physiology of pregnancy and its impact on blood pressure regulation. This case highlights the challenges of diagnosing primary hyperaldosteronism in the peripartum period and the high index of suspicion required by the obstetric physician.