Abstract 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) (Δ β ≥ 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 (Δ β ≥ 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.
Abstract 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.
Masculinising hormone therapy with testosterone is used to align an individual's physical characteristics with their gender identity. Standard testosterone doses and formulations recommended for hypogonadal cisgender men are typically administered, although there are currently limited data evaluating the use of 1% testosterone gel in gender-affirming hormone therapy regimens.
Trans and gender diverse individuals (people who identify with a gender different to what was presumed for them at birth) are one of the most medically and socially marginalized groups in our community. The COVID-19 pandemic may compound preexisting depression and thoughts of self-harm or suicide.We aimed to explore the impact of the COVID-19 pandemic on the Australian trans community.An online cross-sectional survey was conducted between 1st May 2020 and 30th June 2020, amidst strict Australia-wide social restrictions. Australian trans people aged ≥16 years were eligible to participate. Survey questions explored the impact of the COVID-19 pandemic on living situation, employment, financial situation, and healthcare. Logistic regression to assess negative impacts due to COVID-19 on depression and thoughts of self-harm or suicide (measured by Patient Health Questionnaire-9 (PHQ-9) are presented as odds ratios (95% confidence interval)).Of 1019 participants, 49.6% reported experiencing financial strain, 22% had reduced working hours, and 22.4% were unemployed (three times the national rate). Concerningly, 61.1% experienced clinically significant symptoms of depression (Patient Health Questionnaire-9 score ≥10), considerably higher than pre-COVID rates for the trans community and over twice the national rate. Moreover, 49% reported thoughts of self-harm or suicide (over three times the national rate) which was more likely if a person experienced cancelation or postponement of gender-affirming surgery (OR 1.56 (1.04, 2.35)), financial strain (OR 1.80 (1.36, 2.38)), or felt unsafe or afraid in their household (OR 1.96 (1.23, 3.08)).Given rates of clinically significant depression and thoughts of self-harm or suicide are far higher in trans people than the general population, specific strategies to improve mental health in the trans community during the COVID-19 pandemic must be made a priority for policymakers, researchers, and health service providers to prevent suicide.Supplemental data for this article is available online at https://doi.org/10.1080/26895269.2021.1890659.
Summary Primary aldosteronism is one of the most common (affecting up to 10%) yet treatable causes of hypertension in our community, notable due to an associated elevated risk of atrial fibrillation, stroke and myocardial infarction compared to essential hypertension. Guidelines have focussed on improving case detection due to significant underdiagnosis in the community. While our case experienced significant delay in diagnosis, we highlight a state of protracted, persistent post-operative hypoaldosteronism which manifested with severe hyponatraemia and hyperkalaemia, necessitating long-term mineralocorticoid replacement. We discuss whether pre-operative mineralocorticoid receptor antagonists to stimulate aldosterone secretion from the contralateral gland may have prevented this complication. Learning points Hypoaldosteronism is an uncommon complication of adrenalectomy for primary aldosteronism, typically manifesting with hyperkalaemia and hyponatraemia. While most cases are transient, it may be persistent, necessitating ongoing mineralocorticoid replacement. Routine electrolyte monitoring is recommended post-adrenalectomy. Risk factors for hypoaldosteronism include age >50 years, duration of hypertension >10 years, pre-existing renal impairment and adrenal adenoma size >2 cm. Mineralocorticoid receptor antagonists may assist in the management of hypokalaemia and hypertension pre-operatively. However, it is unclear whether this reduces the risk of post-operative hypoaldosteronism.
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.To assess the prescription patterns and serum total testosterone concentrations achieved with AndroForte 5% testosterone cream in trans and gender diverse individuals.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.Testosterone dose and serum total testosterone concentration.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.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.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.AndroForte 5% testosterone cream represents an alternative formulation of testosterone administration for trans and gender diverse individuals seeking masculinization.
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