Gender-affirming hormone therapy for transgender and gender-diverse adults in Australia.

Gender-affirming hormone therapy (GAHT) is used by many transgender and gender-diverse adults to align physical characteristics with their gender identity, reduce gender incongruence and improve psychological functioning. This narrative review provides an overview of the initiation and monitoring of GAHT in an Australian context. Trans individuals treated with testosterone typically receive standard testosterone doses and formulations recommended for cisgender men, whereas those receiving estradiol GAHT are typically treated with estradiol in combination with an anti-androgen in those without orchidectomy. Proactive monitoring and mitigation of cardiovascular risk factors is pertinent in all transgender and gender-diverse adults and bone health is an important consideration in those using estradiol GAHT.

Clinical features and prevalence of Klinefelter syndrome in transgender individuals: A systematic review.

OBJECTIVE: Previous studies have suggested a higher prevalence of Klinefelter syndrome amongst transgender individuals. We undertook a systematic review to determine the prevalence of Klinefelter syndrome amongst transgender individuals presumed male at birth and summarize the clinical features and potential treatment implications for individuals with Klinefelter syndrome commencing gender-affirming hormone therapy. DESIGN: Using preferred reporting items for systematic review and meta-analysis guidelines, we searched EMBASE, MEDLINE and the Cochrane Central Register of Controlled Trials (CENTRAL) up to 31 December 2021. All studies reporting on the prevalence or clinical features of transgender individuals with Klinefelter syndrome were included. This study is registered with the International Prospective Register of Systematic Reviews, number CRD42021227916. RESULTS: Our search strategy retrieved 11 cohort studies comprising 1376 transgender individuals. In all, 14 of 1376 (1.02%) individuals were diagnosed with Klinefelter syndrome. Based on the seven studies in which karyotype was undertaken in all individuals, the prevalence is 9/1013 (0.88%; 95% CI, 0.41%-1.68%). Case reports highlight unique treatment considerations in this population, including azoospermia, venous thromboembolism, and monitoring of breast cancer and bone health. CONCLUSIONS: Compared to the general population, observational studies document a higher prevalence of Klinefelter syndrome amongst transgender individuals, though underdiagnosis in the general population limits conclusions. Routine karyotype in transgender people initiating gender-affirming hormone therapy is not supported unless clinical features of Klinefelter syndrome, such as small testicular volume, or hypergonadotropic hypogonadism are present. Transgender individuals with Klinefelter syndrome need to manage a unique risk profile if they desire feminizing gender-affirming hormone therapy.

Single-center real-life experience with testosterone treatment in adult men with Prader-Willi syndrome.

Hypogonadism is the most frequent hormonal deficiency in individuals with Prader-Willi syndrome (PWS). This often necessitates testosterone treatment, but limited data are available to guide testosterone treatment in adult men with PWS. We aimed to evaluate the serum testosterone concentrations and adverse effects of testosterone treatment in individuals with PWS attending a specialist obesity management service. A retrospective audit was undertaken at Austin Health, Melbourne between January 2010 and April 2021. Main outcome measures were testosterone formulation and dose, serum total testosterone concentration, and prevalence of polycythemia and behavioral disturbance. Data were available for eight individuals with median baseline age 19 years (range, 19-42) and BMI 37 kg/m2 (range, 27-71). Six men had obstructive sleep apnea; none were smokers. Baseline testosterone concentration was 1.8 nmol/L (IQR, 1.1-3.3) with hematocrit 0.43. Testosterone formulations were intramuscular testosterone undecanoate (TU) 1000 mg (n = 5), transdermal testosterone gel 50 mg daily (n = 1), and oral TU 80-120 mg daily (n = 2). Median total testosterone concentration was 9.7 nmol/L (IQR, 8.5-14.7). Nine of 25 (36%) hematocrit results in six patients measured >0.50 (range, 0.50-0.56). Intramuscular TU was well tolerated and was the only formulation to achieve serum total testosterone concentrations in the adult male reference range. Worsening behavioral disturbance resulted in treatment discontinuation in one individual. Our experience reinforces the need to regular monitoring of hematocrit in men with PWS treated with testosterone. However, a worsening of behavior problems was uncommon in this series.

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.

Intensive management of obesity in people with severe chronic kidney disease: A review.

Obesity is highly prevalent worldwide, including among people with chronic kidney disease (CKD). The presence of severe and/or end-stage kidney disease complicates the treatment of obesity for several reasons, including restrictions on protein and fluid intake and renal excretion of several medications indicated for the treatment of obesity. The aim of this review is to assess the safety of intensive obesity treatments, such as very-low-energy diets (VLEDs), obesity pharmacotherapy and/or bariatric surgery, in people with end-stage kidney disease. A literature search was conducted to identify studies reporting safety outcomes for VLEDs, liraglutide, phentermine, phentermine-topiramate, naltrexone-bupropion and bariatric surgery in people with an estimated glomerular filtration rate of less than 30 mL/min/1.73m2 or on dialysis. Limited data were insufficient to recommend VLEDs but highlighted their potential efficacy and the need for close clinical and biochemical monitoring. There were no data regarding centrally acting obesity pharmacotherapy in this population, although some glucagon-like peptide-1 analogues appear to safely induce weight loss at doses used for the treatment of type 2 diabetes. Some studies suggest an increased rate of complications of bariatric surgery in individuals with severe or end-stage CKD. Further prospective evaluation of intensive obesity management in the growing population with obesity and severe, end-stage and dialysis-dependent CKD is required.

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.

Estradiol Therapy in the Perioperative Period: Implications for Transgender People Undergoing Feminizing Hormone Therapy.

Venous thromboembolism is a documented risk of some estradiol formulations, but evidence evaluating the perioperative risk of continuation of estradiol therapy is limited. This narrative review summarizes literature related to the perioperative venous thromboembolic risk of estradiol, with a focus on feminizing genitoplasty for trans people undergoing feminizing hormone therapy. Given the dearth of evidence underlying gender-affirming hormone therapy regimens, much of the risk is based on the menopausal hormone therapy literature. However, the doses used for trans people undergoing feminizing hormone therapy can be significantly higher than those used for menopausal hormone therapy and escalating estradiol dose is associated with an increased thrombotic risk. Transdermal formulations are not associated with an increased risk in postmenopausal people. Feminizing genitoplasty is associated with a low thromboembolic risk. However, many patients are instructed to cease estradiol therapy several weeks preoperatively based on reports of increased thrombotic risk in trans people undergoing feminizing hormone therapy and hemostatic changes with the oral contraceptive pill. This can result in psychological distress and vasomotor symptoms. There is insufficient evidence to support routine discontinuation of estradiol therapy in the perioperative period. There is a need for high-quality prospective trials evaluating the perioperative risk of estradiol therapy in trans people undergoing feminizing hormone therapy to formulate evidence-based recommendations.

Giant Intracranial Meningiomas Requiring Surgery in 2 Transgender Women Treated With Cyproterone Acetate.

Progestin-associated meningioma is a rare complication of cyproterone acetate (CPA), an anti-androgen commonly prescribed in feminizing hormone therapy regimens for transgender and gender-diverse individuals. A dose-response association has been observed, particularly with longer-term exposure to doses ≥ 50 mg daily; however, the dose below which CPA use is safe remains unclear. We herein report the cases of 2 transgender women using CPA who developed meningioma. Novel aspects of our cases include: (i) the presence of symptomatic giant meningiomas (> 5 cm), including multiple meningiomas in one patient, requiring urgent surgical intervention; (ii) meningioma development with both high-dose, long duration and low-dose, shorter duration CPA; and (iii) the presence of a PIK3CA missense variant in one patient, which may play a role in the pathogenesis of progestin-associated meningioma. Our cases highlight the real-world risk of this likely underreported adverse effect and underscore the importance of clinician vigilance for neurological sequelae. We suggest using the lowest dose of CPA that maintains adequate androgen suppression, with consideration of alternative anti-androgens where appropriate.

The Impact of Gender-Affirming Hormone Therapy on Physical Performance.

CONTEXT: The inclusion of transgender people in elite sport has been a topic of debate. This narrative review examines the impact of gender-affirming hormone therapy (GAHT) on physical performance, muscle strength, and markers of endurance. EVIDENCE ACQUISITION: MEDLINE and Embase were searched using terms to define the population (transgender), intervention (GAHT), and physical performance outcomes. EVIDENCE SYNTHESIS: Existing literature comprises cross-sectional or small uncontrolled longitudinal studies of short duration. In nonathletic trans men starting testosterone therapy, within 1 year, muscle mass and strength increased and, by 3 years, physical performance (push-ups, sit-ups, run time) improved to the level of cisgender men. In nonathletic trans women, feminizing hormone therapy increased fat mass by approximately 30% and decreased muscle mass by approximately 5% after 12 months, and steadily declined beyond 3 years. While absolute lean mass remains higher in trans women, relative percentage lean mass and fat mass (and muscle strength corrected for lean mass), hemoglobin, and VO2 peak corrected for weight was no different to cisgender women. After 2 years of GAHT, no advantage was observed for physical performance measured by running time or in trans women. By 4 years, there was no advantage in sit-ups. While push-up performance declined in trans women, a statistical advantage remained relative to cisgender women. CONCLUSION: Limited evidence suggests that physical performance of nonathletic trans people who have undergone GAHT for at least 2 years approaches that of cisgender controls. Further controlled longitudinal research is needed in trans athletes and nonathletes.

Early Access to Testosterone Therapy in Transgender and Gender-Diverse Adults Seeking Masculinization: A Randomized Clinical Trial.

Importance: Testosterone treatment is a necessary component of care for some transgender and gender-diverse individuals. Observational studies have reported associations between commencement of gender-affirming hormone therapy and improvements in gender dysphoria and depression, but there is a lack of data from randomized clinical trials. Objective: To assess the effect of testosterone therapy compared with no treatment on gender dysphoria, depression, and suicidality in transgender and gender-diverse adults seeking masculinization. Design, Setting, and Participants: A 3-month open-label randomized clinical trial was conducted at endocrinology outpatient clinics and primary care clinics specializing in transgender and gender-diverse health in Melbourne, Australia, from November 1, 2021, to July 22, 2022. Participants included transgender and gender-diverse adults aged 18 to 70 years seeking initiation of testosterone therapy. Interventions: Immediate initiation of testosterone commencement (intervention group) or no treatment (standard care waiting list of 3 months before commencement). This design ensured no individuals would be waiting longer than the time to standard care. Main Outcomes and Measures: The primary outcome was gender dysphoria, as measured by the Gender Preoccupation and Stability Questionnaire. Secondary outcomes included the Patient Health Questionnaire-9 (PHQ-9) to assess depression and the Suicidal Ideation Attributes Scale (SIDAS) to assess suicidality. Questionnaires were undertaken at 0 and 3 months. The evaluable cohort was analyzed. Results: Sixty-four transgender and gender-diverse adults (median [IQR] age, 22.5 [20-27] years) were randomized. Compared with standard care, the intervention group had a decrease in gender dysphoria (mean difference, -7.2 points; 95% CI, -8.3 to -6.1 points; P < .001), a clinically significant decrease in depression (ie, change in score of 5 points on PHQ-9; mean difference, -5.6 points; 95% CI, -6.8 to -4.4 points; P < .001), and a significant decrease in suicidality (mean difference in SIDAS score, -6.5 points; 95% CI, -8.2 to -4.8 points; P < .001). Resolution of suicidality assessed by PHQ-9 item 9 occurred in 11 individuals (52%) with immediate testosterone commencement compared with 1 (5%) receiving standard care (P = .002). Seven individuals reported injection site pain/discomfort and 1 individual reported a transient headache 24 hours following intramuscular administration of testosterone undecanoate. No individual developed polycythemia. Conclusions and Relevance: In this open-label randomized clinical trial of testosterone therapy in transgender and gender-diverse adults, immediate testosterone compared with no treatment significantly reduced gender dysphoria, depression, and suicidality in transgender and gender-diverse individuals desiring testosterone therapy. Trial Registration: ANZCTR Identifier: ACTRN1262100016864.

Implications of gender-affirming endocrine care for sports participation.

Many transgender (trans) individuals utilize gender-affirming hormone therapy (GAHT) to promote changes in secondary sex characteristics to affirm their gender. Participation rates of trans people in sport are exceedingly low, yet given high rates of depression and increased cardiovascular risk, the potential benefits of sports participation are great. In this review, we provide an overview of the evidence surrounding the effects of GAHT on multiple performance-related phenotypes, as well as current limitations. Whilst data is clear that there are differences between males and females, there is a lack of quality evidence assessing the impact of GAHT on athletic performance. Twelve months of GAHT leads to testosterone concentrations that align with reference ranges of the affirmed gender. Feminizing GAHT in trans women increases fat mass and decreases lean mass, with opposite effects observed in trans men with masculinizing GAHT. In trans men, an increase in muscle strength and athletic performance is observed. In trans women, muscle strength is shown to decrease or not change following 12 months of GAHT. Haemoglobin, a measure of oxygen transport, changes to that of the affirmed gender within 6 months of GAHT, with very limited data to suggest possible reductions in maximal oxygen uptake as a result of feminizing GAHT. Current limitations of this field include a lack of long-term studies, adequate group comparisons and adjustment for confounding factors (e.g. height and lean body mass), and small sample sizes. There also remains limited data on endurance, cardiac or respiratory function, with further longitudinal studies on GAHT needed to address current limitations and provide more robust data to inform inclusive and fair sporting programmes, policies and guidelines.

Intensive management of obesity in people with Prader-Willi syndrome.

PURPOSE: Prader-Willi syndrome (PWS) is characterised by childhood-onset hyperphagia and obesity however limited data are available to guide treatment of obesity in this population. We aimed to evaluate the safety, tolerability, and efficacy of intensive medical weight loss interventions (very-low-energy diets [VLED] and/or pharmacotherapy) in individuals with PWS attending a specialist obesity management service. METHODS: A retrospective audit was undertaken of individuals with PWS attending the Austin Health Weight Control Clinic between January 2010-April 2021. Main outcome measures were weight outcomes, duration of use, and adverse effects. RESULTS: Data were available for 18 patients, of whom 15 were treated with intensive weight loss interventions. Median (interquartile range, IQR) age at baseline was 20 years (19-32) with median body weight 90 kg (75-118) and BMI 37 kg/m2 (30-51). Median weight loss during VLED (n = 7) was 14 kg (1-20 kg) over 60 weeks. Median weight loss with phentermine-topiramate (n = 7) was 17 kg (IQR 9-19 kg) over 56 weeks. Median weight loss with liraglutide 0.6-3 mg (n = 7), prescribed with topiramate in 3 individuals, was 9 kg (2-14 kg) over 96 weeks. Naltrexone-bupropion resulted in weight loss in 2 of 4 individuals. Thirteen individuals achieved ≥10% weight loss but only 5 individuals maintained ≥10% weight loss at last follow-up. Five individuals discontinued pharmacotherapy due to adverse effects. CONCLUSIONS: VLED and pharmacotherapy can achieve substantial weight loss in some individuals with PWS though non-adherence results in substantial weight regain. Adverse effects were ascribed to phentermine and topiramate, whereas liraglutide was well-tolerated in this population.

Effects of low-dose oral micronised progesterone on sleep, psychological distress, and breast development in transgender individuals undergoing feminising hormone therapy: a prospective controlled study.

Objective: The role of micronised progesterone in hormone regimens for transgender individuals undergoing feminising hormone therapy remains uncertain. We aimed to determine the effect of oral micronised progesterone on sleep quality, psychological distress, and breast development in transgender individuals undergoing feminising hormone therapy. Design: Prospective case-control study. Twenty-three transgender individuals on stable oestradiol treatment newly commencing 100 mg oral progesterone (n = 23) and controls continuing standard care (n = 19) were assessed over 3 months. Methods: Pittsburgh Sleep Quality Index (PSQI), Kessler psychological distress scale (K10), and Tanner stage to assess breast development were assessed at 0 and 3 months. Non-parametric analysis of covariance was used to compare differences between groups. Results: Compared with controls over 3 months, there was no difference in PSQI (P = 0.35), K10 (P = 0.64), or Tanner stage (P = 0.42). There was no significant difference in the proportion of individuals with clinically significant improvement in PSQI (25% vs 22%, P = 0.84). One individual had a significant deterioration in psychological distress that improved following the cessation of progesterone. Conclusions: Low-dose progesterone was not associated with changes in sleep quality, psychological distress, or breast development over 3 months follow-up, though there was significant inter-individual variability. Larger, placebo-controlled trials are required to further evaluate different doses of progesterone in feminising hormone therapy regimens.

Testosterone concentrations and prescription patterns of 1% testosterone gel in transgender and gender diverse individuals.

Background: 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. Objectives: The objective of the study was to assess the prescription patterns and serum total testosterone concentrations achieved with 1% testosterone gel in trans and gender diverse individuals. Materials and Methods: A retrospective cross-sectional analysis was undertaken of trans individuals at a primary and secondary care clinic in Melbourne, Australia. Sixty-seven individuals treated with 1% testosterone gel were included. Primary outcomes were testosterone dose and serum total testosterone concentration achieved. Results: Median age was 25 (22-30) years and median duration of testosterone therapy was 12 (7-40) months. Thirty-five (52%) individuals had a nonbinary gender identity. Initial median testosterone dose was 25 mg (12.5-31.3) daily. Fifty-two (78%) individuals commenced doses <50 mg daily, the recommended starting dose for hypogonadal cisgender men. Median total testosterone concentration achieved was 11.9 nmol/l (7.3-18.6). Polycythaemia (haematocrit >0.5) was documented in eight of 138 (6%) laboratory results in six individuals. Discussion and Conclusions: One percent testosterone gel achieves serum total testosterone concentrations in the cisgender male reference range. A high proportion of individuals had a nonbinary gender identity and most individuals commenced a lower dose than that typically administered to hypogonadal cisgender men, potentially related to slow or 'partial' masculinisation goals.

Uncovering the effects of gender affirming hormone therapy on skeletal muscle and epigenetics: protocol for a prospective matched cohort study in transgender individuals (the GAME study).

INTRODUCTION: Gender affirming hormone therapy (GAHT) is increasingly used by transgender individuals and leads to shifts in sex hormone levels. Skeletal muscle is highly responsive to hormone activity, with limited data on the effects of GAHT on different human tissues. Here, we present the protocol for the GAME study (the effects of Gender Affirming hormone therapy on skeletal Muscle training and Epigenetics), which aims to uncover the effects of GAHT on skeletal muscle 'omic' profiles (methylomics, transcriptomics, proteomics, metabolomics) and markers of skeletal muscle health and fitness. METHODS AND ANALYSIS: This study is a prospective age-matched cohort study in transgender adults commencing GAHT (n=80) and age-matched individuals not commencing GAHT (n=80), conducted at Austin Health and Victoria University in Victoria, Australia. Assessments will take place prior to beginning GAHT and 6 and 12 months into therapies in adults commencing GAHT. Age-matched individuals will be assessed at the same time points. Assessments will be divided over three examination days, involving (1) aerobic fitness tests, (2) muscle strength assessments and (3) collection of blood and muscle samples, as well as body composition measurements. Standardised diets, fitness watches and questionnaires will be used to control for key confounders in analyses. Primary outcomes are changes in aerobic fitness and muscle strength, as well as changes in skeletal muscle DNA methylation and gene expression profiles. Secondary outcomes include changes in skeletal muscle characteristics, proteomics, body composition and blood markers. Linear mixed models will be used to assess changes in outcomes, while accounting for repeated measures within participants and adjusting for known confounders. ETHICS AND DISSEMINATION: The Austin Health Human Research Ethics Committee (HREC) and Victoria University HREC granted approval for this study (HREC/77146/Austin-2021). Findings from this project will be published in open-access, peer-reviewed journals and presented to scientific and public audiences. TRIAL REGISTRATION NUMBER: ACTRN12621001415897; Pre-results.

Relationship Between Serum Estradiol Concentrations and Clinical Outcomes in Transgender Individuals Undergoing Feminizing Hormone Therapy: A Narrative Review.

Transgender, including gender diverse and nonbinary, individuals are treated with estradiol with or without antiandrogen to align their physical appearance with their gender identity, improve mental health and quality of life. Consensus guidelines give target ranges for serum estradiol concentration based on premenopausal female reference ranges. However, limited studies have evaluated the relationship between serum estradiol concentrations and clinical outcomes in transgender individuals undergoing feminizing hormone therapy. The available evidence has not found that higher serum estradiol concentrations, together with suppressed testosterone, enhance breast development, or produce more feminine changes to body composition. However, ensuring testosterone suppression appears to be an important factor to maximize these physical changes. Higher serum estradiol concentrations have been associated with higher areal bone mineral density. Although the resultant long-term clinical implications are yet to be determined, this could be a consideration for individuals with low bone mass. The precise serum estradiol concentration that results in adequate feminization without increasing the risk of complications (thromboembolic disease, cholelithiasis) remains unknown. Further prospective trials are required.

Efficacy of Micronized Progesterone for Sleep: A Systematic Review and Meta-analysis of Randomized Controlled Trial Data.

CONTEXT: Preclinical data has shown progesterone metabolites improve sleep parameters through positive allosteric modulation of the γ-aminobutyric acid type A receptor. We undertook a systematic review and meta-analysis of randomized controlled trials to assess micronized progesterone treatment on sleep outcomes. EVIDENCE ACQUISITION: Using preferred reporting items for systematic review and meta-analysis guidelines, we searched MEDLINE, Embase, PsycInfo, and the Cochrane Central Register of Controlled Trials for randomized controlled trials of micronized progesterone treatment on sleep outcomes up to March 31, 2020. This study is registered with the International Prospective Register of Systematic Reviews, number CRD42020165981. A random effects model was used for quantitative analysis. EVIDENCE SYNTHESIS: Our search strategy retrieved 9 randomized controlled trials comprising 388 participants. One additional unpublished trial was found. Eight trials enrolled postmenopausal women. Compared with placebo, micronized progesterone improved various sleep parameters as measured by polysomnography, including total sleep time and sleep onset latency, though studies were inconsistent. Meta-analysis of 4 trials favored micronized progesterone for sleep onset latency (effect size, 7.10; confidence interval [CI] 1.30, 12.91) but not total sleep time (effect size, 20.72; CI -0.16, 41.59) or sleep efficiency (effect size, 1.31; CI -2.09, 4.70). Self-reported sleep outcomes improved in most trials. Concomitant estradiol administration and improvement in vasomotor symptoms limit conclusions in some studies. CONCLUSIONS: Micronized progesterone improves various sleep outcomes in randomized controlled trials, predominantly in studies enrolling postmenopausal women. Further research could evaluate the efficacy of micronized progesterone monotherapy using polysomnography or validated questionnaires in larger cohorts.

Feminizing Hormone Therapy Prescription Patterns and Cardiovascular Risk Factors in Aging Transgender Individuals in Australia.

Context: The safety and efficacy of feminizing hormone therapy in aging transgender (trans) individuals is unclear. Current recommendations suggest transdermal estradiol beyond the age of 45 years, especially if cardiometabolic risk factors are present. Objective: To evaluate feminizing hormone therapy regimens and cardiovascular risk factors in aging trans individuals. Design: Retrospective cross-sectional analysis. Setting: Primary care and endocrine specialist clinic in Melbourne, Australia. Participants: Trans individuals on feminizing therapy for ≥6 months. Main Outcomes Measures: Feminizing hormone regimens and serum estradiol concentrations by age group: (a) ≥45 years, (b) <45 years, and prevalence of cardiometabolic risk factors in individuals ≥45 years. Results: 296 individuals were stratified by age group: ≥45 years (n=55) and <45 years (n=241). There was no difference in median estradiol concentration between groups (328 nmol/L vs. 300 nmol/L, p=0.22). However, there was a higher proportion of individuals ≥45 years treated with transdermal estradiol (31% vs. 8%, p<0.00001). Of those treated with oral estradiol, the median dose was lower in the ≥45 years group (4mg vs. 6mg, p=0.01). The most prevalent cardiometabolic risk factor in the ≥45 years group was hypertension (29%), followed by current smoking (24%), obesity (20%), dyslipidaemia (16%) and diabetes (9%). Conclusions: A greater proportion of trans individuals ≥45 years of age were treated with transdermal estradiol. Of those who received oral estradiol, the median dose was lower. This is important given the high prevalence of cardiometabolic risk factors in this age group, however cardiovascular risk management guidelines in this demographic are lacking.