Impact of Distinct Anti-Androgen Exposures on the Plasma Metabolome in Feminizing Gender-Affirming Hormone Therapy.

CONTEXT: The plasma metabolome is a functional readout of metabolic activity and is associated with phenotypes exhibiting sexual dimorphism, such as cardiovascular disease. Sex hormones are thought to play a key role in driving sexual dimorphism. OBJECTIVE: Gender-affirming hormone therapy (GAHT) is a cornerstone of transgender care, but longitudinal changes in the plasma metabolome with feminizing GAHT have not been described. METHODS: Blood samples were collected at baseline and after three and six months of GAHT from transgender women (n = 53). Participants were randomized to different anti-androgens, cyproterone acetate or spironolactone. NMR-based metabolomics was used to measure 249 metabolic biomarkers in plasma. Additionally, we used metabolic biomarker data from an unrelated cohort of children and their parents (n = 3,748) to identify sex- and age-related metabolite patterns. RESULTS: We identified 43 metabolic biomarkers altered after six months in both anti-androgen groups, most belonging to the very low- or low-density lipoprotein subclasses, with all but one showing a decrease. We observed a cyproterone acetate-specific decrease in glutamine, glycine, and alanine levels. Notably, of the metabolic biomarkers exhibiting the most abundant 'sex- and age-related' pattern (higher in assigned female children and lower in assigned female adults, relative to assigned males), 80% were significantly lowered after GAHT, reflecting a shift toward the adult female profile. CONCLUSION: Our results suggest an anti-atherogenic signature in the plasma metabolome after the first six months of feminizing GAHT, with cyproterone acetate also reducing specific plasma amino acids. This study provides novel insight into the metabolic changes occurring across feminizing GAHT.

Effect of Feminizing Hormone Therapy on QTc Interval: A Secondary Analysis of a Randomized Clinical Trial.

This secondary analysis of a randomized clinical trial investigates the effect of spironolactone and cyproterone acetate hormone therapy on the QT interval corrected for heart rate among transgender women and nonbinary or transfeminine individuals.

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.

Dermatological considerations for transgender and gender diverse patients: An Australian perspective.

Transgender and gender diverse (TGD) individuals are a group that experiences significant health disparities. In the multidisciplinary management of TGD patients, dermatologists may participate in managing skin- and hair-related issues which contribute to gender affirmation and to the cutaneous sequelae of gender-affirming hormone therapy. This review aims to highlight the unique needs of TGD patients, particularly from the perspective of Australian dermatologists. We review appropriate terminology critical for TGD care, gender affirmation in the Australian healthcare landscape, dermatological considerations for TGD patients and considerations for management.

Disruption of gender-affirming health care, and COVID-19 illness, testing, and vaccination among trans Australians during the pandemic: a cross-sectional survey.

OBJECTIVES: To assess rates of disruption of gender-affirming health care, of coronavirus disease 2019 (COVID-19) illness, testing, and vaccination, and of discrimination in health care among Australian trans people during the COVID-19 pandemic. DESIGN, SETTING: Online cross-sectional survey (1-31 May 2022); respondents were participants recruited by snowball sampling for TRANSform, an Australian longitudinal survey-based trans health study, 1 May - 30 June 2020. PARTICIPANTS: People aged 16 years or older, currently living in Australia, and with a gender different to their sex recorded at birth. MAIN OUTCOME MEASURES: Proportions of respondents who reported disruptions to gender-affirming health care, COVID-19 illness, testing, and vaccination, and positive and negative experiences during health care. RESULTS: Of 875 people invited, 516 provided valid survey responses (59%). Their median age was 33 years (interquartile range, 26-45 years); 193 identified as women or trans women (37%), 185 as men or trans men (36%), and 138 as non-binary (27%). Of 448 respondents receiving gender-affirming hormone therapy, 230 (49%) reported disruptions to treatment during the pandemic; booked gender-affirming surgery had been cancelled or postponed for 37 of 85 respondents (44%). Trans-related discrimination during health care was reported by a larger proportion of participants than in a pre-pandemic survey (56% v 26%). COVID-19 was reported by 132 respondents (26%), of whom 49 reported health consequences three months or more after the acute illness (37%; estimated Australian rate: 5-10%). Three or more COVID-19 vaccine doses were reported by 448 participants (87%; Australian adult rate: 70%). CONCLUSIONS: High rates of COVID-19 vaccination among the trans people we surveyed may reflect the effectiveness of LGBTIQA+ community-controlled organisation vaccination programs and targeted health promotion. Training health care professionals in inclusive services for trans people could improve access to appropriate health care and reduce discrimination.

Pain management for persistent pain post radiotherapy in head and neck cancers: systematic review.

OBJECTIVES: To systematically review the existing literature for evidence of efficacy around interventions in the management of persistent pain post radiotherapy for head and neck cancers. METHODS: A systematic review of the literature was conducted to assess the effectiveness and safety of interventions for the management of persistent post-radiotherapy pain in head and neck cancers. The primary outcome evaluated whether an intervention resulted in a reduction in pain which was determined using validated pain tools. RESULTS: Two randomised controlled trials involving 196 participants fulfilled the inclusion criteria, one evaluating the effect of hypnotherapy and the other evaluating the effect of pregabalin on radiotherapy related pain in head and neck cancer patients. In one study by Thuma et al. (2016) there was a decrease in pain scores in the hypnotherapy group (p<0.001). In the other study, by Jiang et al. (2018) patients treated with pregabalin had a greater reduction in pain intensity, pain severity and a reduction in pain functional interference (p<0.001). CONCLUSIONS: The findings of our review suggest that in chronic post-radiotherapy pain for head and neck cancers there is very-low level evidence for the use of hypnotherapy in reducing pain scores and for the use of pregabalin in reducing pain intensity, severity, functional interference and psychological distress with significant improvement in quality of life.

Epidemiology of Intensive Care Patients Classified as a Third Sex in Australia and New Zealand.

BACKGROUND: Patient sex affects treatment and outcomes in critical illness. Previous studies of sex differences in critical illness compared female and male patients. In this study, we describe the group of patients classified as a third sex admitted to ICUs in Australia and New Zealand. RESEARCH QUESTION: What are the admission characteristics and outcomes of ICU patients classified as belonging to a third sex group compared with patients classified as female or male? STUDY DESIGN AND METHODS: Retrospective observational study of admissions to 200 ICUs, recorded in the Australian and New Zealand Intensive Care Society's Adult Patient Database from 2018 to 2022. We undertook mixed effect logistic regression to compare hospital mortality across the sex groups, adjusted for illness severity, diagnosis, treatment limitation, year, and hospital. RESULTS: We examined 892,161 admissions, of whom 525 (0.06%) were classified as third sex. Patients classified as third sex were represented across all diagnostic categories, jurisdictions, and hospital types. On average, they were younger than the groups classified as female (59.2 ± 20.0 vs 61.3 ± 18.4 years; P = .02) or male (63.2 ± 16.7 years; P < .001), respectively. Patients classified as third sex were more likely to be admitted after orthopedic surgery (10.1% third sex admissions [95% CI, 7.7%-13.0%]; 6.2% female [95% CI, 6.1%-6.3%]; 4.8% male [95% CI, 4.7%-4.9%]) and drug overdose (8.8% third sex admissions [95% CI, 6.5%-11.5%]; 4.2% female [95% CI, 4.1%-4.2%]; 3.1% male [95% CI, 3.0%-3.1%]). There was no difference in the adjusted hospital mortality of patients classified as third sex compared with the other groups. INTERPRETATION: Patients classified as third sex composed a small minority group of adult ICU patients. This group had a different diagnostic case mix but similar outcomes to the groups classified as female or male. Further characterizing a third sex group will require improved processes for recording sex and gender in health records.

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.

Management of transgender patients in critical care.

As clinicians working in critical care, it is our duty to provide all of our patients with the high-quality care they deserve, regardless of their gender identity. The transgender community continues to suffer discrimination from the media, politicians and general public. As healthcare workers we often pride ourselves on our ability to safely care for all patients. However, there remains a distinct lack of understanding surrounding the care of critically ill transgender patients. This is likely in part because the specific care of transgender patients is not included in the Faculty of Intensive Care Medicine's, Royal College of Anaesthetists', Royal College of Physician's, or Royal College of Emergency Medicine's curriculum. There are several important considerations relevant for transgender patients in critical care including anatomical changes to the airway, alterations to respiratory and cardiovascular physiology and management of hormone therapy. Alongside this, there are simple but important social factors that exist, such as the use of patient pronouns and ensuring admittance to correctly gendered wards. In this review we will address the key points relevant to the care of transgender patients in critical care and provide suggestions on how education on the subject may be improved.

The impact of the first three months of the COVID-19 pandemic on the Australian trans community.

Background: 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. Aim: We aimed to explore the impact of the COVID-19 pandemic on the Australian trans community. Methods: 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)). Results: 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)). Discussion: 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.

Infective complications in cancer patients treated with subcutaneous versus intravenous trastuzumab and rituximab: An individual patient data meta-analysis.

BACKGROUND: Investigation of infection risk with subcutaneous versus intravenous trastuzumab and rituximab administration in an individual patient data (IPD) and published data meta-analysis of randomised controlled trials (RCTs). METHODS: Databases were searched to September 2021. Primary outcomes were serious and high-grade infection. Relative-risk (RR) and 95% confidence intervals (95%CI) were calculated using random-effects models. RESULTS: IPD meta-analysis (6 RCTs, 2971 participants, 2320 infections) demonstrated higher infection incidence with subcutaneous versus intravenous administration, without reaching statistical significance (serious: 12.2% versus 9.3%, RR 1.28, 95%CI 0.93to1.77, P = 0.13; high-grade: 12.2% versus 9.9%, RR 1.32, 95%CI 0.98to1.77, P = 0.07). With exclusion of an outlying study in post-hoc analysis, increased risks were statistically significant (serious: 13.1% versus 8.4%, RR 1.53, 95%CI 1.14to2.06, P = 0.01; high-grade: 13.2% versus 9.3%, RR 1.56, 95%CI 1.16to2.11, P < 0.01). Published data meta-analysis (8 RCTs, 3745 participants, 648 infections) demonstrated higher incidence of serious (HR 1.31, 95%CI 1.02to1.68, P = 0.04) and high-grade (HR 1.52, 95%CI 1.17to1.98, P < 0.01) infection with subcutaneous versus intravenous administration. CONCLUSIONS: Results suggest increased infection risk with subcutaneous versus intravenous administration, although IPD findings are sensitive to exclusion of one trial with inconsistent results and identified risk-of-bias. Ongoing trials may confirm findings. Clinical surveillance should be considered when switching to subcutaneous administration. PROSPERO registration CRD42020221866/CRD42020125376.

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.

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.

Gender-Affirming Hormone Therapy for the Trans, Gender Diverse, and Nonbinary Community: Coordinating World Professional Association for Transgender Health and Informed Consent Models of Care.

Purpose: Before commencing gender-affirming hormone therapy, people undergo assessments through the World Professional Association for Transgender Health (WPATH) model (typically with a mental health clinician), or an informed consent (IC) model (without a formal mental health assessment). Despite growing demand, these remain poorly coordinated in Australia. We aimed to compare clients attending WPATH and IC services; compare binary and nonbinary clients; and characterize clients with psychiatric diagnoses or longer assessments. Methods: Cross-sectional audit of clients approved for gender-affirming treatment (March 2017-2019) at a specialist clinic (WPATH model, n=212) or a primary care clinic (IC model, n=265). Sociodemographic, mental health, and clinical data were collected from electronic records, and analyzed with pairwise comparisons and multivariable regression. Results: WPATH model clients had more psychiatric diagnoses (mean 1.4 vs. 1.1, p<0.001) and longer assessments for hormones (median 5 vs. 2 sessions, p<0.001) than IC model clients. More IC model clients than WPATH model clients were nonbinary (27% vs. 15%, p=0.016). Nonbinary clients had more psychiatric diagnoses (mean 1.7 vs. 1.1, p<0.001) and longer IC assessments (median 3 vs. 2 sessions, p<0.001) than binary clients. Total psychiatric diagnoses were associated with nonbinary identities (ß 0.7, p=0.001) and health care cards (ß 0.4, p=0.017); depression diagnoses were associated with regional/remote residence (adjusted odds ratio [aOR] 2.2, p=0.011); and anxiety disorders were associated with nonbinary identities (aOR 2.8, p=0.012) and inversely associated with employment (aOR 0.5, p=0.016). Conclusion: WPATH model clients are more likely to have binary identities, mental health diagnoses, and longer assessments than IC model clients. Better coordination is needed to ensure timely gender-affirming care.

The Effect of Gender-Affirming Hormones on Gender Dysphoria, Quality of Life, and Psychological Functioning in Transgender Individuals: A Systematic Review.

Gender-affirming hormone therapy (GAHT) is an essential part of gender affirmation for many transgender (including people with binary and nonbinary identities) individuals and although controlled studies are unethical, there remains limited evidence on the impact of GAHT on gender dysphoria, quality of life (QoL), and psychological functioning. Some clinicians and policy makers use the lack of evidence to argue against providing gender-affirming care. The aim of this review is to systematically and critically assess the available literature on the influence of GAHT on improving gender- and body-related dysphoria, psychological well-being, and QoL. Using Preferred Reporting Items for Systematic Review and Meta-analysis guidelines, we searched Ovid MEDLINE®, Embase®, and Ovid PsycINFO® from inception to March 6, 2019 to assess the influence of GAHT on (1) gender dysphoria, (2) body uneasiness, (3) body satisfaction, (4) psychological well-being, (5) QoL, (6) interpersonal and global functioning, and (7) self-esteem. Our search strategy found no randomized controlled trials. Ten longitudinal cohort studies, 25 cross-sectional studies, and 3 articles reporting both cross-sectional and longitudinal data were identified. While results are mixed, the majority of studies demonstrate that GAHT reduces gender dysphoria, body dissatisfaction, and uneasiness, subsequently improving psychological well-being and QoL in transgender individuals. However, all current researches are of low to moderate quality comprising longitudinal cohort studies and cross-sectional studies, making it difficult to draw clear conclusions and do not reflect external social factors unaffected by GAHT, which significantly impact on dysphoria, well-being, and QoL.

Pelvic Pain in Transgender People Using Testosterone Therapy.

Purpose: This descriptive study aimed to assess the characteristics of pelvic pain and explore predictive factors for pelvic pain in transgender (trans) individuals using testosterone therapy. Methods: An online cross-sectional survey was open between August 28, 2020, and December 31, 2020, to trans people presumed female at birth, using testosterone for gender affirmation, living in Australia, and >16 years of age. The survey explored characteristics of pelvic pain following initiation of testosterone therapy, type and length of testosterone therapy, menstruation history, and relevant sexual, gynecological, and mental health experiences. Logistic regression was applied to estimate the effect size of possible factors contributing to pain after starting testosterone. Results: Among 486 participants (median age = 27 years), 351 (72.2%)* reported experiencing pelvic pain following initiation of testosterone therapy, described most commonly as in the suprapubic region and as "cramping." Median duration of testosterone therapy was 32 months. Persistent menstruation, current or previous history of post-traumatic stress disorder, and experiences of pain with orgasm were associated with higher odds of pelvic pain after testosterone therapy. No association was observed with genital dryness, intrauterine device use, previous pregnancy, penetrative sexual activities, touching external genitalia, or known diagnoses of endometriosis, vulvodynia, vaginismus, depression, anxiety, or obesity. Conclusions: Pelvic pain is frequently reported in trans people following initiation of testosterone therapy. Given the association with persistent menstruation and orgasm, as well as the known androgen sensitivity of the pelvic floor musculature, further research into pelvic floor muscle dysfunction as a contributor is warranted.

Effects of estradiol on bone in men undergoing androgen deprivation therapy: a randomized placebo-controlled trial.

Objective: In men, many effects of testosterone (T) on the skeleton are thought to be mediated by estradiol (E2), but trial evidence is largely lacking. This study aimed to determine the effects of E2 on bone health in men in the absence of endogenous T. Design: This study is a 6-month randomized, placebo-controlled trial with the hypothesis that E2 would slow the decline of volumetric bone mineral density (vBMD) and bone microstructure, maintain areal bone mineral density (aBMD), and reduce bone remodelling. Methods: 78 participants receiving androgen deprivation therapy for prostate cancer were randomized to 0.9 mg of 0.1% E2 gel daily or matched placebo. The outcome measures were vBMD and microarchitecture at the distal tibia and distal radius by high-resolution peripheral quantitative CT, aBMD at the spine and hip by dual-energy x-ray absorptiometry, and serum bone remodelling markers. Results: For the primary endpoint, total vBMD at the distal tibia, there was no significant difference between groups, mean adjusted difference (MAD) 2.0 mgHA/cm3 (95% CI: -0.8 to 4.8), P = 0.17. Cortical vBMD at the distal radius increased in the E2 group relative to placebo, MAD 14.8 mgHA/cm3 (95% CI: 4.5 to 25.0), P = 0.005. Relative to placebo, E2 increased estimated failure load at tibia, MAD 250 N (95% CI: 36 to 465), P = 0.02, and radius, MAD 193 N (95% CI: 65 to 320), P = 0.003. Relative to placebo, E2 increased aBMD at the lumbar spine, MAD 0.02 g/cm2 (95% CI: 0.01 to 0.03), P = 0.01, and ultra-distal radius, MAD 0.01 g/cm2 (95% CI: 0.00 to 0.02), P = 0.01, and reduced serum bone remodelling markers. Conclusion: Relative to placebo, E2 treatment increases some measures of bone density and bone strength in men and reduces bone remodelling, effects that occur in the absence of endogenous T.