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