Limitations
depression
There are several limitations to this analysis. First, this study had a short follow-up period of 3 months, so we were unable to establish the long-term impact of testosterone on gender dysphoria, depression, or suicidality. This short period was designed for participant acceptability and feasibility so that transgender and gender-diverse participants would not be disadvantaged by waiting longer than standard care waiting times of 3 months for an initial consultation. Second, participants were not blinded to their intervention group. Therefore, it is possible that the effect of testosterone or patient knowledge of treatment has been evaluated. However, randomization of participants to no treatment or placebo over longer follow-up is unethical, particularly given preexisting barriers to accessing GAHT.Total testosterone levels were measured by immunoassay rather than by liquid chromatography/tandem mass spectrometry. However, testosterone concentrations were measured to confirm the increase of testosterone concentrations in the intervention group and a large magnitude of change was expected. The quality-controlled immunoassay routinely used in our hospital for clinical decision-making was thought to be appropriate for this purpose.Although we used the locally developed GPSQ for our primary outcome of gender dysphoria, this tool has not been validated to measure longitudinal changes in gender dysphoria. Similarly, the SIDAS has not been validated in transgender and gender-diverse cohorts. We did not quantify other factors known to influence mental health, including social support or discrimination. Participants were given the option of 2 testosterone formulations as per standard care in Australia. However, these formulations may not be bioequivalent. Finally, the trial participants were predominantly of White race and based in metropolitan areas in Australia, so findings might not be generalizable to other cohorts.Despite these limitations, to our knowledge, this is the first randomized clinical trial of transgender and gender-diverse adults desiring commencement of testosterone therapy comparing individuals initiating testosterone with a control group of transgender and gender-diverse individuals randomized to no treatment.