Background: Although there are sex differences in metabolomic profiles, little is known about the effects of testosterone on the metabolomic profile of people with a female sex. We evaluated the effect of endogenous versus exogenous testosterone on the plasma metabolomic profile. Methods: Participants included 20 individuals with a female sex designated at birth. Ten transgender male (TGM) adolescents [age 15.5 + 0.9 years, BMI percentile 74% (32, 94)] were evaluated at baseline and after one

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... nth of exogenous testosterone treatment (TGM-1M). TGM-1M were compared to 10 BMI-matched cisgender female adolescents with polycystic ovary syndrome [PCOS, age 15.8 + 1.8 years, BMI 85% (78, 98)]. All participants had fasting laboratory evaluation and targeted fasting plasma metabolomic analysis. Results: There were no significant differences in metabolomics after 1 month of testosterone therapy in the TGM group. There were significant differences in the targeted metabolomic analysis between the adolescents with PCOS and TGM-1M. Eight bile acids, 5 fatty acids and 2 amino acids were higher in the PCOS group (fold change>2) compared to TGM-1M. Five amino acids, 2 acylcarnitines, and one fatty acid were higher in TGM-1M compared to participants with PCOS. Participants with PCOS had more signs of metabolic syndrome, including higher waist/hip ratio, systolic blood pressure, and dyslipidemia compared to TGM-1M.Conclusions: Long-term endogenous testosterone exposure in PCOS is associated with an altered metabolic profile and changes in bile acid and fatty acid metabolism relative to short-term exogenous exposure in TGM-1M, suggesting other features, besides testosterone are responsible for the metabolic features of PCOS.