Shepherd, R.Angus, L.M.Mansell, T.Arman, B.Kim, B.W.Lange, K.Burgner, D.Kerr, J.A.Pang, K.Zajac, J.D.Saffery, R.Cheung, A.Novakovic, B.2025-05-132025-05-132024Journal of Clinical Endocrinology and Metabolism (JCEM), 2024; 109(11):2857-28710021-972X0021-972Xhttps://hdl.handle.net/2440/144521Context: 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 3 and 6 months of GAHT from transgender women (n = 53). Participants were randomized to different anti-androgens, cyproterone acetate or spironolactone. Nuclear magnetic resonance-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 = 3748) to identify sex- and age-related metabolite patterns. Results: We identified 43 metabolic biomarkers altered after 6 months in both anti-androgen groups, most belonging to the very low- or lowdensity lipoprotein subclasses, with all but 1 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 6 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.en© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.transgender; GAHT; sex hormones; metabolome; metabolism; estradiolHumansSpironolactoneCyproterone AcetateAndrogen AntagonistsHormone Replacement TherapyTranssexualismAdolescentAdultMiddle AgedChildFemaleMaleMetabolomicsMetabolomeYoung AdultBiomarkersTransgender PersonsGender-Affirming ProceduresJournal article10.1210/clinem/dgae226717607Arman, B. [0000-0003-0314-378X]