Cardiometabolic Protein Profile Changes During Gender‐Affirming Hormone Therapy: A Prospective Clinical Study

Objective Cardiovascular disease (CVD) risk is elevated in transgender individuals during gender‐affirming hormone therapy (GAHT) with expected different mechanisms between T‐ and E2‐based GAHT. We investigated prospective changes in cardiometabolic proteins relating to complement, inflammation, and transport during GAHT. Design Prospective clinical study with assessment at baseline and after 1 year of GAHT. Patients The main study population comprised 55 GAHT‐naïve individuals (34 TM, 21 TF). An additional 35 GAHT‐ongoing individuals (26 TM, 9 TF) were included as a cross‐sectional comparison group at baseline. Measurements 19 cardiometabolic proteins relating to atherosclerotic and thrombotic processes were analysed using targeted proteomics. Body composition was assessed by dual‐energy X‐ray absorptiometry. Results In GAHT‐naïve TM individuals, the mean age at baseline was 27 years and median BMI was 26.5 (22.3–28.9) kg/m 2 . Following T‐based GAHT, complement factor H and B, 3, 4b, and transport proteins (sex hormone‐binding globulin, ceruloplasmin, corticosteroid‐binding globulin, vitamin D ‐binding protein, vitronectin, and afamin) decreased, and transthyretin increased. In GAHT‐naïve TF individuals, the mean age at baseline was 27 years and median BMI was 21.5 (20.3–23.6) kg/m 2 . Following E2‐based GAHT, complement factor H and B, 3, 4b, 9, C‐reactive protein, immunoglobulin heavy constant alpha 1 (IGHA1), and transport proteins increased. In cross‐sectional analyses, complement factor H and B, 3, 4b, 9, C‐reactive protein, IGHA1, and afamin were higher in GAHT‐ongoing TF individuals at baseline compared to GAHT‐naïve TF individuals at 1 year. Conclusion T‐ and E2‐based GAHT were associated with opposite directional changes in cardiometabolic protein profiles. Trial Registration ClinicalTrials. gov (Identifier: NCT04254354, NCT05169762).