Changes in uric acid metabolism and associated plasma proteomics during sex hormone therapy

<h4>Introduction</h4>Men generally have higher plasma uric acid (PUA) concentrations and are at greater risk for hyperuricemia-related diseases. Sex hormones may underlie this difference, though mechanisms remain unclear. Sex hormone therapy offers a unique opportunity to study these effects.<h4>Methods</h4>Participants were included from two prospective observational cohorts: ENIGI (n = 544, 12 months of feminizing [n = 260] or masculinizing [n = 284] hormone therapy) and KNIGHT (n = 28, 3 months of feminizing [n = 15] or masculinizing [n = 13] hormone therapy). Outcomes included changes in PUA (ENIGI), uric acid clearance (UAC; KNIGHT), fractional excretion of uric acid (FE-UA; KNIGHT), fat distribution (ENIGI), and PUA-associated plasma proteomics (KNIGHT).<h4>Results</h4>PUA decreased during feminizing hormone therapy (-86  μmol/L [95% CI, -95; -77]) and increased during masculinizing hormone therapy (+61  μmol/L [95% CI, 53; 70]). During feminizing therapy, UAC increased (+1.1  mL/min [95% CI, 0.1; 2.1]) without changing FE-UA. During masculinizing therapy UAC and FE-UA decreased (UAC: -1.0  mL/min [95% CI, -1.7; -0.3]; FE-UA: -0.8% [95% CI, -1.3; -0.4]). Android-to-gynoid and visceral-to-subcutaneous fat ratios decreased with feminizing and increased with masculinizing therapy (p < 0.05) and correlated positively with PUA changes (p < 0.001). Proteomics identified 126 PUA-associated proteins differentially expressed during sex hormone therapy. While proteins directly involved in uric acid production were unchanged, proteins related to fat distribution (adiponectin, leptin, SHBG) associated with PUA changes.<h4>Discussion</h4>PUA significantly changes during sex hormone therapy, most likely through changes in UAC and fat distribution. These findings emphasize the role of sex hormones in uric acid metabolism and provide insight into sex differences in hyperuricemia-related conditions.<h4>Trial registration knight</h4>Dutch Trial Register (ID: NL9517); ClinicalTrials.gov (ID: NCT04482920).