MON-303 The Influence of Sex on Biochemical and Steroid Profiles in Nonclassic Apparent Mineralocorticoid Excess

Abstract Disclosure: A. Tapia-Castillo: None. J.A. Pérez: None. P. Carrión: None. R. Baudrand: None. T. Uslar: None. M. Hernández: None. R. Pinilla: None. A. Martinez: None. C.E. Fardella: None. C.A. Carvajal: None. The nonclassic apparent mineralocorticoid excess (NCAME) is a prevalent endocrine disorder affecting 7% of the population. Characterized by reduced activity of the 11β-hydroxysteroid dehydrogenase type 2 enzyme (11βHSD2), disrupting the balance between cortisol and cortisone, potentially influencing other redox reactions (11-OH >11-Keto) crucial for steroid metabolism. Since endogenous (adrenal and gonadal) and exogenous steroids could be influenced by sex, identification of a sex-specific steroidomic profiles in NCAME, would provide valuable insights associated to the pathophysiologic mechanisms associated to NCAME. Objective: To identify a sex-differentiated steroid profile in subjects with NCAME. Subjects: A cross-sectional study was conducted in a cohort of 41 subjects classified as having NCAME (F/E > 4.1 ug/dl; E < 2.1 ug/dl) and controls. Clinical variables (blood pressure (BP), BMI, % fat, age) and biochemical variables (renin activity (PRA), sodium (Na) and potassium (K) excretion, urinary albumin, and NGAL) were determined. Women using oral contraceptives were excluded. The cohort was dichotomized by sex. Methods: An analysis of 21 steroids was performed using mass spectrometry (UPLC-Q-TOF/MS). Statistical analysis was performed using the Mann-Whitney T-test with Prism v9. Results: 21 subjects with NCAME were identified, of whom 14 were women and 7 were men. No difference in age or percentage of fat was observed between the groups. In women with NCAME, we observed lower PRA (1.4 ± 0.7 vs 1.7 ± 0.4 ng/ml/h; p<0.05), urinary Na/K ratio (2.6 ± 1.2 vs 3.0 ± 0.9; p<0.05), and higher urinary albumin (12.6 ± 6.7 vs 6.0 ± 4.6 mg/24h; p=0.02) and potassium excretion (52 ± 19 vs 32 ± 12 mEq/24h; p=0.02) than in control women. Their steroid profile showed lower levels of cortisone (1.6 ± 0.4 vs 2.5 ± 0.4 ug/dl; p<0.0001), increased 11-hydroxyandrosterone (2.2 ± 0.2 vs 1.9 ± 0.2; p=0.003), and decreased 17-hydroxypregnenolone sulfate (15.5 ± 7.3 vs 25.7 ± 6.0; p=0.002) and 11-oxo-androsterone glucuronide (7.6 ± 2.0 vs 10.5 ± 3.5; p=0.04) than controls.In men with NCAME, we observed higher levels of NGAL (145.8 ± 64 vs 86.6 ± 31 ng/ml; p=0.03), and their steroid profile showed higher levels of cortisol (14.7 ± 4.4 vs 11.1 ± 4.9 ug/dl; p<0.05) and F/E ratio (7.3 ± 2.7 vs 4.4 ± 1.3; p=0.01), and decreased 6β-hydroxycortisol (4.6 ± 1.7 vs 11.0 ± 4.2; p=0.01). Conclusion: This study provides novel insights into the sex-dependent biochemical and steroidomic signatures of NCAME. The identification of 11-hydroxyandrosterone as a key player in female NCAME suggests that this metabolite could act as an endogenous inhibitor and could modulate the activity of the 11βHSD2 enzyme, support the development of innovative biomarkers and personalized interventions for NCAME. Presentation: Monday, July 14, 2025