Benefits of Airway Androgen Receptor Expression in Human Asthma

Rationale: Androgens are potentially beneficial in asthma, but AR (androgen receptor) has not been studied in human airways.Objectives: To measure whether AR and its ligands are associated with human asthma outcomes.Methods: We compared the effects of AR expression on lung function, symptom scores, and fractional exhaled nitric oxide (Fe_NO) in adults enrolled in SARP (Severe Asthma Research Program). The impact of sex and of androgens on asthma outcomes was also evaluated in the SARP with validation studies in the Cleveland Clinic Health System and the NHANES (U.S. National Health and Nutrition Examination Survey).Measurements and Main Results: In SARP (n = 128), AR gene expression from bronchoscopic epithelial brushings was positively associated with both FEV₁/FVC ratio (R² = 0.135, P = 0.0002) and the total Asthma Quality of Life Questionnaire score (R² = 0.056, P = 0.016) and was negatively associated with Fe_NO (R² = 0.178, P = 9.8 × 10^-6) and NOS2 (nitric oxide synthase gene) expression (R² = 0.281, P = 1.2 × 10^-10). In SARP (n = 1,659), the Cleveland Clinic Health System (n = 32,527), and the NHANES (n = 2,629), women had more asthma exacerbations and emergency department visits than men. The levels of the AR ligand precursor dehydroepiandrosterone sulfate correlated positively with the FEV₁ in both women and men.Conclusions: Higher bronchial AR expression and higher androgen levels are associated with better lung function, fewer symptoms, and a lower Fe_NO in human asthma. The role of androgens should be considered in asthma management.