Benefits of Airway Androgen Receptor Expression in Human Asthma

Abstract

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.

Keywords: airflow obstruction; airway inflammation; androgens; asthma.

Figure 1.

AR (androgen receptor) gene expression in bronchial epithelial cells from subjects with asthma enrolled in the Severe Asthma Research Program I and II is positively associated with the (A) FEV₁PP, (B) FEV₁/FVC ratio, and (C) total Asthma Quality of Life Questionnaire (AQLQ) score. The AR normalized gene expression and the total AQLQ score are plotted on a log-2 scale. The gray shaded regions represent SEs. FEV₁PP = percent predicted FEV₁.

Figure 2.

AR (androgen receptor) gene expression in bronchial epithelial cells from subjects with asthma enrolled in the Severe Asthma Research Program is positively associated with (A) Fe_NO and with (B) inducible NOS2 (nitric oxide synthase gene) expression. AR NOS2, and the fractional exhaled nitric oxide are plotted on a log-2 scale. The gray shaded regions represent SEs. Fe_NO = fractional exhaled nitric oxide.

Figure 3.

Asthma exacerbation and asthma-related emergency department (ED) visits in adults stratified by sex. The risk for asthma exacerbation and ED visits for a respiratory problem the year before SARP and NHANES participation and in 2018 in CCHS was higher in adult women than in adult men in all three cohorts. The sampling weights are used to produce the correct population estimates because each sample person does not have an equal probability of selection. CCHS = Cleveland Clinic Health System; CI = confidence interval; NHANES = U.S. National Health and Nutrition Examination Survey; SARP = Severe Asthma Research Program.

Figure 4.

Prebronchodilator percent predicted FEV₁ (FEV₁PP) by sex hormone levels in SARP (Severe Asthma Research Program) I, II, and III adult participants. (A) In women enrolled in SARP I, II, and III, the FEV₁PP correlated positively with dehydroepiandrosterone sulfate (DHEA-S) (R² = 0.156; <2.2 × 10⁻¹⁶) but not with free testosterone (P = 0.15). (B) In adult men, the FEV₁PP correlated positively with DHEA-S (R² = 0.158; P = 1.5 × 10⁻¹⁰) and testosterone (R² = 0.034; P = 0.004). The gray shaded regions represent SEs.