Airway Androgen Receptor Expression: Regulator of Sex Differences in Asthma?

Abstract

A sex disparity in asthma incidence and severity is supported by epidemiological studies that demonstrate males having a higher prevalence of asthma in childhood compared with females and women having the higher prevalence as adults (1). This switch occurs during puberty when androgen levels increase in males (1). Asthma prevalence converges in late adulthood, when androgen levels decline in males and estrogen, progesterone, and androgen levels decline in females, inferring a modulatory role for sex hormones in asthma pathogenesis. Animal models of asthma have provided insight into the effects of individual sex hormones on lung inflammation through interventions that are otherwise not possible in human studies. Using these models, estrogen signaling through estrogen receptor (ER)-a increases ovalbumin-induced eosinophilic inflammation and methacholine responsiveness, with mice deficient in ER-a having diminished allergen-induced responses compared with wild-type mice (2). Progesterone treatment exacerbates these responses, whereas androgens, dehydroepiandrosterone (DHEA), and testosterone have an opposite effect (2). Women with asthma have more type2–polarized alveolar macrophages, with the number in the airway corresponding to asthma severity, whereas androgen receptor (AR) deficiency in monocytes/macrophages results in reduced lung inflammation in male mice, suggesting other factors may be important, particularly in females (3). Group 2 innate lymphoid cells (ILC2s) are a significant source of IL-5andIL-13,andactivationof thesecells isnowconsideredakeyearly event in type-2 inflammatory diseases (4). In the lower airways, ILC2s aredetected ingreaternumbers in thesputumof individualswithsevere eosinophilic asthma compared with mild asthma despite high-dose inhaledcorticosteroid therapy (5),with femaleswithmoderate tosevere asthma having increased circulating ILC2s compared with males (6), whereas no sex disparity was seen in healthy control subjects (6). In individualswithmildallergicasthma,airwaylevelsofILC2aregreater in females, indicating that sex hormones regulate proliferation of lung ILC2s (7). This is supported by murine studies in which testosterone reduces allergen-induced expression of IL-33 and TSLP (thymic stromal lymphopoietin) in the lungs, type 2 cytokine production by ILC2s (Figure 1) (6), and the development of mature ILC2s from precursors that express AR, in which AR signaling reduces differentiation to mature ILC2s (8). Therefore, androgens and AR signaling play a crucial protective role in type-2 airway inflammation, perhaps most importantly within the airways. In addition, the importance of assessing ovarian hormone receptor levels within the airways is highlighted in a recent study showing that signaling through ER-a expressed on human bronchial epithelial cells induced increased IL-33 production in vitro and that, in mice, this signaling indirectly triggered increased allergen-induced airway IL-5 and IL-13 production by ILC2s and eosinophilia compared with wild-type mice (9). In this issue of the Journal, Zein and colleagues (pp. 285–293) report the expression of AR at the gene and protein level in human airways froma cohort of individuals with severe asthma, andusing two additional cohorts (CCHS [Cleveland Clinic Health System] and NHANES [National Health and Nutrition Examination Survey]), they compare the presence of AR expression in bronchial epithelial cells on asthma outcomes (10). This cross-sectional analysis of 1,659 adults enrolled in SARP (Severe Asthma Research Program), 32,527 adults in CCHS, and 2,629 adults in NHANES shows that women hadmore asthma exacerbations and emergency department visits thanmen. The authors did a subgroup analysis of 128 patients in the SARP study, after excluding women receiving exogenous hormone treatments, to compare the presence ofARand its ligandswith asthmaoutcomes.The studyshowedARgeneexpressionwaspositivelyassociatedwithpercent predictedFEV1 (FEV1PP), asthmaqualityof lifequestionnaire,whereas AR gene expression was negatively associated with fractional exhaled nitricoxideand induciblenitricoxide synthase (Figure1). Interestingly, AR gene expression did not vary by sex or correlate with asthma exacerbations in theyearbeforeSARPenrollment.Given the significant interaction of AR expression on FEV1PP, the authors showed that FEV1PP correlated positivelywith bothDHEAsulfate and testosterone in men; however, in women, there was a positive correlation between FEV1PP andDHEA sulfate but notwith free testosterone. The lack of a significant difference in AR gene expression between sexes contrasts a previous study of airway smooth muscle cells in which AR gene expression is lower in females with asthma compared with males with asthma (11). BecauseARexpression is not limited to the epithelial cells, the presence of AR expression on other cells within the airways may confound the authors’ results.Although these results are novel, support the protective nature of androgens on the pathogenesis of asthma, and furtherourunderstandingofsexdifferences insevereasthmaoutcomes, they should be interpreted with caution. A small sample size (n=664) had androgen hormone levels measured, which resulted in the authors being unable to stratify patients by obesity;Han and colleagues recently showedobesitymodifies the effects of sexhormones in adults (12). This studydidnot considermenopauseormenstrual cyclephases inwomen. Androgen levels can fluctuate significantly in premenopausal women, and in men, testosterone levels can have a significant diurnal variation (13), which may result in inaccurate correlations. Importantly, this study did not include estradiol or progesterone levels, which vary in menstruating women and could explain sex-specific differences in asthma.Theauthorsdidnotexcludepatientswithahistoryofpolycystic This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (https://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usage and reprints, please contact Diane Gern ([email protected]).