# Sex-Based Differences in Bronchial Asthma: What Are the Mechanisms behind Them?
## 5 Factors Contributing to Gender-Based Differences in Asthma
### Sex Hormones
#### 5.1.3 Testosterone  
The effects of testosterone and its highly active metabolite 5\(\alpha\)-dihydrotestosterone (DHT) are mediated via androgen receptors (ARs), leading to binding to androgen-responsive elements and downstream upregulation or downregulation of the target genes [166]. Similarly to ERs, ARs are distributed in many tissues, including the lungs, in which high concentrations of ARs have been detected in the alveolar type II cells and bronchial epithelium [167]. Androgens show potent anti-inflammatory action. They reduced populations of Th2 and ILC2 cells, which subsequently led to reduced eosinophil inflammation, but also decreased Th17-mediated production of IL-17A and reduced neutrophil inflammation [156; 168]. Via suppression of IL-17A, testosterone may reduce Ca\({}^{2+}\) sensitization and airway smooth muscle contractions [169]. However, in a murine model, it was demonstrated that male sex hormones may promote airway responsiveness to cholinergic stimulation via vagal nerve-mediated reflex mechanisms [170].  
Lower levels of testosterone may be associated with higher risk of asthma not only in women but also in men older than 50 years [86]. [PERSON] et al. found that serum testosterone was inversely associated with current asthma prevalence regardless of sex, and this value correlated with better lung function [171]. In accordance with these results, higher expression of bronchial ARs and higher androgen levels were associated with better lung function, fewer symptoms, and a lower FeNO in human asthma [172], while lower expression of ARs in the airways was linked to more frequent occurrence of asthma in both sexes [173]. Decreased values for the testosterone precursors dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) were also found in postmenopausal asthmatic women compared to non-asthmatic subjects [174].  
The therapeutic effect of testosterone on neutrophilization may be partially related to testosterone-induced decreases in IL-17A. IL-17A induces expression of glucocorticoid receptor (GR)-\(\beta\), which inhibits GR-\(\alpha\) and is primarily responsible for anti-inflammatory action via the suppression of the expression of genes relating to inflammatory cytokines. Thus, testosterone-induced declines in IL-17A may decrease expression of GR-\(\beta\), resulting in enhanced corticoid action [175]. Potent therapeutic action was also demonstrated for precursors of testosterone produced by adrenal glands. For instance, DHEA inhibited the epithelial-mesenchymal transition, an important mechanism involved in airway remodeling, via the inhibition of the PI3K/Akt-dependent signaling pathway stimulated by transforming growth factor (TGF)-\(\beta\)1 [176]. The anti-inflammatory action of DHEAS was confirmed in an in vitro study where DHEAS dose-dependently inhibited chemotaxis of human peripheral blood neutrophils and airway smooth muscle cells [177]. Supplementation with DHEAS improved lung function in asthma patients; in particular, those women who had low DHEAS levels [178]. These and other studies suggest a potential future role for testosterone supplementation in the treatment of asthma [175; 179; 180; 181].  
However, further research is needed to identify an appropriate androgen derivative and establish appropriate dosing, delivery methods, etc.  
An outline of the actions of the abovementioned sex hormones is provided in Figure 2.