# Sex-Based Differences in Bronchial Asthma: What Are the Mechanisms behind Them?
## 5 Factors Contributing to Gender-Based Differences in Asthma
### Obesity and Lifestyle  
As mentioned above, obesity is an important risk factor for asthma. [PERSON] et al. demonstrated that obesity is associated with higher risk of asthma and increased asthma severity in women but not in men [108]. This was later confirmed by other studies, including a cluster analysis, which demonstrated female predominance in the less atopic--but corticosteroid-unresponsive--asthma associated with obesity [185]. More recently, several authors have suggested that obesity-associated phenotyping should differentiate between two phenotypes: (1) obese asthmatics with an age of onset \(<\) 12 years, more atopic features, poor control, significant airway hyperreactivity (AHR), and increased type 2 biomarkers,  
Figure 2: Outline of the actions of estrogens, progesterone, and testosterone in bronchial asthma. Abbreviations: AHR: airway hyperreactivity, ER-\(\alpha\) and -\(\beta\): estrogen receptors, IgE: immunoglobulin E, IL: interleukin, IFN-\(\gamma\): interferon gamma, ILC2: group 2 innate lymphoid cell, MCP-1: monocyte chemoattractant protein-1, NF-\(\kappa\)B: nuclear factor kappa B, NO: nitric oxide, PAI: plasminogen activator inhibitor, TGF-\(\beta\)1: transforming growth factor beta 1, TLR: Toll-like receptor, TNF\(\kappa\): tumor necrosis factor alpha, TSLP: thymic stromal lymphopoetin, \(\uparrow\): increased, \(\downarrow\): decreased.  
who do not demonstrate sex predominance; and (2) obese asthmatics with an age of onset > 12 years, fewer atopic features, lower AHR, better control, and normal values for type 2 biomarkers, who do show female predominance [186; 187; 188].  
The mechanisms proposed for how obesity can interact with asthma have still not been fully elucidated [188; 189]. Obesity is associated with increased macrophages and ILC2s producing IL-5 and IL-13. Obesity-associated inflammation is also linked with elevated levels of pro-inflammatory cytokines, such as IL-1\(\beta\), IL-6, TNF\(\alpha\), and IFN-\(\gamma\), and increased oxidative stress. In addition, adipose tissue produces estrogens, leptin, and adiponectin. Adiponectin predominantly exerts anti-inflammatory effects via the inhibition of pro-inflammatory NF-\(\kappa\)B, IL-6, and TNF\(\alpha\)[190; 191]. On the other hand, potentially increased levels of leptin due to estrogens and progesterone treatment affect both immune and adaptive immune responses [192]. They enhance production of Th1 cytokines (IL-2, IFN-\(\gamma\), and TNF\(\alpha\)) and decrease production of Th2 cytokines (IL-4, IL-5, and IL-10) [191]. In analyses of estrogens and leptin concentrations in serum, no differences between obese and non-obese women were found for estrogens [111], but increased leptin levels were detected in women compared to men at any given BMI [193]. High obesity-induced concentrations of pro-inflammatory cytokines may also be responsible for poor response to corticosteroids, as the cytokines reduce the induction of mitogen-activated kinase phosphatase 1 by glucocorticoids [194; 195].  
Furthermore, increases in chest wall loading in severe obesity may reduce lung volume and thereby worsen dyspnea [196]. Weight loss may improve the situation, as demonstrated in the study by [PERSON] et al., where reducing BMI improved asthma symptoms and pulmonary function tests [197]. However, the response to the weight loss may depend on the asthma subtype. [PERSON] et al. found that weight loss in obese patients could enhance lung function only in T2-high but not in T2-low asthmatics, suggesting a complex interplay between asthma and obesity [198].  
In relation to obesity, adults with asthma usually show lower physical activity [199], and women are generally less engaged in regular physical activity than men [200], which may contribute to the association between obesity and asthma in women [181].