# Sex-Based Differences in Bronchial Asthma: What Are the Mechanisms behind Them?
## 5 Factors Contributing to Gender-Based Differences in Asthma
### Sex Hormones
#### 5.1.1 Estrogens  
A group of endogenous estrogens containing 18 carbons are known as C18 steroids. While estradiol (or 17-\(\beta\) estradiol) is produced in ovarian follicles and _corpora lutea_ and represents the predominant circulating estrogen during the reproductive period, estirol and estretol are synthesized during pregnancy in the placenta or fetal liver, while estrone is generated by extragalundular tissues during menopause [133].  
In cells, estrogens act by binding to specific nuclear estrogen receptors (ERs), ER-\(\alpha\) and ER-\(\beta\). They activate transcriptional processes and/or signaling events that result in the control of gene expression. The actions of estrogens can be mediated through direct binding of ER complexes to specific sequences in gene promoters (genomic effects) or through mechanisms that do not comprise direct binding to DNA (non-genomic effects) [134].  
In genomic signaling, after binding of estrogen to ER-\(\alpha\) or ER-\(\beta\), the complex translocates to the nucleus, inducing transcriptional changes in estrogen-responsive genes with or without DNA estrogen-response elements [135]. In indirect genomic signaling, estrogen receptor complexes exert their actions via protein-protein interactions with other transcription factors and response elements [136]. Non-genomic effects are mediated via membrane-associated estrogen receptors and contribute to modulation of intracellular Ca\({}^{2+}\) and activation of signal-transduction mechanisms, with subsequent production of intracellular second messengers, regulation of cyclic adenosine monophosphate (cAMP), and protein-kinase activation of signaling cascades, leading to rapid biological effects [137]. In addition, as an ER-independent action, estrogen may exert antioxidant effects, and as estrogen-independent actions, ligand-independent genomic events may occur [134]. Nevertheless, the actions of estrogens in the various cells are likely mediated by a combination of processes comprising genomic and non-genomic pathways, as well as additional convergent pathways enhancing transcriptional activity in specific tissues and physiological processes [138; 139].  
Estrogens exert a broad spectrum of effects, including induction of primary and secondary sexual characteristics, regulation of the menstrual cycle and reproduction, effects on bone density, effects on brain function (including cognitive processes and memory), and cholesterol mobilization [140]. Moreover, estrogens have many direct biological effects in the lungs, where significant distributions of ER-\(\alpha\) and ER-\(\beta\)--with more abundant ER-\(\beta\)--have been demonstrated [141]. ER-\(\beta\) acts as an inhibitor of ER-\(\alpha\)-mediated activity and may reduce the cell response to estrogens [142].  
In the lungs, twice as much ER-\(\beta\) as ER-\(\alpha\) is expressed in human bronchial epithelial cells, regulating epithelial Ca\({}^{2+}\) signaling [143; 144]. Estradiol stimulates the production of nitric oxide (NO) from bronchial epithelial cells and increases the activation of endothelial NO synthase (eNOS), contributing to bronchodilation, largely via ER-\(\alpha\)[145]. In addition, estradiol may modulate epithelial-to-mesenchymal transition and barrier function in bronchial epithelial cells [144; 146]. Estrogens also increase the number of goblet cells and the production of mucus, mainly via ER-\(\beta\)[147]. Although data from animal studies are not consistent, they suggest that estrogens may have a protective effect on airways, modulating airway responsiveness via activation of the NO-cyclic guanosine monophosphate (cGMP) pathway or by decreasing Ca\({}^{2+}\) influx [148; 149; 150; 151]. However, estrogens stimulate airway inflammation, as confirmed in animal studies [152; 153; 154]. Estrogens enhance the differentiation of dendritic cells [155] and elevate counts of ILC2s [156], eosinophils [152; 154; 157], and IFN-\(\gamma\)-producing Th1 cells [158] more obviously in females.