**4.2. Effect of sex hormones in immune responses and lung development**

Currently, there is an increasing evidence for sex differences in incidence, morbidity, and mortality of lung diseases. Whether sex steroids play a role in modulating these differences is currently under investigation.

Estradiol levels in the fetus emerge in week 20 during the canalicular phase of lung development, and rise throughout birth [125]. Differences in estrogen levels have been observed in lung maturation, preservation, and regeneration, alveoli development and surfactant synthesis suggesting an active role of estrogen in sexual dimorphism [126–131]. Moreover, it is known that estrogen plays a complicated immunomodulatory role in humans and in animal models, suppressing inflammation in some states while enhancing it in others [116]. In animal models, estrogen blocks both B and T cell development, increases thymic atrophy, and decreases all developing T cell populations, while it enhances B cell survival in response to antigen [132–134]. In humans, hormone replacement therapy reduced the amount of T cells, while B cells were unaltered or upregulated in postmenopausal women, increasing the risk of developing B cell-dependent autoimmune diseases [123, 135]. Other studies propose that estrogen enriches the accumulation of Th1 CD4+ T cells in response to antigen in female mice [136]. It was also stated that estrogen inhibits the induction of Th1 pro-inflammatory cytokines (IL-12, IFNγ, and TNFα), while it enhances Th2 anti-inflammatory cytokines (IL-4, IL-10, and TGFβ) in female mice [137]. However, little is known about how puberty affects lung diseases later in life and how the changes in estrogen levels contribute to the pathophysiology of pulmonary diseases. This is important because estrogen can cause effects on the immune system by binding to estrogen receptors (ER) expressed by immune cells, such as B cells, T cells, and macrophages [138]. Variations in the expression of ER in the bronchial and alveolar epithelium suggest a role in estrogen signaling, which can contribute to the gender dimorphism seen in males and females [130, 131, 139, 140]. In addition, estrogen has the ability to indirectly stimulate airway and parenchymal responses by acting on airway and alveolar epithelial cells, which are structural cells [141]. In the case of infection with *P. aeruginosa*, researchers found that female mice were more susceptible than males [115]. Furthermore, in a study where chronic infection of cystic fibrosis (CF) airway by *P. aeruginosa* was studied, researchers found that estrogen increased the severity of pneumonia in adult CF male mice, and proposed two potential mechanisms: enrichment of Th17-regulated inflammation and suppression of innate antibacterial defenses [116]. On the contrary, fetal levels of testosterone are found on week 9 of gestation during the pseudoglandular phase [125]. In this context, elevated levels of androgens, which are any hormones that primarily influence the growth and development of the male reproductive system, are found associated with slow fetal lung development [142–144]. In this context, studies have shown that anti-androgen flutamide can produce high levels of surfactant phospholipid in the male fetal lung, however, androgen dihydrotestosterone (DHT) blocks the synthesis of surfactant phospholipid in the female fetal lung [1, 145]. The development of male fetal lungs depends on the expression of the androgen receptors (AR) [46]. Whether testosterone, and/or its receptors, play a role in modulating sex differences in lung diseases, such as pneumonia remains unknown.
