**4.1. Sex hormones and mechanisms of action**

Sex and gender differences in clinical disorders are mostly driven by genetics and sex hormones. In order to understand hormonal effects not only in lung diseases, but also in other health conditions, it is essential to recognize their mechanisms of action, signaling pathways, and active metabolites. The major sex steroid hormones, such as estrogen, progesterone, and testosterone are derived from a common lipid precursor, cholesterol, by a complex series of reactions catalyzed by multiple enzymes [119]. In brief, cholesterol is converted to pregnenolone by the cytochrome P450 enzyme. Pregnenolone, which is a precursor and metabolic intermediate in the biosynthesis of the steroid hormones, can be transformed either to progesterone by the action of 3β-hydroxysteroid dehydrogenase (3β-HSD), or alternatively be converted to dehydroepiandrosterone (DHEA) via cytochrome P450c17 action. DHEA can turn into androstenedione via 3β-HSD and consequently testosterone or estrone via 17β-HSD and aromatase, respectively. Estrone may be further converted to estradiol via 17β-HSD. Testosterone can be also transformed into estradiol via aromatase.

Sex steroids are primarily produced by the gonads (ovaries and testes). Significant evidence suggest that production of sex steroids is also found in peripheral tissues of non-reproductive organs, such as the adrenal gland, heart, breast, and lung implying a dependency on the enzymes present in the organs [120, 121]. It is thought that the source of hormone production can affect the metabolism, circulation, regulation, and concentration of local steroid versus that of circulation, which can play a role in the paradoxical effects observed for some sex hormones [43, 122, 123]. One example is the "estrogen paradox", observed in women with pulmonary hypertension. A large number of animal studies have found estrogen to be protective in the coronary circulation with better outcomes in female mice, and exasperation after ovariectomy. Contrarily, there is a higher prevalence of pulmonary hypertension in women. While some studies in humans have suggested that estrogen may increase the risk of portopulmonary hypertension, others have shown that estrogen enhances pulmonary vascular remodeling [124].

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

Understanding the Intersection of Environmental Pollution, Pneumonia, and Inflammation: Does...

http://dx.doi.org/10.5772/intechopen.69627

15

differences in lung diseases, such as pneumonia remains unknown.

found pollutants and their health effects is summarized in **Table 4**.

**5.1. Outdoor air pollution and lung health**

**5. Pneumonia and air pollution: epidemiological and experimental data**

In the last several decades, an accumulative body of epidemiological, toxicological, and experimental evidence, including various exposure agents, times, doses, and combinations of pollutants, have linked exposure of air pollution to negative cardiovascular and pulmonary health effects [146], and infection rates (**Table 1**). These include increased inflammation, exacerbation of pre-existing inflammatory lung disease (e.g. asthma, wheezing, and COPD) and allergies, altered lung function and immunity, and increased susceptibility to infection and pneumonia. Extensive epidemiological evidence demonstrated inter-individual differences in the susceptibility to environmental exposures, with age, gender, and genetic polymorphisms significantly contributing to its negative health effects [12]. A summary of the most frequently

Air pollutants are generally present in the environment as a mixture of several gases and particles that are products of combustion of fossil fuels, diesel traffic, wood smoke, and other industrial processes. Some sources of domestic energy used around the world, especially in developing countries, are the result of combustion of fuels, such as wood, dung, and charcoal but also result in the generation of large amounts of indoor pollutants including small

Circulating levels of testosterone range from 2 to 15 ng/ml or 6 to 50 nM in males, and less than 1.5 ng/ml or 5 nM in females throughout life. Even though men produce both estrogen and progesterone, the levels of these hormones are significantly higher in women, fluctuating from 20 pg/ml estrogen and 0.3 ng/ml progesterone in the follicular phase in non-pregnant and postmenopausal women, to 40 ng/ml estradiol and 300 ng/ml progesterone in pregnant women [43]. The significance of the oscillations of hormonal levels consists in their contribution to the local level of any sex steroids. For example, the estrogen produced in tissues may become more prominent in postmenopausal women, while the effect of progesterone may decline. At present, there is not much information available on this issue relevant to the lung.
