Sex steroid signaling: Implications for lung diseases

Abstract

There is increasing recognition that the sex hormones (estrogen, progesterone, and testosterone) have biological and pathophysiological actions in peripheral, non-reproductive organs, including the lung. Clinically, sex differences in the incidence, morbidity and mortality of lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, lung cancer and pulmonary hypertension have been noted, although intrinsic sex differences vs. the roles of sex steroids are still not well-understood. Accordingly, it becomes important to ask the following questions: 1) Which sex steroids are involved? 2) How do they affect different components of the lung under normal circumstances? 3) How does sex steroid signaling change in or contribute to lung disease, and in this regard, are sex steroids detrimental or beneficial? As our understanding of sex steroid signaling in the lung improves, it is important to consider whether such information can be used to develop new therapeutic strategies to target lung diseases, perhaps in both sexes or in a sex-specific manner. In this review, we focus on the basics of sex steroid signaling, and the current state of knowledge regarding how they influence structure and function of specific lung components across the life span and in the context of some important lung diseases. We then summarize the potential for sex steroids as useful biomarkers and therapeutic targets in these lung diseases as a basis for future translational research in the area of gender and individualized medicine.

A potential role for estrogen in cigarette smoke-induced microRNA alterations and lung cancer

“…Sex steroids modulate airway and lung functioning, mainly estrogens via estrogen receptors (ERα or ERβ) (5-7), and their alterations by CS can be associated with any type of lung disease (8)(9)(10)(11). Some reports suggest the development of NSCLC is correlated between the expression of ER (α or β) with aromatase expression and/ or the epidermal growth factor receptor (EGFR) pathway (12,13).…”

Serum estradiol concentration, estradiol-toprogesterone ratio and sputum IL-5 and IL-8 concentrations are increased in luteal phase of the menstrual cycle in perimenstrual asthma patients

“…Animal studies have provided evidence that both estrogen and progesterone have effects on humoral and cellular immunity and smooth muscle function (36). Estrogen receptor come in two nuclear subtypes ER-α and ER-α (acting as transcription factors on gene expression) and is expressed in airway epithelial cells (37,38). Eosinophils bind estradiol (39) and show increased degranulation and adhesion (39,40).…”

Understanding the Intersection of Environmental Pollution, Pneumonia, and Inflammation: Does Gender Play a Role?

“…On the contrary, estrogen leads to an increase of cell-mediated and humoral immune responses in females, making them more resistant to some infectious diseases [41]. However, the role of estrogen in modulating the immune response remains controversial [42,43].…”

“…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.…”

“…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.…”