Sex steroid signaling: implications for lung diseases

Abstract

There is increasing recognition that 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.

Keywords: Airway; Alveoli; Asthma; COPD; Estrogen; Hormone; Progesterone; Pulmonary fibrosis; Testosterone.

Figure 1

Synthesis of estrogen, progesterone and testosterone from cholesterol. Pregnenolone is the first product from cholesterol, and can be further processed through 2 pathways, both leading eventually to testosterone (producing progesterone along the way via one pathway), and estradiol as an end product. Here, enzymes such as CYP17 and CYP19 (aromatase) are particularly important and could substantially modulate local (tissue) levels of sex hormones.

Figure 2

Sex steroid effects in asthma. It is recognized that asthma is a multifactorial disease involving the effects of allergic, infectious and environmental triggers on both the immune system, and structural cells of the bronchial airway. Overall, inflammation drives structural and functional airway leading to epithelial thickening, increased mucus production, proliferation of epithelial, smooth muscle and fibroblast cells, remodeling of the extracellular matrix and overall airway hyperreactivity and fibrosis. Here, studies to date suggest complex effects of estrogen vs. progesterone vs. testosterone on relevant cell types, involving both cooperative vs. opposing effects of the different sex steroids within a cell type, but not necessarily across cell types. For example, dendritic cells, mast cells, CD4+ T lymphocytes (Th2), and eosinophils are particularly important. The effects of estrogen (E), progesterone (P), or testosterone (T) on these immune cells can vary substantially, particularly in the context of concentration, timing and duration.

Figure 3

Sex steroid effects in COPD. Environmental exposures, particularly that from tobacco products, as well certain infects can contribute to COPD, which is also characterized by airway inflammation, mucus hypersecretion, airway fibrosis, alveolar emphysema. The effects of estrogen (E), progesterone (P), or testosterone (T) on resident cells of the airway (as in Figure 2) continue to play a part. In terms of immune cells, Th1 polarized T-lymphocytes as well as CD8+ cytotoxic T cells are also involved. Sex steroid effects on neutrophils and monocyte/macrophages may be particularly important, but there is currently little mechanistic data. In general, female sex steroids appear to be “protective” in terms of lymphocytes.