Sex Steroids and Their Influence in Lung Diseases Across the Lifespan

Abstract

The economic burden of lung diseases continues to be on the rise, with increasing annual expenditures every year. However, the pathophysiology of lung diseases remains complex. Sex steroids are known to influence the development and the physiology of lungs across the life course. During puberty, there is a progressive increase in sex-steroid levels, which results in anatomical and physiological differences between the sexes, and the interactions are most likely causes of the observable sexual dimorphism in the incidence, prevalence, and severity of multiple lung pathologies. Notably, fluctuations during the menstrual cycle and pregnancy impact many lung pathologies, suggesting a link between female sex steroids and lung health. This chapter highlights the influence of sex steroids in lung diseases across the lifespan, adding to our understanding of their complex roles. Focusing on various time points, we aim to understand the following: (1) the inherent function of sex steroids in lung physiology, (2) their differential nature in lung diseases, (3) contribution of sex steroids in males versus females across the lifespan, (4) the implications of sex-steroid signaling, and (5) the probing questions on sex steroids and their interactions influencing the lungs. With the intention of appreciating the nuances of sex steroids in humans pertaining to epidemiological sex differences, we inform readers about the mechanisms involved in the sex–age interaction and sex steroids’ contributions in lung diseases across the lifespan.

Sex steroids skew ACE2 expression in human airway: a contributing factor to sex differences in COVID-19?

“…Multiple groups, including our own, have shown a role for sex steroids, especially estrogen (3-5, 12, 15-17, 21, 22, 31, 33, 37-39) and testosterone (11,18,22,24,27) in regulating the pathophysiology of lung diseases such as asthma or COPD as well as the known sex differences in these conditions (9). In this regard, sex steroids can differentially influence the expression and functionality of multiple signaling pathways in lung cells including ASM, contributing to altered airway reactivity and remodeling.…”

Kisspeptins inhibit human airway smooth muscle proliferation

“…The relevance of Kp/KISS1R expression and signaling in airways also lies in the known sex differences of asthma (1,3,4,75). Although there has been much exploration of sex-steroid effects, particularly estrogens and their effects on ASM proliferation (13), intracellular calcium handling (16,76,77), extracellular matrix dynamics (14), and cell migration (43), it remains unclear whether female sex steroids are protective or detrimental in asthma, given clinical observations of catamenial asthma, and some laboratory studies showing estrogens enhance inflammation (23,78) but others associating estrogens with an asthma-mitigating role (13,24,(79)(80)(81)(82)(83)(84).…”

“…Asthma is a chronic inflammatory disease of the airways involving both intrinsic and extrinsic (i.e., environmental) factors (1)(2)(3)(4) and affecting more than 339 million people worldwide (5). The key features of asthma include exaggerated airway inflammation in conjunction with airway hyperresponsiveness (AHR) and remodeling, resulting in narrowing of the airways (6)(7)(8)(9)(10).…”

Sex Steroids Effects on Asthma: A Network Perspective of Immune and Airway Cells

“…Sex steroids regulate reproductive and metabolic body functions throughout the lifespan of an individual [ 2 , 61 ]. In addition, sex steroids also influence immune cell function and disease conditions.…”

“…Asthma is a common chronic respiratory disease afflicting more than 300 million people worldwide [ 1 ]. Hallmark asthma symptoms include chest tightness, shortness of breath, and coughing, all of which fluctuate over time, leading to increased respiratory distress and worsening symptoms, characteristic features of severe asthmatics [ 2 , 3 , 4 , 5 , 6 , 7 ]. Asthma etiology revolves around classical features of an immune response, primarily regulated and maintained by the persistent activation of chronically activated T-cells [ 8 , 9 ].…”