Cigarette smoke exposure differentially affects male and female steroid hormone production and lung function in a COPD mouse model

Sex-specific differences have been widely reported in patients with Chronic Obstructive Pulmonary Disease (COPD), ranging from disease prevalence to pulmonary function. Despite these findings, our understanding of the biomolecular basis of sex differences in COPD remains unclear. Murine cigarette smoke exposure (CSE) models have long been considered the most clinically relevant models in recapitulating the pathogenesis of human COPD.

To address this, we analysed the effect of sex differences on COPD features in males and females using a nose-only murine CSE model. Pathological features including airway inflammation, lung function, body weight, airway epithelial thickness, collagen deposition, and sex steroid levels were assessed.

CSE significantly decreased lung function and induced inflammation, airway remodelling, and weight loss. Key sex differences were observed on parameters such as lung function, body length, and sex steroid levels. Specifically, females exhibited a greater reduction in lung function and body length compared to males following CSE, however no effect of CSE on ovaries size or estrogen levels was observed. Intriguingly, males exhibited a significant increase in lung testosterone levels following CSE, despite a reduction in testes size and weight.

These findings reveal a complex relationship between sex and COPD pathology. Contrary to previous findings, we observed significant elevation of testosterone levels following CSE in males, which may have attenuated impairments in lung function. These findings may have implications for the utility of testosterone replacement therapies in COPD.