Sexual dimorphism in chronic respiratory diseases

Abstract

Sex differences in susceptibility, severity, and progression are prevalent for various diseases in multiple organ systems. This phenomenon is particularly apparent in respiratory diseases. Asthma demonstrates an age-dependent pattern of sexual dimorphism. However, marked differences between males and females exist in other pervasive conditions such as chronic obstructive pulmonary disease (COPD) and lung cancer. The sex hormones estrogen and testosterone are commonly considered the primary factors causing sexual dimorphism in disease. However, how they contribute to differences in disease onset between males and females remains undefined. The sex chromosomes are an under-investigated fundamental form of sexual dimorphism. Recent studies highlight key X and Y-chromosome-linked genes that regulate vital cell processes and can contribute to disease-relevant mechanisms. This review summarises patterns of sex differences in asthma, COPD and lung cancer, highlighting physiological mechanisms causing the observed dimorphism. We also describe the role of the sex hormones and present candidate genes on the sex chromosomes as potential factors contributing to sexual dimorphism in disease.

Keywords: Asthma; COPD; Inflammation; Lung cancer; Remodelling; Sex chromosomes; Sexual dimorphism.

Fig. 1

Micrographs of airways from a healthy patient A and an asthmatic patient B stained with haematoxylin and eosin. A thickened basement membrane (BM) can be seen in the asthmatic patient with hyperplasia of the epithelial (Ep) layer. A noticeable increase in the airway smooth muscle (ASM) thickness can also be seen. A slight mucus exudate can be seen in the airway lumen of the asthma patient. Scale bars = 100 µm

Fig. 2

Asthma prevalence by age group and sex in Australia recorded by the National Health Survey 2017–2018 [29]. The pink line indicates female asthma prevalence (%), and the blue line indicates male asthma prevalence (%)

Fig. 3

Unweighted analysis of the relationship between age and gender-related differences in the annual decline in lung function (FEV₁%) pred/year according to smoking. The squares/dotted line represents never smokers, the triangles/dashed line represents former smokers, and the diamonds/solid line represents current smokers. Recreated with permission from BioMed Central publisher and was first published by Gan et al. [64]

Fig. 4

Lung cancer incidence, mortality and survival, collected by the Australian Institute of Health and Welfare [90]. A Age-adjusted lung cancer incidence rates by sex B age-adjusted lung cancer mortality by sex C lung cancer survival rates (%) each year after diagnosis by sex [90]. The blue line represents males, whilst the pink line represents females

Fig. 5

Illustration of genome regulators on the X and Y chromosome and their contribution to various diseases. AA amino acids, H3K27me3 Histone 3 Lysine residue 27 trimethylation [, –, –173]