The Cystic Fibrosis ‘Gender Gap’: Past Observations Present Understanding and Future Directions

Cystic Fibrosis (CF) is a systemic disease impacting upon several organ systems. These include gastrointestinal, reproductive, endocrine and pulmonary manifestations of which the latter contributes the heaviest burden of disease morbidity, mortality and impact on quality of life. The defective protein in the disease state is the Cystic Fibrosis Transmembrane Regulator (CFTR) that normally functions as an ion channel permitting intracellular chloride escape. Regulated by cyclic adenosine monophosphate (cAMP) and localized to the apical membrane of epithelial cells, CFTR’s function is diminished or absent in CF precipitating a cycle of events including sodium hyper-absorption, mucus hypersecretion, impaired mucociliary clearance and pathogenic colonization with microorganisms. This in turn leads to the clinical picture of recurrent infections, bronchiectasis and airway destruction culminating in respiratory failure and premature death (Davis et al., 1996). Several hundred mutations of the CFTR gene have been described with a sub-group causing disease. Differing mutations impact upon CFTR channel expression, localization and activity and in some cases a combination of these important functions. Dependent on these factors, CFTR mutations have been stratified into six distinct classes for example the class II ΔF508 mutation encodes a CFTR protein that is both defectively folded and processed resulting in disease (Rowe et al., 2005). Whilst the Republic of Ireland has both the highest incidence and carrier rates of CF worldwide, ΔF508 accounts for >95% alleles identified (Farrell, 2008). An important long-standing observation in CF remains the fact that a gender dichotomy has been described. Females have poorer survival, worse lung function and earlier colonization with Pseudomonas aeruginosa when compared to males without adequate explanation. The following chapter will initially outline past epidemiological observations that have been made with regard to the CF ‘gender gap’ followed by our present understanding of potential explanations for these gender differences. A special focus on the major female sex hormone estrogen will be emphasized particularly its impact on the inflammatory and immune state within the female CF airway. Finally, directions for future basic science and clinical research in the area will be outlined.