Female patients with cystic fibrosis may continue to experience worse pulmonary morbidity and earlier mortality than male patients despite advances associated with highly effective cystic fibrosis transmembrane conductance regulator modulator therapy, according to a review published in BMC Pulmonary Medicine. The review noted that female sex has remained an independent risk factor for death even following adjustment for comorbidities and chronic airway infection.
In the review, Emma McNally, of the Department of Respiratory Medicine at Beaumont Hospital in Dublin, Ireland, and Michelle Casey, of Beaumont Hospital and the Royal College of Surgeons in Ireland, summarized registry analyses, observational studies, mechanistic investigations, and clinical studies evaluating sex disparities in cystic fibrosis before and following the introduction of highly effective modulator therapy (HEMT).
The researchers reviewed evidence suggesting female patients with cystic fibrosis experienced more frequent pulmonary exacerbations, required longer treatment courses, and were less likely to recover baseline lung function following exacerbations compared with male patients. Female patients also appeared to acquire common airway pathogens earlier, including Pseudomonas aeruginosa, and transitioned earlier to the mucoid phenotype associated with accelerated lung function decline and greater morbidity.
Several proposed mechanisms underlying the disparity were discussed, including airway anatomy, cystic fibrosis–related diabetes (CFRD), microbial acquisition, immune response differences, and sex hormone signaling. The review also highlighted molecular findings suggesting female sex disparities may not be fully explained by comorbidities or infection alone. A 2023 RNA-sequencing analysis identified sex-biased expression of genes involved in cystic fibrosis transmembrane conductance regulator (CFTR) signaling, inflammation, the interleukin-17 pathway, and ciliary function, while female patients also appeared to have a greater burden of immunity-related genes on the X chromosome that may contribute to chronic inflammatory responses.
Mechanistic evidence reviewed by the researchers suggested estrogen may contribute to cystic fibrosis lung disease through several airway-level effects. Experimental studies showed estrogen may reduce airway surface liquid height by inhibiting calcium-activated chloride secretion, reducing CFTR expression, and promoting epithelial sodium channel–mediated sodium absorption, collectively contributing to airway dehydration and impaired mucociliary clearance. Estrogen also appeared to increase mucin production and promote bacterial virulence and biofilm formation.
The review emphasized that many of these findings were derived from mechanistic, in vitro, animal, or observational studies and therefore may not fully reflect clinical physiology.
The researchers also summarized evidence linking hormonal fluctuations to pulmonary outcomes. Pulmonary exacerbations were reported more frequently during phases of the menstrual cycle associated with higher estrogen levels, particularly during the follicular phase. Findings regarding oral contraceptive therapy were inconsistent. Some studies reported improved lung function, reduced inflammatory markers, or lower antibiotic use among patients receiving oral contraceptives, whereas others found no statistically significant pulmonary benefit.
The review additionally discussed pregnancy and menopause as potentially important hormonal states in cystic fibrosis care. Although studies generally did not demonstrate significantly greater lung function decline during pregnancy, pregnant patients experienced higher pulmonary exacerbation rates, more intravenous antibiotic days, and more health care visits compared with nonpregnant patients. In a separate US survey of perimenopausal and postmenopausal patients with cystic fibrosis, 30% reported worsening cystic fibrosis symptoms during menopause and 42% reported worsening symptoms following menopause. The researchers also highlighted the ongoing MAYFLOWERS prospective study evaluating maternal and fetal outcomes in the era of CFTR modulators.
HEMT has substantially improved outcomes across the broader cystic fibrosis population. The review cited evidence that elexacaftor/tezacaftor/ivacaftor (ETI) improved lung function, reduced pulmonary exacerbation rates, improved BMI, enhanced mucociliary clearance, and reduced airway inflammation. However, available evidence suggested sex disparities may persist despite treatment.
In a single-center study of 251 patients treated with ETI, pulmonary exacerbations declined in both sexes, but reductions were greater among male patients compared with female patients, at 43% vs 25%, respectively. Posttreatment differences in P aeruginosa prevalence, BMI, and percent predicted forced expiratory volume in 1 second did not statistically significantly differ by sex. A subgroup analysis of ETI-naive patients also suggested a trend toward greater lung function improvement among male patients, although the review noted prior modulator exposure may attenuate these differences.
The review also highlighted emerging data regarding sweat chloride response as a marker of in vivo CFTR restoration. Some studies of ivacaftor and lumacaftor/ivacaftor demonstrated greater sweat chloride reductions among female patients despite no corresponding sex-specific lung function improvements. More recent findings from the PROMISE study identified, for the first time, an association between sweat chloride response and lung function improvement among patients receiving ETI. The researchers noted that ETI’s larger effect sizes, genotype heterogeneity, and broader patient population may partially explain the association. They also noted that sex-specific pharmacokinetics and microRNA-mediated regulation of CFTR activity may contribute to differences in treatment response, although additional study is needed.
The review also addressed CFRD, which appeared more common among female patients than male patients in registry analyses. The researchers cited Canadian registry data showing CFRD prevalence of 30% among female patients vs 17% among male patients and noted that ETI’s long-term effects on glucose homeostasis and insulin requirements remain uncertain because existing studies have produced conflicting findings.
Although ETI improved sputum viscoelastic properties, airway microbiome diversity, mucociliary clearance, and inflammatory markers, the review noted that airway pathogens and residual inflammation frequently persisted following treatment initiation. The researchers suggested these persistent inflammatory and infectious processes may continue to place female patients at a disadvantage because of estrogen-associated effects on airway biology and immune signaling.
The researchers cited several limitations in the available evidence, including reliance on retrospective, observational, and mechanistic studies; limited prospective sex-specific data; heterogeneity in prior modulator exposure; and relatively short long-term follow-up for ETI therapy. They also noted that outcomes may differ between adult patients initiating modulators after established lung disease and pediatric patients treated earlier in the disease course before substantial lung damage develops.
“While HEMT has significantly advanced CF care and increased life expectancy in the CF population as a whole, early data in this field suggest sex-specific disparities persist,” wrote McNally and Casey.
The researchers reported no competing interests.
Source: BMC Pulmonary Medicine.
