Beyond obstructive azoospermia: emerging insights into reproductive health in men with cystic fibrosis.

Cystic fibrosis (CF) is a genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and is classically associated with male infertility due to obstructive azoospermia secondary to congenital bilateral absence of the vas deferens. Increasing evidence suggests that CFTR dysfunction may also contribute to nonobstructive forms of male infertility. Accordingly, CFTR is widely expressed throughout the male reproductive tract, including Sertoli cells, germ cells, and mature spermatozoa. This review summarizes current evidence linking CFTR mutations and variants to hypogonadism, impaired spermatogenesis, altered sperm function, and reduced reproductive outcomes. Clinical studies indicate a high prevalence of testosterone deficiency in men with CF or CBAVD, often occurring in the presence of normal gonadotropin levels. Genetic and meta-analytic data support an association between CFTR variants, particularly the IVS8-5 T polymorphism, and nonobstructive azoospermia. Experimental studies further demonstrate that CFTR plays a critical role in spermatogenesis via regulation of the cAMP-CREB signaling pathway in Sertoli cells and through modulation of microRNA expression affecting germ cell proliferation. CFTR expression in spermatozoa is also implicated in capacitation, motility, and fertilizing capacity through coordinated chloride and bicarbonate transport and interactions with SLC26 family members. Emerging evidence additionally suggests a role for CFTR in early embryonic development, with potential implications for assisted reproductive technology outcomes. Collectively, these findings challenge the traditional view of CF-related male infertility as purely obstructive and highlight CFTR mutations as a potential contributor to nonobstructive infertility. Further studies are required to clarify pathogenic mechanisms and explore targeted therapeutic strategies.