CFTR-Related Male Infertility

Abstract

Infertility is seen in around 15% of couples worldwide, and 40% of cases have a male cause. Azoospermia (the absence of spermatozoa in the ejaculate) is classified as non-obstructive or obstructive. Congenital bilateral absence of vas deferens (CBAVD) occurs in 6% of obstructive azoospermia (OA) and 1–2% of all cases of male infertility. CBAVD is a feature of a spectrum of conditions, including classical and atypical forms of cystic fibrosis (CF), caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR encodes a protein functioning as a cAMP-regulated chloride- and bicarbonate-conducting channel. More than 2000 CFTR mutations have been described to date and are often individually rare, making genotype–phenotype correlations complex. The most common mutation is p.Phe508del, and this accounts for more than 75% of all UK mutations. Most males with CF and with isolated CBAVD are infertile due to OA with typical clinical and biochemical findings on semen analysis. Testing for CFTR mutations in both the male patients and their female partners is essential to define offspring risks before discussions about possible reproductive options take place. If both partners are found to carry at least one CFTR mutation each, offspring risks are high and pregnancy options including preimplantation genetic diagnosis (PGD) may be desired. CBAVD is not amenable to microsurgical reconstruction; therefore, microsurgical epididymal sperm aspiration (MESA) with artificial reproductive therapy (ART) in the form of in vitro fertilization (IVF) and intra-cytoplasmic spermatozoa injection (ICSI), with or without PGD, may be the treatment of choice.