**2. Fertility in men with cystic fibrosis**

CF is a systemic illness that affects multiple organ systems, including lungs, endocrine and epithelial tissues, gastrointestinal system, pancreas, and reproductive tract. Because of the dramatic improvement made in prognosis in CF population in the last two decades, reproduc‐ tive function has become one of the new red flags in the management of CF adult patients. Infertility in CF males has been extensively studied and found in most cases to be secondary to atrophy or malformation of the vas deferens, leading to an obstructive azoospermia (Figure 1).

**Figure 1.** Spermiogram performed in our 34-year-old patient affected by CF documents azoospermia

### **2.1. Pathogenesis**

Cystic fibrosis transmembrane conductance regulator (CFTR) is a gene located on chromosome 7 (7q31.2), encoding for a protein located in the apical membranes of epithelial cells; it was identified in 1989 and its role in the pathogenesis of CF is now well known. CF is a disease characterized by a defect in electrolyte and fluid transport in exocrine tissues; it could present several different clinical manifestations, including chronic lung disease, pancreas insufficien‐ cy, and infertility [1].

In literature, it is reported that almost 97% of male CF patients are infertile [2]: this infertility is primarily secondary to an obstructive azoospermia. The defective CFTR ion channel function causes an early obstruction of male genital tract, due to the dehydrated secretions: this mechanism drives to deep structural changes in reproductive tract, causing in most cases a congenital bilateral absence of the vas deferens (CBAVD). In early studies on CF adult patients with azoospermia, CBAVD was reported in all the population studied. At the light of these findings, Holscalaw et al. [3] speculated a unique genetic cause of CF and CBAVD. Usually, the proximal part of epididymis is present and this allows the sperm collection in CF patients to obtain spermatozoa.

Obstructive dysfunction is not the only cause of infertility in males with CF: further studies demonstrated that CFTR may also play a critical role in spermatogenesis and sperm maturation [4]; an increased CFTR mutation frequency in a population of men with reduced sperm quality is also reported [5]. Histological examination of CF testicular biopsies shows a wide range of spermatogenesis abnormalities, including a decreased count of mature spermatids and maturation arrest. These findings could be the expressions of CFTR abnormalities in seminif‐ erous tubules or spermatozoa.

CFTR plays a role in many aspects of male reproduction, with well-known consequences in CBAVD and CF. It has not only ion channel functions but also it is a versatile signaling molecule and interacts with more than 180 other proteins. CFTR is expressed throughout the whole genital tract [6], but we do not know yet what is CFTR's role in the male accessory glands other than the epididymis.

A significant role in sperm function was also suggested by the involvement of CFTR in uterine HCO3 – secretion and its effect on the fertilizing capacity of sperm [7]. CFTR is present in human sperm and it is involved in both sperm motility and capacitation phases. CF mice sperm has reduced sperm motility and capacitation with reduced fertility rate in vitro and in vivo [8]: these findings suggest a significant role of CFTR in sperm functions also.
