9.4.10 Obstructions

Azoospermia, the absence of sperm, is the most challenging of clinical conditions despite recent progress in diagnosis and treatment. The prevalence of azoospermia is less than 1% among all men, and approximately 10–15% among infertile men. Its incidence in the general male population is 2–3% (1). Testicular (secretory) azoospermia is untreatable in most cases, and even when a cure can be attempted, success is usually low. Obstructive azoospermia, in contrast, is characterized by normal spermatogenesis and is therefore potentially treatable. Accordingly, this condition has always been the focus of physicians’ interest and attention.

In the past, when knowledge of the presence of seminal obstructions derived essentially from surgical exploration and deferento-vesiculography, the classification of the condition was pathogenic. Currently, thanks to laboratory diagnosis and the use of ultrasonography, it is possible to distinguish full or partial obstructions, both proximal and distal.

Proximal obstructions affect the epididymis and/or the vas deferens and can be complete or partial. Complete obstruction results in azoospermia; in cases of varying degrees of incomplete obstruction, oligozoospermia is observed.

The nature of the anatomical problem is clarified when there is a coincident absence of seminal vesicles, when seminal pH is less than 7.0, and when trace levels of seminal fructose are observed. In addition, if spermatogenesis is present, FSH values will remain normal.

Proximal obstructions are divided into the pathological conditions denoted as malformation, inflammatory, functional, and iatrogen. The most common cause of congenital malformative obstructions is agenesis of the vas deferens. This condition is characterized by total or partial agenesis of the epididymis and seminal vesicles. Agenesis may also be unilateral. Cysts and microcysts, single or multiple, are another cause of malformative obstruction, which occur at the level of the head or body of the epididymis. Such cysts are of varying size and usually contain a clear liquid, which may be turbid with the presence of spermatozoa. Cysts may obstruct or dilate the epididymal tubules. Removal of cysts must be undertaken with great care as damage to the nearby tubules could compromise future fertility.

Infections have a decisive effect on the aetiology of obstructive azoospermia. Gonorrhoea, once responsible for 65% of duct obstructions, is readily cured with antibiotic therapy. Infections such as Chlamydia and Mycoplasma have become the most frequent causes of epididymitis.

Young’s syndrome is the classic condition responsible for creating functional obstruction of the vas deferens. This syndrome is characterized by obstructive azoospermia and chronic pulmonary infection, which are exhibited from early infancy but improve as the patient reaches adolescence. It is unclear to date whether this condition is caused by genetic or environmental factors. In patients with Young’s syndrome, fertility may be compromised even after microsurgical vasoepididymostomia. Moreover, even when sperm reappear in the seminal fluid in sufficient numbers, their motility is often limited (2).

The most common causes of iatrogenic obstruction are accidental surgical lesions of the vas deferens incurred during hernioplastic procedures or orchiopexy. Vasectomy represents a voluntary blocking of such structures.

Distal obstructions are represented by the obstruction of ejaculatory ducts and, rarely, by the obstruction of the seminal vesicle ducts. They can be complete or partial, congenital (see below), or may result from prostatovesiculitis. Distal obstructions are an uncommon cause of infertility, representing less than 1% of all cases.

Current treatment of obstruction of the male genital ducts involves microsurgical correction of the pathology, and/or the removal of sperm from the epididymis or from the testis using microsurgical epididymal sperm aspiration (MESA) or testicular sperm extraction (TESE), in combination with intracytoplasmic sperm injection (ICSI). Alternatively, fine needle biopsy of the testis or direct testicular sperm aspiration (TESA) can be used to obtain sperm (3).

Congenital bilateral absence of the vas deferens (CBAVD), OMIM ID 277180, a clinical condition often associated with the congenital disease cystic fibrosis (4) OMIM ID 219700, represents a small but significant fraction of cases of male infertility due to azoospermia. Cystic fibrosis is the most common severe autosomal recessive disease in the Caucasian population. The gene responsible has been isolated and mapped to the short arm of the seventh chromosome. Subsequently, the corresponding protein CFTR (cystic fibrosis transmembrane conductance regulator) OMIM ID 602421 was identified, along with the most common mutation: a deletion of a single codon in position 508, causing the loss of one molecule of phenylalanine. Approximately 75% of men with CBAVD have at least one detectable common CFTR mutation. Over 1500 mutations have been described in the Cystic Fibrosis Mutation Database (5, 6), grouped in six different classes, including defective CFTR biosynthesis, defective protein processing, alteration in CFTR regulation, disruption of the pore activity, alteration of CFTR localization, and genesis of unstable CFTR (7).

Cystic fibrosis is a multisystemic disease that affects the exocrine glands. It encompasses a disease spectrum from focal male reproductive tract involvement in CBAVD, to multiorgan involvement in classic cystic fibrosis. The reproductive, gastrointestinal, and exocrine manifestations of CTFR deficiency are correlated with CFTR genotype, whereas the respiratory manifestations that are the main cause of morbidity and mortality in cystic fibrosis are less predictable. It is characterized by insufficient intestinal absorption, resulting from reduced pancreatic function, and chronic respiratory problems due to obstruction of small air passages with unusually dense and thick bronchial secretions (8). Cystic fibrosis in males almost invariably results in azoospermia. In 80–90% of cases this is due to partial or total absence of the vas deferens; this condition is frequently accompanied by absence or hypoplasia of the body or tail of the epididymis, even in the presence of normal testicular development. The efferent ducts may also be hypoplastic or absent, or there may be anomalies in the seminal vesicles and ampulla (9).

Sperm retrieval is almost always possible from CBAVD patients, and thanks to techniques such as ICSI, CBAVD patients are now able to father children. As the carrier frequency of CFTR mutations in many Caucasian populations is in the order of 1/22 to 1/30, it is highly recommended that genetic testing for CFTR mutations be offered to the couple prior to ICSI (10, 11).