Male infertility: Causes and cures

Infection/inflammation 

A history of urogenital inflammation is present in 5%–12% of men who attend infertility clinics.2 Infectious conditions degrade sperm quality by reducing both their concentration and motility. The number of morphologically normal spermatozoa is also possibly affected. In addition, infection may be associated with the formation of auto-antibodies against spermatozoa.

Urogenital infections may have obstructive consequences at various levels of the male reproductive tract. Genital tuberculosis, for instance, can result in epididymal blockage or vasal obstruction, while other infections and inflammatory processes, such as chronic prostatitis, can cause scarring and obstruction of the ejaculatory ducts. Interestingly, Chlamydia trachomatis, a common pathogen in male genital inflammation, has not been shown to be directly related to male infertility.

Infertility caused by ejaculatory duct obstruction is usually characterized by severe oligospermia or azoospermia and low seminal volume, even though testis size and gonadotropin levels remain normal. Transurethral resection of the ejaculatory ducts has been effective in treating 50% of these infertile men, resulting in a significant improvement of sperm quality and spontaneous pregnancies in up to 25% of couples.2

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Pyospermia, characterized by elevated white cell counts in semen, is present in the semen analysis of up to 23% of infertile men, and has been found to be associated with reduced sperm parameters and diminished fertility.3 While it is not known if pyospermia itself causes such changes in sperm function, various antibiotic regimens have proved beneficial in treating pyospermia by temporarily reducing the white blood cell count in semen and consequently improving fertility rates.4 Despite initial successes, further evaluation of this therapeutic modality has been suggested.

Immunologic factors 

The incidence of sperm antibodies has been shown to be higher in infertile men (8%–21%) compared to fertile subjects (1%–4%).5 The susceptibility of sperm cells to autoantibody formation is explained by the very early development of the immune system's tolerance to autoantigens, in conjunction with a much later onset of sperm cell formation. Sperm protection from the immune system is attributed to certain anatomic and/or physiologic mechanisms. These include tight junctions between Sertoli cells, which form after puberty and protect post-meiotic spermatocytes, and more mature germ cells in the adluminal compartment.

Other immunosuppressive mechanisms are, however, also necessary given the fact that mature sperm must pass through areas of the distal male reproductive tract that do not have welldefined barriers, such as the Sertoli tight junctions. Additional protective mechanisms recently suggested include predominance of CD8 lymphocytes and soluble CD8 activators in semen, and small leakage of sperm-specific antigens, leading to development of late tolerance.

The locations of the specific anatomic sites where antibodies bind to sperm in the male reproductive tract remain an object of controversy. Several studies indicate that antibodies can bind to sperm in the vas deferens and epididymis,6 and possibly even in the seminiferous tubules.7

The prefertilization effects of antisperm antibodies include a higher incidence of sperm agglutination, associated with impaired sperm motility and cervical mucus penetration capability; sperm cytotoxicity; impairment of the acrosome reaction; and binding to the zona pellucida. Post-fertilization effects of antisperm antibodies have also been reported, including reduction of cleavage and pregnancy loss.8

Several risk factors for the development of male antisperm antibodies have been identified. Vasectomy is the most common factor, associated with a postoperative presence of serum antibodies in 34%–74% of cases.4 Other causes of genital duct obstruction, such as accidental ligation of the vas deferens during hernia repair and congenital bilateral absence of the vas deferens, can also induce sperm autoimmunity. Testicular torsion has been shown to cause an immune response in post-pubertal animals, but as solid evidence in humans is lacking, this phenomenon remains theoretical.

Testicular cancer is also connected with heightened sperm autoimmunity and subfertility, as evidenced by recent studies showing an incidence of sperm antibodies in 18% to 73% of men with testicular carcinoma.9 Other conditions associated with antisperm antibodies include previous cryptorchidism and genitourinary infections. The causative role of varicocele and spinal cord injury in the development of sperm autoimmunity is currently controversial.

Immunoinfertility has been approached by different therapeutic modalities. Immunosuppression, mostly corticosteroid therapy, has shown some promise in several reports, but the increase in pregnancy rate is modest, while adverse effects may be significant. Simple laboratory techniques are not effective in preventing sperm-antibody binding or in separating antibodies from sperm. At this time, a number of more sophisticated immunosuppressive methods are available, including immunomagnetic separation, immunobead separation, proteolytic enzyme treatment, and antigen-specific immunoadsorption. These techniques, however, are not used routinely pending additional investigation of their clinical efficacy.

Advanced assisted reproductive techniques, namely in vitro fertilization and intracytoplasmic sperm injection (discussed below), currently offer the best prospects for pregnancy in patients with immunoinfertility, also sparing the adverse effects of immunosuppressive treatment.

Trauma and surgical insult to the genitalia 

Trauma may cause direct damage to testicular tissue, thus decreasing its sperm-producing capacity; it may also disrupt the sperm draining system. Impairment of sperm production and transport may occur acutely following an obvious injury to the seminiferous tubules or ductal system, but may also develop later as a consequence of chronic post-traumatic scarring and fibrosis, distorting the normal testicular or ductal architecture.

Inadvertent insult to the male reproductive tract during certain surgical procedures might cause infertility through various mechanisms. For instance, inguinal hernia and hydrocele repair may be complicated by entrapment of the vas deferens and epididymal obstruction, respectively; retrograde ejaculation may develop after surgery of the prostate and the bladder neck. Surgical interventions involving the male reproductive organs may predispose to the development of antisperm antibodies, as discussed above

Toxic exposures 

Male infertility may result from exposure to a variety of gonadotoxins and other substances that have an inhibitory effect on spermatogenesis. These may include chemicals such as solvents and pesticides, various medications (including testosterone replacement therapy), recreational drugs, alcohol and tobacco, and radiation, among others (Table 2).

Varicocele 

Varicocele is the most commonly identifiable, surgically correctable lesion associated with male-factor infertility, found in approximately 30% of infertile men. Surgical correction of a varicocele, whether unilateral or bilateral, improves semen parameters as well as spontaneous and assisted pregnancy rates.

Adverse changes in testicular microenvironment, involving temperature, hemodynamics, and reactive oxidative species and antioxidant concentrations, seem to be induced by varicoceles and have been demonstrated to impair spermatogenesis. However, despite current knowledge in the pathophysiology of varicocele-associated male infertility, the exact mechanism by which varicoceles impair fertility remains unknown.1

Endocrine abnormalities 

Endocrine disorders of the hypothalamic-pituitary-gonadal axis are associated with male infertility. These relatively rare abnormalities are usually caused by defects in genes encoding modulators of sexual development and function—hormones and growth factors, or their receptors.

Significant advances in the fields of genetics and molecular biology have provided information about the basis of some endocrine abnormalities. For example, Kallmann's syndrome, the most common X-linked disorder of male infertility, is characterized by deficient hypothalamic secretion of gonadotropin-releasing hormone (GnRH), leading to hypogonadotrophic hypogonadism. Kallmann's syndrome results from a mutation in the KAL-1 gene, thought to encode a neural cell adhesion molecule.

While mutations in GnRH and androgen receptors have been associated with a wide range of reproductive disorders, only a few disorders are reported to be associated with gonadotropins. In particular, there have been some reports of luteinizing hormone mutations and resistance, associated respectively with absent spermatogenesis and pseudohermaphroditism. On the other hand, follicle-stimulating hormone deficiency is rare, and defects in its receptor cause very mild phenotypic disturbance, if at all.

Other genetic causes 

The genetic background of male infertility has been extensively investigated in recent years. In addition to certain chromosomal disorders, such as Klinefelter syndrome, a large number of gene abnormalities are associated with male infertility. Gene abnormalities in chromosome Y are of special importance, as they can be identified in up to 13% of azoospermic men.1 Three distinct regions have been mapped on the long arm of chromosome Y—azoospermia factors (AZF) a, b, and c, including multiple genes needed for normal spermatogenesis, such as DAZ (deleted in azoospermia). Screening for chromosome Y deletions, usually within the AZF regions, is now routinely ordered for non-obstructive azoospermic men.2

Congenital bilateral absence of the vas deferens coupled with cystic fibrosis is the most frequent disorder of the extratesticular ductal and ejaculatory systems, occurring in 1%–2% of infertile men.10 This condition, caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, located on chromosome 7, is now considered to be part of the phenotypic spectrum of cystic fibrosis. While only about 30 of some 500 identified CFTR mutations are regularly screened, the female partners of patients with congenital bilateral absence of the vas deferens should be assessed for these mutations, and the couple offered genetic counseling.

Intracytoplasmic sperm injection (ICSI) 

ICSI has revolutionized the treatment of severe male infertility, as it requires only one isolated sperm microinjected into an ovum to achieve fertilization with subsequent in vitro fertilization. Thus, all natural barriers to sperm entry are bypassed, allowing genetically or otherwise abnormal sperm to create an embryo. While currently available genetic screening tests provide important information for counseling the infertile couple and designing a treatment plan, certain precautions in using ICSI are advised.

First, the use of ICSI may possibly be circumvented with an initial evaluation of the infertile male and subsequent treatment of a correctable male factor. In addition, as other genetic abnormalities might be associated with those causing male infertility, the use of ICSI may have as yet unknown consequences for the offspring.

Surgical sperm retrieval 

New surgical techniques have been developed to address the problem of identifying areas of spermatogenesis in patients with non-obstructive azoospermia. Microdissection testicular sperm extraction (TESE), described by Schlegel, involves the use of the operating microscope for the identification and sampling of the particular enlarged, opaque seminiferous tubules assumed to have active spermatogenesis.11 This technique has been reported to provide better sperm retrieval through smaller volumes of testicular tissue removed, as compared to standard biopsies. Additional advantages of this method include identification and preservation of the subtunical vessels, and potential lowering of the risk of testicular function impairment that is seen in larger-volume standard testicular biopsies. The long-term implications of this procedure are currently under investigation in an effort to evaluate whether subtle changes in testicular function occur.

Testis fine-needle aspiration mapping, described by Turek et al, may also be applied in patients with non-obstructive azoospermia.12 This technique, performed under local anesthesia, involves systematic fine-needle aspiration from adjacent testicular sites. Compound maps, in which more than 4 sites per testis are aspirated, have been suggested as efficient measures to help increase the chance of locating areas of spermatogenesis when planning for TESE and ICSI in cases of non-obstructive azoospermia. There is the additional advantage of minimizing the removal of valuable hormone-producing testicular tissue.

Simple fine-needle aspiration maps, in which 4 or fewer aspiration sites per testis are obtained, can be performed in the office and may confirm the diagnosis of ductal obstruction. However, further investigation is needed regarding the applicability of this procedure for men with non-obstructive azoospermia, including the assessment of its long-term safety and a determination of its false-positive and false-negative ratios.

On the horizon 

Future methods for evaluation and treatment of male infertility may include germ cell transplantation, which has been reported to restore fertility in sterile mice. This has significant clinical potential regarding possible restoration of fertility in sterile patients after cancer therapy. It is also expected that other advanced methods, such as the molecular microarray technology and the laser capture microdissection technique, will be useful for the future identification of the molecular basis of many male infertility disorders, while minimizing the size of the investigated specimen, possibly to the level of an isolated single cell.