9.4.9 Infections/inflammation of the genital tract

Sexually-transmitted diseases (STDs) are the primary cause of infections of the genital apparatus, and are an important cause of morbidity worldwide. These diseases diminished after the advent of antibiotics, but in the 1970s new sexual behaviour and use of non-protective contraceptive methods brought about a significant increase in genito-urinary infections, especially in young adults of fertile age. New diseases appeared alongside the classic infections syphilis, gonorrhoea, soft ulcers, venereal lymphogranuloma, and inguinal granuloma, and increased continuously in industrialised nations. Previously unknown pathogens such as Chlamydia trachomatis, genital Mycoplasma, and others came to the attention of andrologists, particularly because of often irreversible complications in the sexual and reproductive realm (1).

The incidence of urogenital tract infection in infertile males confirms the correlation between fertility and genital inflammatory pathology. Such infections, at times aggravated by other conditions, are a primary reason for failure to induce pregnancy. Inflammation of the genital tract is one of the most frequent causes of lowered fertility in males, especially in so-called ‘silent’ cases where clinical signs are absent due to a multiyear interval between sexual transmission and resultant infertility (2).

The causes of infections of the male genital apparatus merit particular attention, as treatment of this type of infection requires precise aetiological diagnosis using appropriate tests (3). Moreover, it must be kept in mind that a sexually transmissible infection in the male can result in pelvic inflammation in the female partner, with resultant loss in fertility. Infertility is, in fact, a problem of the couple and thus the evaluation of potential causes must take both partners into consideration (4).

Male fertility is tied to both normal testicular activity and to that of the accessory glands, which produce seminal fluid. Inflammation of the male genital apparatus may thus involve all of these structures, either singularly (orchitis, epididymitis, vesiculitis, prostatitis, urethritis, etc.) or in association (mixed forms). An infection in the male genital tract can, therefore, reduce the fertilising capacity either directly, due to effects on the spermatozoa (hypomotility), or indirectly. As a result of genital tract infection, there may be obstruction in the epididymis or vas deferens, which in turn may provoke an immune response via the reabsorption of antigenic material or in cross-reaction with bacterial or sperm antigens. For instance, the presence of prostatovesiculitis can interfere with the biochemical properties of seminal fluid, reducing concentrations of citric acid, fructose, zinc, magnesium, and phosphoric acid, and altering pH. Even when these parameters are normal, the presence of infection can never be excluded.

Finally, an active infection can bring about an increase in the production of reactive oxygen species, which have been shown to reduce the stability of the sperm membrane and thus lower the fertilising capacity of the semen. Moreover, urogenital infections lead to the release of inflammatory cytokines, most probably by immunocompetent cells of lymphocyte/macrophage origin. Cytokines such as IL-1, IL-6, and/or TNFα may influence sperm motility.

The main pathogenic agents responsible for infection of the male genital tract are Neisseria gonorrhoeae, Mycoplasma, Chlamydia trachomatis, and various gram negative bacteria, among which are E. coli, Proteus, Klebsiella, Enterobacter, and Pseudomonas. E. coli is the most common cause of urinary tract infections, responsible for 85% of community-acquired infections and about 50% of nosocomial infections. The role of gram positive bacteria in the aetiopathogenesis of prostatovesiculitis is, while important, a subject of some controversy.

Neisseria gonorrhoeae is a gram negative coccus 0.6 to 0.8 µm in diameter, and is either aerobic or anaerobic, asporogenous, and immobile. It is the principle causative agent of gonorrhoea, the classic venereal disease, the incidence of which has seemingly increased in recent years in industrialised countries, especially among young people. After a 4–5 day incubation period, 80% of infected males present symptoms of primary infection, including an abundance of creamy, yellowish urethral exudate (5).

Mycoplasma are the smallest organism with reproductive autonomy—i.e. the ability to grow in culture—although they require a rich substrate. M. hominis, U. urealyticum, and M. genitalium are those which cause human disease such as urethritis, prostatitis, and prostatovesiculitis, or even epididymitis and balanitis (6).

Chlamydia trachomatis was first considered a virus, but in the 1960s was classified as a gram negative bacterium. An obligate endocellular parasite, C. trachomatis causes more than 50% of nongonococcal urethritis and the majority of postgonococcal urethritis. Chlamydial urethritis often goes undetected due to its subtle symptoms, thus leading to more serious orchiepididymitis, prostatitis, or vesiculitis. The latency of this type of infection and its chronic nature dictate treatment of even asymptomatic subjects whose partners test positive for this organism (7).

Viral infections are increasingly common causes of infections of the male genital tract in industrialised countries (8). However, debate surrounding the impact of viruses on male infertility is controversial. Cytomegalovirus (CMV) and human herpes virus type 6 (HHV6) were shown to be present in semen, but there are no data on an association with impaired semen parameters. The presence of human papilloma virus (HPV) in semen samples has been associated with alterations of sperm parameters (8), most notably sperm motility and pH (10). This is also true for herpes simplex virus (HSV), which was demonstrated to impair semen parameters (11).

The most relevant sources of HIV in the male reproductive tract are infected leukocytes. The presence of HIV-1 in spermatozoa has been a matter of debate, since the sperm cell fraction may contain somatic infected cells that confound the attribution of the detected virus to the spermatozoa. In a recent paper, molecular evidence showed that HIV-1 infected subjects can ejaculate small amounts of HIV-1 DNA-positive abnormal spermatozoa. Their possible role in HIV-1 sexual transmission remains to be clarified (12).

The classic division of infections of the genital tract into acute, subacute, and chronic categories can fail to reflect clinical reality; symptoms may even be absent in the case of chronic infections of the genital tract. Symptoms vary, moreover, according to the regions of the genital tract affected, and can be associated with sexual dysfunction such as premature or painful ejaculation, or change in libido.

Urethritis primarily affects the anterior urethra with slight symptoms, which include difficulty in voiding, itching, and reduced secretion. While urethritis is a common consequence of genital infections, it rarely affects fertility. Rather, its importance is due to diffusion of infection from the urethra to other zones of the genital tract.

Epididymitis was, until a few years ago, most commonly caused by gonorrhoea or tuberculosis. Today, as in infections of other regions of the genital tract, epididymitis is most commonly nonspecific, caused either by the habitual presence of bacteria in the lower urinary tract (especially Gram-negative), or by sexually transmitted pathogens such as C. trachomatis. Acute forms of the infection show symptoms of intense pain radiating into the groin and hypogastrium, swelling of the corresponding hemiscrotum, and high fever. The resultant effects on histopathology can be occlusion of the epididymal tubule, and fibrosis causing increased volume and consistency of the infected epididymis. Potentially, these inflammations lead to genital tract obstruction and antisperm antibody formation.

Prostatitis is one of the most common clinical diagnoses in cases of genital inflammation. It is a serious problem, due both to its potential negative impact on reproductive function and the difficulty of detection. Careful, detailed collection of anamnestic data is often necessary to find a previously undiscovered prostatitis. Nonspecific complaints in the perineal region, prostatorrhoea, pollakiuria, and urinary urgency are common symptoms of prostatitis; unfortunately these are often not reported accurately by patients and can lead to chronic forms. The pathogenesis of prostatitis is still poorly understood; recently, evidence indicating an autoimmune component has begun to emerge. This is also supported by the observation that these patients show higher levels of seminal plasma proinflammatory cytokines (IL-1β, IL-6, TNFα), and chemokines (IL-8) compared to controls (13).

Treatment of acute infections of the male reproductive tract must be based on the identification of the aetiologic agent, and on the colony count and antibiotic sensibility (antibiogram). The species most commonly involved in various forms of genital tract infection are Neisseria gonorrhoeae, C. trachomatis, U. urealyticum, M. hominis, and various Gram-negative bacteria. The preferred drug for N. gonorrhoeae is ceftriaxone (250 mg IM, single dose). As C. trachomatis is metabolically active only inside cells, only those antibiotics that can penetrate the host cell are effective. Therefore, the recommended treatment consists of a seven-day cycle of tetracycline (500 mg four times dauly), minocycline or doxycycline (100 mg two times daily), or erythromycin, (500 mg four times daily). A single dose of azithromycin is currently a valid alternative, especially as patient compliance is increased. Because U. urealyticum and M. hominis lack cell walls, β-lactam antibiotics are totally ineffective. Preferred antibiotics are tetracycline (with the same treatment plan as C. trachomatis) or erythromycin (2 g/day PO for 7–10 days). The gram negative bacteria most often involved in male reproductive tract infections are coliform, Pseudomonas, Proteus, and Enterococci. In these cases, treatment indications are for administration of ofloxacin (200 mg twice daily for 7–10 days) and ciprofloxacin (500 mg/day for 7–10 days), because of their favourable antibacterial spectrum and pharmacokinetic profiles.

The concomitant use of anti-inflammatory agents (indomethacin, naproxen, and nimesulid), is justified by the negative effect of prostaglandins on spermatogenesis, and by the advantages that the use of these prostaglandin inhibitors could have for the quality of the seminal fluid.

α-1 selective blockers may relieve symptoms of prostatodynia in cases of nonbacterial and bacterial prostatitis (14).

In conclusion, when an infection of the genital tract is suspected a detailed diagnostic procedure is necessary prior to treatment for eradication of the infection without further complications. This may also warrant inclusion of the patient’s partner in the investigation, in cases of STDs that may be present in healthy carriers who are nonetheless the principal reservoir of infection.