Urogenital Infection as a Risk Factor for Male Infertility

Globally, approximately 15% of couples of reproductive age experience infertility; however, significant regional differences exist (1, 2). Male infertility accounts for at least half of these cases. With a prevalence of 6% to 10%, infections and the resulting inflammatory reactions within the male genital tract are among the main causes for male infertility (3�5). Ascending infections caused by sexually transmitted pathogens, such as Chlamydia (C.) trachomatis or typical uropathogens, such as Escherichia (E.) coli, play a key role in the etiopathogenesis of the condition; other factors include the hematogenous spread of systemic, typically viral infections (5�7). Nosological classification differentiates between urethritis, prostatitis/prostato-vesiculitis, epididymitis/epididymo-orchitis, and orchitis. These pathogens or components of these pathogens or inflammatory cells and their mediators may cause irreversible damage, especially to the testis and epididymis (Table 1) (7�9).

Table 1

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The conditions resulting from acute infections can be diagnosed with great certainty and pertinent recommendations on their treatment and the management of complications are in place (e1, e2). However, the majority of infertility patients with signs of urogenital tract infections/inflammations are asymptomatic, suggesting a high rate of chronic disease (7, 8). In these cases, the diagnosis is primarily based on the detection of the pathogen, increased white blood cell counts and/or inflammatory mediators in ejaculate, prostate secretion and urine samples. Since a compartment-specific differential diagnosis is challenging, abnormal findings are typically summarized under the term �male accessory gland infection� (MAGI), according to the definition of the World Health Organization (WHO) (eTable) (10). The lack of differentiation between infection and inflammation is of concern, as inflammatory reactions not primarily related to a pathogen may also occur (Box) (11). Another problem is that asymptomatic testicular inflammatory reactions are not covered by the WHO criteria (7). Therefore, the potential impact of urogenital infections on male fertility and its management remain the subject of controversy (5). In the light of the above, it appears relevant to clinical practice to summarize the currently available evidence and recommendations in regard to diagnosis and treatment approach.

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Methods

This review is based on a selective search of the PubMed database using the MeSH terms �male infertility�, �bacteriospermia�, �leukocytospermia�, �urogenital infection�, �male accessory gland infection + MAGI�, �inflammation�, �chronic urethritis�, �chronic prostatitis + CP/CPPS�, �epididymitis, orchitis�. In addition, we included current guidelines in our review.

Disease presentations

Chronic prostatitis

Approximately 10% of all men experience symptoms of prostatitis syndrome, such as pelvic pain and urinary discomfort (12). However, only 5% to 10% of these patients are diagnosed with chronic bacterial prostatitis. The classification of the National Institute of Health (NIH) differentiates between chronic bacterial prostatitis (CBP, NIH category II) and inflammatory (NIH category IIIA) or non-inflammatory chronic pelvic pain syndrome (CPPS) (NIH category IIIB) (e3).

In chronic bacterial prostatitis, the bacterial count in urine after prostatic massage is, by definition, at least 10-times higher in the 2-glass test compared with the baseline urine; in 50% of cases, a significant bacterial count of the same pathogen is found in the ejaculate (bacteriospermia) as well (Figure 1) (12). Besides the bacterial spectrum of complicated urinary tract infections, atypical pathogens and pathogens causing sexually transmitted infections (STIs) may play a role (6, e4, e5). Furthermore, CBP (NIH category II) and inflammatory CPPS (NIH category III A) are associated with increased white blood cell counts in prostate secretions/urine after prostatic massage and in ejaculate (Figure 1) (12). Among the inflammatory markers, interleukin 8 (IL-8) has attracted special attention; in contrast, traditional biochemical ejaculate parameters are of little diagnostic value (e6, e7) (Table 2).

Table 2

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In view of the prevalence of the disease among younger men, the question of the potential impact of chronic prostatitis on male fertility arises. Here, the available studies report conflicting results. Recently published meta-analyses indicate a negative effect on sperm motility and morphology (13, e8�e10) (Table 2). However, the diagnostic value of basic semen analysis is limited, as demonstrated by changes in sperm function and epigenetic markers in patients with chronic prostatitis (14, e11).

Epididymitis, epididymo-orchitis and orchitis

The annual incidence of acute epididymitis is approximately 400/100 000 men (15). Typically, the cardinal symptoms of pain and swelling of the epididymis manifest on one side. Since in up to 60% of patients testicular involvement is present, many authors primarily use the term epididymo-orchitis (7). The ascent of pathogenic bacteria from the urethra into the epididymis plays a key role in the etiology of the disease. The most commonly detected microorganisms include typical uropathogens, such as E. coli, and STI pathogens (16).

From the perspective of etiopathogenesis, the notion that there is a connection between male infertility and epididymitis/epididymo-orchitis resulting from STI-related urethritis seems plausible (e12, e13). The deterioration of sperm concentration observed in the ejaculate during the acute phase of the disease is usually reversible within 3 to 6 months; however, an analysis of pooled data revealed persistent azoospermia in approximately 10% of patients and oligozoospermia in another 30% (13). Proteome analyses suggest that, despite appropriate antimicrobial treatment, qualitative sperm changes may occur in addition to reduction in sperm concentration (e14). Bacterial virulence factors, such as hemolysins, may also have an impact on the course of the disease (e15).

Despite the lack of epidemiological data on the chronification of epididymo-orchitis, testicular atrophy with permanent loss of spermatogenesis is a much-dreaded complication (7, e16). However, a recent ultrasonography study involving 80 patients with unilateral epididymitis/epididymo-orchitis showed that testicular volume returned to normal after an initial increase compared with the unaffected contralateral side, with no resulting testicular atrophy (17). These data support the view that male reproductive tract obstructions play an important role as the cause of persistently reduced semen quality.

Primary orchitis is typically observed along with the hematogenous spread of systemic, viral infections (e.g. mumps); chronic granulomatous orchitis can occur with tuberculosis, lepromatous leprosy, syphilis or brucellosis (7, 18). Epidemiological data on the prevalence of azoospermia/infertility after infection-related orchitis are almost entirely lacking. A Mongolian study confirmed the increased risk of reduced ejaculate quality after mumps orchitis or orchitis of other etiology (Odds Ratios [OR]: 3.4 and 2.3, respectively) (19).

Remarkably, asymptomatic testicular inflammatory reactions were observed in about 25% of male patients undergoing testicular biopsy as part of their infertility work-up. These primarily focal lymphocytic infiltrates correlate with the degree of damage to spermatogenesis and clinical endocrinological parameters of testicular function (7). However, only about 2% of these patients report a previous episode of (epididymo-)orchitis.

Obstruction of the male reproductive tract due to infection/inflammation

Studies following up patients after acute epididymitis found an increased risk for infection/inflammation-related azoospermia (13). Compared with obstructions of the ductus epididymidis or ductus deferens, obstructions of the ejaculatory ducts are rare (20, e17). With an overall prevalence of azoospermia in andrology centers of 5% to 15%, so-called obstructive azoospermia is present in about 40% of cases; the proportion of obstructions due to infection/inflammation among these cases ranges from 18% to 47% (21, e18, e19).

Besides normal testicular volumes and serum follicle-stimulating hormone (FSH) levels, indicating intact spermatogenesis, the differential diagnosis of obstructive azoospermia is based on volume, pH and biochemical parameters of the ejaculate (Table 1) (22, e1). In addition to the site of obstruction, the differentiation between acquired infectious-inflammatory forms and congenital forms of obstructive azoospermia is a key prerequisite for the potential use of surgical treatment options, such as vasoepididymostomy (20, e18, e20).

Asymptomatic patients desiring to have children

Prevalence data on male subfertility or infertility caused by genital tract infections and inflammations are typically based on information about male accessory gland infection (MAGI), as defined by the WHO classification (eTable) (10). However, due to the lack of noninvasive diagnostic markers, asymptomatic testicular inflammatory reactions are not taken into account (7). While rates of approximately 9% have been reported from andrology centers in Germany (4, 5), this percentage can rise to over 30% in countries where healthcare is inadequate (23). These regional differences are suggestive of a direct connection between STI and secondary infertility (2, e21).

In the light of the potential contamination of ejaculate samples with urethral commensals, bacteriospermia does not necessarily indicate genital infection (6, 24). For uropathogenic bacteria, a threshold of 10� colony-forming units (CFU)/mL has been suggested to define �significant� bacteriospermia (5, e22). In a Canadian study with almost 5000 subfertile men, however, an association between bacteriospermia, which was detected in 15% of the examined subjects, and semen parameters was only observed in patients with concomitant increase in white blood cell counts in the ejaculate (25). Studies evaluating the connection between ejaculate quality and the presence of C. trachomatis and Mycoplasma spp. reported conflicting results, despite the high prevalence of positive polymerase chain reaction (PCR) testing for these pathogens; however, significant effects on sperm function and quality were demonstrated (26, e23�e26). The available data on human papilloma viruses, for which prevalences of 10% to 36% in ejaculate have been reported (27), does not allow to draw final conclusions on their role in male infertility. Current data suggest that Trichomonas vaginalis infections do not have a negative effect on male fertility (5).

The pathological relevance of leukocytospermia, determined using the WHO threshold of 10⁶ peroxidase-positive cells per mL of ejaculate, remains the subject of controversy (9, 22, e27, e28). In subfertile men, however, a negative correlation between white blood cell count levels and sperm concentration, motility and morphology was demonstrated (e27, e29, e30). Likewise, a negative association was found between the number of neutrophilic granulocytes in smears on the one hand and basic semen parameters as well as sperm DNA integrity on the other hand (25). Yet, the prognostic value of leukocytospermia with regard to the detection of relevant bacteria or viruses is low (25, 28).

Apart from reduced sperm motility, infection and inflammation of the male genital tract can have other negative effects on critical sperm functions (Table 2) (14, e31). Oxidative damage to sperm, including DNA fragmentation caused by increased levels of reactive oxygen species (ROS) in the ejaculate, may already occur below the WHO�s 10⁶ leukocytes/mL threshold (e32, e33). Likewise, an association between granulocyte elastase and cytokines in the ejaculate and sperm DNA fragmentation was found (e34). Macrophages play a major role as a source of proinflammatory cytokines (29, 30, e35, e36).

The prevalence of so-called immune-mediated infertility�the detection of sperm-immobilizing or sperm-agglutinating auto-antibodies in the ejaculate�is reported to be 4% to 6% (4, e37, e38). While after vasectomy sperm autoantibodies are detected in over 50% of patients, evidence in support of the induction of autoantibodies after genital tract infection/inflammation is inconclusive (31, 32). Cross-reactivity of pathogen-specific antibodies with sperm antigens is currently discussed as the cause of an association between Helicobacter pylori infection and male infertility (e39).

Diagnosis of urogenital infections and inflammations

Clinical diagnosis

Apart from fertility-relevant aspects, patient history should pay special attention to previous diseases such as STIs and other urogenital or systemic infections. Validated questionnaires to assess sexual dysfunction and prostatitis-associated symptoms are available (e1, e40).

The clinical examination of the genital organs should always be complemented by ultrasonography of the scrotal content (33). Using color-coded duplex ultrasonography, organ vascularization and perfusion can be visualized (17). Transrectal ultrasonography is indispensable in patients with suspected abscess formation due to prostatitis; yet, the relevance of the common finding of prostate calcifications remains unclear (e8).

In cases of acute urogenital infection/inflammation, laboratory testing, including blood count as well as CRP and serum PSA (indicative of concomitant prostatitis), is useful (CRP, C-reactive protein; PSA, prostate-specific antigen). Hormone status should be ordered to assess endocrine testicular function (basic: follicle-stimulating hormone [FSH], luteinizing hormone [LH], total testosterone; extended: estradiol, sexual hormone�binding globulin [SHBG], inhibin B).

Fractionated sampling and analysis of urogenital secretions

In combination with semen analysis, the 4-glass test was developed to detect the localization of inflammation/infection within the male genital tract, in particular for the diagnosis of prostatitis (12). The test involves comparative quantifying testing of urine portions before and after prostatic massage and prostatic exprimate. A simplified version of the test, the 2-glass test, has proven clinical value (Figure 1) (12).

Figure 1

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Semen analysis

The examination of the ejaculate according to WHO recommendations (22) plays a key role in the diagnosis of infectious and inflammatory processes in the male genital tract. However, sperm concentration, total sperm count, and sperm motility and morphology represent only surrogate parameters in the evaluation of fertility. In addition, these are not specific for abnormalities resulting from infection/inflammation. Ejaculate volume, pH and biochemical parameters reflect the secretory function of the accessory glands (Table 1). Sperm agglutination may indicate the presence of membrane-bound auto-antibodies (IgG, IgA; detection by mixed antiglobulin reaction test) (22).

Quantification of leukocytes as markers of inflammation in the ejaculate is based on the detection of peroxidase-positive granulocytes (5, 22). Further analyses extending beyond the scope of the above are currently still considered facultative/experimental by the WHO. Compared with the peroxidase method, immunocytochemical detection or flow cytometry of leukocytes have a much higher sensitivity and allow for the differentiation of leukocyte subpopulations in the ejaculate (22, 29). Other indicators of inflammation include granulocyte elastase and proinflammatory cytokines (8, e8, e34, e41).

Microbiological testing

In patients with suspected urogenital infections, urine samples and secretions/swaps are obtained for microbiological testing (Figure 1). However, urogenital samples can get contaminated by the normal microbiota of the urethra, including bacteria such as S. epidermidis and viridans group streptococci. These bacteria are generally classed as non-pathogenic commensals. In healthy male subjects, only about 10% of urogenital samples are free of microorganisms (5, 24). In contrast, facultative pathogenic bacteria, such as enterobacteria (e.g. E. coli, Klebsiella spp., Proteus spp.), enterococci, ureaplasms, mycoplasms, and Staphylococcus (S.) saprophyticus as well as obligatory pathogenic bacteria, such as Neisseria (N.) gonorrhoeae and C. trachomatis, can trigger an infection (6).

According to microbiological/infectiological quality standards (MiQ), it is thus required to determine the type of the pathogen and the bacterial count when urogenital samples are tested to evaluate their etiological relevance (e42). Furthermore, proper sampling, sample transport and sample processing within 2 to 4 hours after sampling is critical (e43). Pre-analytical mistakes include lack of cleaning of the urethral orifice and its surrounding; microbiological analysis of the ejaculate should be performed only after prior urination (22, e42).

The detection of microorganisms in urogenital secretions is best achieved with a combination of culture and nucleic acid amplification techniques (NAT) (34�36). Fast-growing bacteria are detected using culture techniques (e42), while difficult to cultivate and very sensitive bacteria are detected using culture-independent NAT (for example STI PCR) (e44). In case of negative culture and negative STI PCR, an additional universal bacterial PCR can be performed, using the 16S rDNA gene as target sequence which is highly conserved in all bacteria. The highly sensitive universal bacterial PCR with subsequent sequencing detects 99% of human pathogenic bacteria (16, 36, e45). This approach detects bacteria missed with cultural methods and STI PCR.

Treatment options

Treatment aims at the reduction or eradication of pathogenic bacteria in the ejaculate or prostate secretions, the normalization of inflammatory parameters, and the improvement of abnormal sperm parameters. Antibiotic treatment of asymptomatic genital tract infections in sub-/infertile patients follows the recommendations primarily made for acute/symptomatic conditions (16, e1, e2) (Figure 2). In case an STI is detected, antimicrobial therapy is always required and should be administered as recommended in available guidelines and include the partner of the patient (37, 38, e46). The treatment for uropathogens is guided by bacterial counts and resistance testing; in the absence of chronic bacterial prostatitis or symptomatic epididymitis, the microbiological results should first be confirmed at a follow-up examination. In symptomatic patients requiring ad-hoc treatment, fluoroquinolones with activity against C. trachomatis are considered the first-line treatment because of their good local tissue penetration (e2, 12, 16).

Figure 2

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The example of epididymitis/epididymo-orchitis shows that the development of persistent subfertility or infertility remains unpredictable even if acute antibiotic treatment achieves the eradication of the pathogen (13, 16, e47). Likewise, successful antibiotic therapy of MAGI does not necessarily result in an improved conception rate (e48, e49). Despite reports of negative effects of antibiotics, such as sulfonamides or tetracyclines, on spermatogenesis or sperm function, irreversible treatment-related damages appear unlikely (e50), but the induction of cellular and humoral immune responses in the genital tract seems to play an important role (Box) (39). Thus, despite diagnostic limitations, treatment with nonsteroidal anti-inflammatory drugs should be considered in the presence of positive inflammatory parameters in the ejaculate (without pathogen or after antibiotic therapy), since several open studies reported improvements of ejaculate quality along with a decrease in white blood cell counts (e51, e52) (Figure 2). Similar results were observed with mast cell blockers (e53, e54). Weak evidence supports the efficacy of adjuvant medications, such as antioxidants (e55). In patients with anti-sperm auto-antibodies, assisted reproductive techniques are preferred over immunosuppression with glucocorticosteroids (e8, e56).

Box

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(Re-)fertilizing surgical procedures are indicated with obstructions of the epididymis and along the course of the ductus deferens (microsurgical vasoepididymo- or vasovasostomy) as well as in central parts of the prostate (transurethral resection of the ejaculatory ducts) (20). The only option for patients with non-obstructive azoospermia as the result of epididymo-orchitis or orchitis is multilocular testicular biopsy for testicular sperm extraction (20, 40).

Conclusion

Adequate pathogen-specific antimicrobial therapy does not necessarily achieve restitution of sperm parameters or fertility. New diagnostic technologies, such as transcriptome and proteome analysis, are likely to open new perspectives which allow us to differentiate between inflammatory reaction due to persistent infection and post-infectious, primary non-infectious and autoimmune processes and to identify compartment-specific markers. These methods and the research into the underlying pathomechanisms are the foundation on which new treatment strategies can be established.

FundingThe authors were funded as members of the focus �Male Infertility along with Infection and Inflammation (MIBIE)� of the Landesoffensive zur Entwicklung wissenschaftlich-�konomischer Exzellenz (LOEWE) by the state of Hesse.

Conflict of interest statement

Prof. Schuppe has received lecture fees from Merck-Serono and Ferring.

PD Dr. Diemer holds shares in Lilly Deutschland GmbH. He received consultancy fees from AMS, Jenapharm, Bayer Vital, Cheplapharm, and Pfizer.

Prof. Wagenlehner received consultancy fees and study support (third-party funding) from Achaogen, Astellas, AstraZeneca, Bionorica, Calixa Pharmaceuticals, Cerexa Pharmaceuticals, Cubist Pharmaceuticals, LEO, MSD, Pfizer, Rempex Pharmaceuticals, Rosen Pharma, Shionogi, and Vifor Pharma.

The remaining authors declare that no conflict of interest exists.

Manuscript received on 13 July 2015; revised version accepted on 13 March 2017.

Translated from the original German by Ralf Thoene, MD.

Corresponding author
Prof. Dr. med. Hans-Christian Schuppe
Sektion Konservative Andrologie
Klinik und Poliklinik f�r Urologie, Kinderurologie und Andrologie
Universit�tsklinikum Gie�en und Marburg GmbH � Standort Gie�en
Gaffkystr. 14, 35392 Gie�en, Germany
Hans-Christian.Schuppe@derma.med.uni-giessen.de

Supplementary material
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