The Role of Chronic Prostatitis in Male Infertility: Is There a Relationship?




© Springer International Publishing Switzerland 2016
Tommaso Cai and Truls E. Bjerklund Johansen (eds.)Prostatitis and Its Management10.1007/978-3-319-25175-2_13


13. The Role of Chronic Prostatitis in Male Infertility: Is There a Relationship?



Vitaly Smelov1, 2  


(1)
Screening Group, International Agency for Research on Cancer, World Health Organization, Lyon, France

(2)
Department of Urology and Andrology, North-Western State Medical University named after I.I. Mechnikov, St. Petersburg, Russia

 



 

Vitaly Smelov




13.1 Introduction



13.1.1 Infertility and Prostatitis


The World Health Organization (WHO) classifies infertility as “a disease of the reproductive system defined by the failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse” [102]. In fact, the period when practicing regular unprotected sex might result in pregnancy varies from the first 3 months in 20–37 % of the couples younger than age 30 [76] till up to 3 years in 93 % for every 100 couples from the general population [66]. Depending on the definition used, the prevalence estimates across populations vary widely between 3.3 % and 26.4 % for current infertility and between 2.6 % and 31.8 % for lifetime infertility, respectively [34]. Studies suggest that about 15% and 10% of couples, who have not achieved pregnancy within 1 and 2 years, seek a medical treatment for infertility [33, 54, 76]. Current general understanding is that for couples, who have been trying to conceive for more than 3 years without success, the likelihood of pregnancy occurring within the next year is 25 % or less [66].

Importantly, while a common belief is that infertility remains a “women’s problem,” it is a couple-based clinical problem. In fact, male factors have been accepted for approximately 20 % of couple infertility with another 30–40 % presenting with reproductive abnormalities in both partners [4, 91].

Multiple factors can lead to reduced male fertility. In about 50 % of cases, the cause of male infertility cannot be determined [40]. Among the known [97] categories, 6.6–12 % of accepted causes are due to urogenital tract infections [21, 94, 97]. It is unknown how many of these cases are caused by prostatitis (inflammation of the prostate gland). The prostate disorder is listed by the WHO among male accessory genital gland infections [97] and is one of the most common urological problems affecting men in their reproductive age, accounting for 8 % of all urologist visits [15] and an overall lifetime prevalence of 14 % [63]. Recent discoveries on the prostate and its function provide new insight to the magnitude of the problem.


13.1.2 Prostate Gland and Prostatic Secretion


The prostate is the largest male accessory genital gland. The normal prostate reaches 20 ± 6 g in men between 21 and 30 years old, and this weight remains essentially constant with increasing age unless benign prostatic hyperplasia develops [8]. The 25–30 prostate glandular units (acini) and their ducts, which enter the prostatic urethra, are lined with secretory epithelium and surrounded by a variable amount of stroma, housing different stromal cell types with distinct phenotypes [31, 61].

Prostate secretions represent the second portion of the ejaculate and contribute up to 30 % to the total volume of human semen, which is a mixture of components produced by several different glands and should exceed 1.5 mL, or even 2.5 mL, as the lower limit of normal semen volume [16, 72]. Notably, impaired sperm parameters in patients with prostate disorders have been shown in some studies [93]. The prostate gland has the highest concentration of zinc in the human body [12] and is rich with citric acid [43]. Decreased quantities of zinc, citric acid, phosphatase and fructose [95], alpha-glutamyl transferase activity [95], and, potentially, quantities of potassium, sodium, and calcium [101] can be considered as indicators of disturbed prostatic secretion.

The physical access to the prostate gland is limited, and current guidelines [9, 32] recommend the evaluation of expressed prostatic secretion (EPS) by microscopy and culture in patients with prostatitis-like symptoms or a prostate biopsy for confirming or ruling out malignancy when indicated. EPS can be obtained during digital rectal examination (DRE, a routine urological diagnostic procedure) with massage of the prostate. The investigation of EPS has been commonly used in urology ever since the Meares-Stamey 4-glass test was described. The test includes a quantitative culture of pure EPS and was launched in 1968 [62] and became the gold standard for assessing the bacteriological and inflammatory state of the lower urinary tract in urological patients. The test has later been replaced by an easier-to-perform two-glass or pre-post-massage screening test [67, 68]. Since infections of the prostate impair the gland’s excretory function, the investigation of EPS is currently recommended in clinical routine assessment of non-acute conditions [32].


13.1.3 Classification of Prostatitis


The predominant symptoms of prostatitis are pain at various locations and lower urinary tract symptoms [2, 3, 103]. In fact, the term “prostatitis” has included bacterial prostatitis, with a detected infective agent, and the term “prostatitis syndrome” or chronic pelvic pain syndrome (CPPS), when no infective agent is found and which is presumably of multifactorial origin [32].

The currently recommended [32] classification distinguishes prostatitis from CPPS and employs such criteria as the duration of symptoms (classified as chronic, if they persist for at least 3 months) and evidence of inflammation and infection [62] localized to the prostate. It was suggested by the US National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) and includes four types of prostatitis: acute (type I) and chronic (type II) bacterial prostatitis; chronic abacterial prostatitis or CPPS (type III), with inflammatory (IIIA) and noninflammatory subtypes (IIIB); and asymptomatic inflammatory prostatitis (type IV) [44, 51, 79].


13.1.3.1 Acute Bacterial Prostatitis


Ascending urethral infection, the reflux of infected urine into the prostate, or the lower urinary tract manipulations might result in developing acute bacterial prostatitis (ABP). It is a life-threatening infection with fever, nausea, intense perineal or suprapubic pain, and voiding symptoms, which might culminate in urosepsis or the development of prostatic abscess. In this situation, prostatic massage is contraindicated, and the most important bacteriological investigation of the patient is the midstream urine culture. Among the most common causative organisms are gram-negative urinary pathogens, such as E. coli, followed by Klebsiella, Proteus, Pseudomonas, and Enterococcus [26]. An additional group of microorganisms of debatable significance includes staphylococci, streptococci, Corynebacterium sp., Chlamydia trachomatis, Ureaplasma urealyticum, and Mycoplasma hominis [83, 96]. Acute prostatitis usually requires parenteral treatment with bactericidal antibiotics of high doses [32]. Although current data provides no evidence for the direct impact of this condition on male infertility, the latter can be affected through the complications of ABP, such as epididymitis and chronic prostatitis. It has been reported that chronic infection, predominantly chronic bacterial prostatitis or epididymo-orchitis, and inflammatory chronic pelvic pain syndrome are the outcomes of acute bacterial prostatitis in 10.2 % and 9.6 % of patients, respectively [100].


13.1.3.2 Chronic Bacterial Prostatitis


Chronic bacterial prostatitis (CBP) has been considered as a relatively rare clinical condition, since a causative pathogen is detected by routine methods in only 5–10 % of cases [96]. The current clinical definition of bacterial prostatitis describes it as “a disease entity diagnosed clinically and by evidence of inflammation and infection localized to the prostate” [32]. The most common pathogens in CBP are similar to the ones detected in ABP [32].

A better understanding of the direct impact of pathogens is necessary to shed light on the significance of CBP for the development of male infertility. In fact, the prevalence of different bacterial species in male populations – and their relevance to the etiology of male infertility – varies according to geographical distribution [70]. It has been speculated that, due to an impairment of the secretory capacity of the prostate, proven bacterial infections of the male reproductive tract might impact negatively on all parameters evaluated in semen [22, 56].

Most of the studies have been done with Escherichia coli. The pathogen is usually cultured from bladder urine during infectious episodes but not at other times [81] and has been considered to be responsible for the great majority of cases of CBP [96]. It has been reported that infection with E. coli results in mitochondrial changes and membrane alterations in sperm cells [29], decreased percentage of sperm with intact mitochondrial membrane potential [84], immobilization, and impaired acrosomal function in human spermatozoa [18], that finally causes the decrease of sperm viability and motility [56, 84]. Observational studies on the significance of positive bacterial semen cultures have speculated a potential harm of Enterococcus, S. epidermidis, S. aureus, P. aeruginosa, and Klebsiella on male fertility [7, 27, 56, 71]. In addition to obtaining relief of clinical symptoms, all the effects on fertility provide a rationale [32] for start of antibacterial treatment.


Chlamydia trachomatis

Another intensively studied pathogen is C. trachomatis. Chlamydia is the most commonly detected bacterial sexually transmitted infection (STI) worldwide, and the numbers of infections keep increasing [13, 23, 98]. Mostly asymptomatic [14], chlamydia infection is a major cause of infertility [98], mostly among females. Although no significant differences between infertile and fertile men in terms of the prevalence of C. trachomatis have been reported [52], large epidemiological data suggest an association of a past C. trachomatis infection with infertility in men [41]. Chlamydia has been directly associated with decreased sperm motility as well as abnormal sperm concentration and morphology [10, 24]. The pathogen has been reported to be able to attach to human spermatozoa, which results in their C. trachomatis-induced death in vitro [38]. Albeit the proven biological significance of chlamydia infection in male infertility has only been accepted for acute epididymitis and subsequent azoospermia [78], the pathogen has been associated with decreased sperm motility and abnormal sperm concentration and morphology in young prostatitis patients [59].

Nevertheless, the role of chlamydia infection in the pathogenesis of prostatitis remains inconclusive and controversial. C. trachomatis has been detected in semen samples of male partners in infertile couples [50], in the fluid of dilated seminal vesicles [30] and EPS [87], and in prostate tissue removed by transurethral resection or by open surgery [17], or obtained via perineal approach [45], but the discrimination from possible urethral contamination of the obtained material remains impossible to exclude.

Interestingly, chlamydia infection has been associated with increased leukocyte counts and pain severity in men with CPPS [73], and the role of immune system activation in the pathophysiology of chronic prostatitis has been proposed [60]. Some studies suggested anti-C. trachomatis immunoglobulin A (IgA) as a more sensitive marker for detection of C. trachomatis prostatitis than currently used amplification or culture techniques. Interestingly, a significant increase in mucosal IgA has been detected in the ejaculate of men with chronic prostatitis as compared to controls, and, also, significant correlations between IL-8 and mucosal IgA and between IL-8 levels and prostate symptom score results were found [59, 60].


Genital Mycoplasmas

Among genital mycoplasmas, Mycoplasma genitalium has also been considered as an STI [77]. However, their role in chronic prostatitis and related male subfertility is even more controversial that in the case of chlamydia infection. In fact, M. genitalium has been detected by amplification techniques in semen from some men with chronic abacterial inflammatory prostatitis [55] and, also, in a small number of prostatic biopsy specimens [46]. On the other hand, an earlier study failed to detect mycoplasmas in all biopsy specimens [20].

No significant differences have been reported between infertile and fertile men in terms of the prevalence of U. urealyticum and M. hominis [52]. Importantly, being untreated or successfully treated, the ascending urethral infection caused by genital mycoplasmas might trigger the immune response that would involve the prostate. In fact, an early infection might set in motion immunological processes that culminate in chronic prostatitis [90], which may potentially affect male fertility.


Novel Diagnostic Approaches Are Changing the Routine

Further studies, employing novel diagnostic approaches, are required to investigate the clinical significance of the infective pathogens and potential mechanisms of action in male infertility. Culture tests and microscopy have been considered as the gold standard for diagnosing urinary tract infections (UTIs), with an additional amplification system used if sexually transmitted pathogens are suspected [32, 51]. However, the current evaluation of UTIs, under the umbrella of “significant bacteriuria” first introduced in 1960 [42], was based on analyses of a cultured single bacterial isolate assembly representing the dominant pathogen. A significant limitation in the current widely used method is the detection of only culturable bacteria. The method is also limited in the detection of multiple pathogens or the strain diversity. Thus, caution is required when considering studied human-ejaculated sperm or EPS as “sterile” based on the lack of bacteria detected by classical methods alone. The wide use of amplification methods in detection of urogenital pathogens, in particular STIs [23], is a result of the methods’ good specificity and sufficient sensitivity. Noteworthily, only good laboratory practice and monitoring reference reagents should be employed [92], to be able to differentiate between infection and contamination. These detection methods are rapid and some of them allow detection of several pathogens during the same experiment. For instance, a novel bead-based multiplex assay is using a multiplex PCR followed by Luminex bead-based hybridization and has shown its effectiveness in assessing 18 urogenital infections in the same experiment [82]. However, the abovementioned tests are able to detect already known pathogens. The novel metagenomic sequencing (MGS) approach allows comprehensive high-throughput analyses in a sample without prior cloning, and it has become instrumental in detecting a broad range of non-culturable bacteria in “sterile” (based on “classical” diagnostic practices) EPS. The recent first-in-principle study on MGS of EPS found several bacterial reads in men with chronic prostatic inflammation. Most of the obtained bacterial sequences belonged to the family Proteobacteria, which includes such main causative agents of bacterial prostatitis as E. coli, Klebsiella, Shigella, Proteus, Enterobacter, etc. [86]. These findings raise the question of whether MGS could be useful for microbiological diagnosis in some cases, when conventional diagnostics may have failed to identify an appropriate treatment [6]. MGS studies would be also beneficial in exploring the prostate microbiome and in discovery of the role of potential non-culturable bacterial or viral cofactors in particular. For instance, in a population of prostatitis-related symptoms attributable to chlamydia infection, coinfection with human papillomavirus (HPV) was found to have a significant role in decreasing male fertility, in particular with regard to sperm motility and morphology [11]. A highly statistically significant correlation between pregnancy loss rate after the assisted reproductive technologies and positive HPV DNA testing in semen samples has been reported [75], providing an additional support that HPV coinfection may be related to impaired sperm motility [58], as well as other potential bacterial and viral coinfections. For cost reasons it will take time before novel assays become clinically applicable, but while the MGS methods remain expensive, the sequencing-related costs have decreased rapidly. This might significantly change the current viewpoint on the pathogenesis of prostatic disorders where bacteria may not play a role, such as chronic abacterial prostatitis.


13.1.3.3 Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS)


The current culture- and microcopy-based diagnostic approach discriminates most cases of chronic prostatitis as abacterial or chronic pelvic pain syndrome (CPPS). The impact of chronic abacterial prostatitis on semen parameters remains controversial [36, 49, 53, 64, 74]. Interestingly, no difference was found in the sperm parameters between the two subcategories of CPPS (NIH CPPS IIIA versus IIIB) [36]. The exact etiology of CPPS is not completely understood, and several mechanisms have been speculated to affect the male fertility in the absence of the pathogen.


Prostate Ejaculatory and Secretory Dysfunctions

The reduced volume of EPS may result in decreased semen volume. This can be a result of both secretory and ejaculatory dysfunctions. The role of male sex gland infections in diminishing the volume of EPS was observed in 1999 [95], but the mechanism of dysfunction in prostatitis remains unclear. The prostate infection may decrease the production of enzymes or secretion of citric acid, alpha-glucosidase, fructose, and zinc [56] or increase semen viscosity [25, 48], which adversely affects sperm motility. A complete lack of sperm occurs in about 10–15 % of infertile men. In fact, the most common problems in such cases are related to the testicles, hormone imbalances, or blockages in the male reproductive organs. However, chronic prostatitis may result in premature ejaculation [104] and ejaculatory and erectile dysfunctions [48]. The lack of sexual desire can be an additional component of sexual dysfunctions. These situations may lead to a decreased number of sexual intercourses. In order to optimize the likelihood of conception, a frequency of sexual intercourse from 2 to 3 times weekly was recommended [89].


Inflammatory Mediators

Inflammation in the prostate gland has been speculated to promote an autoimmune response, which might be leading to deleterious effects on semen quality and function [28, 65]. Moreover, anti-inflammatory treatment has been reported to have a positive impact on sperm parameters [93], although the exact details remain unclear. The originally suggested [39] role of prostatitis-induced antisperm antibodies against human sperm has not been supported in later studies [37, 56]. Instead, poor semen quality has been linked with the potential role of multiple cytokines, such as seminal interleukins 6, 8, 10, 12, and 18 and TNF-alpha [57, 65], in which detection might also be dependent on the presence of leukocytes or bacterial pathogens [57]. Although the leukocyte (or white blood cell (WBC)) counts may not correlate with the severity of symptoms [80], they are known to produce seminal reactive oxygen species (ROS) in response to infection or inflammation stimuli [74]. An abnormal ROS level is associated with human infertility in several ways, including some STIs, in particular C. trachomatis [10]. Increased levels of ROS are associated with leukocytospermia [85] and may lead to damage of cell membranes, intracellular proteins, organelles, [69] and sperm DNA [1, 69], with subsequent impairment of sperm motility [5] and decreased seminal total antioxidant capacity [74]. Interestingly, while increased seminal WBCs in the ejaculate of patients with CPPS were not found to affect semen parameters [53], elevated seminal leukocytes alone were associated with poor semen parameters [22]. An increased amount of ROS in semen is also linked to high DNA fragmentation index (DFI), a measure of the proportion of sperms with chromosome breaks and a predictor of male fertility independent of standard sperm parameters. Urogenital infections have been reported to imply increase in DFI [88]. However, although the role of oxidative stress has been associated with prostatitis and male infertility [47], the true pathways remain controversial, requiring further studies.


13.1.3.4 Asymptomatic Inflammatory Prostatitis


Asymptomatic inflammatory prostatitis (AIP) has been considered as a relatively rare disorder. However any prevalence data on AIP might be biased because of the nature of this prostate disorder: men with AIP present no symptoms, and, thus, the disorder is incidentally detected by prostatic biopsies to rule out prostate cancer or during an infertility workup [19]. The evidence of infections is based on the detection of increased number of leukocytes in prostate biopsy, seminal fluid, EPS, or voided bladder urine. The WHO defines leukocytospermia as the presence of ≥1 × 106 WBC/ml [99]. In prostatic fluid, 5–15 WBCs per high power field are generally considered as abnormal [80]. Studies on the potential role of AIP in male infertility are very limited. One retrospective study reported that a 3-week course of empirical antibiotic therapy applied to the male partners of infertile couples resolves leukocytospermia and improves the natural pregnancy rate among infertile couples, suggesting that low-level leukocytospermia has deleterious effects on male fertility [35]. AIP should be distinguished from CBP and CPPS.


Conclusions


The prostate gland plays an important role in the production of seminal fluid and the delivery of sperm during male ejaculation. Prostate infection and inflammation may affect the male fertility, and chronic prostatitis has been recognized as one of the causes of male infertility. However, several speculated pathways are poorly understood, and there is no general consensus on the exact mechanisms of prostatitis-induced infertility. In fact, while the vast majority of chronic prostatitis has been considered as abacterial, novel diagnostic approaches as MGS and some others are close to change this paradigm by discovering non-culturable microorganisms in men with chronic prostate disorders. These discoveries on prostate microbiome will help to determine the role of pathogens as potential cofactors in prostatitis-related infertility. Importantly, chronic prostatitis is a long-lasting, often recurrent, disorder with controversial evidence of infections in a gland with limited physical access. Future studies should also focus on the importance of prostate cellular and humoral anti-inflammatory response for male fertility, with contemporary biomarkers.


Take-Home Message





  • Infertility workup should include the evaluation of prostate infection and inflammation.


  • The impact of chronic prostatitis on semen parameters remains controversial.


  • Current detection methods do not detect non-culturable pathogens.


  • Further research on the role of prostate microbiome and inflammatory markers is warranted.


References



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Aitken RJ, Krausz C (2001) Oxidative stress, DNA damage and the Y chromosome. Reprod Camb Engl 122:497–506


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Alexander RB, Ponniah S, Hasday J, Hebel JR (1998) Elevated levels of proinflammatory cytokines in the semen of patients with chronic prostatitis/chronic pelvic pain syndrome. Urology 52:744–749CrossRefPubMed


3.

Alexander RB, Trissel D (1996) Chronic prostatitis: results of an Internet survey. Urology 48:568–574CrossRefPubMed

Jul 17, 2017 | Posted by in UROLOGY | Comments Off on The Role of Chronic Prostatitis in Male Infertility: Is There a Relationship?
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