The prostatitis syndrome is one of the most common entities encountered in urological practice. Classification of the prostatitis syndrome is based on the clinical presentation of the patient, the presence or absence of white blood cells in the expressed prostatic secretion (EPS) and the presence or absence of bacteria in the EPS (Schaeffer 1999). Depending upon the duration of symptoms, prostatitis is described as either acute or chronic, if symptoms are present for at least 3 months. Following various classification periods, the classification of the prostatitis syndrome suggested by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)/National Institutes of Health (NIH) from 1995 is currently applied in clinical routine as well as research (NIDDK Workshop Committee 1995; Krieger et al. 1999) (Table 13.2).
Table 13.2
Prostatitis NIH classification
I | Acute bacterial prostatitis |
II | Chronic bacterial prostatitis |
III | Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) |
(a) Inflammatory | |
(b) Noninflammatory | |
IV | Asymptomatic prostatitis |
Unfortunately, although prostatic secretions and seminal vesicles fluid are the main parts of the ejaculate, published data comparing both classification systems concerning urogenital infections do not exist.
13.2.1 Bacteriospermia and Leukocytospermia
Bacteriospermia means evidence of common microorganisms in semen, e.g. E. coli, enterococci, proteus and others.
A prerequisite for the detection of a ‘significant’ bacteriospermia is to avoid a microbiological contamination from non-semen sources (WHO 2010). Cleaning of the foreskin and the glans penis reduces contamination, whilst the ejaculation into a sterile container – only after passing urine – is suggested by the WHO (WHO 2010). Unfortunately, ejaculate is usually contaminated by the flora of the anterior urethra (Weidner et al. 2010). It has been assumed that about 70 % of semen samples are contaminated with urethral commensals, so bacteriospermia does not inevitably mean infection (Cottell et al. 2000). Accepted pathogenic bacteria are Escherichia (E.) coli and Enterococcus (E.) faecalis (Lackner et al. 2006), which are typical pathogens in urinary tract infections (UTIs) and causative in up to 90 % of all men with chronic bacterial prostatitis (WHO 2010; Schaeffer et al, 2006). For the daily work, ≥103 cfu/ml of common uropathogenic bacteria in the ejaculate has been suggested as ‘significant’ bacteriospermia (WHO 2010).
Traditionally, leukocytes in human semen are counted after a histochemical procedure that identifies the peroxidase enzyme (WHO 2010). The presence of ≥1 × 106 WBC/ml defines leukocytospermia (WHO 2010). Some authors consider this limit to be too high (Ludwig et al. 2003; Gdoura et al. 2008a, b), whereas others found leukocyte counts below the WHO threshold to be associated with deterioration of semen quality (Punab et al. 2003). The great majority of leukocytes are polymorphonuclear granulocytes identified by the specific staining of the peroxidase reaction (PPL = peroxidase-positive leukocytes).
Although most authors consider leukocytospermia to be a sign of bacterial induced inflammation, the condition is not necessarily associated with bacterial infections (Virecoulon et al. 2005). Notably, in proven bacterial prostatitis (Weidner et al. 2008), the concentration of PPL is very high. It is in accordance with earlier findings that elevated leukocyte numbers in semen do not inevitably result in male subfertility (Kopa and Berényi 2010). The impact of leukocytes depends upon the stages and sites at which WBCs enter the semen pathways (Kopa and Berényi 2010). There is also an obvious resolution of leukocytospermia after antibiotic therapy (Branigan and Muller 1994). We usually reconfirm leukocytospermia always by a second investigation. Then, in a case of a proven inflammatory situation, the subsequent exclusion of a bacterial infection of the prostate seems to be mandatory (Weidner et al. 2008). Until today, the role of macrophages in the ejaculate is not really identified although up to one third of all leukocytes are macrophages (overview in Rusz et al. 2012).
13.2.2 Other Characteristic Inflammatory Ejaculate Findings
Other markers in the ejaculate and the seminal plasma may be indicative for inflammation.
Seminal plasma elastase (polymorphonuclear elastase) measured in the seminal plasma by enzyme-linked immunosorbent assay also assists in the diagnosis of inflammation as elastase concentrations are correlating with the number of peroxidase-positive cells (Zorn et al. 2003; Kopa et al. 2005). Clinically, in our hands ≥280 ng/ml are indicative for further investigations (Wagenlehner et al. 2009) (Table 13.3).
Table 13.3
Giessen cutpoints for EPS, urine after P.M. (VB3) and ejaculate/seminal plasma parameters indicative for inflammation
Parameter | Cutpoint | |
|---|---|---|
EPS | Leukocytes | ≥10–20/1,000× |
VB3 | Leukocytes | ≥10/mm3 |
Semen | PPL | ≥0.113 × 106/ml |
Seminal plasma | Elastase | ≥280 ng/ml |
Seminal plasma | IL-8 | >10,600 pg/ml |
Cytokines such as the interleukin (IL) family are inflammatory mediators secreted by activated leukocytes or other immunocompetent cells in semen. Levels and types of cytokines have a crucial effect on the initiation, progression, magnitude or resolution of an inflammatory response. For a range of pro-inflammatory cytokines including IL-1, IL-6, IL-8 and TNF-α, a close correlation with seminal leukocyte numbers has been reported (Kopa and Berényi 2010).
The relevance of sperm antibodies (ASA) in the seminal plasma antibodies, measured by the MAR or immunobead test (Marconi et al. 2009a, b) in genitourinary infections and inflammation is still debatable. Some authors suggest an association between increased levels of sperm antibodies and prostatitis and epididymitis (Bates 1997; Hinting et al. 1996). Also an association to chlamydial infections has been described (Dimitrova et al. 2004). The prevalence of MAGI in patients with a positive mixed antiglobulin (MAR) test seems to be in the range of 20 %, whereby it is generally accepted that only antibodies bound to surface antigen of vital spermatozoa are clinically significant (Mazumdar and Levine 1998). Own data in chronic urethritis, epididymitis and prostatitis do not demonstrate any association between proven inflammatory/infectious diseases of the male reproductive tract and the presence of ASA (Marconi et al. 2009a, b).
Reactive oxygen species (ROS) interact theoretically with sperm abnormalities either by increased ROS production or depressed antioxidant mechanisms (Agarwal and Saleh 2002). The main sources of ROS in semen are the polymorphonuclear granulocytes (PMN) and the seminal macrophages in response to cytokine-stimulating factors, enhanced in the presence of cytokines and LPS. During infection/inflammation these antioxidant mechanisms may create a situation called ‘oxidative stress’ due to the elevated levels of ROS beyond the available total antioxidant capacity in the semen (Agarwal and Saleh 2002) resulting in sperm damage.
Table 13.3 summarizes inflammatory ejaculate findings indicative for MAGI and prostatitis.
13.2.3 Poor Semen Quality in MAGI and Prostatitis
In chronic urogenital inflammation, obstruction at the level of the veromontanum has been hypothesized as one cause of decreased ejaculate volume (Weidner et al. 1999). In chronic prostatitis (CBP, CP/CPPS Type A) a reduced ejaculate volume has not been found in general (Ludwig et al. 2002); in MAGI patients with significant bacteriospermia, a reduction of the sample volume has been detected (Marconi et al. 2009a, b). Decreased concentrations of prostatic secretory parameters, e.g. citric acid, phosphatase, zinc and alpha-glutamyl transferase, and reduced fructose levels as indicator of the seminal vesicles have been consented as signs for disturbed secretory function of the glands (overview in Weidner et al. 1999). Our own data reconfirm the detection of secretory damage of the prostate gland in inflammatory prostatitis (Ludwig et al. 2002) and in MAGI (Marconi et al. 2009a, b).
One key point in this context is the detection of reduced sperm counts and impaired sperm motility as a sequel of the different inflammatory entities. For prostatitis, a recent meta-analysis of our group demonstrated reduced sperm counts in 1 of 5 and reduced motility in 3 of 5 studies (Rusz et al. 2012). In proven chronic bacterial prostatitis, associated with significant bacteriospermia and leukocytospermia our group failed to show any differences compared to healthy controls (Weidner et al. 1991). Other data are not available.
Concerning morphology, in chronic inflammatory prostatitis, a deterioration of standard morphology seems not be proven (Weidner et al. 2008). Based on strict criteria for the definition of morphologically normal sperm, the group from Tygerberg has evaluated systematically the effect of male urogenital infections on sperm morphology and defined leukocytal activity as key point for hyperelongation and DNA damage of sperm (Menkveld 2010). Own data in inflammatory and noninflammatory chronic prostatitis/chronic pelvic pain syndrome demonstrate poorer sperm morphology (Menkveld et al. 2003) in inflammatory specimen associated with a reduced acrosomal inducibility (Henkel et al. 2006). Chronic epididymitis is of higher importance in this context (Haidl et al. 2008) with alterations of spermatozoa such as ‘tapering’ of sperm heads and differences in tail colouring (Menkveld et al. 2003; Haidl et al. 2008).
13.3 Role of Sexually Transmitted Microorganisms
13.3.1 HIV and Other Virus Infections
Investigations on viruses in the ejaculate are focused on hepatitis B (HBV), hepatitis C (HCV), human immunodeficiency virus type 1 (HIV) and papilloma virus infections. One major problem for the clinical impact of HBV and HCV infections is the viral load, especially after sperm washing procedures (Garrido et al 2005). Changes of sperm density, motility and morphology have been reported in different grades depending upon the examined population and antiviral treatment (Vicari et al. 2006; Moretti et al. 2008; Lorusso et al. 2010). One mechanism behind debatable deleterious effects may be the different integration of these viruses into sperm chromosomes (Huang et al. 2002).
Concerning HIV infections, already in 1991, Krieger and co-workers investigated the impact of HIV on fertility in 21 HIV-positive men and compared the sperm characteristics with semen from 40 donors. Interestingly, no differences in sperm parameters were detected (Krieger et al. 1991). Several cross-sectional studies have focused on the effect of HIV infection on sperm parameters, and conflicting results have been published (overview in Rusz et al. 2012). The discrepancies in these reports may be due to the small numbers in some studies, methodological variations, differing stages of HIV disease in the study groups as well as considerable variation in the choice of control groups (overview in Rusz et al. 2012). Nevertheless, in most studies, HIV-infected men in early-stage disease had semen parameters consistent with fertility (Krieger et al. 1991; Dulioust et al. 2002). A long-term investigation of 55 men over 96 weeks confirmed these results and revealed no significant changes in semen parameters between the first and last investigation (van Leeuwen et al. 2008). However, with disease progression a detrimental effect on semen variables was noted (Dulioust et al. 2002; van Leeuwen et al. 2008).
Interestingly, in several studies at least one of the parameters ejaculate volume, sperm motility, sperm concentration or normal sperm morphology was significantly correlated with the number of CD4+ blood cells (van Leeuwen et al. 2008; Dondero et al. 1996). HPV virus infections have been shown in 25 % of the sperm heads of infected men with a decrease of sperm motility (Foresta et al. 2010a, b). These data have not been reconfirmed until today. The authors believe in the relevance of these findings for the transmission of this virus, especially for sperm donors (Punab et al. 2003).
13.3.2 Chlamydia (C.) trachomatis
Using nucleic acid amplification techniques, C. trachomatis has been detected in asymptomatic men in 2.5 % (Bezold et al. 2007). Depending upon the analyzed patient cohort, the prevalence of C. trachomatis infections in semen is between 1.6 and 10.9 % (Cunningham and Beagley 2008). Obviously, the possibility of a urethral infection reduces the significance of positive chlamydial findings in the ejaculate (Wagenlehner et al. 2006). Increased IL-8 levels and evidence of antichlamydial mucosal IgA in the seminal plasma are suggested to provide a clearer diagnosis (Mazzoli et al. 2007). There is no debate that C. trachomatis ascends the seminal pathways questionable up to the testicles, but a proven biological significance seems only to be accepted for acute epididymitis and consecutive azoospermia (Weidner et al. 2008; Rusz et al. 2012). Although the spread into the different accessory glands seems logical, until today proven prostatic infections have not been confirmed (Wagenlehner et al. 2006; Rusz et al. 2012). Normally, a leukocytal reaction of the ejaculate is associated with chlamydial infections (Hosseinzadeh et al. 2004; Kokab et al. 2010), partially including C. trachomatis inclusion inside the seminal leukocytes (Gallegos-Avila et al. 2009) and a cytokine response of IL-6 and IL-8 in the seminal plasma (Kokab et al. 2010). Direct effects on sperm may be caused by alive microorganisms but also by C. trachomatis LPS (Hosseinzadeh et al. 2003).
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