The specific cause of most cases of non-acute prostatitis is unknown. Likewise, important aspects concerning the route of possible infection and pathogenesis remains uncertain even in clear instances of bacterial prostatitis (Kretschmer 1939, Krieger 1984, Meares 1984, Blacklock 1991). Anatomical/clinical examinations of prostatitis patients have shown that two factors are needed for the development of prostate inflammation: dysfunctional voiding with high pressure due to anatomical or physiological obstruction (Blacklock 1991) and intraductal reflux of urine into the prostate gland (Kirby et al. 1982, Barbalias et al. 1983, Hellstrom et al. 1987, Chapple et al. 1990).
The causative agents in bacterial prostatitis are similar in type and prevalence to those responsible for urinary tract infections with common strains of Escherichia coli (Kretschmer 1939, Domingue & Hellstrom 1998), although infections caused by species of Proteus, Klebsiella, Enterobacteria, Pseudomonas, Serratia (Domingue & Hellstrom 1998) and lately Chlamydia, Ureaplasma, Mycoplasma (Weidner et al. 1988), Corynebacteria and viruses (cyto-megalo virus, human immunodeficiency virus, herpes etc.), not to mention bacterial infections in acquired immune deficiency syndrome (AIDS) patients (Leport et al. 1989, Staiman & Lowe 1996) and fungi (Wise et al. 1999) can also occur. Special interest was aroused in the 1970s and 1980s when antibody-coated bacteria were detected in immunological tests and it was hypothesized that chronic prostatitis may be a problem of altered immunity due to an antigenic stimulus (parts of bacteria and/or toxins) (Shortliffe et al. 1981, Fowler & Mariano 1982, Fowler 1991, Riedasch et al. 1991, Kumon 1992) and is under research again (Alexander et al. 1997, John et al. 2001).
Much information on the aetiology and pathogenesis of prostatitis has been gathered through the use of animal models, which have shown that immunologically or chemically mediated prostatic inflammation is the reason for hyperplastic changes (Nickel et al. 1990, Keetch et al. 1994, Takechi et al. 1999). Escherichia coli is the predominant organism causing acute and/or chronic inflammation, followed by other gram-negative pathogens. Rat and canine models have been used to confirm the importance of E. coli in the disease process and also to follow the distribution of antibiotics in the prostate gland (Neal et al. 1990, Nickel et al. 1990, Bahk et al. 2000). Experimental results have confirmed the pathophysiological mechanism of the route by which bacteria ascend from the urethra into the prostate gland through reflux. Urethral inoculation of monkeys with bacteria also resulted in similar findings to those observed in humans (Neal et al. 1990).
PSA behaviour in prostatitis was studied experimentally in monkeys (Neal et al. 1990, Neal et al. 1992) confirming that it takes 8 weeks for PSA to return to the base level after acute prostatitis.
The rat model used by Nickel et al. (1990) gave reliable and consistent results regarding the role of bacteria in acute and chronic bacterial prostatitis, showing that bacteria entering the ducts and acini of the prostate will multiply rapidly and induce a host response with infiltration of acute inflammatory cells into the ducts. Infiltrates of dead and live bacteria, and also inflammatory cells, desquamated epithelial cells and cellular debris, will block the ducts and may cause systemic clinical urosepsis. It has also been shown that infection can be eradicated with proper antibiotic treatment, but if the bacteria form small microcolonies coated with exopolysaccharide slime or glycocalyx they can ”hibernate” out of range of the antibiotics. Lymphatic invasion with infiltration of plasma cells and macrophages can be seen around the colonies, leading later to fibrosis and permanent scarring (Nickel et al. 1990).
Naslund et al. (1988) showed experimentally that genetic background and hormonal imbalance with advancing age are important factors in the process of non-bacterial prostatitis. It has also been shown that prostatic inflammation is at least partially immune-mediated, explaining the close association between non-bacterial and bacterial-induced chronic inflammation (Keetch et al. 1994).
Experimental studies have also confirmed that bacteria can persist in the prostate tissue following treatment with antibiotics and remain undetectable in the prostate secretion. It is possible that the pharmacokinetics of the drugs may be altered by local inflammation, blockage of ducts, calculi in the acini, microabscesses and pH changes through tissue hypoxia (Klimas et al. 1985, Nickel et al. 1990, Nickel et al. 1995).
The rat model used by Nickel et al. (1990) showed that antibiotic concentrations in the inflammed glandular ducts were not significantly higher than in non-inflammed ducts, but bacterial aggregates in the slime were more resistant to normal concentrations of antibiotics and to host defence.
Fulmer and Turner (2000) showed that there is a blood-prostate barrier that restricts the movement of cells and molecules from the blood or interstitium into the prostatic ducts. This may explain the situation in which prostatitis symptoms occur but diagnostic methods fail to prove it. On the other hand, it was shown in a rat experiment that the protective barrier of the epithelium can be damaged and local resistance to cytokines/mediators reduced, possibly leading to inflammation (Lang et al. 2000), because otherwise harmless agents from the urine can start the inflammation process by reflux.
Four main aetiological reasons for the induction of prostate inflammation are generally accepted, and the recovery or chronicity of the process depends on balances or imbalances between the predisposing factors and/or host defence mechanisms.
The bacterial component is indisputable in cases of acute or chronic bacterial prostatitis, but it is questionable in cases of chronic non-bacterial prostatitis or prostatodynia (Berger et al. 1989, Shortliffe et al. 1992, Lowentritt et al. 1995, Berger et al. 1997, Krieger et al. 2000b).
The role of urine reflux has also been demonstrated experimentally in the human prostate gland (Kirby et al. 1982, Chapple et al. 1990, Turner et al. 1996) and in animal models (Nickel et al. 1990). A lot of evidence is available to support the importance of high voiding pressure, explaining the chronicity of symptoms in a certain group of men with prostatitis (Kirby et al. 1982, Barbalias et al. 1983, Hellstrom et al. 1987).
The immunological status of the host and the adherence capacity of the infective agents (Mårdh et al. 1979) play a role in the results of the treatment and also in development of chronic disease (Fowler & Mariano 1982, Doble et al. 1990, Nickel & Costerton 1992, Nickel & Costerton 1993, Nishimura et al. 1998).
And last but not least, the importance of mental stress has been underestimated and forgotten, but there is now agreement that psychic aspects must also be taken into account seriously when treating patients with prostatitis (Kretschmer 1937, Keltikangas-Järvinen et al. 1982, Miller 1988, Keltikangas-Järvinen et al. 1989, de la Rosette et al. 1993b, Egan & Krieger 1994, Berghuis et al. 1996).
The true prevalence of histologically confirmed prostatitis in the absence of other prostatic disease is very difficult to determine, for three reasons: firstly, most studies of prostatitis have used tissue obtained from patients over 40 years of age by surgery, secondly, the prostate tissue is altered by hyperplasia or carcinoma processes which contribute to the development of inflammatory signs, and thirdly, the clinical definition of prostatitis is not uniform between various investigators (McNeal 1988, Bennett et al. 1993).
With certain reservations, the prevalence of histologically proved prostatitis is reported to be from 31% to 98% (Kohnen & Drach 1979, Melhorn 1987, Doble et al. 1989a, Nickel et al. 1999a, True et al. 1999), while Schatteman et al. (2000) found signs of inflammation in 100% of cases.
Considerable variation exists in the histological classification of chronic inflammation. Most pathologists agree with the basic definition characterizing the process of acute prostatitis: the presence of polymorphonuclear leukocytes (PMNL) and macrophages in the glandular ducts, the epithelium and/or the adjacent stroma. Stromal involvement varies, however, and increases with the density of intraluminal inflammation. Luminal infiltration by PMNL is accompanied by periglandular accumulation of lymphocytes and monocytes, and occasionally plasma cells. It has been speculated that the inflammation starts from the peripheral zone and spills over into the central periurethral zone (Maksem et al. 1988, McNeal 1988, Matsumoto et al. 1992, Bennett et al. 1993).
Histological findings based on prostatic tissue samples from clinically diagnosed chronic prostatitis patients show mononuclear cell infiltrates (lymphocytes, monocytes and plasma cells) in the stromal connective tissue around the acini or ducts, but it may also be that only focal inflammation is present. The infiltrates are most commonly multifocal (Gardner & Bennett 1992, Matsumoto et al. 1992, Bennett et al. 1993).
There is little or no correlation between the histological presence of chronic prostatitis and the clinical symptoms. The histological signs of chronic prostatitis also include distortion of the glandular ducts, disruption of the epithelium, atrophy and loss of the secretory activity of the epithelium, and hyperchromasia with polymorphism of the epithelial cell nuclei and cytoplasmic basophilia. These dysplastic changes can be misinterpreted as carcinoma of the prostate if the association with chronic prostatitis is not recognized, and this situation can be worsened by changes such as squamous metaplasia, which occurs frequently in the inflammatory areas of chronic prostatitis (McNeal 1988, Bennett et al. 1993).
A fine-needle aspiration (FNA) method was also developed for this purpose, but it is contraindicated in cases of acute symptomatic prostatitis due to the risk of sepsis, especially in patients with immunosuppression (Maksem et al. 1988, Matsumoto et al. 1992, Bennet et al. 1993).
The most common change observed in chronic prostatitis is glandular atrophy with stromal fibrosis, accompanied by a mild residual inflammation reaction occurring in several stages. Epithelial changes are frequent, ranging from squamous metaplasia to dysplastic changes (Maksem et al. 1988, McNeal 1988).
It is essential to be able to demonstrate bacteria reliably in the EPS, semen or both in order to reach the correct treatment decisions and to ensure a good outcome. Laboratory findings have shown in practice that almost all standard localization cultures are negative and that success in culturing bacteria from EPS is complicated by the presence of inhibitory substances known to exist in prostate secretion and by a history of multiple previous courses of antibiotics (Fair & Parrish 1981, Nickel et al. 1998, Bjerklund Johansen et al. 1998).
Clear confirmation of the pathogenicity of bacteria in prostate tissue and/or ducts has been obtained with a group of gram-negative uropathogens including E. coli, Klebsiella spp., Serratia and Pseudomonas spp (Kretschmer 1937, Meares & Stamey 1968, Domingue & Hellstrom 1998, Meares 1998). There can also sometimes be gram-positive uropathogens such as Enterococcus spp. and Staphylococcus spp. present (Bergman et al. 1989, Nickel & Costerton 1992, Nickel & Costerton 1993, Domingue & Hellstrom 1998).
Possible temporary pathogens in prostate tissue and/or ducts under certain conditions can be: coagulase-negative Staphylococcus species, Chlamydia, Ureaplasma, Candida and Trichomonas (Poletti et al. 1985, Weidner et al. 1988, Bergman et al. 1989, Nickel & Costerton 1992, Krieger et al. 1993b, Ohkawa et al. 1993, Ostrazewska et al. 1998, Wise et al. 1999, Nickel 2000, Potts et al. 2000).
Acknowledged not to be pathogens so far are: Diphteroids, Lactobacilli and Corynebacteria spp. (Domingue & Hellstrom 1998, Nickel 2000).
A number of prostatitis studies provide some support for a new concept, the use of immunochemistry, electron microscopy and ultrasensitive molecular PCR methods for detecting bacteria or their remnants in prostate tissue, implying that at least the majority of patients with prostatitis, and perhaps all of them, have a microbiological cause for their symptoms (Shurbaji et al. 1988, Nickel & Costerton 1993, Berger et al. 1997, Domingue & Hellstrom 1998, Tanner et al. 1999, Hochreiter et al. 2000, Krieger et al. 2000c, Terai et al. 2000).
Last but not least, we must also mention cryptic non-culturable organisms such as altered ”biofilm-forming colonies”, viruses and cell wall-deficient bacteria, the importance of which for the immune system of the host is not finally clear (Nickel & Costerton 1993, Staiman & Lowe 1996, Berger et al. 1997, Domingue & Hellstrom 1998, Nickel & McLean 1998, Choong & Whitefield 2000).
The secretory immune response is an essential factor in helping the mucosal barrier to resist bacterial invasion into the glandular-epithelial system of the prostate gland. The prostate secretes local antibodies in response to infection or to the remnants of bacterial protein, and this local response is often different from the systemic one reflected in the serum findings. The amounts of immunoglobulins G and A (IgG and IgA) have been found to be much lower in normal human prostatic fluid than in patients with prostatitis. It thus appears that measurements of antigen-specific IgA and IgG levels in the prostatic fluid can be helpful in the diagnosis of prostatitis and in determining the possible response to long-term courses of antibiotics in patients with a confirmed aetiology (Shortliffe et al. 1981, Fowler & Mariano 1982, Wishnow et al. 1982, Fowler 1991, Kumon 1992, Meares 1998).
The most common aetiological factor having a strong immunological effect on the secretion of antigen-specific IgA into the prostatic fluid, independent of the systemic immune response, is E. coli (Wishnow et al. 1982) and very occasionally certain enterococcus species, the role of staphylococci being more questionable (Fowler & Mariano 1982, Bergman et al. 1989).
On the other hand, Nickel and Costerton (1992, 1993) showed in cultures from prostate tissue that coagulase-negative staphylococci formed focal microcolonies that adhered to the walls of the prostatic ducts and were protected with glycocalyx–slime, and deduced that it was not the bacteria themselves that led to tissue damage but the immune-mediated inflammation (Nickel & Costerton 1992, Nickel & Costerton 1993).
Typical over-reactions of the host response and delayed hypersensitivity reactions are represented by inflammatory infiltrates from T-lymphocytes (CD4+ T helper/inducer cells and CD8+ T cytotoxic/suppressor cells), which are distributed variously between the epithelial and stromal components. This can be due to intraprostatic spermatozoa intrusion, which is known to have a powerful autoimmunization capacity and activity in some cases (McClinton et al. 1990). It has been shown in autopsy material that sperm may penetrate into the somatic cells and that this can produce tissue changes similar to those induced by a variety of carcinogens in experiments performed with human tissue (Gardner & Bennett 1992). This phenomenon was confirmed by Alexander et al. (1997), who showed that the CD4 /T-cell proliferative response to seminal plasma was significant in cases of CP/CPPS as compared with normal men. Ponniah et al. (2000) showed that some men with symptoms of chronic prostatitis have evidence of a proliferative CD4 /T-cell response to PSA, one antigen candidate for possible autoimmune prostatitis. John et al. (2001) have confirmed that T-lymphocytes have a role in the excretion of inflammatory mediators such as complements C3, C4 and IL-6 in the serum and ejaculate. They also found an increase in IgA in the ejaculate. The concentrations of these markers decreased with the relief of prostatitis symptoms.
Persson and Ronquist (1996) studied the chemical composition of expressed prostatic secretion (EPS) and urine, showing that the origin of the chemical reaction and the basis for tissue inflammation was reflux into the prostatic ducts. Analogical findings were described by Ramirez et al. (1980) and by Klimas et al. (1985), showing that prostatic calculi are partly composed of the remains of ingredients coming from the urine by reflux (Kirby et al. 1982, Chapple et al. 1990, Turner et al. 1996).
If prostatic ducts are obstructed by calculi, there may be a mechanical reaction on the epithelia through rising intraductal fluid pressure or direct irritation from calculi, and age can also be a co-reflecting factor (Sutor & Wooley 1974, Ramirez et al. 1980, Klimas et al. 1985, Söndergaard et al. 1987).
It cannot be judged what came first: anatomical structural changes or functional disorders (Blacklock 1974, Blacklock 1991). It may be that reflux comes first, leading to chronic inflammation, upon which local reactions and tissue oedema or the increased intracompartmental tissue pressure lead to voiding disturbances with more reflux of urine, sterile or infected (Kirby et al. 1982, Barbalias et al. 1983, Hellstrom et al. 1987, Chapple et al. 1990, Persson & Ronquist 1996, Turner et al. 1996, Theodorou et al. 1999).
Measurement of urine flow rate should be an integral part of the evaluation of prostatitis patients, as most patients with prostatodynia have abnormal flowmetry parametres and distinct flow patterns (Ghobish 2000). Synchronous video-pressure-flow studies using a triple-lumen catheter with synchronous electromyography of the external urethral sphincter have demonstrated increased maximum urethral clossure pressure in the proximal prostatic and membranous urethral segments as compared with controls (Barbalias et al. 1983, Barbalias 1990), and also decreased maximum and average flow rates. The findings were originally confirmed in patients with prostatodynia, but identical observations were made in patients with an inflammatory prostate (Barbalias 1990), causing the author to abandon the term prostatodynia in favour of “painful urethral syndrome”. It was concluded that the findings could be attributed to a sympathetically mediated spasm.
Increased pressure in the prostatic urethra causes reflux into the prostatic ducts and ejaculatory ducts accompanied by prostate tissue irritation (chemical reaction of urine component, seminal vesiculitis and even epididymitis in cases of infected urine) (Kirby et al. 1982, Hellstrom et al. 1987, Chapple v. 1990, Thind et al. 1992, Turner et al. 1996). It is appropriate to perform video-urodynamic assessment to rule out possible neurological reasons for voiding disturbances and/or to validate any findings of organic causes of LUTS and recurrent symptoms of CP/CPPS, thus also exploring the indications for alpha-blocker treatment (Turner-Warwick et al. 1973, Barbalias et al. 1983, Hellstrom et al. 1987, de la Rosette et al. 1992b, Kaplan et al. 1994, Neal & Moon 1994, Kaplan et al. 1997, Barbalias et al. 1998).
Some patients with CP/CPPS appear to suffer mainly from tension myalgia of the pelvic floor and symptoms thought to arise from habitual contraction or spasm of the pelvic floor muscles (Lilius & Valtonen 1972, Segura et al. 1979, Barbalias et al. 1983, Ricchiuti et al. 1999, Zermann et al. 1999). Patients also report pain and discomfort associated with sitting, running or other physical activities that lead to spasms in the perineal muscles. It is possible that a rectal examination may demonstrate a spastic anal sphincter and paraprostatic tenderness, but not a tender prostate at all (Lilius & Valtonen 1972, Segura et al. 1979).
As pointed out by Kretschmer in 1939, sexual neurasthenia can occur in a small but very definitive group of prostatitis patients in association with maritual difficulties, melancholia, nervousness, irritability, depression and also suicidal tendencies (Kretschmer 1939). Psychological factors are considered to play an important role in the aetiology of chronic prostatitis, and as early as the late 1960s and the 1970s, a long time before prospective studies related to personality changes in prostatitis patients, professor Jack Lapides wrote, ”…the management of the patient with symptoms and no objective findings involves a work-up as complete as that of the individual with recurrent infection and then a therapeutic regimen aimed toward support of the psyche with help from the psychiatrist if necessary” (Lapides 1976).
Urological patients with chronic complaints generally tend to exhibit psychiatric problems, and there is a widely held belief among urologists, that these patients are ”neurotic” (Kretschmer 1937). In this view chronic prostatitis patients as well often tend to be characterized as having problems with their male sexual identity. Symptoms such as anxiety, depression, fear, sexual disturbances and feelings of insecurity in human relationships have been reported. Psychosomatic factors were found to be important aspects in connection with a ”psychosomatic personality” and in the expression of psychological emotional problems as a whole (Keltikangas-Järvinen et al. 1981, Keltikangas-Järvinen et al. 1982, Keltikangas-Järvinen et al. 1989, de la Rosette et al. 1993b, Egan & Krieger 1994, Berghuis et al. 1996). Patients have reported that their symptoms greatly affect sexual or romantic relationships (Kretschmer 1937, Keltikangas-Järvinen et al. 1989, Egan & Krieger 1994, Berghuis et al. 1996,).
Psychological evaluation, relationship counselling and even medical treatment for depression may play an important role in the overall approach to chronic prostatitis patients. This is in some cases obligatory in order to achieve any improvement in the symptoms or to avoid worsening of the mental distress (Kretschmer 1937, Keltikangas-Järvinen et al. 1982, Keltikangas-Järvinen et al. 1989, Egan & Krieger 1994, Berghuis et al. 1996).