The term prostatodynia, or chronic pelvic pain syndrome (CPPS), is used to designate unexplained chronic pelvic pain in men. This pain is associated with irritative voiding symptoms and/or pain located in the groin, genitalia, or perineum in the absence of pyuria and bacteriuria (no pus cells or bacteria seen on microscopic analysis of the urine). However, excess white blood cells (WBCs) or bacteria seen on Gram stain and culture of expressed prostatic secretions (EPS) may be found. (See Workup.)
The use of the term prostatodynia is not encouraged in current practice. This term carries the negative historical connotation of being a "wastebasket" designation for a melange of psychosomatic symptoms and suggests that the source of the patient's symptoms invariably lies within the prostate gland itself. Current research has provided evidence of numerous extraprostatic considerations, including neuropathic and other systemic pathologies. (See Etiology.)
Categories of prostatitis
The National Institutes of Health (NIH) describes four categories of prostatitis, as follows:
Type I - Acute bacterial prostatitis
Type II - Chronic bacterial prostatitis
Type III - Chronic abacterial prostatitis, ie, CPPS, categorized as either type IIIa (inflammatory CPPS) or type IIIb (noninflammatory CPPS)
Type IV - Asymptomatic inflammatory prostatitis
An academic distinction is currently made between (1) patients with excess WBCs in their prostatic secretions (chronic nonbacterial prostatitis, class IIIa) and (2) those with normal prostatic secretions (prostatodynia, class IIIb). However, the clinical value of this distinction is now being challenged. The sole parameter is the number of WBCs seen within a smear of prostatic secretions, yet this number may vary widely within the same specimen and even more so from sample to sample taken from the same patient. (See Workup.)
Furthermore, asymptomatic control patients devoid of any evidence of pelvic pathology have also been found to have a significant number of WBCs in their prostatic secretions. At present, the distinction seems to provide no meaningful differential with respect to either etiology or treatment options. (See Clinical, Differentials, and Treatment.)
Chronic pelvic pain syndrome (CPPS) in the male is not a syndrome; it is not a discrete, narrowly defined constellation of consistent symptoms and objective findings ultimately traceable to a single, known etiology. Rather, CPPS in the male is a catch-all category of convenience into which physicians arbitrarily group the heterogeneous admixture of male patients who meet the following three criteria:
Patients have a variety of long-standing symptoms, a significant number of which relate to anatomical structures located within an arbitrary radius of the prostate gland (somewhere below the umbilicus and above the midthigh)
Physicians can find no objective explanation for the patients’ symptoms
Physicians can offer no satisfactory treatment, let alone a cure, for the patients’ symptoms
Pontari and Ruggieri reviewed the numerous pathophysiologic mechanisms implicated as the potential etiologies of CPPS and concluded that, although the causes of CPPS remain unknown, the condition’s symptoms seem to arise from the interaction between psychological factors and immune, neurologic, and endocrine system dysfunction. 
The number of WBCs (pus cells) found in the prostatic fluid under microscopic examination—long considered the hallmark of this disease process—does not correlate with the degree of pain or with other symptoms experienced by patients with CPPS. Histologic signs of inflammation were found in only one third of all patients diagnosed with CPPS who underwent prostatic biopsy, according to Pontari and Ruggieri’s report, further suggesting an extraprostatic etiology for CPPS. This indicated that perhaps CPPS is not directly associated with the prostate or with inflammation within it, at least in some cases.
Special signaling molecules called cytokines, which are produced by WBCs (and by other cells), may play a role. While certain cytokines stimulate an inflammatory reaction, others inhibit inflammation. Moreover, the same cytokine may act as either an inciting influence or an inhibiting influence at different sites under varying conditions. Tissue necrosis factors, interleukins, interferons, and epithelial neutrophil-activating factors are but a few of these cytokines. To complicate matters, each of these terms indicates a whole, separate family of closely related molecules, not a single agent. An imbalance in this complex network of cytokines (ie, of proinflammatory cytokines and endogenous cytokine inhibitors) has been linked to the development of pelvic inflammation and pain in patients with CPPS.
Genetic predisposition to CPPS may be the result of differences in DNA sequences at chromosomal sites that regulate the production and action of these various cytokines.
Autoimmunity has long been thought to play a role in the development of CPPS. In this context, immunity refers to the body's ability to reject foreign material, such as bacteria or toxins. This process can sometimes turn on itself and lead to rejection of the body's own healthy tissues. In CPPS, the body may be attempting to reject its own prostate.
Testosterone has been shown to protect against inflammation within the prostate. Perhaps a low testosterone level (or, more likely, a breakdown in the mechanism whereby testosterone inhibits prostatic inflammation) may be at work in some men with CPPS.
Abnormal functioning of the nervous system, at the local level and/or within the central nervous system (CNS), may also play a role in the development of CPPS. For example, a substance known as nerve growth factor (NGF) can cause an increase in the number and the sensitivity of the pelvic nerves that transmit pain. An increase in NGF has been correlated with the development of CPPS symptoms.
Each of the above factors has been individually identified as a culprit in the causation of CPPS; additionally, at least in some cases, they may interact with each other to cause CPPS. For instance, cytokines may adversely affect the suppression of NGF, leading to a flare of CPPS symptoms.
Psychological stress and depression have long been associated with CPPS flare-ups. This observation has led some researchers to mistakenly conclude that CPPS is "all in your head” or that such mental stress results in a lower psychological threshold for the same objective degree of pain. Data now suggest, however, that psychological stress and depression may measurably influence the local production of cytokines (eg, interleukin 10, interleukin 6) in the pelvis, thus directly exacerbating CPPS inflammation.
Some cases of "abacterial" prostatitis may not actually be abacterial. Data suggest that gram-positive bacteria, which have traditionally been dismissed as normal florae in prostatic fluid cultures, may not be so normal in men with CPPS. Normal defense mechanisms allow healthy men to render these bacteria harmless, turning them into mere microbial "hitchhikers." However, these defense mechanisms may be defective in men with CPPS. This theory helps to explain why prolonged courses of antibiotics sometimes provide symptomatic relief for men with CPPS despite the absence of bacteria that are traditionally considered pathogenic.
Pontari and Ruggieri conclude, "To what degree these factors interact in a given patient and to what degree there is a common pathway or several pathways that lead to the end point of pelvic pain remains to be determined." 
Fastidious organisms in CPPS
Among the fastidious bacteria (ie, bacteria that cannot be isolated on standard culture media) that have been implicated in CPPS are the following:
Genital mycoplasmas (ie, Ureaplasma urealyticum, Mycoplasma hominis, M genitalium)
In addition, a protozoan (ie, Trichomonas vaginalis), genital tract viruses (eg, herpes simplex virus types 1 and 2, cytomegalovirus), and fungi have also been implicated.
In a study by Krieger and Riley, only 10 (8%) of 135 patients with chronic prostatitis (CP)/CPPS tested positive for fastidious organisms. However, in another series, 79 (47%) of 170 specimens from patients with CP/CPPS exhibited gene sequencing (16S rDNA) that was positive for the presence of microbes, while only 21 (20%) of 117 control specimens from patients undergoing radical prostatectomy were positive (P < 0.01). These observations support a potential role for uncommon organisms in CP/CPPS. 
Bacteriologic breakthroughs in understanding CPPS
Intriguing findings from collaborating investigators in Australia and California suggest that persistent microbial infection with an indolent, but persistent, organism that is difficult to detect and difficult for the host to eradicate may act as an etiologic agent for CP and for the subsequent development of prostate cancer. 
The presence of this organism, Propionibacterium acnes, could be detected only via sophisticated gene-sequencing and polymerase chain reaction (PCR) assay technology. P acnes could not be identified using routine histology, Gram stain, or routine culture techniques.
These preliminary findings suggest that chronic abacterial prostatitis may, in certain cases, actually be due to an occult, chronic bacterial infection. Further, persistence of this smoldering infection may lead to the development of prostate cancer.
Confirmation of these findings, along with the identification of effective methods to eradicate these bacteria, could lead to cure and prevention, at least in some cases, of CP and prostate cancer.
Escherichia coli infection is a common cause of acute bacterial prostatitis. However, these bacteria cannot be cultured in patients with chronic abacterial prostatitis. Certain strains of these bacteria may have developed a cloaking defense that allows them to conceal their activity and to resist antibiotic therapy.
Laboratory studies suggest that specific strains of E coli are specifically uropathogenic, ie, uropathogenic E coli (UPEC). These UPEC bacteria have the capability of penetrating into prostate cells. Once they have invaded prostate cells, they trigger a genetically linked reaction that sustains the pain by immunological and/or neurological mechanisms, even after the bacteria have been eradicated. These findings might help explain why antibiotics can be helpful in treating an initial bout of acute prostatitis, and yet be ineffective in relieving subsequent bouts. Only certain strains of E coli are capable of invading the prostate cell; some men may be more at risk than others. 
Biofilms develop when large numbers of bacteria embed in a microscopic slime layer called an exopolysaccharide matrix. Entrenched within this biofilm layer, the bacteria may resist antibacterial treatment, counter the human body's natural defenses, and defy detection by routine culture techniques.
By forming these biofilms within the prostate, E coli and related bacterial pathogens may cause chronic, treatment-resistant prostatitis. In some cases, they may also be the cause of chronic abacterial prostatitis. Prolonged (6-wk) courses of effective antibiotics (eg, a quinolone), when used to treat the first bout of acute prostatitis, may prevent the bacteria from forming a biofilm. Early, vigorous treatment of the first case of prostatitis using this method may help to prevent the inflammation from progressing into the chronic phase of bacterial or abacterial prostatitis. 
Neuropathy in CPPS
Findings of spastic hyperactivity on videourodynamic studies, in the absence of a definable underlying neuropathy, suggest the presence of either an occult neural etiology or an acquired functional voiding disorder.
Myofascial pain syndrome has been postulated as a cause for CP/CPPS. Even in the face of clinical inflammation, a reflex triggering of spasm in the musculature of the pelvic floor can be a secondary, but clinically significant, source of much of the symptomatology. 
Immunology in CPPS
An autoimmune basis for chronic prostatitis has been well established in different murine models. Unfortunately, a clinical correlation in humans has not yet been well elucidated.
Stromal cells in benign prostatic hyperplasia (BPH) tissue have been shown to be capable of acting as antigen-presenting cells and activating CD4(+) lymphocytes, as well as producing interleukins. 
Several studies now demonstrate that men with CP/CPPS show evidence of having a “pan-pelvic hypersensitivity syndrome.” Using the fibromyalgia tender point scale, men with CP/CPPS tend to be more tender than normal, not only in the pelvic region, but also at every other point throughout their entire body. Whatever causes CP/CPPS leads to a serious and hard-to-treat hypersensitivity of the entire CNS. This difference in lowered pain tolerance holds true, whether or not the CP/CPPS patient was experiencing a flare-up of prostatitis. 
CP most commonly affects men older than 50 years. It is only slightly less common in men younger than 50 years.
Occurrence in the United States
Chronic prostatitis (CP) is the most common urologic diagnosis in men older than age 50 years and is the third most common diagnosis in men younger than age 50 years. This diagnosis results in at least 2 million office visits per year. The average urologist sees approximately 10 patients with prostatitis per month, 30% of whom are new patients. Specific urinary pathogens are detected infrequently after culture. The vast majority of these patients are categorized as having chronic nonbacterial prostatitis, that is, CPPS.
The following Web sites are helpful for both patients and physicians:
The International Association for the Study of Pain special interest group on Pain of Urogenital Origin (PUGO)
For patient education information, see the Men's Health Center and the Cancer Center, as well as Prostate Infections (Prostatitis), Impotence/Erectile Dysfunction, Bladder Cancer, and Bladder Control Problems.
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