In the 20 th century, the term “prostatitis” traditionally referred to inflammation in the prostate, often attributed to infection. Prostatitis in this century usually refers to a chronic pain syndrome for which the presence of inflammation and involvement of the prostate are not always certain. This article discusses chronic prostatitis/chronic pelvic pain syndrome and the various factors associated with diagnosis and treatment.
In the 20 th century, the term “prostatitis” traditionally referred to inflammation in the prostate, often attributed to infection. Prostatitis in this century usually refers to a chronic pain syndrome for which the presence of inflammation and involvement of the prostate are not always certain.
Definition and classification
The traditional classification of prostatitis, proposed by Drach and colleagues in 1978, included acute prostatitis, chronic bacterial prostatitis, chronic nonbacterial prostatitis, and prostatodynia. A more recent classification was adopted in 1995 after a National Institutes of Health (NIH)-sponsored consensus conference and expands the classification ( Table 1 ) . In the current system, Category I and II reflect acute and chronic bacterial prostatitis, respectively. Together, both account for no more than 5% to 10% of all cases . These cases are clearly associated with bacterial infection and will have a urine culture that grows uropathogens. Acute prostatitis is characterized by the sudden onset of fever and dysuria, whereas chronic bacterial prostatitis typically involves relapsing episodes of urinary tract infections, usually with the same organism seen on urine cultures. These patients are usually asymptomatic between infections. Category IV refers to asymptomatic inflammatory prostatitis that is diagnosed incidentally during a work up for infertility, an elevated prostate-specific antigen (PSA), or benign prostatic hyperplasia (BPH). The recent MTOPS study linked prostate inflammation to increased progression of symptoms or urinary retention in a cohort of BPH subjects , so the idea that type IV is asymptomatic may be outdated. More accurately it may reflect lower urinary tract symptoms without pelvic pain, but this has not been unequivocally established.
| Category | Description/Type | |
|---|---|---|
| I | Acute bacterial prostatitis | |
| II | Chronic bacterial prostatitis | |
| III | Chronic prostatitis/chronic pelvic pain syndrome | |
| IIIA | Inflammatory a | |
| IIIB | Noninflammatory a | |
| IV | Asymptomatic inflammation of the prostate |
a Inflammation is determined by the presence of white blood cell counts in one of the following: after prostate massage urine specimen, seminal plasma, or expressed prostatic secretions.
Category III, known as chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), constitutes the vast majority (more than 90%) of cases, and is divided into IIIA and IIIB. IIIA refers to the presence of white blood cells in semen, after prostate massage urine specimen (VB3), or expressed prostatic secretion (EPS). This corresponds to the previously used classification of nonbacterial prostatitis. Category IIIB is comparable to the formerly used term “prostatodynia,” and refers to patients with pelvic pain but no evidence of inflammation on semen, VB3, or EPS. The symptom that distinguishes CP/CPPS from other voiding dysfunction is the presence of pain . The current NIH definition of CP/CPPS is that of genitourinary pain in the absence of uropathogenic bacteria detected by standard microbiologic methods .
Epidemiology
To examine health care use in men with prostatitis, a review of available outpatient visit data was conducted through the Urologic Diseases in America project . Physician office visit rates for patients with prostatitis listed as any diagnosis were determined from National Ambulatory Medical Care Survey data for the even years between 1992 and 2000. The age-adjusted visit rate in 2000 was 1,867 per 100,000 population, with the number of physician office visits totaling 1,795,643. Until recently, prostatitis was considered a problem only in younger men. In the NIH sponsored Chronic Prostatitis Collaborative Research Network (CPCRN) study, the mean age was 42 years old but the age range was 20 to 83 .
Men with CPPS suffer significant declines in quality of life. The sickness impact for chronic prostatitis is similar to scores reported in the literature for patients with myocardial infarction and Crohn’s disease . McNaughton-Collins and colleagues used the twelve item short form health survey to evaluate the mental and physical health of CP/CPPS patients and found that the mental component summary score for CPPS patients was lower than that observed in the most severe subgroups of congestive heart failure and diabetes .
Men with CP/CPPS are more likely to have several other conditions. In the CPCRN study, men with CP/CPPS, as compared with age-matched controls, were six times more likely to have cardiovascular disease, five times more likely to have neurologic disease (especially vertebral disk disease), and twice as likely to have sinusitis and anxiety or depression . These associations raise the question of what common abnormalities may be present in CP/CPPS and these other conditions. The most common diagnosis under cardiovascular history in the author’s patients was hypertension, followed by atherosclerotic disease.
A study of prostatitis in a large managed care database found that men with prostatitis were more likely to have 35 other diagnoses, which fell under the categories of other urologic conditions (10), unexplained somatic symptoms (19), and psychiatric conditions (4) . Sexual dysfunction is also common in men with CP/CPPS. In a study of a large urban population in Austria, 2.7% of men reported a pain score of at least 4 out of 10, and in men with the most severe prostatitis symptoms, the risk of erectile dysfunction was increased 8.3 fold .
Epidemiology
To examine health care use in men with prostatitis, a review of available outpatient visit data was conducted through the Urologic Diseases in America project . Physician office visit rates for patients with prostatitis listed as any diagnosis were determined from National Ambulatory Medical Care Survey data for the even years between 1992 and 2000. The age-adjusted visit rate in 2000 was 1,867 per 100,000 population, with the number of physician office visits totaling 1,795,643. Until recently, prostatitis was considered a problem only in younger men. In the NIH sponsored Chronic Prostatitis Collaborative Research Network (CPCRN) study, the mean age was 42 years old but the age range was 20 to 83 .
Men with CPPS suffer significant declines in quality of life. The sickness impact for chronic prostatitis is similar to scores reported in the literature for patients with myocardial infarction and Crohn’s disease . McNaughton-Collins and colleagues used the twelve item short form health survey to evaluate the mental and physical health of CP/CPPS patients and found that the mental component summary score for CPPS patients was lower than that observed in the most severe subgroups of congestive heart failure and diabetes .
Men with CP/CPPS are more likely to have several other conditions. In the CPCRN study, men with CP/CPPS, as compared with age-matched controls, were six times more likely to have cardiovascular disease, five times more likely to have neurologic disease (especially vertebral disk disease), and twice as likely to have sinusitis and anxiety or depression . These associations raise the question of what common abnormalities may be present in CP/CPPS and these other conditions. The most common diagnosis under cardiovascular history in the author’s patients was hypertension, followed by atherosclerotic disease.
A study of prostatitis in a large managed care database found that men with prostatitis were more likely to have 35 other diagnoses, which fell under the categories of other urologic conditions (10), unexplained somatic symptoms (19), and psychiatric conditions (4) . Sexual dysfunction is also common in men with CP/CPPS. In a study of a large urban population in Austria, 2.7% of men reported a pain score of at least 4 out of 10, and in men with the most severe prostatitis symptoms, the risk of erectile dysfunction was increased 8.3 fold .
Etiology and pathogenesis
The etiology of CP/CPPS is unknown. Many different theories and mechanisms for the pathogenesis of prostatitis have been proposed. One question is whether the prostate inflammation is actually a source of symptoms in men with CP/CPPS. True and colleagues found prostatic inflammation in only 33% of patients with CP/CPPS who underwent transperineal prostate biopsy. These findings raise the question of whether the prostate is even actually involved in the symptoms of CP/CPPS. The name “chronic pelvic pain syndrome” recognizes that the prostate may not be the sole source of discomfort, and that there may be other factors or anatomic sites involved.
Traditionally, white blood cells (WBCs) in the prostatic fluids have been studied and thought to be markers for an inflammatory process that contributes to the symptoms of prostatitis. The use of WBCs as markers of inflammation is limited for several reasons. WBCs can be found in the prostatic fluid or seminal plasma of asymptomatic men, as well as those with pelvic pain . In addition, in symptomatic men, none of the measures of the NIH-chronic prostatitis symptom index (NIH-CPSI), including subsets for pain, urinary, and quality of life, show any correlation with WBCs in either EPS, VB3, or seminal plasma . Another argument against the association between inflammation and symptoms is that category IIIB patients have symptoms but no inflammation.
Infection
The symptoms of CP/CPPS are identical to those of a true prostatic infection. Therefore, one of the most prevalent theories as to the development of symptoms in these men is that of an occult or undertreated infection. Despite the lack of an ongoing infection in men with CP/CPPS, in the NIH cohort study, there was a significantly greater self-reported history of nonspecific urethritis as compared with age-matched controls; gonorrheal, trichomonal, and genital herpetic infections were not significantly different . The NIH cohort study found no differences between cases and controls in sexual practices, including types of sexual contact and numbers of partners . Controls tended to be younger at age of first intercourse. This data does not support a difference in sexual practices or frequency in men with CPPS compared with controls. However, it does not rule out and may even suggest the possibility of a sexually transmitted disease as an initial source of inflammation that in susceptible men goes on to cause chronic pain long after the initial acute infection has resolved. This is also consistent with findings from a study of over 30,000 male health professionals, in which those men reporting a history of sexually transmitted disease had 1.8-fold greater odds of a self-reported history of prostatitis .
Newer studies have also increasingly used molecular techniques to try to answer the question of infection in these patients. Shoskes and Shahed found that performing polymerase chain reaction (PCR) on EPS detected the presence of bacterial DNA in category IIIA patients in 23 (70%) of 33 specimens, whereas culture was positive (for Gram-positive bacteria) in only 17 (51%) of 33 specimens. Only 2 of 14 category IIIB patients had bacterial DNA. Nevertheless, 13 (57%) of the total patients with bacterial DNA improved with antibiotics, while patients that lacked bacterial DNA by PCR did not improve with antibiotics. Direct comparison of PCR performed in prostate tissue, taken at the time of radical prostatectomy for prostate cancer in men with and without symptoms of chronic pelvic pain, have shown no differences in product for herpes simplex virus, cytomegalovirus, papillomavirus, nor bacterial DNA . Using PCR on perineal biopsies from men with and without pelvic pain and no prostate cancer showed no differences in rates of positive findings for bacteria .
Overall, it seems unlikely that there is an ongoing acute infection. Particularly intriguing is the finding of cultures localizing uropathogenic bacteria to the prostate in 8% of asymptomatic men with CPPS, and what are considered to be nonuropathogens in 74% of asymptomatic age-matched controls . This suggests that the prostate of normal asymptomatic males harbors bacteria.
Another possibility in men with symptoms is that of a dysregulation of pro- and anti-inflammatory cytokines leading to inflammation from otherwise normal prostate bacteria. There have been multiple reports of abnormal level cytokines in EPS and seminal plasma, including interleukin (IL)-8 , IL-10 IL-1B and tumor necrosis factor (TNF)-α . However, although there have been differences shown between CP/CPPS patients and controls, there has been no consistent pattern across all studies .
Finally, a confounding factor that has not been resolved nor even closely studied so far in CP/CPPS, is that of bacterial biofilms. Bacteria that grow in standard culture techniques are free floating so called “planktonic” bacteria. However, bacteria may also exist in biofilms, in which they form communities of surface adherent organisms embedded in extracellular matrix . The biofilms certainly pose a different environment for standard antibiotics, and even may elicit cytokine responses from leukocytes . What role these biofilms play in the development of prostate infections and CP/CPPS needs to be addressed in the future.
Neurologic factors
The fact that men suffering from CPPS have pain indicates some neurologic involvement, either on a local level or in the central nervous system. Therefore, one hypothesis of the etiology and pathogenesis of CPPS is that there is dysfunction of the nervous system leading to pain. Experimental evidence for central remodeling is provided by the finding that chemical irritation of rat prostate and bladder causes c-fos expression at spinal cord levels L6 and S1, along with plasma extravasation in the skin at the identical L6 and S1 dermatomes, underscoring the overlap of afferent nerve fiber distribution . This corresponds in the human being to the distribution of the umbilicus to mid thigh, which is the common distribution of pain in individuals with CPPS. Retrograde labeling of both prostate and pelvic floor indicates that there are double labeled cells in the dorsal root ganglion in the lumbar and sacral cord in an animal model, indicating the close relationship neurologically between the two areas .
The presence of central sensitization in patients with CPPS was demonstrated by Yang and colleagues , who compared thermal algometry in men with CPPS and asymptomatic controls. Sensitivity to noxious heat stimuli is thought to be a reflection of central sensitization. The men with CPPS reported a higher visual analog scale to short bursts of noxious heat stimuli to the perineum, but no difference to the anterior thigh. Thus, these patients have altered sensation in the perineum when compared with controls. This is similar to other chronic pain syndromes, such as reflex sympathetic dystrophy and fibromyalgia, where patients also have heightened responses to noxious heat stimuli in areas of chronic pain, compared with controls. Similar findings were reported using capsaicin applied to the skin overlying the perineal body .
Psychologic factors and stress response
Psychologic factors also appear to be involved in producing symptoms in men with CP/CPPS and psychologic stress is a common finding in men with CPPS . In addition to pain intensity, depressive symptoms significantly predict a worse quality of life in men with CP/CPPS than in men without . Psychologic variables also affect pain perception. Pelvic pain in CP/CPPS also is dependent upon helplessness, catastrophizing, and depression .
Ullrich and colleagues prospectively examined whether perceived stress was associated longitudinally with pain intensity and pain-related disability in a sample of men with nonbacterial prostatitis and pelvic pain. Over 200 patients with CP/CPPS completed measures of perceived stress, pain intensity, and pain-related disability 1 month after a health care visit, with a new nonbacterial prostatitis or pelvic pain diagnosis 3, 6, and 12 months later. They found that greater perceived stress during the 6 months after the health-care visit was associated with greater pain intensity ( P = .03) and disability ( P = .003) at 12 months, even after controlling for age, symptom duration, and pain and disability during the first 6 months. Lee and colleagues recently reported on elevated levels of catecholamines in the urine of men with CPPS, compared with controls, as well as increased allostatic load. Measuring the allostatic load or stress response of a large group of patients as a correlate of symptoms and clinical course should be studied.
Genetics
Several genetic differences between men with CP/CPPS and controls have been identified. Differences in the DNA sequence or polymorphisms have been identified in the promoter regions of several cytokines. Polymorphisms in the genes or promoters for IL-10 and TNF-α are associated with low IL-10 or TNF-α production . In a recent study, significantly more men with CPPS expressed the IL-10 AA genotype compared with controls (11 of 36 or 31% versus 33 out of 272 or 12%; P = .007) . All eight IIIA patients had the low TNF-α production genotype. There was no difference in the TNF-α genotype in the 22 IIIB patients versus 272 controls, but all eight of the IIIA patients had the low TNF-α genotype. Differences have been reported in the frequency of three alleles near the phosphoglycerate kinase (PGK) gene, between CPPS patients and controls . The alleles differed in the number of short tandem repeats. The PGK1 gene in the region assessed has been found to be associated with familial prostate cancer, hypospadias, and androgen insensitivity. Another gene in the same region of the X chromosome, Xq11 to Xq13, is the androgen receptor. This finding raises the possibility of androgen insensitivity or dysfunction in the pathogenesis of CPPS.
Association with other diseases
The systemic symptoms for CP/CPPS—including fatigue, pain, disability out of proportion to physical examination, and an association with stress or psychosocial factors—are similar to those seen in other poorly explained clinical conditions, including fibromyalgia, irritable bowel syndrome, and chronic fatigue syndrome . In a recent study, functional somatic syndromes and psychologic disorders were significantly more prevalent among men with CP/CPPS as compared with the general population . Thus, there is a growing perception that CP/CPPS may be one manifestation of one or more of these somatic syndromes . For instance, cardiovascular history is of interest in men with CPPS, given the presence of cardiac signs of autonomic neuropathy in these other poorly explained chronic diseases .
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