Definitions

BPH is correctly defined as enlargement of the prostate gland from the progressive hyperplasia of stromal and glandular prostatic cells . Clinical BPH refers to the lower urinary tract symptoms (LUTS) associated with benign prostatic enlargement (BPE) causing bladder outlet obstruction (BOO). Clinical prostatitis can be divided into acute and chronic bacterial prostatitis (National Institutes of Health [NIH] Categories I and II), rare infectious diseases of the prostate gland, the much more common chronic prostatitis/chronic pelvic pain syndrome (Category III CP/CPPS), and asymptomatic inflammatory prostatitis (Category IV) . Histologic prostatitis refers to the confirmation of prostate inflammation by microscopic examination. Asymptomatic prostate inflammation would be categorized as Category IV. Table 1 presents definitions and classifications of these various BPH and prostatitis conditions.

Lack of association of histologic prostatitis and clinical prostatitis

Traditionally, prostatitis has referred to a clinical condition associated with infection and/or inflammation of the prostate. The clinical diagnosis of a symptomatic prostatitis syndrome is made on the basis of clinical symptoms, some clinical findings, culture results, and in some cases, demonstration of inflammation in prostate fluid (expressed prostatic secretions or postprostatic massage urine). Although this concept does hold true for bacterial prostatitis (Categories I and II) confirmed with specific bacterial cultures, it may not be as simple in the much more common Category III CP/CPPS.

An examination of the 488 men enrolled in the NIH-Chronic Prostatitis Cohort (CPC) study determined that leukocytes in the prostate-specific specimens (expressed prostatic secretions [EPS] or postprostatic massage urine specimens [VB3]) did not correlate with any specific symptoms or symptom severity . The inflammatory status (leukocyte counts in EPS and/or VB3) in a total of 463 men enrolled in the NIH CPC study were compared with 121 age-matched control men without any urinary or pain symptoms . Men with CP/CPPS had significantly higher leukocyte counts in these specimens (50% and 32% had 5 or more, or 10 or more white blood cells per high power field in EPS, respectively) than asymptomatic men (40% and 20%, respectively). The high prevalence of leukocytes in the asymptomatic control population certainly raised questions about the clinical relevance of inflammation detected by current diagnostic tools. A small-scale study , which examined correlations between the symptoms and histology of prostatitis in biopsies of men with a clinical diagnosis of CP/CPPS, suggested that histologic inflammation may not be a significant factor in the disease process. Of the 97 patients examined, just 33% had histologic evidence of inflammation, with only 5% having a moderate or severe grading.

An examination of 5597 men with biopsy and clinical evaluation of prostatitis-like symptoms (completion of chronic prostatitis symptom index [CPSI]) enrolled in the REduction by DUtasteride of prostate Cancer Events (REDUCE) study provides the largest body of data examining relationships between symptoms of CP and histologic prostate inflammation. The study population consisted of aging men with elevated levels of prostate-specific antigen (PSA), but with a negative prostate cancer biopsy, recruited as an “at-risk” group for the development of prostate cancer . Chronic histologic inflammation was found in more than 78% of men in REDUCE , reflecting its almost ubiquitous nature in aging men. Acute inflammation was found in 16.5% of the study population, and when present was almost always graded as mild. Data from this analysis of REDUCE population failed to establish substantive links between the CPSI and the presence of histologic inflammation. In men with acute inflammation, no correlations between total or component CPSI scores, including presence of prostatitis-like symptom complex, and inflammation were observed. For those with chronic inflammation, a weak but statistically significant association was observed between inflammation status and total CPSI score, but no significant relationships with pain were observed. From a clinical perspective, presence of chronic prostatitis-like symptoms did not provide any discriminative value for a histologic diagnosis of either acute or chronic inflammation.

Lack of association of histologic prostatitis and clinical prostatitis

Traditionally, prostatitis has referred to a clinical condition associated with infection and/or inflammation of the prostate. The clinical diagnosis of a symptomatic prostatitis syndrome is made on the basis of clinical symptoms, some clinical findings, culture results, and in some cases, demonstration of inflammation in prostate fluid (expressed prostatic secretions or postprostatic massage urine). Although this concept does hold true for bacterial prostatitis (Categories I and II) confirmed with specific bacterial cultures, it may not be as simple in the much more common Category III CP/CPPS.

An examination of the 488 men enrolled in the NIH-Chronic Prostatitis Cohort (CPC) study determined that leukocytes in the prostate-specific specimens (expressed prostatic secretions [EPS] or postprostatic massage urine specimens [VB3]) did not correlate with any specific symptoms or symptom severity . The inflammatory status (leukocyte counts in EPS and/or VB3) in a total of 463 men enrolled in the NIH CPC study were compared with 121 age-matched control men without any urinary or pain symptoms . Men with CP/CPPS had significantly higher leukocyte counts in these specimens (50% and 32% had 5 or more, or 10 or more white blood cells per high power field in EPS, respectively) than asymptomatic men (40% and 20%, respectively). The high prevalence of leukocytes in the asymptomatic control population certainly raised questions about the clinical relevance of inflammation detected by current diagnostic tools. A small-scale study , which examined correlations between the symptoms and histology of prostatitis in biopsies of men with a clinical diagnosis of CP/CPPS, suggested that histologic inflammation may not be a significant factor in the disease process. Of the 97 patients examined, just 33% had histologic evidence of inflammation, with only 5% having a moderate or severe grading.

An examination of 5597 men with biopsy and clinical evaluation of prostatitis-like symptoms (completion of chronic prostatitis symptom index [CPSI]) enrolled in the REduction by DUtasteride of prostate Cancer Events (REDUCE) study provides the largest body of data examining relationships between symptoms of CP and histologic prostate inflammation. The study population consisted of aging men with elevated levels of prostate-specific antigen (PSA), but with a negative prostate cancer biopsy, recruited as an “at-risk” group for the development of prostate cancer . Chronic histologic inflammation was found in more than 78% of men in REDUCE , reflecting its almost ubiquitous nature in aging men. Acute inflammation was found in 16.5% of the study population, and when present was almost always graded as mild. Data from this analysis of REDUCE population failed to establish substantive links between the CPSI and the presence of histologic inflammation. In men with acute inflammation, no correlations between total or component CPSI scores, including presence of prostatitis-like symptom complex, and inflammation were observed. For those with chronic inflammation, a weak but statistically significant association was observed between inflammation status and total CPSI score, but no significant relationships with pain were observed. From a clinical perspective, presence of chronic prostatitis-like symptoms did not provide any discriminative value for a histologic diagnosis of either acute or chronic inflammation.

Association of clinical prostatitis and benign prostatic hyperplasia

BPH is a disease of aging men: an estimated 42% of men 51 to 60 years of age have histologic BPH . The incidence increases to more than 70% in men 61 to 70 years of age and to almost 90% in those 81 to 90 years of age. The prevalence of LUTS associated with BPH parallels that of pathologic BPH; more than 50% of men over 50 are believed to experience LUTS secondary to an enlarged prostate gland.

Prostatitis has traditionally been considered a condition that afflicts younger men, but it is apparent that it is as common in older men . Compared with men 51 years and older, the odds of a documented prostatitis diagnosis is only twofold greater in younger men . Approximately 8% of men over 50 report at least some mild prostatitis-like symptom in the past week compared with 11% of younger men . Little attention has been given to the association between BPH and prostatitis, despite the high prevalence of both conditions in aging men.

Many physicians have trouble clinically distinguishing prostatitis from BPH in the older male population . In 1992, 31,681 United States health professionals without prostate cancer provided information on urologic diagnoses and lower urinary tract symptoms . Of the 5053 men with prostatitis, 57.2% also reported a history of BPH, whereas 38.7% of the 7465 men with BPH reported a history of prostatitis.

Clinical BPH is characterized by voiding LUTS. Prostatitis is characterized primarily by pain. Pain and/or discomfort on ejaculation is one of the most common and bothersome symptoms, but also the most differentiating symptom experienced by men with CP . Painful ejaculation has been reported by approximately 5% to 31% of men with LUTS related to BPH in both community and clinic populations .

There is no doubt that the clinical syndromes of prostatitis and BPH can coexist, but is the diagnosis of clinical prostatitis at a young age a risk factor for development of later BPH? A population-based sample of 2447 men residing in Olmsted County, Minnesota, was evaluated to determine whether physician-diagnosed or self-reported prostatitis was associated with development of clinical BPH or related outcomes . Physician-diagnosed prostatitis was associated with a 2.4-fold increase in the odds of receiving a later diagnosis of BPH. Men with a history of prostatitis were also more likely to receive treatment for BPH compared with men without prostatitis. A diagnosis of prostatitis may be an early marker for later development of BPH.

Association of inflammation and clinical benign prostatic hyperplasia

Histologic inflammation can be demonstrated in the majority of BPH pathologic specimens . For years, the importance and clinical relevance of these seemingly asymptomatic inflammatory infiltrates were only speculated on.

REDUCE is an ongoing, large-scale, 4-year clinical study designed to determine whether and to what extent the dual 5α reductase inhibitor dutasteride reduces the risk of biopsy-detectable prostate cancer compared with placebo in men at high risk of developing prostate cancer . The entrance criteria for the REDUCE study included the requirement of a prostate cancer-negative biopsy before enrollment. The data from the entrance biopsy have enabled additional protocol-defined investigations to be made, including examination of the baseline relationships between histologic prostate inflammation and LUTS, as measured with the International Prostate Symptom Score (IPSS) in over 8000 men. Using a modification of the histologic classification of prostatitis proposed by Nickel and colleagues , a central pathology laboratory (Bostwick Laboratories, Richmond, VA) graded average acute and chronic inflammation across all biopsy cores on a 4-point scale (none, 0; mild, 1; moderate, 2; marked, 3) based on average cell density and extent of tissue involvement in each biopsy core.

Given that the mean prostate volume in men enrolled in the REDUCE study was 46 mL and the PSA 5.8 ng/mL, it is likely that histologic BPH is common in the REDUCE population. As would be expected, chronic histologic inflammation was found in more than 78% of men in REDUCE . Statistically significant but clinically small increases in IPSS symptoms were noted in men with inflammation compared with those without (eg, Wilcoxon rank-sum test for differences in total IPSS by presence versus absence of maximum chronic inflammation unadjusted, P <.0001). Similarly, statistically significant correlations were found between average chronic inflammation score and the IPSS variables. However, the magnitude of these correlations was small, indicating very weak associations. The clinical relevance of the small, but statistically significant difference in IPSS in patients with and without chronic inflammation and the statistically significant, but weak associations between chronic inflammation and IPSS demonstrates a consistent pattern—namely, that inflammation in BPH may be important.

If inflammation is indeed associated with BPH symptoms, anti-inflammatory agents should be investigated as new targets for the pharmacologic treatment of BPH. Given that nonsteroidal anti-inflammatory drugs are well known for their ability to decrease pain and inflammation, the effectiveness of ibuprofen together with the alpha-blocker, doxazosin, on BPH was evaluated for their efficacy in decreasing the expression of JM-27, a protein particularly expressed in the prostate that appears to be highly up-regulated in symptomatic BPH . This study showed that doxazosin, as well as ibuprofen, significantly decreased cell viability and induced apoptosis in BPH prostate cell lines. In addition, it decreased the expression of JM-27. Unfortunately, there are few good data available to assess the clinical response of anti-inflammatory therapy in BPH. A single-center, unblinded trial randomized 46 men with LUTS and BPH to receive rofecoxib (a COX-2 inhibitor) 25 mg/day plus finasteride 5 mg/day versus finasteride 5 mg/day alone for 24 weeks . The study found that, although there was not a significant difference between symptom improvement at 24 weeks, there was a statistically significant advantage of the combination therapy compared with finasteride alone in a short-term interval (4 weeks). It was hypothesized that the association of rofecoxib with finasteride induced a more rapid improvement in clinical results until the effect of finasteride becomes predominant. Phytotherapy has become one of the most popular treatment modalities for BPH. One of the primary mechanisms of why these herbal agents work is the anti-inflammatory effects of the various herbal preparations .