Chronic Prostatitis/Chronic Pelvic Pain Syndrome in Elderly Men

Transcription

1 REVIEW ARTICLE Drugs Aging 2003; 20 (15): X/03/ /$30.00/0 Adis Data Information BV All rights reserved. Chronic Prostatitis/Chronic Pelvic Pain Syndrome in Elderly Men Toward Better Understanding and Treatment Michel A. Pontari Department of Urology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA Contents Abstract Aetiology Evaluation Treatment Conclusions Abstract Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is the most common of the prostatitis syndromes. It is characterised by pelvic pain, with or without voiding symptoms. CP/CPPS accounts for 2 million office visits in the US alone. Recent epidemiological studies have shown that CP/CPPS can affect men at any age, including those in their 80s. The aetiology is unknown but proposals include infectious, autoimmune, neurologic and psychiatric causes. Men with CP/ CPPS are much more likely to have had a past medical history of cardiovascular, neurologic, psychiatric or infectious disease (particularly sinusitis) as compared with asymptomatic individuals. Although leucocytes are commonly found in the prostatic fluid of these men, they do not correlate with the symptoms. The clinical evaluation now includes a validated, self administered symptom score, the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI), which was designed as an outcome measure for treatment trials. This can aid in diagnosis and follow-up of patients response to therapy. Treatment for CP/CPPS is empiric and limited by a lack of randomised, placebo-controlled clinical trials. Antimicrobials are commonly used to treat the symptoms of CP/CPPS. However, the finding that asymptomatic men have equal or greater numbers of bacteria which localise to the prostatic fluid, compared with men with CP/CPPS, has raised doubts about the contribution of infection to the symptoms. Other commonly used drugs include α-adrenoceptor antagonists, anti-inflammatory drugs, tricyclic antidepressants and anticholinergic agents. The adverse effects of these medications are a concern in older men with CP/CPPS. Other therapies available include minimally invasive procedures such as microwave thermotherapy and transurethral needle ablation, and now neuromodulation devices. Although much progress has been made, particularly in the last 7 years, considerable work still remains to be done to determine the aetiology and

2 1112 Pontari pathogenesis of CP/CPPS, and to develop mechanism based therapy that is shown to be effective in controlled trials. massage urine specimen (VB3) or expressed pro- static secretion (EPS). This corresponds to the pre- viously used classification of chronic non-bacterial prostatitis. Category IIIB is comparable to the for- merly used term prostatodynia, and refers to patients with pelvic pain but no evidence of inflammation in semen, VB3 or EPS specimens. The new classifica- tion does not correlate exactly with the old system, mostly because the use of seminal fluid and VB3 as sources of leucocytes will increase the number of men considered to have inflammation compared with the traditional system which distinguished chronic non-bacterial prostatitis from prostatodynia on the basis of an examination of EPS alone. [4] The symptom that distinguishes CP/CPPS from other voiding dysfunction is the presence of pain. [5] The current NIH definition of CP/CPPS is that of genitourinary pain in the absence of uropathogenic bacteria detected by standard microbiological meth- ods. [2] There has been an increase in interest in CP/ CPPS starting with the consensus conference in To facilitate research in the natural history and epidemiology of CP/CPPS, as well to start to develop treatment trials, the NIH formed the Chronic Prostatitis Collaborative Research Network (CPCRN) in October [6] One of the findings of this group is that CP/CPPS is not limited to younger and middle aged men as previously thought. In the CPPS study, the average age of the men was 42 years, with a range of years. Of the cohort, 39% were aged >45 years and 13% were >55 years of age. Several studies have looked at the prevalence of prostatitis by age in population based studies. Using data from the Health Professionals Follow-Up study of > individuals, Collins et al. found that 16% of men reported having a history of prostatitis. Of these men, the age of first treatment increased steadily up to 60 years. [7] In a longitudinal study of a cohort of men from Olmsted County, Minnesota, USA, Roberts et al. [8] found that the age specific incidence of chronic prostatitis remained low until the fifth decade, and then markedly increased after the age of 60 years, with an even greater incidence Prostatitis is a term that refers to several clinical syndromes. These range from well-defined bacterial infections to poorly defined chronic pelvic pain, to asymptomatic inflammation in the prostate found in pathology specimens. The traditional classification of prostatitis included acute prostatitis, chronic bacterial prostatitis, chronic non-bacterial prostatitis and prostatodynia. [1] A more recent classification was adopted in 1995 after a US National Institutes of Health (NIH)-spon- sored consensus conference (see table I). [2] In the current system, category I and II reflect acute and chronic bacterial prostatitis, respectively. Together, both account for 5 10% of all cases. [3] These cases are clearly associated with bacterial infection and will have a urine culture that grows uropathogens. Acute prostatitis is characterised by the sudden on- set of fever and dysuria, whereas chronic bacterial prostatitis typically is characterised by relapsing episodes of urinary tract infections (UTIs), usually with the same organism seen on urine cultures. These patients are usually asymptomatic between infections. Category IV refers to asymptomatic in- flammatory prostatitis that is diagnosed incidentally during a work up for infertility, an elevated prostate-specific antigen (PSA) or benign prostatic hy- perplasia (BPH). The most common type of prosta- titis and the least understood is category III. Category III, known as chronic prostatitis/chron- ic pelvic pain syndrome (CP/CPPS), constitutes the vast majority (>90%) of cases and is divided into IIIA and IIIB. IIIA refers to the presence of white blood cells (WBCs) in either semen, post-prostate Table I. National Institutes of Health classification of prostatitis syndromes [2] Category I Acute bacterial prostatitis Category II Chronic bacterial prostatitis Category III Chronic prostatitis/chronic pelvic pain syndrome IIIA Inflammatory (leucocytes in VB3, EPS or semen) IIIB Non-inflammatory (no leucocytes in VB3, EPS or semen) Category IV Asymptomatic inflammatory prostatitis EPS = expressed prostatic secretion; VB3 = post-prostate massage urine specimen.

3 Chronic Prostatitis in Elderly Men 1113 Enterobacter and Pseudomonas, [16,17] the aetiology of category III prostatitis is unknown. Many causes have been proposed including infectious, [18] autoim- mune, [19] neurologic [20] and psychiatric diseases (see table II). [21] As part of the CPCRN, an epidemiologi- cal study was performed that tested some of these hypotheses. The men in the CPCRN cohort with CP/ CPPS were compared with a group of 120 asymp- tomatic individuals. Patients and control individuals did not differ in age, education, employment status or sexual history. Patients reported a significantly greater lifetime prevalence of non-specific urethritis as well as several other items in their self-reported medical history. This included a 6-fold greater incidence of cardiovascular disease, which was predom- inantly hypertension. Patients also reported a 5-fold greater history of neurological disease and a 2.5-fold greater history of psychiatric disease than control individuals. Hematopoietic, lymphatic or infectious disease, specifically sinusitis, was twice as common in the patients as in the control individuals. [22] Is there a relation between infection and sexual activity? A Finnish population-based study by Mehik et al. [23] reported on 1832 (75%) respondents to a non-nih questionnaire of men in the two most northern provinces of Finland. Interestingly, di- vorced and single men had a lower risk than married men, independent of age. The authors speculated that this difference might be because of the exposure of married men to potential pathogens from their wives genital tract. Despite these findings and those of the CPCRN epidemiology study, other studies to date have failed to identify an ongoing infection in these men from any sexually transmitted organisms including Chlamydia trachomatis, Ureaplasma after the age of 70 years. The cumulative probability of having chronic prostatitis reached 9% at the age of 85 years. Those with a history of prostatitis had an increased risk of recurrent episodes with age, being 20%, 38% and 50% among men 40, 60 and 80 years old, respectively. [8] In two counties in Ontario, Canada, Nickel et al. [9] found that prostatitis symptoms as determined on the pain and voiding domains of the NIH Chronic Prostatitis Symptom Index (NIH-CPSI) were present in 11.5% of men <50 years of age who responded to their survey, compared with 8.5% of men >50 years of age. After a peak of 12.8% among men aged years, there was a steady decrease each decade to 10.2% for age years, 9.1% for age years and 6.9% for age years. [9] Using questions similar to the NIH-CPSI, Roberts et al. [10] found that overall, 12% of respondents had at least one urogenital pain symptom. The mean pain score was relatively con- stant with increasing age, but the urinary symptom and quality-of-life impact scores increased with age. [10] Thus, it appears that men can experience symptoms of chronic pelvic pain at any point in their lifetime. Epidemiological studies have shown that overall CP/CPPS is much more common than previously assumed. This condition accounts for 2 million outpatient visits per year, which are 8% of visits to urologists and 1% of primary care visits in the US. [11] The sickness impact for chronic prostatitis is similar to scores reported in the literature for patients with myocardial infarction and Crohn s disease. [12] Collins et al. [13] used the 12-item Short Form (SF-12) [14] to evaluate the mental and physical health of CP/CPPS patients and found that the mental component summary score for CP/CPPS patients was lower than that observed in the most severe subgroups of congestive heart failure and diabetes mellitus. Recent data also indicate that there is a substantial cost associated with prostatitis, with 25% of patients reporting loss of work time over the past 3 months, 49% reporting lost leisure time and 13% reporting hospitalisation at some point in their lives because of the condition. [15] 1. Aetiology Whereas category I and II prostatitis are caused by bacteria including Escherichia coli, Klebsiella, Table II. Possible aetiological factors in chronic prostatitis/chronic pelvic pain syndrome Non-specific urethritis (Occult) infection Cardiovascular disease a Neurological disease a Psychiatric conditions Environmental factors Autoimmune disorder Functional somatic syndrome Interstitial cystitis a May be particularly important in older men.

4 1114 Pontari urealyticum, Mycoplasma hominis or Trichomonas ial DNA from radical or open prostatectomy specivaginalis. [16,24-28] mens with samples from healthy organ donor prostates. The symptoms of pelvic pain and voiding dysinflammation In the former group, they found samples with function are similar to those that occur with a true that correlated with the presence of bacterial infection. Therefore, it is not surprising bacterial DNA by PCR, while a negative PCR result that one of the most common theories of aetiology is was seen in the healthy group with no inflammation. that of an occult infection. This idea has also been They concluded that healthy prostates contain no bolstered by the discovery of fastidious microbes as flora. Another study also found that bacterial RNA the cause of other previously poorly characterised in the prostate was not specific for men with prostaconditions such as Helicobacter pylori for stomach titis and was also found in men undergoing implan- ulcers and Tropheryma whippelii for Whipple s disrecent tation of radioactive seeds for prostate cancer. [34] A ease. [29] One limitation to isolating organisms in study by Krieger et al. [35] supports the associ- prostatitis patients may be the culture method itself. ation between bacterial DNA and inflammation. Shoskes et al. [30] suggested that increasing culture Sterile prostate biopsies were retrieved from radical time from 2 to 5 days yields 7.5% more positive prostatectomy specimens and category III patients cultures, and that these cultures correlated with intected using perineal approach. Bacterial DNA was de- flammation secondary to Gram-positive bacteria. by PCR in 20% of prostates with cancer, The longer culture time seemed to make the biggest and 46% of prostates with chronic prostatitis. difference in cultures of semen and EPS, indicating DNA sequences from typical and non-typical that there may be local environmental factors in uropathogenic bacteria were found. This finding these fluids that may inhibit their growth initially, was contrary to the authors hypothesis that older but can be overcome by the longer incubation time. men, i.e. older prostates, would have higher bacter- Newer studies have also increasingly used mo- ial rates, as they might have been catheterised or had lecular techniques to try to answer the question of UTIs in the past. The authors concluded that bacteria infection in these patients. In a recent study using might be associated with prostate disorders, but not polymerase chain reaction (PCR), several unusual necessarily a reflection of the medical history. organisms were identified. [31] Using PCR on the The most recent evidence does not support a role pellet of samples from CPPS patients and control for the bacteria that can be detected by standard individuals, investigators found that the most com- culture methods as being pathogenic in men with mon species discovered were from the genera CP/CPPS. In a case control study as part of the Paenibacillus and Proteobacterium and were much CPCRN, Nickel et al. [36] found no difference in the more common in men with CPPS. Shoskes and rates of positive cultures localising bacteria to the Shahed [32] found that performing PCR on EPS detomatic prostate between men with CP/CPPS and asymptected the presence of bacterial DNA in category men. This argues against commonly de- IIIA patients in 23 (70%) of 33 specimens, whereas tected bacteria as a cause of the symptoms of chronthe culture was positive (for Gram-positive bacteria) ic prostatitis and points out that bacteria seem to be in only 17 (51%) of 33 specimens. Only 2 of 14 normally found in the prostate of asymptomatic category IIIB patients had bacterial DNA. Nevertheless, men. 13 (57%) of the total patients with bacterial Whether or not there is an ongoing infection or a DNA improved with antimicrobials while patients remote infection, a common finding in patients with who lacked bacterial DNA by PCR did not improve CPPS is that of ongoing inflammation. The 1995 with antimicrobials. classification retains the distinction between men Further questions to the answer are: (i) if bacteria with leucocytes in EPS, VB3 or semen and those are present in the prostate of men with pelvic pain, without leucocytes. Several studies indicate that the are they responsible for the symptoms? and (ii) are inflammatory response in men with CP/CPPS may bacteria present in the prostates of men without be autoimmune. The EPS of CP/CPPS patients consymptoms? Hochreiter et al. [33] compared PCR re- tain markers for cytotoxic T cells, a cell type not sults of prostatic tissue samples searching for bacter- typical of antimicrobial immunity, but more consis-

5 Chronic Prostatitis in Elderly Men 1115 tent with autoimmune inflammation or secondary role in pain of these cytokines is questionable beremodelling of the injured tissue. [37] A thorough cause of no increase in their levels in category IIIB study of seminal fluid, EPS and serum in CP/CPPS patients. Also, it cannot be conclusively said if these confirmed this observation, as intra-acinar T lym- cytokines are released after WBCs activation or phocytes were dominated by cytotoxic T cells precede and stimulate their arrival. The Northwest- (CD8). [38] This study also showed that the levels of ern group [41] also found elevated levels of IL-1β and serum complement, serum interleukins (ILs) and tumour necrosis factor (TNF)-α levels in EPS in ejaculate ILs correlated with T cells levels including category IIIA as opposed to category IIIB patients CD3, CD4 and CD8 types. No differences were and control individuals. No correlation between observed in the proportion of B lymphocytes in CP/ these cytokines and WBCs was noted. Elevated CPPS patients compared with control individuals, levels of TNF-α and IL-1β have also been reported demonstrating that the reaction in CP/CPPS is via in the seminal plasma of men with chronic prostacellular and not humoral response. Changes in clin- titis as compared with asymptomatic control indiical symptoms correlated with changes in serum and viduals. [42] Ruggieri et al. [43] found no correlation ejaculate IL-6 levels and ejaculate IgA. One propo- between levels of IL-1β and TNF-α in seminal sal for the target autoantigen is PSA. [19] plasma and symptoms in CP/CPPS patients. However, Does inflammation correlate with symptoms? In Hochreiter et al. found that cytokine levels in the CPCRN cohort study, the presence of WBCs EPS changed in association with symptoms. [44] In correlated poorly with symptoms. [39] This study the absence of antimicrobial treatment, 80% of pa- looked at 278 men with CP/CPPS. Category IIIA tients showed increased cytokines (by a mean of was defined as 5 WBCs in EPS or >1 in VB3 or 1.725%) when symptoms developed and a mean semen. Urethral inflammation was defined as 1 decrease of 49% when symptoms disappeared. In- WBC in first voided urine (VB1). Of these patients, creases or decreases in cytokine levels also correlat- 56% had urethral inflammation, 51% had 5 WBCs ed with WBC levels in EPS. When antimicrobials in EPS and 87% were classified as category IIIA. were given, in 93% of the cases cytokine levels None of the symptom index measures, including decreased (mean decrease 51%) regardless of subsets for pain, urinary and quality of life, were changes in symptoms or inflammatory status. different for WBCs subgroups. The overall rank Correlation between IL-10 and both pain severity correlation between WBCs and urinary symptoms and quality-of-life measures has been reported. [45] was not significant and weak. Another argument IL-10 has been shown to be involved in the pathoagainst the association of inflammation and symp- genesis of several autoimmune diseases including toms is that category IIIB patients have symptoms rheumatoid arthritis, systemic lupus erythematosus, but no inflammation, and conversely category IV myasthenia gravis and asthma. [46] Thus, it is also patients have inflammation but no symptoms. possible that while static measurements of immune Although WBCs do not correlate with symptoms, mediators may not correlate with symptoms, other markers of inflammation are present that may changes in the levels of these mediators may be have a stronger association. Several groups of researchers clinically meaningful. have measured the levels of inflammatory Another marker of inflammation is reactive oxy- mediators in the EPS of men with chronic prostatitis. gen species (ROS). Neutrophils release ROS, which Hochreiter et al. [40] reported that levels of IL-8 and are free radicals, in response to antigenic stimulaepithelial neutrophil activating factor-78 (ENA-78) tion. Release of such species (O2, HO, H2O2) or were significantly elevated in categories IIIA, IV oxidative stress, within the prostatic fluid of cateand I prostatitis patients as compared with control gory III patients, is a hot concept for investigation. individuals and category IIIB prostatitis patients. Oxidative stress in EPS, as a marker of tissue injury, These cytokines are direct mediators of leucocytic secondary to pathogenic bacterial infection, was chemotaxis and activation. An association was studied by Shahed and Shoskes. [37] Their premise shown between leucocytes and levels of IL-8, but was that infection by Gram-positive bacteria in catenot between cytokines and pelvic pain. The ultimate gory IIIA, and not prostatic colonisation, results in

6 1116 Pontari oxidative stress, since tissue injury by definition study by Miller et al. [52] there was no difference in follows infection and not colonisation. Thus, after levels of seminal plasma NGF in men with CP/ antimicrobial treatment for infection, the oxidative CPPS and control individuals, our studies and others stress would be reduced, proving Gram-positive have demonstrated increased NGF compared with bacteria to be true pathogens. Less ROS minimises control individuals in both seminal plasma [53] and tissue injury and ultimately results in less pain. post massage urine. [54] Category IIIA patients had significantly higher oxi- Although pain is the common symptom in these dative stress levels than category IIIB patients. patients, there may be psychological and even envi- However, oxidative stress levels were independent ronmental factors that may affect how the patient of leucocyte count in the EPS, and therefore not a perceives the pain. In a study by Mehik et al., [23] men marker per se of leucocytes, but rather a marker of >50 years of age had a 3-fold greater risk of having tissue injury. Less oxidative stress was subsequently or having had prostatitis than their younger cohort. detected in the EPS after clinically successful treat- Of these men, 63% had their worst symptoms during ment with oral antimicrobials or antioxidants. In- the winter months of November-March, while very creased ROS levels and low antioxidant levels in few (3%) had their worst symptoms in the summer. seminal plasma of men with CPPS compared with The authors concluded that the higher prevalence control individuals were also reported by Pas- they reported might in part be owing to the cold qualotto et al. [47] Thus, the concept of non-wbc climate. The authors also reported that psychologiinflammation must be considered in future models cal stress was a common finding in this populaof prostatitis. tion. [21] Self-assessment of personality showed that The presence of pain leads to the question of these men were more nervous and busy than healthy whether there is a neurologic cause for the symping control individuals. They also showed fears of havtoms. Zermann et al. [20] found significant abnormaliing a sexually transmitted disease and suicidal think- ties in the coordination of voiding and activity in the was more common. A Korean study found that pelvic floor/external urethral sphincter in >80% of longer exposure to sunlight was protective against men with symptoms of pelvic pain. This kind of developing symptoms of CPPS. [55] The authors also dysfunction is classically found in patients with a found that a lower education level was associated supra-sacral spinal cord lesion, which raises the with a higher incidence of CPPS. Overall, the psy- question as to whether these men have a subclinical chological health of men with CPPS appears to be neural injury in the spinal cord that would contribute inferior to those of the healthy population. Although to such dyssynergy and thus pelvic pain. Also, some it is unlikely that depression is a cause of the original chronic pelvic pain patients respond to sacral symptoms, it certainly may be a result of the chronic neurostimulation [48] supporting the idea that whatthe symptoms worse. pain and disability, and may make the perception of ever the inciting insult, there may be a common pathway to nerve dysfunction in these patients. An Furthermore, there is a growing perception that association has also been made between nerve CPPS may be one manifestation of a series of disorgrowth factor (NGF) and CP/CPPS. NGF is a pro- ders labelled functional somatic syndromes. [56] As tein produced by cells in a target organ, which is compared with the general population, functional then absorbed by sympathetic and small sensory somatic syndromes and psychological disorders fibres via a tyrosine kinase A (trka) receptor, and were significantly more prevalent among men with transported retrograde to the cell body. [49] NGF has CPPS. The symptoms of functional somatic synbeen implicated in inflammation that may lead to drome included irritable bowel syndrome, chronic hyperalgesia by mechanisms including sensitising headache, fibromyalgia, and non-specific dermatonociceptors, elevating levels of substance P and logical and rheumatological symptoms. These findcalcium gene related peptide, which may cause his- ings are also similar to those with interstitial cystitis tamine release from mast cells and central sensitisa- (IC) [57] in which patients were found to be 100 times tion. [50,51] NGF levels have been shown to correlate more likely to have inflammatory bowel disease and with pain in men with CP/CPPS. [52] Although in the 30 times more likely to have lupus than the general

7 Chronic Prostatitis in Elderly Men 1117 population. This again raises the question of wheth- the question has been raised as to whether changes er the two entities are either related, or the same in the prostatic epithelium, from infection or even process. A significant question to address in the reflux, could be responsible for patient sympdefinition, evaluation and treatment of CP/CPPS is toms. [74] The concept of a neurogenic aetiology and whether this is the same syndrome as IC. especially neurogenic inflammation is well established Both IC and CP/CPPS are clinical syndromes in IC. C fibres are sensory nerves associated characterised by chronic pelvic pain and voiding with pain transmission and also innervate mast dysfunction. Neither has an identifiable objective cells. [75] These sensory nerves release substance P parameter such as histological, biochemical or raes which is a nociceptive neurotransmitter that produc- diological findings with which to make the diagcontents, pain and also stimulates mast cells to release their nosis. Traditionally, the majority of patients diaglevels including histamine and tryptase. Elevated nosed with IC are female, [58] while the diagnosis of of substance P containing neurons have been chronic prostatitis is necessarily made in males. found in the bladder of patients with IC. [76,77] Mast Currently accepted clinical diagnostic criteria for IC cells may also release their contents in response to and prostatitis allow for men with pelvic pain and cytokines, bacterial toxins, hypoxia and stress voiding symptoms to be included in either diagcells among other stimuli. [78,79] Elevated numbers of mast nosis. A good example is that one of our patients have been reported in patients with IC [80] as qualified for inclusion in both the Interstitial Cystitis well as elevated levels of histamine in the bladder Data Base cohort [59] and CPCRN. Clinically, IC and wall. [81] Mastocytosis has been suggested in CP/ CP/CPPS are often similar if not indistinguishalso CPPS. [82] The idea of an autoimmune response has able. [60,61] In addition to the symptoms, both are been widely theorised for IC. [83] known to have a detrimental impact on quality of Data on aetiologic mechanisms of CP/CPPS spelife. [13,62] Studies have documented the similarity in cifically in elderly men are very limited. Most studseeing glomerulations with hydrodistention under ies do not stratify for age in their evaluation, espe- anaesthesia in patients with both IC and prostamay cially those looking at biomarkers. Several areas titis. [63] The importance of this comparison is diminneurological be particularly important in the elderly. One is ished with more recent data indicating that glomeruspinal causes, as with aging there can be lations are not pathognomonic of IC. [64] However, degeneration, which based on the CPCRN pain with bladder filling is a hallmark of IC and also epidemiological study [22] may play a role in CP/ has been reported in 45% of men with CP/CPPS. [65] CPPS. This study also highlighted the association Urodynamic findings common to both groups inwhich between a history of cardiac disease and CP/CPPS, clude sensory urgency [66,67] and poor relaxation of would be expected to be more common in the the pelvic floor with bladder contractions and voidfound elderly. The work by Mehik et al. on pain perception ing. [20,68] a difference between young and older pa- The aetiology and much of the pathogenesis of tients. [23] Whether or not there are differences in both IC and CP/CPPS are unknown. However, many aetiology and pathogenesis in CP/CPPS in young of the theories of aetiology of CP/CPPS have also versus older men is not known, and will await the been applied to IC and vice versa. As in CP/CPPS, discovery of what these factors are in any popula- the idea of occult infection as a cause of IC has been tion. popular. [69,70] One recent report identified Ureaplasma urealyticum in 48% of patients diagnosed with 2. Evaluation IC and 90% of these patients improved after an- There is no accepted standard evaluation for men timicrobials. [71] Another popular theory in the patho- with CP/CPPS. However, the results of a recent genesis of IC has been that of a leaky epithelium in symposium on CP/CPPS outlining suggestions for the bladder caused by a deficiency of glycosaminog- evaluation have been published (see table III). [84] lycans on the bladder epithelium. [72] Although this Mandatory measures include history, physical has not been tested in the prostate, it has been noted examination including digital rectal examination, that the prostate does contain surface mucus [73] and urinalysis and urine culture. In the older man with

8 1118 Pontari Table III. Clinical, laboratory, and imaging evaluations for chronic prostatitis/chronic pelvic pain syndrome Mandatory Recommended Optional History (includes Post-void Localisation studies: 2- (VB2, NIH-CPSI) residual volume VB3) or 4-glass (VB1, VB2, EPS, VB3) test Physical Imaging: transrectal ultrasound examination Urinalysis and Urethral swab culture Urine cytology Urodynamic studies EPS = expressed prostatic secretion; NIH-CPSI = National Institutes of Health Chronic Prostatitis Symptom Index; VB1 = first voided urine; VB2 = midstream urine; VB3 = post-prostate massage urine specimen. commended investigation is determination of postvoid residual urine. This is especially important in older men given the greater risk of retention from BPH than in younger men with CP/CPPS. There are many optional investigative procedures as outlined in a recent summary statement by Nickel. [84] The role of imaging studies is controversial, but prostatic ultrasound may be especially helpful in men who have pain after ejaculation, to look for lesions such as prostatic and mullerian remnant cysts. Patients with urethral discharge should have a urethral swab. Urodynamics can be used in men whose voiding symptoms are refractory to treatment. They should be performed in men with elevated residual urine to assess the reason for difficulty emptying the bladder. In older men, the finding of elevated residual urine is likely to be more common than in younger individuals, either because of pro- static obstruction or reduced bladder contractility. It is important also to further evaluate abnormalities in the workup and not to ascribe these findings neces- sarily to the CP/CPPS alone. Two findings that are particularly relevant to older men are haematuria and an elevated PSA. Haematuria, microscopic or gross, should not be attributed solely to prostatitis and should be further evaluated with cystoscopy and a study of the upper urinary tracts. PSA measure- ment is not standard in the evaluation of CP/CPPS, but is done frequently as a screening test for prostate cancer in men >40 years of age in African Americans or those with a family history of prostate can- cer, or age 50 years in other individuals. PSA is slightly elevated in men with CP/CPPS compared with asymptomatic individuals, [91] but not enough to account for PSA >4.0, which should prompt a pros- tate biopsy. The main goal of the evaluation of patients with category III or CP/CPPS is to try to find a treatable cause of the symptoms. Unfortunate- ly, in the vast majority of men, no such cause will be identified. symptoms of CP/CPPS, the digital rectal examina- tion is very important to look for prostate nodules that should prompt a biopsy to rule out prostate carcinoma. Recommended evaluation includes the assessment of symptoms, which has been greatly facilitated by the CPCRN with the development of the NIH-CPSI, a self administered validated symptom index. [85] Originally designed as an outcome measure for use in treatment trials, it is also very useful for symptom assessment in the office and also is now available in Spanish translation. [86] The index has nine questions divided into domains of pain, urinary symptoms and quality of life. Scoring can be used to identify areas to target in history and to follow-up clinically patients progress. Other recommended investigations include some form of lower urinary tract localisation studies. The evaluation of chronic prostatitis has traditionally used the Meares-Stamey four glass test (VB1, mid- stream urine [VB2], EPS, VB3). [87] Nickel [88] has advocated using the pre- and post-prostate massage urine for culture and microscopic examination. The correlation between leucocytes in the EPS and VB3 has been confirmed, so the use of VB3, which is easier to obtain, provides a surrogate marker. [89] The utility of four glass localisation cultures for diagnosis of category III has been called into question by the findings that asymptomatic men have a similar amount and localisation of bacteria on this test as do symptomatic men with CP/CPPS. [36] Urine should be sent for cytology to rule out bladder cancer or carcinoma in situ as a cause of the symptoms, [90] which is particularly more relevant in older men compared with men aged years. Another re- 3. Treatment Currently used treatments for CP/CPPS are em- piric (see table IV). Limitations include lack of a clear aetiology to guide appropriate therapy, and a dearth of randomised, placebo-controlled trials to support the treatments that are already being used. McNaughton Collins et al. [92] reviewed the available

9 Chronic Prostatitis in Elderly Men 1119 literature from 1966 to March 1999 and found 14 Marked orthostatic effects are most frequently seen randomised and/or controlled treatment trials in CP/ with the first dose, but can also occur following CPPS. One recent advance has been the proposal of dosage increases. In placebo-controlled trials for a uniform set of inclusion and exclusion criteria for BPH, the incidence of these symptoms with the nonresearch trials in CP/CPPS. To facilitate research selective α-1 adrenoceptor antagonist doxazosin studies that include comparable groups of patients 1mg was low (0.3%) and did not increase with and allow for comparisons, the second International increasing dosage to 8 mg/day. [102] The incidence of Prostatitis Consensus Conference adopted the crite- discontinuation of treatment because of hypotension ria that had been developed for use in the NIH or orthostatic symptoms was 3.3%. Other adverse sponsored CPCRN cohort study. [6,93] These guide- reactions seen with doxazosin and placebo had <1% lines have recently been used in studies such as the incidence, but of possible clinical interest were angi- CPCRN randomised clinical trial to evaluate four na pectoris (0.6% and 0.7%, respectively), postural treatments: ciprofloxacin alone, tamsulosin alone, hypotension (0.3% and 0.3%, respectively), syncope ciprofloxacin with tamsulosin, and placebo. [94] (0.5% and 0.0%, respectively) and tachycardia Among the most commonly used treatments of (0.9% and 0.0%, respectively). [102] Thus, one signif- CP/CPPS are antimicrobials. Although there is a icant consideration before starting α-adrenoceptor clear rationale for use in category I and II, the use of antagonists is to check resting blood pressure. antimicrobials for category III is less well sup- Another factor to consider α-adrenoceptor antported. In category III prostatitis, 40 50% of paagonists in older men is that of concurrent coronary tients responded to a 2 4 week therapeutic trial. [95] disease, as hypotension in these men may produce Fluoroquinolones have been the drug of choice bedecreased cardiac perfusion. These cardiovascular cause of good prostate penetration, good bioavailaeffects are much less often observed with tamsulosin bility and equivalence between oral and parenteral used to treat symptomatic BPH. [103,104] One of the formulations. [26] There does not seem to be a differreasons for this may be that the proportion of the α- ence in response to 4 weeks of antimicrobial therapy 1B receptor subtype increases with advancing age in in category III prostatitis compared with an 8 or 12 human blood vessels. [105] Tamsulosin is a selective week course. [96] Thus, an initial 4-week course can antagonist of α-1a and α-1d receptors, [103] so does be attempted, and patients who respond can be treatnot bind to α-1b receptors in the blood vessels of ed for an additional 2 4 weeks, while in those who older men. do not respond, the treatment can be stopped. In older men it is important to look at the urine or VB2 There have been few clinical trials of anti-in- results. If there is a bacterial infection, further evaluone was a randomised, double-blind, placebo-con- flammatory therapy for chronic prostatitis and only ation such as bladder ultrasound should be performed to rule out urinary retention and poor bladder emptying as a cause of the UTI. Table IV. Treatment options for chronic prostatitis/chronic pelvic pain syndrome Another common treatment for CP/CPPS is α- Limited course of antimicrobials adrenoceptor antagonists. Response rates reported α-adrenoceptor antagonists a are in the range of 50% with either non-selective α-1 Anti-inflammatory drugs and α-2 adrenoceptor antagonists or selective α-1 adrenoceptor antagonists. [97-100] A recent study examined the use of tamsulosin and found that this more selective α-adrenoceptor antagonist may also be beneficial in CP/CPPS. [101] One of the considerations for the use of α-adrenoceptor antagonists in older men is that of adverse Pentosan polysulfate Finasteride b Quercetin Tricyclic antidepressants Anticholinergic drugs a Gabapentin Minimally invasive surgical therapies: b microwave thermotherapy, transurethral needle ablation effects. α-adrenoceptor antagonists can cause marked hypotension, syncope, dizziness and lightheadedness a Use with caution in elderly men because of possible adverse effects. or vertigo, especially when standing. b May be particularly useful in elderly men.

10 1120 Pontari trolled trial. Small studies of non-conventional anti- tive barrier in the urinary epithelium. Beneficial inflammatory medications have been reported using effects have been reported with oral dosages of promelase [106] and nimesulide. [107] In 2001, a ran- 200mg twice daily [113] and 100mg three times domised, placebo-controlled trial of rofecoxib, a daily. [114] A randomised, placebo-controlled trial cyclo-oxygenase 2 (COX-2) inhibitor, was complet- compared pentosan polysulfate 900 mg/day orally ed. [108] The theory for the use of a COX-2 inhibitor for 16 weeks with placebo: there was a moderate or in CP/CPPS comes from the association of the marked clinical global improvement with pentosan COX-2 subtype of the cyclo-oxygenase enzyme polysulfate (36.7%) compared with placebo (17.8%) with inflammation. COX-1 is the constitutive [p = 0.04]. [115] The idea of a common aetiology for isoform found in virtually all cell types; the COX-2 IC and CP/CPPS has been again raised by these isoform is undetectable in most tissues, but is rapid- data, as pentosan polysulfate, has been widely used ly induced in inflammation. [109] In vivo, COX-2 can in women with IC. continue to be synthesised for days or weeks given Finasteride, a 5-α reductase inhibitor, may also the persistence of an appropriate stimulus. [110] Com- have anti-inflammatory effects. In patients with catpared with healthy men, EPS and semen of men with egory IIIA prostatitis, 6 months of therapy with CP/CPPS have higher levels of the inflammatory finasteride compared with placebo resulted in a 50% cytokines IL-1β and TNF-α. [41,42] These cytokines improvement in global assessment in 44% of paup-regulate COX-2 gene expression, which may tients receiving finasteride and 27% of placebo refurther contribute to inflammation. [111] cipients. [116] Finasteride is an attractive medication In the rofecoxib trial, [108,112] a tota1 of 161 pa- to use in older men with CP/CPPS because it can tients were randomised to treatment with rofecoxib also be effective on BPH, [117] which can be concur- 50mg, 25mg, or placebo. The NIH-CPSI total, do- rent in men with symptoms of CP/CPPS. A previous main and pain scores significantly decreased from long-term study indicated that the use of finasteride baseline in all groups, and although the mean scores could reduce the risk of acute urinary retention or numerically favoured the rofecoxib groups, the dif- operation for bladder outlet obstruction. [117] A study ference was not statistically significant between from the NIH indicated that the combination of groups. There was a trend for a higher percentage of finasteride and doxazosin could reduce the longpatients with a 25% or 6-point improvement in NIH- term risk of adverse events from bladder outlet CPSI total score on rofecoxib versus placebo, with obstruction such as worsening symptoms, recurrent the difference being significant for the 50mg UTI, urinary retention and renal failure. [118] Another rofecoxib group (p < 0.05). Patient global assess- compound that has anti-inflammatory effect is the ment of pain, response to therapy and disease ac- flavonoid quercetin. In a randomised, placebotivity also favoured rofecoxib over placebo controlled trial, quercetin produced significant re- (p < 0.05, p = 0.07, p = 0.06, respectively). Rofe- duction in NIH-CPSI symptom scores (p = 0.003) coxib was generally well tolerated. Of interest is that and was generally well tolerated. [119] there appeared to be a better response in category Many other drugs are used for CP/CPPS, as evi- IIIB patients, or those without inflammation in their denced by the NIH sponsored CPCRN study [6], but prostatic secretions, compared with category IIIA. these lack controlled trials to document their effi- This leads one to reconsider the importance of in- cacy. Some of the more commonly used drugs to flammation in this condition and what the precise treat CP/CPPS include tricyclic antidepressants, site of action of rofecoxib was in those patients who such as amitriptyline. These are thought to block improved. pain by inhibiting the central neuronal reuptake of There are other drugs which are not NSAIDs but norepinephrine and serotonin, potentiating the inlikely exert an anti-inflammatory effect in treating hibitory effect of these substances on central pain the symptoms of CP/CPPS. Pentosan polysulfate is processing receptors. [120,121] Anticholinergics such a semisynthetic mucopolysaccharide that is chemi- as oxybutynin or tolterodine are used to treat the cally and structurally similar to the naturally occur- increased urinary frequency. Tricyclic antidepresring sulphated polysaccharides that form a protec- sants also have possible anticholinergic side effects.

11 Chronic Prostatitis in Elderly Men 1121 There is some theoretical concern in using anticholinergic drugs in older men for fear of causing difficulty emptying the bladder if there is concomitant BPH. A study looked at using anticholinergic drugs to actually help treat the symptoms of BPH and found them to have good safety profile with very little risk of precipitating urinary retention. [122] Of more concern is the possibility of central nervous system effects from anticholinergic medications in elderly men, and this must be monitored closely. Newer anti-epileptic drugs, such as gabapentin, have also proven to be useful in treating neuropathic pain [123] and have been used in CP/CPPS. [124] Some surgical and minimally invasive options are also available. In patients who have CP/CPPS and documented smooth sphincter/bladder neck dyssynergy, incision of the bladder neck has excellent results. [125] In this study, 74% of men had pelvic pain, so although the study said they were misdiagnosed as chronic prostatitis, they would indeed meet the clinical definition. The point is that they had a treatable lesion causing the pelvic pain. Microwave thermotherapy has been applied both transrectally and transurethrally with good results reported when used for CP/CPPS. [ ] Transurethral needle abla- tion (TUNA) delivers low level radiofrequency en- ergy at 490 khz to heat the tissue and selectively ablate the prostatic tissue. While TUNA has been shown to be effective in the treatment of BPH, reports on its use for treatment of CP/CPPS have been mixed. A prospective, non-randomised trial in 42 patients reported excellent results in terms of improved symptom score and decreased leucocyte count in EPS, [131] while another recent study found no significant treatment difference compared with the sham treatment group. [132] A promising surgical procedure for CP/CPPS is sacral neuromodulation, in which a neuroprosthetic sacral nerve stimulation device is surgically implanted after successful per- cutaneous trial stimulation. Of the ten patients with chronic pelvic pain in a study, [48] six reported signif- icant improvement in pelvic pain symptoms at 19 months follow-up. Pelvic floor physical therapy is also a good option in these patients. [133] 4. Conclusions The study of chronic prostatitis has advanced greatly in the past 7 years. In this time, there has been a new classification system, and advances in epidemiology and treatment. It is now recognised that the most common entity that clinicians con- front, i.e. the patient with unexplained chronic pel- vic pain, is that of category III, now called chronic pelvic pain syndrome. This term is clinically more relevant than the term chronic prostatitis, because it reflects the current thinking that not all pelvic pain in these men is necessarily attributable to the pros- tate. Chronic prostatitis is no longer just thought as a condition of young or middle-aged men, but one that affects men at any point in life, young or old. Other disease processes are also seen in association with CP/CPPS such as cardiovascular and neurological conditions that may be more common in elderly men, which may provide clues to the aetiology and pathogenesis of the disorder. The significance of inflammation in the prostatic fluid of men with pelvic pain has been called into question, as there is tremendous overlap with asymptomatic men and the leucocyte count does not correlate well with symp- toms. Further work into non-leucocyte inflamma- tion is required, and the need for the subcategories of IIIA and IIIB must be readdressed. Recent data indicating the prevalence of bacteria on cultures in asymptomatic men has changed the idea of what constitutes a prostate infection and cast doubt on the role of commonly identified organisms in producing the symptoms of CP/CPPS. The theory that older men may harbour more bacteria in their prostate than younger men has been refuted. The current state of treatment of chronic prosta- titis is limited by both a lack of double-blind, ran- domised, placebo-controlled trials and a lack of understanding of the aetiology and pathogenesis of the condition on which to base rational treatment. However, among the available treatment options, there are some drugs which may be particularly suited for use in older men, such as finasteride and α-adrenoceptor antagonists, although adverse effects must be carefully considered when using the latter agents. Further randomised, controlled trials sponsored by the NIH are due to begin sometime in As part of the continuation of the CPCRN, further investigation into the relationship between CP/CPPS and IC is also planned.

12 1122 Pontari Acknowledgements 19. Ponniah S, Arah I, Alexander RB. PSA is a candidate selfantigen in autoimmune chronic prostatitis/chronic pelvic pain Dr Pontari is a consultant for both Pfizer and Yamanouchi syndrome. Prostate 2000; 44 (1): Zermann DH, Ishigooka M, Doggweiler R, et al. Neurourologiand has been an investigator fo clinical trials for both Merck cal insights into the etiology of genitourinary pain in men. J & Co. and Roche. The authors have provided no information Urol 1999; 161 (3): on sources of funding directly relevant to the content of this 21. Mehik A, Hellstrom P, Sarpola A, et al. Fears, sexual disturreview. bances and personality features in men with prostatitis: a population-based cross-sectional study in Finland. BJU Int 2001; 88 (1): 35-8 References 22. Pontari MA, Litwin MS, O Leary MP, et al. A case-control 1. Drach GW, Fair WR, Meares EM, et al. Classification of benign study of epidemiological factors in men with chronic pelvic diseases associated with prostatic pain: prostatitis or pros- pain syndrome [abstract]. J Urol 2002; 167 Suppl. 4: 24 tatodynia? [letter]. J Urol 1978; 120 (2): Mehik A, Hellstrom P, Lukkarinen O, et al. Epidemiology of 2. Krieger JN, Nyberg Jr L, Nickel JC. NIH consensus definition prostatitis in Finnish men: a population-based cross-sectional and classification of prostatitis. JAMA 1999; 282 (3): study. BJU Int 2000; 86 (4): de la Rosette JJ, Hubregtse MR, Meuleman EJ, et al. Diagnosis 24. Ohkawa M, Yamaguchi K, Tokunaga S, et al. Ureaplasma and treatment of 409 patients with prostatitis syndromes. Urol- urealyticum in the urogenital tract of patients with chronic ogy 1993; 41 (4): prostatitis or related symptomatology. Br J Urol 1993; Krieger J, Jacobs RR, Ross SO. Does the chronic prostatitis/ (6): pelvic pain syndrome differ from nonbacterial prostatitis and 25. Doble A, Thomas BJ, Walker MM, et al. The role of Chlamydia prostatodynia? J Urol 2000; 164: trachomatis in chronic abacterial prostatitis: a study using 5. Krieger JN, Egan KJ, Ross SO, et al. Chronic pelvic pains ultrasound guided biopsy. J Urol 1989; 141 (2): represent the most prominent urogenital symptoms of "chronic 26. Weidner W, Schiefer HG, Brahler E. Refractory chronic bacterprostatitis". Urology 1996; 48 (5): ial prostatitis: a re-evaluation of ciprofloxacin treatment after a 6. Schaeffer AJ, Landis JR, Knauss JS, et al. Demographic and median follow-up of 30 months. J Urol 1991; 146 (2): clinical characteristics of men with chronic prostatitis: the 27. Weidner W, Schiefer HG, Krauss H. Role of Chlamydia trachonational institutes of health chronic prostatitis cohort study. J matis and mycoplasmas in chronic prostatitis: a review. Urol Urol 2002; 168 (2): Int 1988; 43 (3): Collins MM, Meigs JB, Barry MJ, et al. Prevalence and correlates of prostatitis in the health professionals follow-up 28. Weidner W, Schiefer HG. Re: Isolation of Chlamydia tracho- study cohort. J Urol 2002; 167: matis from the prostatic cells in patients affected by nonacute abacterial prostatitis [letter]. J Urol 1986; 136 (3): Roberts RO, Lieber MM, Rhodes T, et al. Prevalence of a physician-assigned diagnosis of prostatitis: the Olmsted 29. Relman D, Schmidt T, MacDermott R, et al. Identidification of County study of urinary symptoms and health status among the uncultured bacillus of Whipple s Disease. N Engl J Med men. Urology 1998; 51: ; 327: Nickel CJ, Downey J, Hunter D, et al. Prevalence of prostatitisof urine, prostatic fluid and semen of men with chronic pelvic 30. Shoskes DA, Mazurick CA, Landis JR, et al. Bacterial cultures like symptoms in a population based study using the National Institutes of Health Chronic Prostatitis Symptom Index. J Urol pain syndrome: role of culture for 2 vs 5 days [abstract]. J Urol 2001; 165: ; 163 Suppl. 4: Roberts RO, Jacobson DJ, Girman CJ, et al. Prevalence of 31. Jarvi K, Wang W, Korithoski B, et al. Identification of unusual prostatitis-like symptoms in a community based cohort of bacteria in the semen and urine of men with NIH type III older men. J Urol 2002; 168: prostatitis [abstract]. J Urol 2001; 165 Suppl. 5: Collins MM, Stafford RS, O Leary MP, et al. How common is 32. Shoskes DA, Shahed AR. Detection of bacterial signal by 16S prostatitis?: a national survey of physician visits. J Urol 1998; rrna polymerase chain reaction in expressed prostatic secre- 159 (4): tions predicts response to antibiotic therapy in men with chron- 12. Wenninger K, Heiman JR, Rothman I, et al. Sickness impact of ic pelvic pain syndrome. Tech Urol 2000; 6 (3): chronic nonbacterial prostatitis and its correlates. J Urol 1996; 33. Hochreiter WW, Duncan JL, Schaeffer AJ. Evaluation of the 155 (3): bacterial flora of the prostate using a 16S rrna gene based 13. McNaughton Collins M, Pontari MA, O Leary MP, et al. Quali- polymerase chain reaction. J Urol 2000; 163 (1): ty of life is impaired in men with chronic prostatitis: the 34. Keay S, Zhang C, Baldwin BR, et al. Polymerase chain Chronic Prostatitis Collaborative Research Network. J Gen reaction amplification of bacterial 16s rrna genes in Intern Med 2001; 16 (10): prostate biopsies from men without chronic prostatitis. 14. Ware JE, Kosinski M, Keller SD. A twelve item short form Urology 1999; 53: health survey-construction of scales and preliminary tests of 35. Krieger JN, Riley DE, Vesella RL, et al. Bacterial dna reliability and validity. Med Care 1996; 34: sequences in prostate tissue from patients with prostate cancer 15. Calhoun E, Collins MM, Pontari M, et al. What is the economic and chronic prostatitis. J Urol 2000; 164 (4): impact of chronic prostatitis [abstract]. J Urol 2001; Nickel JC, Alexander RB, Schaeffer AJ, et al. Leukocytes and Suppl. 5: 25 bacteria in men with chronic prostatitis/chronic pelvic pain 16. Weidner W, Schiefer HG, Krauss H, et al. Chronic prostatitis: a syndrome compared to asymptomatic controls. J Urol 2003; thorough search for etiologically involved microorganisms in 170 (3): patients. Infection 1991; 19 Suppl. 3: S Shahed AR, Shoskes DA. Oxidative stress in prostatic fluid of 17. Roberts RO, Lieber MM, Bostwick DG, et al. A review of patients with chronic pelvic pain syndrome: correlation with clinical and pathological prostatitis syndromes. Urology 1997; gram positive bacterial growth and treatment response. J An- 49 (6): drol 2000; 21 (5): Berger RE, Krieger JN, Rothman I, et al. Bacteria in the 38. John H, Barghorn A, Funke G, et al. Noninflammatory chronic prostate tissue of men with idiopathic prostatic inflammation. J pelvic pain syndrome: immunological study in blood, ejaculate Urol 1997; 157 (3): and prostate tissue. Eur Urol 2001; 39: 72-8