Chronic Pelvic Pain Syndrome & Prostatitis

Prostatitis and chronic pelvic pain syndrome (CPPS)

Epidemiology

• Most common urologic diagnosis in men age < 50 and the 3rd most common urologic diagnosis in men age > 50 (after BPH and prostate cancer)
• Prevalence ≈7% in men age > 18
• Prostatitis accounts for 6-8% of outpatient visits from men to urologists

Histopathology

• Prostatitis
  • Defined as an increased number of inflammatory cells within the prostatic parenchyma
  • Most common pattern of inflammation: lymphocytic infiltrate in the stroma immediately adjacent to the prostatic acini
  • May or may not be noted in patients with a diagnosis of clinical prostatitis, BPH, or prostate cancer
  • Noted in autopsy series in as many as 44% of prostate tissue samples from men without any definitive prostate disease

NIH Classification

• Category I: acute bacterial prostatitis
• Category II: chronic bacterial prostatitis
• Category III: presence of pain in the absence of bacteria (detected by standard microbiological methodology)
  • Subtypes (2)
    • IIIA (inflammatory CP/CPPS): excessive leukocytes in the expressed-prostatic secretion (EPS) or post–prostatic massage urine or semen
    • IIIB (non-inflammatory CP/CPPS): no significant leukocytes in similar specimens
    • No validated cutoff point for the level of WBCs per high-power field that is required to differentiate an inflammatory from a non-inflammatory CP/CPPS.
      • Consensus appears to favor 5-10 WBCs/HPF in EPS as the upper level of normal inflammatory cells in the EPS; this can fluctuate over time and with the frequency of ejaculation
• Category IV: asymptomatic prostatitis; significant leukocytes (or bacteria or both) in prostate specific specimens (EPS, semen, and tissue biopsy specimens) in the absence of pain

Microbiology of bacterial prostatitis

• It has been estimated that < 10% of all environmental bacteria have been identified
• Gram-negative
  • Most common pathogens are from the Enterobacteriaceae family (e.g., E. coli, Serratia, Klebsiella, Proteus, Pseudomonas), which originate in the gastrointestinal flora.
    • Most common organism is E. coli (65-80%)
• Gram-positive
  • Enterococci account for 5-10% of infections
  • The role of other gram-positive organisms, which are also commensal organisms in the anterior urethra, is controversial

Pathogenesis

• Risk factors that allow bacterial colonization or infection of the prostate with potentially pathogenic bacteria include:
  • Intraprostatic ductal reflux
  • Phimosis
  • Specific blood groups
  • Unprotected penetrative anal rectal intercourse
  • UTI
  • Acute epididymitis
  • Indwelling urethral catheters and condom catheter drainage
  • Transurethral surgery, especially in men who have untreated, infected urine
• Nonbacterial prostatitis and CPPS are caused by an interrelated cascade of inflammatory, immunologic, endocrine, muscular, neuropathic, and psychologic mechanisms that begin with an initiator in a genetically or anatomically susceptible man
  • Intraprostatic ductal reflux
    • Reflux of urine and possibly bacteria into the prostatic ducts has been postulated as one of the causative mechanisms involved in the pathogenesis of chronic bacterial and non-bacterial prostatic inflammation in some individuals
    • Prostatic calculi are composed of substances found only in urine, not in prostatic secretions, further evidence that urinary intraprostatic reflux occurs and likely contributes to the formation of prostatic calculi.
      • If pathogenic bacteria reflux into the prostate gland, they may exist in protected aggregates within prostatic calculi themselves. This type of bacterial colonization in protective bacterial aggregates or biofilms associated with prostatic calculi may lead to recalcitrant CP and subsequent recurrent UTIs despite what seems to be adequate antibiotic therapy
  • Chemically induced inflammation
    • Secondary to the noxious substances in the urine that have refluxed into the prostatic duct
  • Dysfunctional voiding
    • Anatomic or neurophysiologic obstruction resulting in high-pressure dysfunctional flow patterns has been implicated in the pathogenesis of prostatitis syndrome.
  • Pelvic floor muscle abnormalities
    • Sensory or motor disturbances or both consistent with neural dysregulation of the lower urinary tract may be a consequence of acquired abnormalities in the central nervous system (CNS). Certainly, extraprostatic tenderness is identified in many patients
  • Neural sensitization
    • Altered autonomic nervous system responses may be responsible for the pain associated with CPPS
  • Immunologic alterations
    • Non-infectious inflammation (non-bacterial prostatitis or CPPS) might also be secondary to immunologically mediated inflammation caused by some unknown antigen or perhaps even related to an autoimmune process
    • CPPS can exist through persistent immunologic mechanisms long after the bacteria have been eradicated.
    • Whatever the initiating event, the immunologic cascade appears to have an important role in the development of prostatitis or CPPS in patients who develop prostatic inflammation
  • Pyschosocial associations
    • Psychological factors have always been considered to play an important role in the development or exacerbation of CP syndromes.

Clinical presentation

• Category I: acute bacterial prostatitis
  • Acute onset of pain combined with LUTS (storage and voiding) and signs of sepsis
    • Pain may be perineal and suprapubic, and there may be associated pain or discomfort of the external genitalia.
    • Usually there are significant systemic symptoms including fever, chills, malaise, nausea and vomiting, and even frank septicemia with hypotension.
  • ≈5% of patients with acute bacterial prostatitis may progress to chronic bacterial prostatitis
• Category II: chronic bacterial prostatitis
  • Associated with a history of documented recurrent UTIs (i.e., cystitis)
    • The recurrent UTIs are secondary to areas of focal uropathogenic bacteria residing in the prostate gland
• Category III: chronic pelvic pain syndrome
  • The predominant symptom is pain, which was most commonly localized to the perineum, suprapubic area, and penis but can also occur in the testes, groin, or low back.
  • Pain during or after ejaculation is one of the most prominent, important, and bothersome features in many patients.
  • Storage and voiding urinary symptoms including urgency, frequency, hesitancy, and poor interrupted flow are associated with this syndrome in many patients.
  • Presenting symptoms of inflammatory category IIIA are indistinguishable from those of non-inflammatory category IIIB CP/CPPS
  • By definition, the syndrome becomes chronic after 3 months’ duration.
  • The symptoms tend to wax and wane over time
    • ≈1/3 of patients improve over 1 year (usually patients with a shorter duration of illness and fewer symptoms)
  • Quality of life of many patients diagnosed with CP/CPPS is greatly diminished
• Category IV: asymptomatic prostatitis
  • Detected incidentally (e.g. prostate biopsy)

Diagnosis and Evaluation

• Mandatory (3):
  1. History and physical exam, including digital rectal examination
  2. Labs: Urinalysis/culture
  3. Other: Pelvic floor assessment
• Recommended (6):
  1. Two-glass lower urinary tract evaluation
  2. Symptom inventory or index (NIH-Chronic Prostatitis Symptom Index [NIH-CPSI])
  3. Sexual function assessment (questionnaire)
  4. Flow rate
  5. Post-void residual
  6. Urine cytology
• Not recommended for routine initial evaluation
  • Four-glass lower urinary tract evaluation
  • Semen analysis and culture
  • Sexually transmitted infection evaluation or urethral culture
  • Urodynamics
  • Video-urodynamics (including flow-EMG)
    • Chronic LUTS in young men may be misdiagnosed as chronic non-bacterial prostatitis when in fact they indicate a cohort of men with undiagnosed chronic voiding dysfunction.
  • Transrectal ultrasound of the prostate
    • The diagnostic value of US in differentiating benign from malignant prostate disease is controversial, and the further differentiation of the various benign conditions of the prostate is even more so
  • Pelvic imaging—US, CT scan, MRI
  • Prostate-specific antigen (PSA)
    • PSA levels can be markedly elevated during an acute episode of bacterial prostatitis and slowly resolve to normal levels over the course of 6 weeks to many months, provided there is no recurrence of infection
  • Cystoscopy
    • Not indicated in the majority of men with CP/CPPS but can probably be justified in men whose condition is refractory to standard therapy
  • Prostate biopsy
    • The importance and interpretation of prostate biopsies in prostatitis performed for reasons other than prostate cancer screening are unclear.
  • Evaluation of Suspected Seminal Vesiculitis
    • Occasionally, seminal vesiculitis can occur as a consequence of local bacterial infection in acute and chronic bacterial prostatitis, and patients can develop seminal vesicle abscesses
• History and Physical exam
  • History
    • Phenotype Assessment in Chronic Prostatitis and CPPS
      • UPOINT is a 6-point clinical classification system that categorizes the phenotype of patients with CPPS into one or more of 6 clinically identifiable domains:
        1. Urinary
        2. Psychosocial
        3. Organ-specific
        4. Infection
        5. Neurologic/systemic
        6. Tenderness (muscle)
      • Guidelines for the management of CP/CPPS have recommended that patients be clinically phenotyped during evaluation and treated according to individual phenotypes identified
  • Physical exam
    • Category I (acute bacterial prostatitis): hot, boggy, and exquisitely tender prostate. The expression of prostatic fluid is believed to be totally unnecessary and perhaps even harmful.
    • Categories II (chronic bacterial prostatitis) and III (CPPS) are usually unremarkable (except for pain)
    • DRE should be performed after the patient has produced pre-prostatic massage urine specimens (see later) and after the perineal and pelvic examination.
    • The degree of elicited pain during prostatic palpation is variable and is unhelpful in differentiating a prostatitis syndrome
• Symptom assessment
  • The validated NIH-CPSI is a useful research and clinical tool for evaluating chronic prostatitis and chronic pelvic pain syndrome patients.
    • The final CPSI consists of 9 questions that address the 3 most important domains of the CP experience:
      1. Pain
      2. Urinary function
      3. Quality of life
• Lower Urinary Tract Cytologic Examination and Culture Techniques
  • Category I (acute bacterial prostatitis): a urine culture is the only laboratory evaluation of the lower urinary tract required
  • Category II/II: 4-glass urine collection
    1. Voided bladder–1 (VB1): the first 10 mL of urine and represents the urethral specimen
    2. VB2: similar to a midstream urine collection and represents the bladder urine
    3. Expressed prostatic secretion (EPS): should be collected directly into a sterile container during prostatic massage
    4. VB3: first 10 mL of urine voided after prostatic massage, includes any EPS trapped in the prostatic urethra
       • See CW11 Figure 13-4
    • All 4 specimens are sent to the clinical microbiology laboratory for quantitative culture. Aliquots of the 3 urine specimens are centrifuged for 5 minutes and the sediment examined under high power for leukocytes (including aggregates of leukocytes), macrophages, oval fat bodies, erythrocytes, bacteria, and fungal hyphae.
    • Interpreting results
      • Category II, chronic bacterial prostatitis, is diagnosed if there is a 10x increase in bacteria in the EPS or VB3 specimen compared with the VB1 and VB2 specimens
      • Category IIIA CP/CPPS is diagnosed when no uropathogenic bacteria are cultured, but excessive leukocytosis (usually defined as more than 5 to 10 WBCs per high-power field [HPF]) is noted in the prostate-specific specimens (EPS or VB3 or both).
      • Category IIIB CP/CPPS is diagnosed when no uropathogenic bacteria are cultured and there is no significant leukocytosis noted on microscopic examination of EPS or the sediment of VB3.
  • 2-glass test
    • A simple, cost-effective alternative to categorize patients with CP
    • Patient provides
      1. Midstream pre-massage urine specimen
      2. Urine specimen (initial 10 mL) after prostatic massage
    • Microscopy (sediment) and culturing of these 2 specimens allows categorization of the majority of patients with a CP syndrome
• Secretory dysfunction of the prostate, characterized by an alteration in the composition of prostatic secretions, can be diagnostic of patients with prostatitis

Management

Acute prostatitis

• Antibiotics Regimen
  • AUA§
    • 1^st Line: Trimethoprim/Sulfamethoxazole or Fluoroquinolone§
      • TMP/SMX 1 tab DS PO BID x 14 days
    • 2^nd Line: 2^nd generation cephalosporin
    • 3^rd Line: 3^rd generation cephalosporin
  • Australian Family Physician§
    • Trimethoprim 300 mg orally daily for 14 days, or
    • Cephalexin 500 mg orally twice daily for 14 days, or
    • Amoxicillin and clavulanic acid 500 mg + 125 mg orally twice daily for 14 days
• Duration
  • Treat for 2 weeks duration
• Therapy is initially with parenteral antibiotics (depending on the severity of the infection) followed by oral antibiotics with wide-spectrum antimicrobial activity
• In patients with acute prostatitis with ESBL or suspected ESBL organisms (usually associated with transrectal prostate biopsies), treatment with a carbapenem (ertapenem, imipenem, or meropenem), amikacin, or colistin for at least 10 to 14 days is recommended

Chronic Pelvic Pain Syndrome (CPPS)

• Medical therapies that have been properly evaluated in RCTs in CPPS: antibiotics, α-adrenergic blockers, anti-inflammatory agents, hormonal therapies, phytotherapies, and pregabalin
• Minimally invasive therapies that have been properly evaluated in RCTs in CPPS: extracorporeal shockwave therapy (ESWT), transurethral microwave therapy (TUMT), and neuromodulation (electrostimulation, botulinum toxin).
• Therapies that have shown benefits in placebo sham-controlled studies in CPPS:
  • Marked benefit—none
  • Moderate benefit in some selected trials (2):
    1. α-adrenergic blockers
    2. Pregabalin
  • Modest benefit
    1. Anti-inflammatory agents
    2. Phytotherapies
    3. ESWT
    4. TUMT
    5. Selected neurostimulation
• Recommended
  1. α-Blocker therapy as part of a multimodal treatment strategy for newly diagnosed, α blocker–naive patients who have voiding symptoms.
  2. Antibiotic trial for selected newly diagnosed, antibiotic-naive patients
  3. Selected phytotherapies: Cernilton and Quercetin
  4. Multimodal therapy directed at individual UPOINT phenotypes may result in better management outcomes
  5. Directed physiotherapy
• Not recommended
  1. α-Blocker monotherapy, particularly in patients previously treated with α-blockers.
  2. Anti-inflammatory monotherapy
  3. Antibiotics as primary therapy, particularly for patients in whom treatment with antibiotics has previously failed
  4. 5α-Reductase inhibitor monotherapy; can be considered in older patients with coexisting benign prostatic hyperplasia
  5. Most minimally invasive therapies such as transurethral needle ablation (TUNA), laser therapies
  6. Invasive surgical therapies such as transurethral resection of the prostate (TURP) and radical prostatectomy
• Requiring further evaluation
  1. Low-intensity shock wave treatment.
  2. Acupuncture.
  3. Biofeedback.
  4. Invasive neuromodulation (e.g., pudendal nerve modulation).
  5. Electromagnetic stimulation.
  6. Botulinum toxin A injection.
  7. Medical therapies including mepartricin, muscle relaxants, neuromodulators, immunomodulators.

• Antibiotics
  • Although bacteria are cultured in only 5-10% of cases of prostatitis, bacteria may be the cause of CP symptoms in a significant percentage of patients with this syndrome
  • Antibiotic therapy may benefit CP/CPPS patients by 3 different mechanisms:
    1. Strong placebo effect
    2. Eradication or suppression of non-cultured microorganisms
    3. Anti-inflammatory effect of some antibiotics
    • For CP caused by E. coli, 1 month of fluoroquinolones is recommended; antibiotics should be continued only for 4-6 weeks if pre-treatment cultures are positive and/or the patient has reported positive effects from treatment
      • The fluoroquinolones have demonstrated improved therapeutic results, especially in prostatitis caused by E. coli and other members of the Enterobacteriaceae but not necessarily in prostatitis caused by P. aeruginosa or enterococci.
      • TMP/SMX is less effective both in bacterial eradication and cost-effectiveness when compared with the newer fluoroquinolones
      • Other than fluoroquinolones, most antibiotics (including minocycline, cephalexin, and carbenicillin) do not demonstrate significant clinical efficacy in clinical studies in which patients were observed for sufficient time
      • No significant differences in microbiologic and clinical efficacy or in adverse effect rates among the oral fluoroquinolones ciprofloxacin, levofloxacin, lomefloxacin, ofloxacin, and prulifloxacin.
      • Macrolides appear to be superior to the fluoroquinolones for the treatment of proven chlamydial infection.
      • As many as 20% of patients in whom an initial treatment period fails could be rescued with a second cycle of treatment with another antibiotic
    • Antibiotics should not be prescribed for previously treated men with CP/CPPS of long duration.
  • Antibiotic treatment may be considered for antibiotic-naive patients with a recent diagnosis of prostatitis, regardless of culture status.
• Alpha-blockers
  • Patients with CP/CPPS have significant lower urinary tract symptoms, which appear to be related to poor relaxation of the bladder neck during voiding; α-adrenergic blockade may improve outflow obstruction, improving urinary flow and perhaps diminishing intraprostatic ductal reflux.
  • However, trials have not supported the use of α-adrenergic blockers in recently diagnosed α-adrenergic blocker–naive men with CP/CPPS.
• Anti-inflammatory agents and immune modulators
  • NSAIDs, corticosteroids, and immunosuppressive drugs theoretically should improve the inflammatory parameters within the prostate and possibly result in a reduction of symptoms
    • At this time, high-dose, long duration monotherapy with cyclooxygenase-2 inhibitors is not recommended.
    • An RCT with pentosan polysulfate, 900 mg/day (three times the usual dose), demonstrated a modest benefit for some men with CPPS
      • Alopecia is associated with pentosan polysulfate.§
  • The potential of various anti-inflammatory agents, immune modulators, and cytokine inhibitors makes these classes of drugs potentially useful as adjunctive therapy for the CP syndromes, but clinical trials suggest that they are not a useful monotherapy
• Muscle relaxants
  • The role of muscle relaxants has yet to be determined
• Hormonal therapy
  • Finasteride and dutasteride cannot be recommended as a monotherapy except in men with associated BPH
• Phythotherapeutic agents
  • Phytotherapy for CP/CPPS may look promising, but further multicenter RCTs with well-characterized, standardized, and stable herbal components should be considered to assess their role in therapy.
• Neuromodulator therapy
  • For neuromodulatory therapy to be effective, it will need to be targeted toward a specific patient phenotype; however, biomarkers, either clinically or laboratory derived, have yet to be confirmed
• Allopurinol
  • Randomized clinical trial further showed no advantage of allopurinol compared with placebo
• Prostatic massage
  • The primary form of therapy for prostatitis during most of the 20th century was repetitive prostate massage. Its benefits are believed to arise from draining theoretically occluded prostatic ducts and improving circulation and antibiotic penetration
  • A subsequent systematic review of the literature concluded that evidence for a role of repetitive prostatic massage as an adjunct in the management of CP is at most “soft” but that the practice could be considered as part of multimodal therapy in selected patients; frequent ejaculation may achieve the same function as prostatic massage
• Pelvic Floor Physiotherapy (including directed perineal and/or pelvic floor massage and myofascial trigger point release)
  • Although level 1 evidence is not available, evidence from multiple weak trials and vast clinical experience strongly suggests benefit for selected patients.
  • Most clinicians with experience in the field believe that variations of pelvic floor physiotherapy can be extremely helpful in patients with demonstrable pelvic floor pathology that was found to be refractory to other therapies
• Acupuncture
  • Reasonable choice of therapy for selected men with CP/CPPS.
• Pudendal Nerve Entrapment Therapy
• Biofeedback
• Psychological support
• Lifestyle modification and other conservative therapies
  • Conservative therapy should always be considered the primary therapy for CP/CPPS, despite the lack of evidence.
  • Education (sometimes the only therapy required); avoidance of food, drink, and/or activities that exacerbate the symptoms; lowimpact exercise (walking, elliptical machine, swimming, yoga, stretching); local heat therapy (hot water bottle, heating pad, hot tub or bath); and positive attitude and development of personal coping skills provide the basis on which all the other therapies rest.
• Minimally invasive techniques
  • Some minimally invasive surgical procedures (electrical neuromodulation, extracorporeal shock wave therapy, electroacupuncture, and perhaps transurethral microwave thermotherapy (TUMT) and botulinum toxin injection may be beneficial for treatment for CP/CPPS in selected patients; however, large, well-designed sham-controlled trials are required before these therapies can be considered recommended.
• Traditional surgery
  • Surgery does not have an important role in the treatment of most CP syndromes unless a specific indication is discovered during the evaluation of the patient
    • A developing prostate abscess that fails to respond quickly to antibiotics is optimally drained (transurethral or percutaneous; percutaneous drainage is the more effective and less morbid)
    • Seminal vesicle abscesses can be managed with antibiotic therapy, transrectal aspiration, and, if necessary, an operation to remove the seminal vesicles.
• Phenotype directed multimodal treatment
  • No one all-encompassing causative mechanism responsible for all cases of CP/CPPS.
  • UPOINT is a clinical tool for urologists to use to direct individually based therapy; each of these domains has been associated with specific therapy based on best evidence and expert experience
• See CW11 Figure 13-9 for suggested diagnostic and therapeutic algorithm for the treatment of CPPS based on UPOINT
• See CW11 Table 13-4 for suggested doses of medical therapy for CPPS

Questions

1. Describe the NIH classification for prostatitis
2. Approximately what percentage of patients with acute bacterial prostatitis develop chronic bacterial prostatitis?
3. What are causative organisms involved in epididimytis and what is the treatment?

Answers

1. Describe the NIH classification for prostatitis
2. Approximately what percentage of patients with acute bacterial prostatitis develop chronic bacterial prostatitis?
3. What are causative organisms involved in epididimytis and what is the treatment?

References

• Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, vol 1, chap 13