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Quercetin for Chronic Prostatitis/Chronic Pelvic Pain Syndromes

Daniel A. Shoskes, MDa,*, J. Curtis Nickel, MDb

Dr Shoskes and Dr Nickel are both consultants to Farr Laboratories. Dr Nickel is a consultant for Triton Pharma.
a Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Desk Q10-1, 9500 Euclid Avenue, Cleveland, OH 44195, USA
b Department of Urology, Queen’s University, Kingston General Hospital, 76 Stuart Street, Kingston, ON, Canada K7L 2V7* Corresponding author. E-mail address: dshoskes@mac.com

KEYWORDS: Prostatitis, Chronic pelvic pain syndrome, Quercetin, Phytotherapy

Urol Clin N Am 38 (2011) 279–284. doi:10.1016/j.ucl.2011.05.003. 2011 Elsevier Inc.

The prostatitis syndromes are some of the most prevalent conditions in urology but also the most poorly understood. Although little controversy exists over the therapy for documented acute or chronic bacterial infections, most patients fall into the nonbacterial or prostatodynia group, now referred to as chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) or National Institutes of Health (NIH) category III. The origin, natural history, and appropriate therapy for these patients are unclear. Patient and physician dissatisfaction with
these syndromes is high, making it an area ripe for patient interest in nontraditional and alternative
therapies.
    The polyphenolic bioflavonoid quercetin is a phytotherapeutic compound that has antiinflammatory and antioxidant properties. Its mechanism of action could be of value for several potential pathways in the origin of CP/CPPS. This article discusses the current understanding of CP/CPPS and how treatment with quercetin can be used alone or as part of multimodal therapy.

CLASSIFICATION
One of the earliest attempts at a classification system for chronic prostatitis was made in 1978 by Drach and colleagues1 and was based on patient symptoms and localizing bacterial cultures published by Meares and Stamey2 10 years earlier.The four-glass test localization study collected first-voided urine (VB1), mid-stream urine (VB2), prostatic fluid (expressed prostatic secretion [EPS]), and post–prostate massage urine (VB3), and subjected each to microscopic white blood cell (WBC) count and EPS. Acute bacterial prostatitis was defined as an acute febrile urinary tract infection (UTI). Chronic bacterial prostatitis was defined as recurrent UTI in which bacteria and WBCs were found in the EPS at levels significantly higher than any found in the premassage urine.
The diagnosis of nonbacterial prostatitis was defined as WBCs but not bacteria in EPS or VB3. Finally, prostatodynia was used to refer to patients with typical symptoms but without any WBCs or bacteria recovered from prostatic secretions.
    Unfortunately, this four-glass localization test was never formally validated as the basis for a classification
system, and is seldom used by most physicians.3 Still no evidence exists that men with no history of recurrent urinary tract infections but uropathogenic bacterial localized to the prostate experience a different response to therapy from similar patients with no uropathogenic localization. Traditional chronic bacterial prostatitis versus nonbacterial prostatitis responds differently to therapy. Recognizing this, a simpler two-glass test was popularized by Nickel and colleagues4 as an adequate replacement of the more cumbersome four-glass test. In the two-glass test, only pre– and post–prostate massage urine is examined and cultured.
    Recognizing the shortcomings of the current classification system, together with the lack of consensus for treatment, the National Institute of Diabetes and Digestive and Kidney Diseases began an initiative to address prostatitis in 1995. The NIH classification system was ultimately published in 1999.5 Given the lack of understanding of the basic origin of CP/CPPS, the original etiologydriven classification system was replaced by a symptom/syndrome driven classification. Category I and category II are identical to the acute and chronic bacterial prostatitis of the previous system. Category III/CPPS is defined as the presence of genitourinary pain in the absence of uropathogenic bacterial. Category III was further divided into category IIIA and category IIIB. Category IIIA represents inflammatory CPPS in which WBCs can be found in semen, EPS, or urine after prostatic massage, whereas in category IIIB (noninflammatory CPPS), WBCs are not seen. Category IV, or asymptomatic prostatitis, includes patients without symptoms but for whom WBCs can be found in prostate secretions or in prostate tissue during an evaluation for other disorders (infertility, benign prostate hyperplasia, or prostate cancer). The new classification system has been validated for both research and clinical practice.6
    CATEGORY III (CPPS) CPPS is both the most common form of prostatitis and the most cryptic. The most common symptom is pain, which may be felt in the lower abdomen, pelvis, perineum, or genitals. Urinary complaints are common and may include both voiding and storage symptoms. Additionally, many complain of erectile dysfunction and ejaculatory pain. CP/ CPPS is a significant health problem. Prevalence is between 2% and 16%, depending on the population studied, the epidemiologic method, and the definitions of prostatitis. This prevalence reflects a significant burden on the health system, wherein prostatitis is diagnosed in two million physician visits annually.7 Furthermore, its financial impact is not negligible, with direct medical costs estimated at $6500 per year per person.8 The origin and pathophysiology are controversial, and in fact the disorder likely represents different underlying origins which produce a common symptom complex. Some patients with CPPS mayhave a true bacterial infection. Detection may be missed because cultures are not properly performed,9 difficult-to-culture organisms are not searched for (eg, ureaplasma, mycoplasma), or the bacteria may not be identifiable using current culture techniques.10 In the absence of infection, evidence shows an inflammatory or autoimmune component to CPPS. Even in the absence of visible WBCs, EPS and semen of men with CPPS have elevated levels of inflammatory cytokine11 and oxidative stress.12 Furthermore, symptomatic response to antibiotics in patients with CPPS may be from direct antiinflammatory rather than antimicrobial effects of these drugs.13 Finally, much of the pain of CPPS is likely related to pelvic muscle spasm, which may be secondary to infective or  inflammatory conditions mentioned earlier, or may be the primary problem in the absence of any prostatic pathology.14 Pelvic muscle spasm can lead to chronic intermittent hypoxia, which may be
improved by antioxidant therapy.15


CLINICAL PHENOTYPING OF CPPS

The authors believe that the only rational approach to patients with these disparate mechanisms and symptoms is to develop a phenotype that is clinically meaningful and, most importantly, that can drive and improve therapy. In response to this need, the UPOINT phenotyping classification system was recently developed for patients diagnosed with chronic pelvic pain.16 UPOINT is a six-point clinical classification system that categorizes patients into six clinically identifiable domains: urinary, psychosocial, organ-specific, infection, neurologic/systemic, and tenderness of skeletal muscle. This clinical classification system is not necessarily based on etiology (but may be
eventually) and remains flexible (can incorporate new epidemiology, therapeutic, and biomarker research as it becomes available). The key features of each domain are that they may be scored as positive or negative based on simple  clinical criteria, they are discriminative in the populations of interest (ie, it would be of no value if almost all patients fell into a very few phenotypes), and each is associated with specific therapies with at least some reasonable evidence for efficacy.  Because mulitmodal therapy is superior to unimodal or stepwise therapy in men17 and women18 with pelvic pain, the UPOINT phenotype provides a framework for rational multiple treatment selection.
    The authors and others19–23 have now studied the UPOINT system in men with category III prostatitis (CPPS). These studies retrospectively evaluated patients with these diagnoses and classified their phenotype as a yes/no for each of the six domains in Box 1.
    In 90 men with CPPS the authors found that the percentage of patients with positive responses in each domain was urinary, 52%; psychosocial, 34%; organ-specific, 61%; infection, 16%; neurologic/ systemic, 37%; and tenderness, 53%. A significant stepwise increase in total symptom severity occurred as the number  of positive domains increased.20 Other investigators have subsequently replicated these initial observations.19,23

Box 1. The six domains of the UPOINT system
1. Urinary
    Patient complaint of bothersome urgency, frequency, or nocturia Post-void residual >100 mL
Obstructive voiding symptoms (or maximum flow rate <15 mL/s)
2. Psychosocial
    Clinical depression
    Evidence of catastrophizing (helplessness, hopelessness)
3. Organ-specific
    Representative tenderness on light palpation of prostate
    Leukocytosis in prostatic fluid
    Hematospermia
4. Infection
    Exclude patients with clinical cystitis or bacterial prostatitis (includes past history of documented UTI associated with initiation or flare)
    Atypical bacteria in urine or positive prostatic fluid cultures in absence of UTI
5. Neurologic/systemic conditions
    Pain beyond abdomen and pelvis
    Irritable bowel syndrome
    Fibromyalgia
    Chronic fatigue syndrome
6. Tenderness of skeletal muscles
    Palpable muscle spasm or myofascial painful trigger points in abdomen and pelvic floor

QUERCETIN: AN ANTIINFLAMMATORY AND ANTIOXIDANT NUTRACEUTICAL
The bioflavonoids are a family of polyphenolic molecules found in a variety of plants that have significant antioxidant and antiinflammatory properties.  Quercetin is a member of this family found in red wine, green tea, and onions (Fig. 1). It is a potent free oxygen scavenger,24 antioxidant,25 and antiinflammatory agent.26 It reduces inflammation through inhibiting the production of cytokines such as interleukin (IL)-6,27 IL-8,28 and tumor necrosis factor29 by inhibiting the promoter nuclear factor kB (NF-kB).30 These cytokines are elevated in the semen and prostate fluid of men with CPPS.31 Furthermore, in an animal model of inflammatory pain, quercetin reduced pain, oxidative stress, and cytokine production.32 Absorption of dietary quercetin is variable and dependent on gut flora.33
    Quercetin has been studied in humans both for epidemiologic links between consumption and disease and for direct interventions through increased intake. In the Zutphen Elderly study, higher dietary quercetin intake was associated with decreased risk of cardiac disease.34 In a British case-control study, increased quercetin intake was associated with reduced risk of developing colon cancer.35 A case-control study in New York state found reduced prostate cancer risk among men with the highest quercetin intake compared with those with the lowest.36 Treatment studies have focused on inflammation and cancer. A prospective controlled study found topical quercetin accelerates the healing of aphthous mouth ulcers.37 Oral quercetin supplementation raises plasma quercetin levels in normal volunteers.38 Six weeks of quercetin therapy reduced systolic blood pressure and oxidized low-density lipoprotein in overweight adults.39 A combination of quercetin and curcumin reduced the number and size of ileal and rectal adenomas in patients with familial adenomatous polyposis.40 Finally, a combination of quercetin and curcumin improved early graft function in recipients of deceased donor kidney transplants.41
    Quercetin has theoretical benefits for patients with an ongoing inflammatory or ischemic process, which may underlie CPPS. In addition, because patients with CPPS often avoid foods rich in flavonoids (green tea [caffeine], red wine [alcohol]), they may have an actual dietary deficiency of quercetin. An initial prospective, double-blind, placebo-controlled trial of 500 mg of quercetin administered twice daily for 4 weeks was done using the National Institutes of Health Chronic Prostatitis Symptoms Index (NIH-CPSI) as the primary end point.42 Patients taking placebo had a mean improvement in NIH-CPSI from 20.2 to 18.8, and those taking quercetin had a mean improvement from 21.0 to 13.1 (P 5 .003). At least a 25% improvement of symptoms was seen in 20% of patients taking placebo and 67% of those taking the bioflavonoid. This 25% threshold is associated with patient perception of improvement after therapy. A third group of patients received Prosta-Q (Farr Laboratories, California USA), a commercial formulation containing quercetin with bromelain and papain, which are digestive enzymes known to increase the intestinal absorption of quercetin. In this group, 82% of the patients showed a significant improvement of symptoms.
    Several mechanisms may contribute to the beneficial effects of quercetin in CPPS. CPPS is associated with elevated oxidative stress in EPS and semen,43 and patients who experience improvement with quercetin have a reduction in oxidative stress metabolite F2-isoprostane in their EPS.42  Furthermore, quercetin therapy reduces inflammation as measured by prostaglandin E2 levels in EPS, and increases the levels of prostatic bendorphins.44 To explain why some patients experience response to quercetin therapy whereas others do not, blood from patients with CPPS treated with quercetin was analyzed for cytokine polymorphisms. Of the 28 patients treated with the antiinflammatory quercetin, all 11 in whom treatment had failed had the low tumor necrosis factor  genotype versus 29.4% of those in whom treatment succeeded (P 5 .0003). Similarly men with quercetin treatment failure were much less likely to have the low IL-10 genotype than those with treatment success (9.1% vs 47.1%; P 5 .04). Therefore, men with a “low inflammation” phenotype were less likely to improve with  quercetin. Finally, quercetin has weak antibacterial and antifungal properties that might conceivably play a role in CPPS.45
    Side effects with quercetin therapy are rare. Some patients experience nausea if taking it on an empty stomach. Some patients have reported transient joint pain when quercetin is taken at high doses. Orange pigment in some preparations may show up in semen, and patients can be reassured that this is caused by the dye and not an infection. Because quercetin binds to the DNA gyrase site on Escherichia coli, where quinolone antibiotics bind, quercetin could theoretically interfere with quinolone antibiotics, and therefore the two should not be used together.46 Quercetin may, however, be safely combined with nonquinolone antibiotics.

ROLE OF QUERCETIN IN CPPS THERAPY
Multimodal therapy for CPPS has advantages given the syndrome’s heterogeneity, and the authors believe that the best results can be obtained through targeting therapy using the UPOINT phenotype system. They have focused on using quercetin primarily for patients with the organ-specific domain, whether the evidence for organ involvement comes from the bladder or prostate. In a prospective study of 100 men with CPPS treated according to the UPOINT phenotype, 84% had significant improvement in symptoms with a minimum follow-up of 6 months.47 In this study, 70% were positive for the organ-specific domain and received either quercetin
alone (Prosta-Q, Farr Laboratories, California USA) or quercetin in combination with pollen extract (Q-Urol, Farr Laboratories, California USA). In the group as a whole, a treatment regimen that included quercetin had the strongest impact on symptom improvement.
    Whether quercetin may have other beneficial effects in patients with CPPS is not proven. Given the relationship between prostatic inflammation and prostate cancer risk, and quercetin’s ability to inhibit prostate cancer cells in vitro, a potential role in prostate cancer prevention is possible.  Furthermore, the increased self-reported incidence of cardiovascular disease in men with CPPS48 suggests that quercetin’s reduction in cardiac event risk may be another potential benefit. The authors recently observed improvement in peripheral arterial tone in patients with CPPS who were treated with quercetin.49
    The authors typically prescribe quercetin at 500 mg two to three times per day, preferably taken with food. Some patients note improvement in symptoms within days, but the authors recommend at least a 6-week trial. If improvement begins within 6 weeks, symptoms usually continue to improve further up to 3 months. The authors often combine quercetin with bromelain and papain to help enhance absorption using the same specific dietary supplements from their successful past prospective clinical studies.42,47 As part of their planned multimodal therapy plan, they use a rationale of adding another potentially effective phytotherapeutic agent, pollen extract preparation (see article on Cernilton elsewhere in this issue), for patients with an organ-specific clinical phenotype. However, as with all multimodal strategies, no evidence from randomized placebo-controlled trials confirms the efficacy of the wide variety of combinations available for these patients. The authors caution against
quercetin preparations that contain high doses of vitamin C, which can acidify the urine and potentially worsen symptoms. They also caution against the theoretical interaction with quinolone antibiotics and suggest that quercetin be held during quinolone therapy. Quercetin is an important component of a multimodal therapeutic program directed by the UPOINT phenotype presentation by each individual patient.

SUMMARY
Quercetin is a polyphenolic bioflavonoid that may benefit men with CPPS through antiinflammatory and antioxidant mechanisms. It may be best indicated for patients with CPPS whose UPOINT phenotype includes the organ-specific domain, as part of a directed multimodal therapeutic strategy.

 

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