Urinary Tract Conditions: Examining the Evidence on Cranberry and Saw Palmetto

http://nccam.nih.gov/news/newsletter/2009_november/urinarytractcond.htm

© Steven Foster© Steven Foster
Patients with urinary tract infections (UTIs) or benign prostatic hyperplasia (BPH) often ask health care providers about using complementary and alternative medicine (CAM) to relieve symptoms or prevent recurrences. There are many reasons that CAM therapies may appeal to these patients—for example, if they are concerned about the side effects or costs of prescription medicines; worried about antibiotic resistance (in the case of UTI); concerned about the potential effects of more invasive treatments on sexual function or continence (in the case of BPH); or seeking "natural" approaches to treating these conditions.
Urinary Tract Infections
UTIs occur at all ages and in both genders, although the incidence is 50 times higher in women. Up to one-third of women have at least one recurrence after their first episode. In men, UTIs are uncommon before age 50 and often are caused by an underlying disorder, such as a urinary or kidney stone or an enlarged prostate. UTIs in older adults may be caused by a condition such as incontinence or incomplete emptying of the bladder.
UTIs are the second most common bacterial infection after respiratory infections. In 2000 in the United States, about 11 million outpatient visits, 1.7 million emergency room visits, 367,000 hospitalizations, and $3.5 billion in health care expenditures were attributed to UTIs in adults. E. coli is most often the cause, but other microorganisms may also play a role.
Cranberry
The natural product that is most used for UTI, and on which there is the most evidence, is cranberry (Vaccinium macrocarpon). In a 2007 national survey on Americans' use of CAM, among those who used natural products, cranberry was used by 6 percent (which translates to about 1.6 million people).
The mechanism of action of cranberry is not fully understood, but basic research has yielded findings that may explain its potential benefit in UTIs, such as the suggestions that:
Proanthocyanidins unique to cranberry inhibit the ability of bacteria to adhere to the surface membrane of host cells in the urinary tract
Cranberry has anti-inflammatory and antioxidant activity.
An early theory, that cranberry inhibits bacteria replication through acidifying the urine, has been largely discredited.
Proanthocyanidins are molecules that help create intense color in fruits and vegetables and are thought to have antioxidant properties.
Snapshots of the Evidence
Practice GuidelinesThe American College of Obstetricians and Gynecologists (ACOG) released an evidence-based clinical practice guideline in 2008 on uncomplicated acute bacterial cystitis in nonpregnant women. Among ACOG's recommendations are to use antibiotics both as first-line therapy and for prophylactic or intermittent treatment. ACOG notes that drinking cranberry juice has been shown to decrease recurrence of symptomatic UTIs, although the optimal length of treatment and concentration of juice still need to be determined.
Systematic Reviews/Meta-AnalysesTwo systematic reviews/meta-analyses on cranberry from the Cochrane Collaboration concluded the following:
A 2008 review on cranberry to prevent recurrent UTIs (updated from 2004) included 10 randomized or quasi-randomized clinical trials. Most (7) studied cranberry in the form of juice, and 4 studied tablets (1,049 participants in total). The review found "some evidence" that cranberry juice may decrease the number of symptomatic UTIs over a 12-month period compared with placebo/control, especially in women with recurrent UTIs. Applicability to other groups was less certain. The review noted uncertainty as to what the optimum dosage or form is for cranberry therapy; a lack of standardization in available cranberry products; a lack of clarity as to whether juice and capsules/tablets are bioequivalent; and high drop-out rates.
A 2009 review on cranberry to treat UTIs concluded that there is no good-quality evidence on this question.
Other ReportsThe scientific literature also includes laboratory and animal studies as well as clinical trials. Although some findings suggest promise, it is difficult to compare cranberry products across studies. Many of these studies have methodological issues such as:
Not being randomized or controlled
Being small in size
Having quality issues in design or reporting
Using products that are not standardized.
Research on cranberry for urinary tract conditions is ongoing, including in NCCAM-supported studies using well-standardized, research-grade cranberry products.
Safety
Cranberry appears to be generally well tolerated in appropriate food amounts. High doses can cause gastrointestinal symptoms. Some commercial products are high in calories. There is indication that long-term use in high amounts might be contraindicated in persons at risk for uric-acid kidney stones. Safety data on long-term use are needed. General cautions that apply to the use of dietary supplements—for example, that product consistency and purity can vary, and that they can interact with drugs and/or other supplements—apply here. For more side effect and safety information, go to nccam.nih.gov/health/cranberry.
Benign Prostatic Hyperplasia
BPH is common in men but rarely produces symptoms before age 40. Not all men with BPH have symptoms. The cause of BPH is not well understood but is thought to be connected with hormones, such as the levels of dihydrotestosterone and/or estrogen. More than half of men aged 50 or older, and as many as 90 percent of men in their 70s and 80s, have symptoms of BPH. As a condition, it is estimated to account for at least 1.7 million office visits to physicians and over $4 billion in health care costs per year in the United States. As the population ages and life expectancy continues to rise, the incidence and prevalence of BPH are expected to rise as well.
Lower urinary tract symptoms (LUTS) associated with BPH can range from mild to very bothersome, and include frequency or urgency of urination, nocturia, slow stream, and leakage. Urinary retention associated with BPH potentially can lead to complications, although these are less common, such as UTI, or bladder or kidney damage. Having BPH is not a risk factor for prostate cancer, although both can occur simultaneously.
An increasing number of men are treating their BPH symptoms with botanical preparations sold over-the-counter, using them as individual agents or in combination with prescribed drugs. A 2006 estimate placed the sales of botanicals marketed for BPH symptoms at over $6 billion per year.
Saw Palmetto
Saw palmetto (Serenoa repens, made from ripe berries of the American dwarf palm) is the botanical that is most used for symptoms of BPH and most studied in clinical trials. In the 2007 national survey on Americans' use of CAM, among respondents who used natural products as CAM, about 5 percent used saw palmetto (translating to about 1.7 million Americans).
Basic research on saw palmetto in laboratory and animal studies has revealed some findings, such as the following, that may be relevant to its potential application in treating BPH:
Saw palmetto appears to contain components that have activity similar to (but weaker than) 5-alpha-reductase inhibitors, which prevent conversion of testosterone to dihydrotestosterone.
Saw palmetto contains substances, including certain fatty acids, that may have weak antiandrogenic effects as well as antiproliferative and anti-inflammatory properties.
Snapshots of the Evidence
Practice GuidelinesThe American Urological Association's (AUA) evidence-based guideline on diagnosis and treatment of BPH—last updated in 2006 and currently being updated—recommends:
For patients whose symptoms (as measured with a validated instrument such as the AUA Symptom Score Index) are mild or moderate, or who have severe symptoms that are not bothersome or do not interfere with daily activities of living, watchful waiting is preferred.
For patients with bothersome moderate-to-severe symptoms, treatment options include watchful waiting and one or more of the following therapies: alpha-adrenergic blockers and 5-alpha-reductase inhibitors, separately or combined; minimally invasive therapies, such as transurethral microwave heat treatments or transurethral needle ablation; and, if earlier interventions have not resolved the problem, surgical treatment.
The AUA also states that phytotherapeutic agents (i.e., plant-derived medications such as saw palmetto) and other dietary supplements cannot be recommended to treat BPH. Despite widespread use, their mechanisms of action, effectiveness, and safety have not been sufficiently documented in high-quality clinical trials.
The 6th International Consultation on New Developments in Prostate Cancer and Prostate Diseases (held in 2005 and including AUA representation) focused on LUTS, including from BPH, in older men. This guideline recommends that only treatments with a strong evidence base for clinical effectiveness be used. With regard to "alternative treatments" (defined as consisting mostly of botanicals and polyene-derived agents), it notes that while progress has been made toward isolating components and identifying possible mechanism(s) of action, it is difficult to compare studies, and further research (including with long-term followup) is needed to draw conclusions.
Systematic Reviews/Meta-AnalysesFindings from systematic reviews of saw palmetto for symptoms of BPH have been mixed, and the topic is an active area of debate. The number of trials available, especially randomized controlled trials (RCTs), is modest. Many earlier trials—in contrast to two more recent, better designed RCTs—have had issues that can affect the validity of findings, such as short duration, small size, and/or not having used standardized outcome measures.
Cochrane Systematic Reviews
A 2009 Cochrane review of 30 trials concluded that saw palmetto has little or no efficacy over placebo for treating BPH symptoms, although it appears to be safe. This conclusion changed from two earlier Cochrane reviews. Here, the review noted the availability of two better quality RCTs, one of which was also adequately powered. [The latter refers to the NCCAM-funded trial published in 2006, the largest and most rigorously designed study on this question to date, which found no improvement from saw palmetto, compared with placebo, in urinary symptoms and objective measures related to BPH.] The review found a certain amount of ambiguity in evidence on this topic and called for additional high-quality studies.
Other systematic reviews/meta-analyses include:
A 2005 review on 38 studies (mostly on one commercial product), by the Natural Standard Research Collaboration, which concluded in favor of efficacy
A 2002 meta-analysis on 17 published studies of a European commercial saw palmetto extract, by the European Institute of Oncology, which found suggestions of effectiveness over placebo on several measures in BPH symptoms.
Given the mixed research results, the high level of consumer interest in phytotherapeutic agents for BPH, and the remaining scientific questions, results are anticipated from a large RCT now under way—Complementary and Alternative Medicine for Urological Symptoms, or CAMUS. This trial is studying saw palmetto, compared with placebo, for preventing clinical progression of BPH over a longer term (18 months) than in earlier RCTs. CAMUS is taking place at 10 clinical centers, led by the University of Alabama at Birmingham. The National Institute of Diabetes and Digestive and Kidney Diseases, NCCAM, and the NIH Office of Dietary Supplements are the cosponsors.
Safety
Saw palmetto is likely safe when used in typical doses, but more needs to be learned about its long-term safety and efficacy. Saw palmetto may cause mild side effects, typically gastrointestinal symptoms such as diarrhea. Some men who use saw palmetto have reported headache, dizziness, tender breasts, or reduction in sexual desire. There have been two case reports possibly linking saw palmetto to increased bleeding time and pancreatitis, but these reports have not been thoroughly researched. Since many of saw palmetto's purported active constituents are fat soluble, product forms that use water extraction (such as teas) might be less effective. For more on this botanical, go to nccam.nih.gov/health/palmetto.
For More Information
National Center for Complementary and Alternative Medicine, NCCAM Clearinghouse, nccam.nih.gov; 1-888-644-6226 (toll free in the U.S.); 1-866-464-3615 (for deaf and hard-of-hearing callers).
National Institute of Diabetes and Digestive and Kidney Diseases, www.niddk.nih.gov.
The Cochrane Collaboration, www.cochrane.org.
PubMed®, www.ncbi.nlm.nih.gov/sites/entrez.
CAM on PubMed®, nccam.nih.gov/research/camonpubmed.
MedlinePlus, www.medlineplus.gov.
ClinicalTrials.gov, www.clinicaltrials.gov.
Sources
Sources consist of Federal publications, recent systematic reviews and meta-analyses in PubMed, the National Guideline Clearinghouse, and a selection of evidence-based databases.
Abrams P, Chapple C, Khoury S, et al. Evaluation and treatment of lower urinary tract symptoms in older men. Journal of Urology. 2009;181(4):1779–1787.
American College of Obstetricians and Gynecologists. Treatment of Urinary Tract Infections in Nonpregnant Women. Washington, DC: American College of Obstetricians and Gynecologists; 2008. ACOG practice bulletin no. 91.
American Urological Association. Guideline on the Management of Benign Prostatic Hyperplasia. 2003 (revised 2006). AUA Web site. Accessed on September 15, 2009.
Barnes PM, Bloom B, Nahin R. Complementary and alternative medicine use among adults and children: United States, 2007. CDC National Health Statistics Report #12. 2008.
Bent S, Kane C, Shinohara K, et al. Saw palmetto for benign prostatic hyperplasia. New England Journal of Medicine. 2006;354(6):557–566.
Boyle P, Robertson C, Lowe F, et al. Updated meta-analysis of clinical trials of Serenoa repens extract in the treatment of symptomatic benign prostatic hyperplasia. BJU International. 2004;93(6):751–756.
Cranberry. Natural Medicines Comprehensive Database Web site. Accessed on June 29, 2009.
Dedhia RC, McVary KT. Phytotherapy for lower urinary tract symptoms secondary to benign prostatic hyperplasia. Journal of Urology. 2008;179(6):2119–2125.
Guay DR. Cranberry and urinary tract infections. Drugs. 2009;69(7):775–807.
Head KA. Natural approaches to prevention and treatment of infections of the lower urinary tract. Alternative Medicine Review. 2008;13(3):227–244.
Jepson RG, Craig JC. Cranberries for preventing urinary tract infections. Cochrane Database of Systematic Reviews. 2008;23(1):CD001321.
Jepson RG, Mihaljevic L, Craig JC. Cranberries for preventing urinary tract infections. Cochrane Database of Systematic Reviews. 2004;(2):CD001321.
Jepson RG, Mihaljevic L, Craig JC. Cranberries for treating urinary tract infections. Cochrane Database of Systematic Reviews. 1998 (updated 2009);(4):CD001322.
Litwin MS, Saigal CS, eds. Urologic Diseases in America. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. Washington, DC: U.S. Government Printing Office, 2007; NIH publication no. 07–5512.
Lynch DM. Cranberry for prevention of urinary tract infections. American Family Physician. 2004;70(11):2175–2177.
National Institute of Diabetes and Digestive and Kidney Diseases. Prostate Enlargement: Benign Prostatic Hyperplasia. NIDDK Web site. Accessed on September 15, 2009.
National Institute of Diabetes and Digestive and Kidney Diseases. Urinary Tract Infections in Adults. NIDDK Web site. Accessed on September 15, 2009.
Natural medicines in the clinical management of benign prostatic hyperplasia. Natural Medicines Comprehensive Database Web site. Accessed at on June 29, 2009.
Tacklind J, MacDonald R, Rutks I, et al. Serenoa repens for benign prostatic hyperplasia. Cochrane Database of Systematic Reviews. 2009;(2):CD001423.
Ulbricht C, Basch E, Bent S, et al. Evidence-based systematic review of saw palmetto by the Natural Standard Research Collaboration. Journal of the Society for Integrative Oncology. 2006;4(4):170–186.
Wilt T, Ishani A, MacDonald R. Serenoa repens for benign prostatic hyperplasia. Cochrane Database of Systematic Reviews. 2002;(3):CD001423.
Wilt T, Ishani A, Stark G, et al. Serenoa repens for benign prostatic hyperplasia. Cochrane Database of Systematic Reviews. 2000;(2):CD001423.
Acknowledgments
NCCAM thanks the following people for helpful reviews of an earlier draft: Andrew Avins, M.D., M.P.H., University of California-San Francisco; Stephen Bent, M.D., University of California-San Francisco; Kevin McVary, M.D., Northwestern University; and Lynn Stothers, M.D., University of British Columbia, Canada.View Upcoming Talks by the Director -->
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